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juniperpublishers-crdoj · 11 months

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Omega-3 Polyunsaturated Fatty Acids, Metabolic Syndrome and Diabetes Mellitus

Authored by Victoria Serhiyenko

Abstract

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) are increasingly being used to prevent cardiovascular diseases (CVD), and cardiac societies recommend the intake of 1g/day of the two ω-3 PUFAs eicosapentaenoic and docosahexaenoic acid for primary and secondary prevention of CVD. Clinical trials clearly suggest beneficial effects of ω-PUFAs consumption on lipid metabolism profile, their anti-inflammatory actions; on endothelial activation, which are likely to improve vascular function; antithrombotic and antiatherosclerotic properties. Experimental studies demonstrate direct antiarrhythmic effects, which have been challenging to document in humans. By targeting arterial stiffness and endothelial dysfunction administration of ω-3 PUFAs may prevent atherosclerosis and CVD development. A synergistic interplay showed by ω-3 PUFAs prescription suggest the potential to beneficially impact on fundamental steps involved in the development of preclinical atherosclerosis. We reviewed available evidence of the benefits of ω-PUFAs administration, especially to patients with CVD, metabolic syndrome and type 2 diabetes mellitus, including their effects on potential molecular pathways, effects on glucose and lipids metabolism parameters, thrombocyte aggregation parameters and haemostasis, endothelial function, antioxidant/anti-inflammation and antiarrhythmic properties.

Keywords: Omega-3 polyunsaturated fatty acids; Coronary heart disease, atherosclerosis; Diabetes mellitus; Glucose, lipids; Inflammation; Platelets; Haemostasis; Endothelium; Heart rate variability; Arrhythmias; Arterial stiffness

Abbrevations: ω-3 and ω-6 PUFAs: Ω-3 and ω-6 Polyunsaturated Fatty Acids; MetS: Metabolic Syndrome; T2DM: Type 2 Diabetes Mellitus; CVD: Cardiovascular Diseases; DLP: Dyslipoproteinemia; OS: Oxidative Stress

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Introduction

Numerous studies report salutary effects of ω-3 polyunsaturated fatty acids (ω-PUFAs), i.e. eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) on cardiovascular diseases (CVD) risk factors. These effects include lowering of serum triglyceride (TG) by reducing of hepatic TG production; lowering of blood pressure (BP) by improving of endothelial cell functution; decreasing of platelet aggregation by reducing of prothrombotic prostanoids; decreasing inflammation via reduction in 4-series leukotrienes (LT) production; protection from arrhythmias by modulation of electrophysiological properties of cardiac myocytes. Systematic meta analysis suggests that high doses of ω-3 PUFAs (~3g/day) produce a small, but significant decrease in systolic blood pressure (SBP) in older and hypertensive subjects [1,2]. The aim of this study was to review the latest evidence about the ω-PUFAs, metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM).

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Discussion

Ω-3 and ω-6 PUFAs are essential fatty acids, as they cannot be synthesized de novo in humans. There are limited data available regarding the exact amount of dietary ω-3 PUFAs consumed by the general population. It is reported that the total daily intake of dietary ω-3 PUFAs in the US is approximately 1.6g. Of this α-linolenic acid (α-LLA) accounts for approximately 1.4g/q.d, and only 0.1–0.2g/q.d. comes from EPA and DHA. The conversion rate from α-LLA to EPA and DHA is variable (0.2-15%). Therefore, in general, the total amount of EPA and DHA available to the body from current dietary patterns is well below the recommended amounts. EPA and DHA didn’t show a significant negative effect on glucose metabolism [3].

Several experimental studies have shown that long-chain ω-PUFAs inhibit the absorption of cholesterol in the intestine and its synthesis in the liver, lead to increased clearance of lipoproteins in the blood, prevent the development of insulin resistance (IR) in experimental diabetes, increase the level of glucose transporter 4 in skeletal muscles, have a positive effect on age related decrease of blood flow in the brain and improve glucose utilization under stress; there isn’t any influence on the development of hypertension (HT) and MetS. Ω-3 PUFAs decrease level of BP, dose-dependent prevent the development of T2DM, IR, contribute to positive changes of blood coagulation parameters; enhance endothelial cell migration and inhibits the proliferation of smooth muscle cells [4]. A meta-analysis of 18 studies found a significant effect of fish oil to lower TG concentrations and increase high-density lipoprotein cholesterol (HDL-C) in the blood; while there were no statistically significant changes in preprandial glucose, glycated hemoglobin A1c, total cholesterol, low density-lipoprotein cholesterol levels. Ω-3 PUFAs may affect the IR and glucose homeostasis by inhibition of IR in the muscle tissue >adipose tissue >>liver, inhibition of insulin secretion, which defer the development of T2DM; and on the state of lipid metabolism (in particular, reduce the concentration of TG, very low density-lipoprotein cholesterol (VLDL-C), increase of HDL-C, improve lipid profile by mixed hyperlipidaemia (HLP), slightly decrease BP, improve endothelial function, have an positive impact on the antioxidant status and inflammatory reactions [5]. Ω-3 PUFAs decrease VLDL assembly and secretion, resulting in diminished TG production, through a decreased sterol receptor element binding protein-1c activity [6,5].

The highly concentrated pharmaceutical preparation Omacor™ (Pronova Biocare, Lysaker, Norway), known as Lovaza™ (Glaxo Smith Kline, St Petersberg, FL, US) in North America is approved by the FDA as an adjunct to diet to reduce very high TG levels (≥500 mg•dL-1) in adults. Each 1-g capsule of ω-3-acid ethyl esters contains ethyl esters of EPA (0.465 g) and DHA (0.375g). Patients take a q.d. dose of 4-g or two 2-g doses (two capsules b.i.d.) [7]. Clinical trials have shown that administration of 4 g•day-1 of Lovaza™ results in a decrease in TG levels of 30-50%; does not affect the efficacy of statins [8,5]. In patients with combined HLP, co-administration of Lovaza™ with statins was a safe and effective means of lowering serum TG, despite the persistent high TG levels when the patients received statins alone [9,5].

The anti-inflammatory actions of marine ω-3 PUFAs are [10]: reduced leucocyte chemotaxis (via decreased production of some chemoattractants (e.g. leukotriene B4 down-regulated expression of receptors for chemoatttactants); reduced adhesion molecule expression and decreased leucocyte-endothelium interaction (via down-regulated expression of adhesion molecule genes [via the nuclear factor kappa B (NF-kB) (i.e. peroxisome proliferator-activated receptor-ɣ (PPAR-ɣ) etc.); decreased production of eicosanoids from arachidonic acid (AA) (via lowered membrane content of AA; inhibition of AA metabolism); decreased production of AA containing endocannabinoids (via lowered membrane content of AA); increased production of ‘weak’ eicosanoids from EPA (via increased membrane content of EPA); increased production of anti-inflammatory EPA and DHA containing endocannabinoids (via increased membrane content of EPA and DHA); increased production of pro-resolution resolvins and protectins (via increased membrane content of EPA and DHA); decreased production of inflammatory cytokines (via down-regulated expression of inflammatory cytokine genes (via NF-kB, i.e. PPAR-ɣ etc.); decreased T cell reactivity (via disruption of membrane rafts (via increased content of EPA and DHA in specific membrane regions).

Ω-3 PUFAs may decrease the risk of atherothrombosis by affecting platelet aggregation and haemostasis. The antithrombotic properties of EPA and DHA have been attributed to the incorporation into platelet phospholipids at the expense of the ω-6 PUFAs, such as AA. An important set of pathways clearly influenced by changes in the ω-3/ω-6 ratio are those for synthesis of eicosanoids. These include the cyclooxygenase (COX), lipoxygenase and cytochrome P450 epoxygenase pathways, for which EPA and DHA compete with AA as a substrate, inhibiting the production of the proaggregatory thromboxane A2 (TXA2) originating from AA. Indeed, the production of TXA2 from platelets stimulated by a variety of agonists decreased by between 60% and 80% after fatty acid supplementation both in vitro and in vivo [11,5]. The mechanism by which ω-3 PUFAs influence endothelial function is mediated by their incorporation into biological membrane phospholipids; this allows modulation of membrane composition and fluidity. The reason lies in the fact that endothelial cell membrane houses caveolae and lipid rafts where several receptors and signaling molecules crucial for cell function are concentrated [12]. Caveolae-associated receptormediated cellular signal transduction includes important pathways such as the, the nitric oxide (NO)/cyclic guanosine monophosphate signaling pathway, the nicotinamide adenine dinucleotide phosphate oxidase and tumor necrosis factor-α/ NF-kB induced COX-2 and prostaglandin E2 activation pathway. By modulating the composition of caveolae, as described for other classes of lipids ω-3 PUFAs may exert their beneficial effects, which include increased NO production and reduced production of proinflammatory mediators [13,12]. In addition to increasing NO production, ω-3 PUFAs decrease oxidative stress.

The incorporation of ω-3 PUFAs in synaptic membranes could potentially influence the autonomic control of the heart. Both nervous tissue and heart tissue have a high content of ω-3 PUFAs (especially DHA) and this may be consistent with the finding that this marine ω-3 PUFAs may modulate cardiac autonomic function as assessed by heart rate variability (HRV) [14]. Thus, ω-3 PUFAs may modulate HRV both at the level of the autonomic nervous system and the heart. Most of the data support that ω-3 PUFAs beneficially modulates cardiac autonomic control thereby possibly reducing the risk of arrhythmias. Accumulating evidence from in vivo and in vitro experiments has demonstrated that ω-3 PUFAs exert antiarrhythmic effects through modulation of myocyte electrophysiology. Ω-3 PUFAs reduce the activity of membrane Na+ channels in cardiomyocytes, thus increasing the threshold for membrane potential depolarization. EPA and DHA also modulate the activity of L-type Ca2+ channels, leading to a reduction in free cytosolic Ca2+ ion, which stabilizes myocyte electrical excitability to prevent fatal arrhythmia. EPA blocks the Na+/Ca2+ channel; however, a single amino-acid point mutation in this channel attenuated the inhibitory effect of EPA. These findings suggested that the cardioprotective effect of ω-3 PUFAs is mediated by direct interaction with membrane ion channels [15].

Ω-3 PUFAs intake has shown to reduce BP especially in HT by interacting with several mechanisms of BP regulation: reduction of stroke volume and heart rate; improvement of left ventricular (LV) diastolic filling; reduction of peripheral vascular resistances; improvement of endothelial-dependent and endothelial-independent vasodilation (stimulation of NO production; reduction of the asymmetric di-methyl-arginine; reduction of endothelin-1; relaxation of vascular smooth muscle cells; metabolic effects on perivascular adipocytes; endothelial regeneration. Mechanisms of HT-related organ damage protection: anti-inflammatory, antioxidant, and antithrombotic effects; reduction of arterial stiffness; experimental effects on LV hypertrophy and abnormal gene expression; effects on atherosclerotic plaque progression and stability [7]. Ω-3 PUFAs offer a scientifically supported means of reducing arterial stiffness and this may account for some of the purported cardioprotective effects of ω-3 PUFAs [16,17].

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Conclusion

The antiarrhythmic effects of ω-3 PUFAs, which occur by blocking various ion channels, are encouraging. So, cardiovascular benefits of ω-3 PUFAs [7,18] are: antidysrhythmic effects (reduced sudden death; possible prevention of atrial fibrillation; possible protection against pathologic ventricular arrhythmias; improvement in HRV; antiatherogenic effects (reduction in non- HDL-C levels; reduction in TG and VLDL-C levels; reduction in chylomicrons; reduction in VLDL and chylomicron remnants; increase in HDL-C levels; plaque stabilization; antithrombotic effects (decreased platelet aggregation; improved blood rheologic flow); anti-inflammatory and endothelial protective effects (reduced endothelial adhesion molecules and decreased leukocyte adhesion receptor expression; reduction in proinflammatory eicosanoids and LT’s; vasodilation); decreased SBP and diastolic BP. Thus, further research to understand the mechanism of action and confirm the beneficially effect of ω-3 PUFAs on BP profile, artery stiffness and HRV parameters in patiens with MetS, T2DM is needed.

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juniperpublishers-crdoj · 11 months

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Anti-hyperglycemic Effect and Regulation of Carbohydrate Metabolism by Phenolic Antioxidants of Medicinal Plants against Diabetes

Authored by HP Gajera

Introduction

Background

Diabetes mellitus is a carbohydrate metabolism disorder of endocrine system due to an absolute or relative deficiency of insulin secretion, action, or both [1]. The disorder affects more than 100 million people worldwide and it is predicted to reach 366 million by 2030. The non-insulin dependent diabetes mellitus (NIDDM, type 2) is the most prevalent form globally which is associated with elevated postprandial hyperglycemia. The occurrence of NIDDM 2 has been shown an alarming increase during the last decade (http//www.who.Int/diabetes/en/).

Plant derivatives with reported hypoglycaemic properties have been used in folk medicine and traditional healing systems. Very few of these traditional antidiabetic plants have received proper scientific or medical scrutiny despite recommendations by WHO. Ayurveda and other Indian traditional approaches have described more than 800 plants in the Indian subcontinent, known to possess antidiabetic potentials. These require to be effectively studied and in fact only few of them have been characterized for their mechanistic action [2,3]. Pancreatic α-amylase, is a key enzyme in the digestive system and catalyses the initial step in hydrolysis of starch to maltose and finally to glucose. Degradation of this dietary starch proceeds rapidly and leads to elevated post prandial hyperglycemia. It has been shown that activity of HPA in the small intestine correlates to an increase in post-prandial glucose levels, the control of an important aspect in treatment of diabetes [4]. Hence, retardation of starch digestion by inhibition of enzymes such as α- amylase would play a key role in the control of diabetes.

The discovery of specific high-affinity inhibitors of pancreatic α-amylase for the development of therapeutics has remained elusive. Inhibitors currently in clinical, use for example, acarbose, miglitol, and voglibose, are known to inhibit a wide range of glycosidases such as α-glucosidase and α-amylase. Because of their non specificity in targeting different glycosidases, these hypoglycemic agents have their limitations and are known to produce serious side effects. Therefore, the search for more safer, specific, and effective hypoglycemic agents has continued to be an important area of investigation with natural extracts from readily available traditional medicinal plants offering great potential for discovery of new antidiabetic drugs [5]. Ponnusamy et al. [6] studied on antidiabetic medicinal plants for human pancreatic amylase inhibitory effect in vitro and found that pancreatic α-amylase lower the levels of post perandial hyperglycemia via control of starch breakdown. The probable mechanism of action of the above fractions is due to their inhibitory action on HPA, thereby reducing the rate of starch hydrolysis leading to lowered glucose levels. Phytochemical analysis revealed the presence of alkaloids, proteins, tannins, cardiac glycosides, flavonoids, saponins and steroids as probable inhibitory compounds.

Anti-hyperglycemic effect of natural phenolic antioxidants

Advanced molecular studies showed that methanol extract of black jamun plant modulate the expression of glucose transporter (Glut-4), peroxisome proliferator activator receptor gamma (PPARγ) and phosphatidylinositol-3-kinase (PI3 kinase) comparable with insulin and rosiglitazone [7]. Evaluation of black jamun containing antidiabetic poly herbal formulation in alloxan induced diabetic rats also showed significant hypoglycemic activity, positive glucose tolerance activity and reduced lipid peroxidation in various organs compared to that of the diabetic control animals [8]. Meshram et al. [9] studied on hypoglycaemic action of black jamun seeds. The possible mechanism by which extracts bring about its may be by affecting the activity of glucoamylase or by increasing the glycogen biosynthesis. Thus, the significant inhibition of glucoamylase suggests that the active hypoglycaemic compound present in methanolic extracts of jamun seeds does not necessarily require the presence of functioning of β-cells for its favourable action seen in type-I. It means the methanol extracts of black jamun seeds may act in a variety of diabetic conditions with or without functioning of pancreatic β-cells.

Hasan et al. [10] studied DPPH radical scavenging activity of black jamun seed extracted in methanol. It has been determined that the antioxidant effect of plant products is mainly due to radical scavenging activity of phenolic compounds such as flavonoids, polyphenols, tannins, and phenolic terpenes [11]. Liang & Yi [12] identified hydrolysable tannins (ellagitannins) extracted from black jamun fruit showed a very good DPPH radical scavenging activity and ferric reducing/antioxidant power. The results are promising and indicating the utilization of the fruit of black jamun as a significant source of natural antioxidants.

Stanely et al. [13] evaluated the protective effects of gallic acid on brain lipid peroxidation products, antioxidant system, and lipids in streptozotocin induced type II diabetes mellitus. The results showed the beneficial effects of gallic acid on brain metabolism in streptozotocin induced type II diabetic rats. A diet containing gallic acid may be beneficial to type II diabetic patients. Meguro et al. [14] investigated the effects of continuous ingestion of a catechin rich beverage in patients with type 2 diabetes. The significant increase in insulin level was observed to patients fed with green tea containing the catechin. Rizvi et al. [15] evaluated the effect of tea catechins (epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG) and epicatechin (EC)) on markers of oxidative stress in erythrocytes from type 2 diabetics. The relative effectiveness of individual catechins are in the order of EGCG>ECG>EGC>EC. Higher intake of catechin rich food by diabetic patients may provide some protection against the development of long term complications of diabetes. Chlorogenic acid is a major component of coffee that may provide more of an explanation for coffee’s effect on risk for type 2 diabetes. Chlorogenic acid proposed beneficial effects on glucose metabolism. The chlorogenic acid may delay glucose absorption in the intestine through inhibition of glucose-6-phosphate translocase 1 and reduction of the sodium gradient driven apical glucose transport. In vitro studies and animal studies showed that chlorogenic acid derivates can be decreased hepatic glucose output through inhibition of glucose- 6-phospatase [16].

Jung et al. [17] investigated the blood glucose lowering effect and antioxidant capacity of caffeic acid in mice. Caffeic acid induced a significant reduction of the blood glucose and glycosylated hemoglobin levels than the control group. Increased plasma insulin by caffeic acid was attributable to an antidegenerative effect on the islets. Caffeic acid also markedly increased glucokinase activity and its mRNA expression and glycogen content and simultaneously lowered glucose-6- phosphatase and phosphoenol pyruvate carboxykinase activities and their respective mRNA expressions, accompanied by a reduction in the glucose transporter 2 expression in the liver. Zhi et al. [18] investigated the antioxidant activity of black jamun leaf extracts. Leaf extracts contained phenolic compounds, such as ferulic acid and catechin, responsible for their antioxidant activity.

Diabetes, when uncontrolled, causes dyslipidemia often followed by atherogenic abnormalities. Balasubashini [19] examined role of ferulic acid (flavonoid) in diabetes induced dyslipidemia. Study demonstrates that ferulic acid lowers the lipid levels in diabetic rats and hence prevents further complications. It has been documented that ferulic acid may lower blood sugar level of Type 1 and Type 2 diabetic mice by enhancing insulin secretion [20]. Diabetic mice was given rice derived ferulic acid for 17 days and results showed that plasma insulin level increased while blood sugar level decreased significantly compared with control [21]. Ferulic acid may be beneficial in Type 2 diabetic and for the management of diabetic complications. Hussain et al. [22] indicated that quercetin can decrease postprandial glucose level after disaccharides loading, which may be mainly attributed to inhibition of α-glucosidase as one of the expected mechanisms for the reduction of plasma glucose. This effect subsequently leads to suppression of postprandial hyperglycemia. Thus, quercetin can be considered as a potential candidate for the management of type 2 diabetes mellitus. Medicines that reduce postprandial hyperglycemia by suppressing the absorption of carbohydrates are shown to be effective for prevention and treatment of non-insulin dependent diabetes mellitus [23]. Quercetin inhibited in vitro the intestinal α-glucosidase activity [24]. It has been also assumed that quercetin activates tyrosine kinase. Phosphorylation of the specific region of the subunit in insulin receptor (including Tyr- 1158, Tyr-1161 and Tyr-1162) correlates with receptor tyrosine kinase activation and the propagation of the biological actions of the hormone [25].

Correlations between antidiabetic, antiradical and phenolic compounds

Our previous study Gajera et al. [26,27] suggested that antidiabetic activity of fruit parts of black jamun landraces was positively correlated with free radical scavenging activity, nutraceuticals profile and individual phenolic constituents. Total phenols and individual phenolics are positively correlated with antidiabetic and antiradical activities but vary with different level of significances. Individual phenolics - gallic, catechin, ellagic and ferulic acids are highly positively correlated (P0.001) with antidiabetic and free radical scavenging activity. The positive correlation (P0.01) was established for caffeic and chlorogenic acids to scavenge free radicals and α amylase inhibitory activity (antidiabetic) for methanolic extract of black jamun fruit parts. The quercetin was found only in seed and its part kernel fraction of BJLR-6 (very small size fruits) and found to be positively correlated (P0.05) with antidiabetic activity. Among the fruit parts of black jamun land races, seed exhibited maximum seven individual phenolics and total phenols, particularly in their kernel parts. Among the individual phenolics, gallic acid was most diverse phenolic constituents which significantly positively correlated (P0.001) with inhibition of α amylase activity and DPPH radical scavengers followed by catechin, ellagic and ferulic acids in different fruit parts of black jamun land races. The study explained correlation of individual phenolics including flavonoids (ferulic) with α amylase inhibition and free radical scavenging activities in fruit parts of indigenous black jamun landraces.

Muniappan et al. [28] reviewed the black jamun as an antidiabetic plant which contained ellagic acid, glycosides, anthocynine, kampferol, marcein and isoquarcetine; and halt the diastolic conversation of starch into sugar. The phenolic constituents may be contributed directly to the antioxidative action. Consequently, the antioxidant activities of plant/ herb extracts are often explained by their total phenolics and flavonoid contents with good correlation.

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juniperpublishers-crdoj · 11 months

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Studies on Glucagon Receptor and Antagonists of Glucagon Receptor for the Management of Diabetes Mellitus

Authored by Ghulam Abbas

Abstract

Glucagon receptor plays an important role in the glucose homeostasis and thus is drug target for the management of hyperglycemia in type-2 diabetes mellitus. The suppression of glucagon secretion from the alpha-cells is the key to control hyperglycemic condition. The identification of non-peptide antagonists of glucagon receptor is an effective therapeutic approach to inhibit the glucagon secretion to achieve normal glucose index.

Keywords: Glucagon receptor; Hyperglycemia; Diabetes mellitus; Antagonists

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Introduction

Background

Diabetes mellitus is a chronic metabolic disorder which is spreading at an alarming rate all over the world. Glucagon receptor belongs to the G protein-coupled receptors (GPCRs) superfamily and an important drug target for type-2 diabetes [1]. G-Proteins (guanine nucleotide binding proteins) actually act as molecular switches to turn on intracellular signaling as a result of GPCRs activation by intracellular stimuli. The GPCRs are also known as membrane bound receptors [2,3].

Both rat and mouse glucagon receptors are composed of 485-amino acids while the human glucagon receptor contains 477 amino acids (62kDa) and seven transmembrane (7TM) domain proteins [4]. The human glucagon receptor is little shorter and about 80% identical to the mouse receptor. The structure-function studies revealed that all seven transmembrane helices are essential for the process of receptor folding and transporting to cell surface. Moreover, it is observed that the pattern of glycosylation may have a critical role in ligand recognition. Hence, for ligand binding, extracellular portion (intact N-terminal) of the receptor is required. It is found that carboxyl-terminal tail is not involved in the ligand binding however it is necessary for desensitization and internalization [5-7].

Glucagon peptide and its biological action

Glucagon is a peptide hormone composed of 29-amino acids which is produced and secreted in the α-cells of the islets of langerhans in order to maintain normal glucose index by producing hepatic glucose to regulate insulin action [4]. The amino acid sequence of glucagon peptide is shown in Figure 1.

Glucagon exerts its effects generally in the liver, where it stimulates the biological events such as glycogenolysis, gluconeogenesis, and ketogenesis to raise hepatic glucose output. Cyclic adenosine monophosphate (cAMP) actually mediates most of the glucagon’s cellular effects. During this process glucagon receptor binds with glucagon peptide to activate adenylyl cyclase via its cognate heterotrimeric G protein Gs to produce cAMP as shown in Figure 2 [4,6,8].

Antagonists of glucagon receptor

The production and release of large quantity of glucose from the liver under the action of glucagon receptor is a major cause of hyperglycemia in type- 2 diabetes. During type- 2 diabetes, the level of glucagon is higher than both the insulin and blood glucose levels. In this situation, one of the most effective strategies for the treatment of hyperglycemia in type- 2 diabetes involved development and discovery of new efficient therapeutic agents (antagonists) to block the effect of glucagon on hepatic glucose production [9]. New therapies capable of maintaining normal glucose index for longer period of time without serious side effects are highly desirable [10]. Non-peptide glucagon antagonists of glucagon receptor are valuable because they are orally useful active hypoglycemic agents as body can absorb them properly [11,12].

In a study, a series of triarylimidazoles and triarylpyrroles was investigated to discover new non-peptide, orally bioavailabile antagonists of glucagons receptor. Compound 2-(4-Pyridyl)- 5-(4-chlorophenyl)-3-(5-bromo-2-propyloxyphenyl)pyrrole as shown in Figure 3, exhibited significant inhibition against binding of isotopic labeled glucagon to the human glucagon receptor with an IC50= 3.7±6 3.4nM [8].

Similarly, in another study, N-[3-cyano-6-(1, 1-dimethylpropyl)-4, 5, 6, 7-tetrahydro-1- enzothien-2-yl]-2- ethylbutanamide (compound 2) exhibited potent GCGR antagonist potential by inhibiting (IC50 of 181±10 nmol/l) the binding of 125I-glucagon to the membrane. Whereas, its structurally related analog (compound 3) as shown in Figure 4, was a poor inhibitor (20±1.5% inhibition at 10μmol/l) on glucagon binding assay [13]. The fungal bisanthroquinone skyrin was investigated for its inhibitory potential against glucagon-stimulated production of cAMP in vivo. Skyrin exhibited significant inhibition of cAMP production from rat liver. The mechanism of antagonistic effect of skyrin was non-competitive type for binding of glucagon to its receptor instead it specifically uncoupled glucagon receptor for adenylate cyclase activation. Skyrin and its oxygenated derivative oxyskyrin are shown in Figure 5. Skyrin and oxyskyrin inhibited glucagon stimulation of cAMP production with an EC50 =42μmol/L and EC50 =106μmol/L, respectively [14,15].

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juniperpublishers-crdoj · 11 months

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Low Grade Chronic Inflammatory Response in Pathogenicity of Diabetes Mellitus

Authored by Shamim Shaikh Mohiuddin

Abstract

Acute phase reaction which is mainly cytokine-mediated is observed to be closely involved in the pathogenesis of type 2 diabetes. Since maximum world populations are at elevated risk of developing diabetes, we tested this hypothesis by estimating circulating acute phase proteins in type 1(T-1), type 2 (T-2) diabetic patients and type 2 diabetic patients under oral hypoglycemic drugs for duration of at least 5 years.

The acute phase proteins, α1- antitrypsin, α1- acid glycoprotein, ceruloplasmin and fibrinogen were estimated in the plasma in newly diagnosed 12 T-1 cases, newly diagnosed 25 T-2 cases and 25 T-2cases under oral hypoglycemic agent for at least 5 years Thirty normal controls to match the age and sex of the test groups were also studied. The levels of these proteins were correlated with their BMI and random plasma glucose values.

In comparison with the controls, the values of all the four proteins studied were significantly elevated in T-1 patients and T-2 patients (p<.00001) and reduced significantly except α1- acid glycoprotein and ceruloplasmin. Interestingly, no correlation was found with BMI or the degree of hyperglycemia in either of the types. A low grade inflammatory process is definitely implicated in the pathogenesis of type 2 diabetes and even type 1 diabetic patients. This line of pathological basis should be further explored for diagnosis, management and follow up.

Keywords: Chronic inflammation; Diabetes mellitus; Acute phase reaction

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Introduction

Diabetes Mellitus is a syndrome with disordered metabolism and inappropriate hyperglycemia due to either deficiency of insulin secretion or to a combination of insulin resistance and inadequate insulin secretion to compensate [1]. Although hyperglycemia is the main characteristic of all form of diabetes mellitus, the pathogenic mechanism by which hyperglycemia arises differs widely. Some forms of Diabetes mellitus are characterized by an absolute insulin deficiency or a genetic defect leading to defective insulin secretion; where as other forms share insulin resistance as their underlying etiology [1]. Recently, there in increasing evidence that an ongoing cytokine induced acute phase response which is sometimes called low grade inflammation, but part of a widespread activation of the innate immune system, is closely involved in the pathogenesis of type 2 diabetes mellitus and associated complications such as dyslipidemia and atherosclerosis. Elevated circulatory inflammatory markers such as C-reactive protein and interleukin-6 predict the development of type 2 Diabetes mellitus and several drugs with anti-inflammatory properties both lower both acute phase reactants and glycemia and possibly decrease the risk of developing type 2 diabetes mellitus. Age, inactivity, certain dietary components, smoking, psychological stress and low birth weight are among the risk factors for type 2 diabetes mellitus, which are also known to be associated with activated innate immunity. Activated immunity may be the common antecedent of developing type 2 diabetes mellitus [2].

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Material and Methods

Study design

Following four groups of subjects were selected for present study:

A. 12 newly diagnosed untreated type 1 diabetes mellitus patients

B. 25 newly diagnosed untreated type 2 diabetes mellitus patients within the age limit of 30-60 years

C. 25 type 2 diabetes mellitus patients who are under treatment of oral hypoglycemic drugs for at least 5 yrs between the age limit of 30-60 yrs.

D. 30 nondiabetic healthy controls.

Height and weight of all subjects were recorded, and body mass index was calculated. None of the ninety-two volunteers were alcoholics or smokers. The participants did not suffer from chronic inflammatory diseases like asthma, chronic bronchitis, and rheumatoid arthritis as was ascertained by clinical history. Informed consent was taken from the individual subjects prior to blood collection. The study was approved by institutional ethical committee.

The following methods were followed for determination of each of the parameters.

Blood glucose estimation

Blood glucose was estimated with Agappe manual diagnostic kit by GOD-POD methodology. The enzymatic procedure of Trinder P was followed [6]. Glucose is oxidized by glucose oxidase to gluconic acid and H2O2. Hydrogen peroxide in presence of phenol and 4-amino antipyrine is acted upon by peroxidase to form red quinine. The absorbance of colored compound was measured at 532nm.

Fibrinogen assay

Fibrinogen assay in plasma was carried out by Biuret method [7]. Fibrinogen present in the plasma is converted to fibrin in presence of calcium chloride. The fibrin clot formed is collected and then digested with NaOH. Protein content of the clot is determined using a red filter. 0.5ml of plasma was mixed with 14 ml of distilled water and 0.5ml of 2.5% calcium chloride solution in a small beaker and incubated at 37ºC until a clot was formed. Then a glass rod was rotated to collect the clot on to it. The rod was pressed against the side of the beaker to squeeze out any solution and to compress the clot. Care was taken to pick up any small piece of clot on the rod, which may have become detached and was dried by pressing carefully against a filter paper. Then it was transferred into a test tube into which the digestion was to be carried out.

After that, the clot was digested with 0.5ml of 0.1N NaOH in a boiling water bath. After cooling, 3.5ml of working Biuret reagent was added to the tube. The OD of the blue color developed was read at 555nm after standing the tube in a water bath at 37 °C for 5minutes. 0.5ml of standard protein solution (800mg/dl) and 0.5 ml of distilled water as blank were treated similarly.

Estimation of serum ceruloplasmin

Ceruloplasmin assay in serum was carried out by the method of Sunderman et al. [8]. At pH 5.4, ceruloplasmin catalyzes the oxidation of PPD to yield a coloured product which is believed to correspond either to Bandrowski’s base or to Weurster’s red. The rate of formation of colored oxidized product is proportional to the concentration of ceruloplasmin, if, a correction is made for the nonenzymatic oxidation of PPD. Therefore, simultaneous assay were carried out with and without sodium azide, which inhibited the enzymatic oxidation of PPD. The difference between the results of the two assays is proportional to ceruloplasmin concentration.

Estimation of α1-antitripsin

α-1 antitrypsin assay in serum was carried out by the modified method described by Sundaresh et al. [9]. The Proteolytic enzyme trypsin hydrolyses casein, with the formation of smaller peptides. The enzyme reaction after suitable interval of time is arrested by the addition of TCA which precipitated the protein, but the peptides are soluble in the acid. The TCA soluble fragments are a measure of Proteolytic activity of the enzyme. When the inhibitor is added to the preincubated mixture, it prevents the release of peptides by the Proteolytic enzymes. Thus, the estimation of TCA soluble components in the presence and absence of inhibitor is a measure of inhibitory activity against Proteolytic enzymes. The TCA soluble fragments are analyzed by the method of Lowry. The final color formed is a result of Biuret reaction of the peptides with copper ions in alkali and reduction of the phosphomolybdic acid reagent by the presence of tyrosine and tryptophan which are present in the treated peptides.

Determination of serum α-1 acid glycoprotein

α-1 acid glycoprotein assay in serum was carried out by the method of Winzler RJ et al. [10]. After removing heat coagulable proteins with perchloric acid, the orosomucoid which remains in the solution is precipitated by phosphotungstic acid and estimated by determining it carbohydrate content by reaction with an orcinol-sulphuric acid reagent, or its nitrogen by Kjeldahl nesslerization or its tyrosine content using FolinCiocalteau reagent.

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Result

The anthropometric data of the subjects participated in the study are presented in Table 1.

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Discussion

The aim of this study was to examine inflammation as a pathogenetic causeof type 2 diabetes mellitus. Twenty-five type 2 newly diagnosed patients showed increased levels of α1- antitrypsin, α1-acid glycoprotein, ceruloplasmin and fibrinogen. The findings were in agreement with most of the authors who worked with acute phase proteins in type 2 diabetes [11-13]. The role of chronic low-grade inflammation in the pathogenesis of type 2 diabetes seems possible beyond doubt. The course of the disease and resulting complications are similar in both type 1 and type 2 diabetes. The most dreaded complication being that of development of atherosclerosis resulting in cardiovascular diseases. Fibrinogen is identified as an independent risk factor in the development of ischemic heart diseases [14]. Irrespective of the patients being type 1 or type 2, the risk of developing atherosclerosis remains the same. Hence there must be some mechanism which links the pathogenecity of type 1 and type 2 diabetes. Barrazzani et al. [15] infused insulin to non-diabetics, type 1 and type 2 diabetics and studied its role in fibrinogen production. Insulin replacement activity suppressed fibrinogen production in non-diabetics and type 1 diabetic individuals.Fibrinogen production and its plasma concentration increased in insulin resistant type 2 diabetics when euglycemia and euaminoaciduria were maintained. They postulated that an altered response to insulin causes hyperfibrinogenemia in type 2 diabetic patients. If this hypothesis holds well, it doesn’t explain hyperfibrinogenemia in type 1 diabetics where the basic pathology is insulin deficiency. Hence there must be some other factors which stimulate increased fibrinogen synthesis in type 1 patients contributing to cardiovascular disease risk. An insulin resistance syndrome score [16] was developed based on clinical risk factor in patient with type 1 diabetes and validated using euglycemic-hyperinsulinemic clamp studies. Fibrinogen levels were significantly associated with this insulin resistance syndrome score. This may explain high fibrinogen level in type 1 diabetes. But it still does not answer the above findings since the type subjects in this study were newly diagnosed. Hence the mechanism of increased fibrinogen synthesis needs to be proved further.

Group I: Type 1 diabetes mellitus patient (newly diagnosed)

Group II: Type 2 diabetes mellitus patient (newly diagnosed)

Group III: Type 2 diabetes mellitus patient (under treatment for at least 5 years)

Group IV: Control

n =Number of Subjects; SD: Standard Deviation; BMI: Body Mass Index

Ceruloplasmin is known to have antioxidant action [17]. It is also an acute phase protein with a response of intermediate magnitude. Ceruloplasmin is known to stimulate cell proliferation and angiogenesis [18]. The higher levels of ceruloplasmin in both in type 1 and type 2 as compared to controls may be due to an oxidative stress that is prevalent in both types of diabetes [19,20]. Ehrenwald [21] showed a very interesting feature of ceruloplasmin. The intact human ceruloplasmin which is 132 KD molecules caused increased oxidation of LDL in vitro. Starkebaum & Harlan et al. [22] also showed that increased serum ceruloplasmin could generate excess oxidized LDL, and cause vascular injury by generating free radicals such as hydrogen peroxide [22]. These findings defined the earlier notions of the antioxidant activity of ceruloplasmin. By further investigations Ehrenwald et al. [21] found that the holoceruloplasmin, which is seen in serum as a 132KD molecule, has a prooxidant effect and the action was attributed to the copper ions present in ceruloplasmin. The commercially available ceruloplasmin is a degraded product containing either 115KD fragment or 19KD fragment or both. These had an antioxidant effect. The works done to show that ceruloplasmin as an antioxidant used these degraded products. The antioxidant action of a commercial ceruloplasmin was observed even in the system where holoceruloplasmin oxidized LDL [23]. Hence considering ceruloplasmin as an antioxidant in vivo is debatable. The LDL oxidizing action of ceruloplasmin could probably explain at least in part of the increased risk of IHD in both type 1 and type 2 diabetes. Also, it could not be wrong to count ceruloplasmin as an acute phase reactant whose levels are increased in both the types of diabetes.

The values of various parameters when compared between the untreated type 1 patients and type 2 patients reveals a significant increase in type 2 patients. Even the ceruloplasmin values, although not statistically significant, were slightly higher in the type 2 patients. The mean random blood sugar (RBS) values in group 1 (Type 1 diabetes) patients was 338.25±50.97mg/ dl and that of group II (Type 2 newly diagnosed diabetics) was 193.26±35.30mg/dl. Despite this huge difference, the inflammatory markers levels were higher in the type 2 patients which go to prove that the glycemic status doesn’t influence the inflammatory markers. This is in accordance with previous findings [24,25]. Evidence is available to say that inflammatory markers are elevated well before the clinical manifestation of hyperglycemia [26-29]. This also gives credence to the thought that activation of innate immunity is not related to hyperglycemia. But research has shown that decreasing plasma glucose levels decrease the concentration of acute phase reactants [30]. Also 2 hrs post load glucose values showed positive correlation with the inflammatory markers in few studies. α1-acid glycoprotein levels remained within normal limits in the type 1 patients whereas significant high levels were seen in the type 2 patients ( p<0.0001). Although both type 1 and type 2 patients showed significant high α1-antitrypsin levels, the comparison between two groups also reached statistical significance (p =0.003) with higher values in type 2 patients. The above findings can be best explained as insulin mediated increased synthesis of the hepatic proteins.

The underlying mechanism for the augmented acute phase response is not well understood and the stimulus for the response is unknown. Many hypotheses have been put forward and these include insulin resistance, obesity, atherosclerosis, other diabetic complications and maladaptation of the normal innate immune response to environmental threats [31-33]. The most widely studied is the association of obesity, insulin resistance, type 2 diabetes and acute phase reactants. It has been shown that adipocytes secret many proinflammatory cytokines in the postprandial state [34-36]. The term ‘diabecity’ has received attention [37] of late for obese diabetics. The ‘common soil’ theory proposed, evaluates the involvement of inflammation in the pathogenesis of diabetes and atherosclerosis. Hyperglycemia and insulin resistance could promote inflammation and inflammation may be a factor linking diabetes mellitus to the development of atherosclerosis. Elevated glucose levels promote inflammation by increasing oxidative stress [38], by the formation of AGEs and increased TNF (kappa B) [39]. In this study, the mean BMI was found to be 19.5±1.23 in type 1 patient and 24.03±1.46 in type 2 patients. No correlation was found between BMI and acute phase reactants. Hence it can be summarized that there could be multiple pathways involved in the activation of the innate immunity system and much work needed to be done to establish either a casual role in the development of mainly type 2 diabetes and could be type 1 diabetes also.

Having demonstrated that there is an inflammatory process going on in type 2 diabetes, we next thought of estimating inflammatory markers in patients on treatment (for at least 5 years) with oral hypoglycemic drugs. Many of the drugs have been shown to have anti-inflammatory effects. Statin drugs inhibits HMG-CoA reductase and prevent atherosclerosis and inhibit the acute phase response by diminishing the deposition of LDL particles rich in cholesterol and phospholipids in macrophages and smooth muscle cells [40]. Statins were found to reduce CRP levels and did not correlate with the reduction of the lipid levels suggesting that the in addition to their ability to reduce LDL, statins may also inhibit the acute phase response [41]. Freeman et al. [40] showed that statin therapy also prevents diabetes mellitus. Pravastatin therapy in the West of Scotland Coronary Prevention Study resulted in a 30% reduction of risk of developing type 2 diabetes. Salicylates in high doses have been known to lower glycosuria in diabetic patients. Although earlier studies were contradictory, these studies have used lower aspirin doses (<3gm/day) and therapeutic duration was only for a few days. Hundal [42] reported that high doses of aspirin (7gm/day) for 2 wks caused 25% reduction in fasting plasma glucose, 50% reduction in triglyceride and 15% reduction of CRP concentration independently of the changes in the plasma insulin concentration. The recently introduced oral hypoglycemic agents thiazolidinedions (Glitazone) are peroxizome proliferators activated receptor γ (PRAR γ) agonist that have been regarded as insulin sensitizes through mechanisms such as altered transcription of insulin sensitive genes controlling lipogenesis, adipocytes differentiation, fatty acid uptake and GLUT 4 ( Glucose Transporter 4) expression. They also have an anti-inflammatory action inhibiting cytokine production, macrophage activation and reducing CRP as well as WBC count in type 2 diabetic subjects [43-46].

n =Number of Subjects; SD: Standard Deviation; RBS: Random Blood Sugar

Angiotensin Converting Enzyme Inhibitors (ACE inhibitors) are also known to decrease insulin resistance in either type 1 or type 2 diabetic patients with concomitant hypertension [47]. Torlone et al. [48] demonstrated improved glycemic control in patients with arterial hypertension and type 2 diabetes using ACE inhibitors [48]. Insulin has a potent anti-inflammatory activity [32]. Insulin was found to be a rapid nonspecific and dose dependent inhibitors of the cytokine and glucocorticoids stimulation of acute phase protein, gene expression and exerted effect at the transcriptional levels. Insulin inhibition applied to all cell cytokines tested but to various degrees depending upon the particular acute phase gene [49].

In this study, of the 25 type 2 diabetic patients on treatment for at least 5 years, 8 patients were in sulfonylurea-metformin combination, 7 were on glitazone, 6 were on sulfonylurea alone, 2 were on glitazone-metformin combination and 2 were on metformin alone. When compared with newly diagnosed untreated group (Group II) the levels of α1-antitrypsin, α1- acid glycoprotein and ceruloplasmin were statistically lower. No significant difference was found in the fibrinogen levels. The values of α1-acid glycoprotein and ceruloplasmin were comparable to those of the control group. The RBS values were like those of untreated group (193.62±33.65 and 193.26±35.30). It is interesting to note that α1-acid glycoprotein levels were almost the same in type 1 diabetes type 2 untreated patients and control (Table 2). Probably α1-acid glycoprotein is the most amenable acute phase protein to treatment modalities. Comparable ceruloplasmin levels in type 2 patients on treatment and controls again raise the question as to the ‘prooxidant’ or ‘antioxidant’ action of ceruloplasmin. No change in fibrinogen values suggest multiple pathway involvement that are poorly understood.

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Influence of Iron Deficiency Anemia on HbA1c: A Review

Authored by Ghulam N Bader

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Abstract

Hemoglobin A1c (HbA1c) is widely used as a diagnostic tool for diabetes. Many clinical conditions affect erythrocyte turnover which influence HbA1c levels. These levels are lowered by different forms of anemia, but reverse is the case in iron deficiency anemia (IDA). This is suggested by various studies which propose an increase in HbA1c levels in patients with IDA. However, there are studies which negate any influence of IDA over HbA1c levels. In both cases the clinical data is not sufficient to confirm or nullify the role of IDA in increasing HbA1c levels.

Introduction

Hemoglobin A1c (HbA1c), a glycated hemoglobin is formed by an irreversible, slow non-enzymatic catalysis of the β chain of globin in mature hemoglobin (Hb) [1,2]. It is used as a gold standard for monitoring glycemic status for the previous three months (the life span of a red blood cell) in patients with diabetes [3]. HbA1c provides an integrated measure of glycemia which is less susceptible to short-term modulation than blood glucose levels. Also, it helps to keep a track of diabetic therapy within individuals suffering from diabetes. WHO and ADA have approved the use of HbA1c determination for diagnosis of type 2 diabetes [4,5]. The normal range of HbA1c in a healthy person is 4 to 6% [6].

Clinically there are three major factors on which HbA1c levels depend.

A. HbA1c in reticulocytes when released from the bone marrow;

B. Hb glycation rate as red blood cells (RBCs) become older, a function of glucose concentration to which Hb is exposed; and

C. The mean age of RBCs in the circulation [7].

HbA1c levels can be affected by number of factors such as structural hemoglobinopathies, thalassemia syndrome, and alteration in quaternary structure of Hb [8]. Also, HbA1c levels can be changed by different types of anemia [9]. Anemia is the most prevalent form of nutritional deficiency both in developed and developing countries. Globally, 50% of anemic burden is contributed alone by Iron deficiency [10,11]. The clinical profile of many systemic diseases is regulated by the iron [12], which is involved in most important metabolic processes viz. transportation of oxygen, regulation of cell growth and differentiation, deoxyribonucleic acid (DNA) synthesis, and electron transport [13,14].

Iron deficiency anemia (IDA) can increase the red blood cell turnover which can increase glycation of Hb leading to higher HbA1c values as observed in blood loss, hemolysis, hemoglobinopathies, red cell disorders and myelodysplastic disease [15]. There are studies to support the idea that diabetes is influenced by changes in the iron level in a body [16]. Lower levels of serum iron or serum ferritin have been linked with increased glycation of HbA1c [17,18]. It has been reported that there is a bidirectional relationship between iron metabolism and glucose homeostasis, higher iron levels modulate both the action and secretion of insulin [12]. Thus, lower the iron levels, higher is the glycation of HbA1C, leading to its false-high values in diabetic as well as non-diabetic individuals [19].

Brooks et al. [20] reported that a relative absence of iron results in the alteration of quaternary structure of the Hb molecule leading to excessive glycation of the beta globin chain. In another study by Sluiter et al. [21] it was reported that glycation of Hb is an irreversible process thus, with the aging of a cell there is a linear increase of HbA1c in the erythrocyte. El Agouza et al. [22] reported that at a constant glucose level, lower levels of Hb can lead to an increase in the glycated fraction because HbA1c is measured as a percentage of total HbA. These studies report relationship between IDA and HbA1c on the basis of structural modification of Hb and HbA1c levels in old and new red blood cells [20]. Coban et al. [19] in his studies showed that patients with IDA had higher HbA1c levels and on treatment with iron these levels significantly decreased. A case study by Mudenha et al. [23] reported that HbA1c levels significantly decreased with correction of IDA. Furthermore, Silva et al. [24] and Rajagopal et al. [7] reported difference in HbA1c levels among diabetic as well as non diabetic patients with mild, moderate, and severe IDA.

On the other hand, Heyningen et al. [25] and Hansen et al. [25] reported that there was no difference between HbA1c levels in patients with IDA and control. These findings gather support from study by Rai et al. [26], who reported no difference in HbA1c levels with respect to IDA using different methods to assay HbA1c. Thus these conflicting reports are enough to create a stir in the minds of clinicians regarding a successful therapy in diabetic patients with IDA. Hence the effect of IDA on HbA1c needs to be evaluated at mechanistic level, so as to be assured about the outcome of the therapy. Iron replacement therapy in diabetic patients with IDA needs to be considered.

Conclusion

IDA is the commonest nutritional deficiency worldwide but the prevalence is higher in developing countries, and most vulnerable groups to IDA are women, children and adolescents [27]. Also, in low and middle income countries diabetes too is increasing and the mostly affected age group is 45-64 years [28]. So, determination of HbA1c levels has increased for both screening and diagnosis of diabetes. Clinicians need to evaluate the nonglycemic factors that could affect the HbA1c levels of a patient [29,30]. Different types of anemia can have a negative effect on HbA1c levels, some investigators have shown that IDA increases the HbA1c levels independent of fasting glucose level [16] whereas others have negated these findings. In either case the clinical data is not sufficient and further studies are required to identify the role of erythrocyte indices in modulation of HbA1c levels. Studies with large population need to be conducted to evaluate the difference between severity and effects of IDA on HbA1c values.

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Evaluation of Glycemic Control Obtained from NPH Insulin in Patients Experiencing Corticosteroid-Induced Hyperglycemia

Authored by Megan N Hodges

Abstract

Objective:To compare the safety and efficacy of neutral protamine Hagedorn (NPH) insulin to other antidiabetic regimens in the treatment of corticosteroid-induced hyperglycemia in non-critically ill; hospitalized patients.

Methods:This retrospective cohort included patients treated with methylprednisolone or prednisone concomitantly with NPH or other antidiabetic medications for at least two days. Patients were screened for inclusion in reverse chronological order and matched based on gender; age; body mass index; steroid dose; and history of diabetes. The primary objective was mean daily blood glucose (BG). Secondary outcomes included percentage of readings between 70mg/dL-180mg/dL; median daily BG; number of hypoglycemic events; daily steroid to NPH ratios; and mean weight-based dose of NPH for each 10mg increment of prednisone when BG readings were within goal.

Results:A total of 72 patients were included in each arm. The primary efficacy endpoint of mean daily BG ranged from 111-217mg/dL in the control group and 163-228mg/dL in the NPH arm; however; there were no statistically significant differences (p>0.05). Overall rates of hypoglycemia were slightly lower in the NPH group but with no statistically significant differences (0.61% vs. 1.12%; p = 0.51).

Conclusions:NPH; compared to other regimens; may not have an impact on achieving glycemic controlin corticosteroid-induced hyperglycemia.

Keywords: Diabetes mellitus; Corticosteroid; Hyperglycemia; Neutral protamine hagedorn

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Introduction

Systemic corticosteroids are commonly used for a wide variety of medical conditions on both an inpatient and outpatient basis for the treatment of inflammation and immune suppression. Acute asthma and chronic obstructive pulmonary disease (COPD) exacerbations, rheumatoid arthritis, and organ transplant comprise just a few of the many indications. Although corticosteroids are highly efficacious, its use is limited by many serious adverse effects during acute and chronic treatment [1-6]. During short-course therapy, patients commonly develop hyperglycemia. Several studies have reported odds ratios from 1.5 to 2.5 for the development of new-onset diabetes relating specifically to steroid utilization [2-5]. Corticosteroids also have the potential to significantly worsen hyperglycemia in patients with a history of diabetes mellitus [1,7] . This represents a substantial health risk to patients since studies have found a correlation between hyperglycemia and decreased wound healing, increased length of stay (LOS) and mortality in hospitalized patients [8].

Several studies have been undertaken to better understand the exact mechanism of steroid-induced hyperglycemia. In patients receiving short-term therapy, skeletal muscle and hepatic cells develop reduced insulin sensitivity leading to decreased glucose uptake. During the post-prandial phase in particular, blood glucose (BG) levels are further elevated by impaired suppression of glucose production secondary to hepatic insulin resistance [6].

Insulin acts on liver, adipose tissue, and skeletal muscle to regulate metabolism of carbohydrates, fat, and protein. A cross- sectional review of 66 patients suggested that patients receiving ≥10mg per day of prednisolone compared to those not receiving corticosteroids experience afternoon and evening hyperglycemia despite receiving basal-bolus insulin regimens [9]. Neutral protamine Hagedorn (NPH) is a crystalline suspension of human insulin with protamine and zinc, which makes it intermediate acting insulin. Neutral protamine Hagedorn insulin produces a peak effect four to eight hours after administration with a total duration of sixteen to eighteen hours. These kinetic properties closely mirror the action of prednisone. Methylprednisolone also has a similar duration of action with a shorter onset of one to two hours [10-12]. In theory, the pharmacokinetic principles of subcutaneous NPH make it a prime candidate for the treatment of glucocorticoid induced hyperglycemia. The objective of this study is to compare NPH to other antidiabetic agents in the treatment of steroid-induced hyperglycemia.

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Materials and Methods

Study design

This single-center retrospective cohort study evaluated patients at a 450-bed community hospital. The trial was approved by the hospital Institutional Review Board before data collection began. Due to the retrospective nature of the study, informed consent was not necessary. All data was obtained through electronic medical records.

Eligibility requirements included age ≥18 years, concurrent treatment with methylprednisolone or prednisone with NPH insulin or other antidiabetic medications for at least two days, and steroid doses ≥10mg prednisone equivalent on day one. Patients receiving NPH for the treatment of steroid-induced hyperglycemia were included in the treatment arm and patients being treated with any other combination of antidiabetic medications were evaluated in the control arm. Patients in the NPH arm with glargine insulin as a home medication were included in the study if the glargine titration was limited to± 20% during the hospitalization since a 20% reduction is recommended at admission to decrease risk of hypoglycemia and to limit confounding adjustments to the glargine during steroid titration [13]. Patients were not eligible for inclusion in the NPH treatment arm if they received any other antidiabetic medications in addition to NPH, rapid acting insulin, or glargine as described above. Oral antidiabetic agents were allowed in the control arm; however, per institutional protocols and American Diabetes Association (ADA) recommendations these agents are routinely discontinued upon admission to the hospital [14]. Patients admitted with a BG>400mg/dL, those in the intensive care unit, patients on insulin pumps, and pregnant patients were excluded. Patients were also excluded if they had less than two BG readings per day or no recorded weight.

Patient characteristics were identified through queries of the hospital electronic medical record. Starting October 2014 through October 2012, all patients receiving ≥10mg of prednisone equivalent of methylprednisolone or prednisone for at least one day were consecutively screened for inclusion in reverse chronological order. After patients were identified for analysis in the NPH arm, controls were then matched by manual chart review to the NPH patients based on age, gender, body mass index (BMI) classification, steroid dose on day one, and history of diabetes.

Study outcomes and definitions

The primary outcome was the mean daily BG. Secondary outcomes included the percent of BG readings within a preset goal of 70mg/dL to 180mg/dL. All BG readings were incorporated in the analysis regardless of the patients’ fasting state, thus a higher goal of <80mg/dL was established based on the ADA random BG recommendations for non-critically ill, hospitalized patients. The low end of this range was based on the ADA definition of hypoglycemia, which is BG<70mg/dL [14]. Other secondary objectives included median daily BG, number of hypoglycemic and severe hypoglycemic events with and without intervention. Intervention was defined as intake of juice, oral glucose tablets or administration of glucagon or dextrose 50% water. As defined by the ADA, BG<40mg/dL is considered severe hypoglycemia. [14] Daily steroid to NPH ratios and steroid to NPH ratios on the index day were also collected. The index day was defined as the last day of steroid therapy or the day of discharge if the patient continued steroids as an outpatient. Mean weight-based dose of NPH for each 10mg increment of prednisone equivalent (8mg methylprednisolone) was collected for days on which all BG readings were within the goal range with the intention of formulating a standardized NPH protocol. Two subgroup analyses were performed on mean blood glucose to compare NPH to sliding scale insulin alone and to compare NPH to other antidiabetic regimens in patients admitted with a documented history of diabetes.

Statistical analysis

The outcomes data was analyzed to determine the glycemic control achieved with each regimen by looking at all available BG readings throughout the patients’ hospitalizations excluding repeat readings within 10 minutes. Baseline characteristics and outcomes were reported using means, medians, and standard deviations for interval level data and percentages for nominal and ordinal level data. Baseline demographics and study outcomes were compared between groups using Student’s t-test for continuous data and Fisher’s exact or chi-square test for categorical data. A p value of <0.05 indicated statistical significance. All analyses were performed with IBM SPSS Statistics for Windows.

To the authors’ knowledge, the only other published trials addressing this treatment regimen included a maximum of 66 patients in each arm and did not find a statistically significant difference; therefore, power was not calculated [15-17]. Based on available information, 72 patients were included in each arm.

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Results

A total of 241 patients were identified through the pharmacy informatics system for potential inclusion in the NPH arm. Of these patients, 72 were eligible based on the inclusion and exclusion criteria. Patients were well matched in regards to baseline demographics (Table 1). The only significant difference between groups was total LOS, which was significantly higher in the NPH group (6.98days vs. 4.88days, p =0.003). However, no differences existed among indication for steroid utilization. Baseline glycemic control was similar between groups: mean BG of 186mg/dL in the NPH group and 177mg/dL in the control group at admission (p=0.492).

*There were no significant differences between the two groups except for LOS (p=0.003)

The primary efficacy endpoint of mean daily BG ranged from 111-217mg/dL in the control group and 164-228mg/dL in the NPH arm; however, no statistically significant differences were detected for any day (Figure 1) & (Table 2). The results on the index day (Table 3) showed numerically though not statistically improved glycemic control for the control group compared with the NPH arm with a mean BG of 195mg/dL for the NPH group and 179mg/dL for the control group (p =0.135).

In regards to efficacy, the only statistically significant difference found was in the percent of BG readings between 70- 180mg/dL for day 1 in favor of the control arm (41.9%vs.28.1%, p=0.01) (Table 4). No trends were observed for the steroid: NPH ratios or weight-based NPH doses. Consistent glycemic control was achieved faster in the control arm; mean daily BG readings were <180mg/dL starting on day 5 compared to day 10 in the NPH arm (Figure 1). In contrast to a previous study, the NPH arm received a significantly higher total daily insulin dose on the index day compared to the control arm (0.37unit/kg vs. 0.21unit/kg, p=0.002). However, these differing results are likely accounted for by the inclusion of glargine insulin in the NPH arm [15].

aData presented as mean ± standard deviation.

Glycemic control was similar in both subgroup analyses (patients with a history of diabetes and those receiving only slide scale insulin compared to NPH) (data not shown). In patients with a documented history of diabetes, the mean BG on the index day was 197mg/dL in the NPH arm compared to 185mg/dL in the control arm (p=0.313). When comparing NPH and sliding scale insulin versus sliding scale insulin alone, BG on the index day was 187mg/dL in the NPH group and 174mg/dL in the sliding scale insulin group (p=0.246).

Overall, the incidence of hypoglycemia was low in both arms, with more events occurring in the control arm (Figure 2). A total of 9(0.61%) hypoglycemic episodes occurred in the NPH arm and 15(1.12%) in the control arm (p=0.51). Only one episode of severe hypoglycemia was noted in the control arm.

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Discussion

When interpreting these results, it is important to note that the number of patients evaluated dropped considerably each consecutive day. By day eleven, only two patients remained in the NPH arm compared to one patient in the control arm. Although daily trends are important to consider, the results on the index day may provide the most insight on glycemic control.

Several limitations exist within this study. Due to the retrospective design, there is also potential for data extraction errors and chart documentation errors. Another limitation is the lack of standardized NPH dosing at this institution. The doses prescribed varied greatly between patients, and the majority of weight-based NPH doses were much lower than other institution protocol recommendations [1,8-15]. Overall glycemic control was also relatively poor in both groups compared to previous studies. This could be partly due to higher daily steroid doses and lack of Diabetes Management Services [15]. Lastly, patients in the NPH group had a significantly longer LOS compared to the control group, which could have resulted in worse overall BG control with increased time of steroid exposure. However, there were no measurements to determine severity of illness to help explain the extended LOS. Although this study was conducted at a single community hospital with a limited sample size, it is the largest study to evaluate this topic.

Despite a lack of evidence, several institutions have implemented protocols for the use of weight-based NPH dosing for hyperglycemic patients treated with steroids. The doses usually range from 0.1units/kg to 0.5units/kg depending on steroid doses [1,8-15]. One retrospective cohort of 120 patients found no difference between NPH versus glargine to control steroid-induced hyperglycemia in patients with type 2 diabetes [15]. A randomized control trial of 50 patients evaluated whether an NPH-based insulin regimen is safer and more effective than a glargine-based regimen in hospitalized adults with prednisolone-induced hyperglycemia. The initial daily insulin dose was 0.5units/kg or 130% of the current daily insulin dose. No differences in either outcome was observed [16]. Another randomized control trial of 53 patients examining glargine versus NPH in type II diabetics with respiratory disease and glucocorticoid induced hyperglycemia yielded similar results [17]. This current trial included patients regardless of their diabetes history or steroid indication. Despite the similarity in pharmacokinetic profiles between corticosteroids and NPH, this approach may not offer better glycemic coverage in steroidinduced hyperglycemia over other regimens as shown in this trial and in the studies by Dhital et al. [15], Ruiz de Adana et al. [17], & Radhakutty et al. [16]. Additional large, randomized-controlled trials are warranted to further help direct future evidence-based treatment strategies for steroid-induced hyperglycemia.

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Conclusion

Based on the results of this study, no conclusions can be determined about the efficacy of NPH insulin for corticosteroidinduced hyperglycemia. Patients receiving standard care (control group) appeared to have better glycemic control over patients in the NPH arm; however, the resulting differences were not statistically significant and hampered by small sample size.

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Association between Complement System, Inflammatory Cytokines and Glucose Control in Obese Subjects

Authored by Essam H Jiffri

Abstract

Background:Obesity is frequently characterized by chronic systemic inflammation and insulin resistance (IR). Obesity-associated low grade systemic inflammation is responsible for the complement system activation of which the third component (C3) plays the central role.

Objective:This study aimed to detect the association between complement system, inflammatory cytokines and glucose control in obese subjects.

Methods:Seventy-nine volunteers obese subjects were interviewed, only 68 of them met eligibility criteria, signed the consent form to participate in this study. Their age ranged from 26-43 years and their body mass index (BMI) ranged from 30 to 37kg/m2. In the other hand sixty lean subjects (BMI ≤25 kg/m2) were participated in the study as a control group, the mean age was 36.18±5.84 year and body mass index (BMI) was ≤25kg/m2. All participants who were assigned into two groups, group (A) consisted of 68 obese subjects and group (B) consisted of 60 lean subjects.

Results: The mean values of HBA1c, HOMA-IR, C3, C4, TNF-α, Il-6, CRP were significantly higher in the obese group than in the lean control group. In the other hand, the mean value of QUICKI was significantly lower in the obese group than in the lean control group. However, HBA1c and HOMA-IR showed a strong direct relationship with C3, C4, TNF-α, Il-6 and CRP, while QUICKI showed a strong inverse relationship with C3, C4, TNF-α, Il-6 and CRP in the obese group (P<0.05).

Conclusion:The present study suggests that in obese subjects there is an association between complement system, inflammatory cytokines and glucose control.

Keywords: Complement system; Cytokines; Obesity; Glucose control

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Introduction

Recently, Obesity is a global medical problem as it affects about 13% of population worldwide [1]. Obesity is usually associated with impaired insulin sensitivity and insulin resistance [2,3]. Adipose tissue is a storage site and has secretory functions for some secretions of certain biological functions [4]. In addition, adipose tissues has adipocytes and non-adipocytes that include immune cells [5]. Adipose tissue in obese subjects contribute to excessive hepatic production of pro-inflammatory cytokines and serum complement proteins 3 &4 (C3 & C4) [6], which are associated with cardiovascular risk factors, insulin resistance, metabolic syndrome and type 2 diabetes mellitus (T2DM) [7,8]. However, there was an association between C3 & C4 with body mass index (BMI) and fat mass [9].

It is well-established that inflammation in obesity is characterized by a low-grade systemic inflammation [10] that leads to an increase in pro-inflammatory proteins such as C-reactive protein (CRP) and interleukin-6 (IL-6) [11] and some components of complement system [12]. The complement system is mainly associated with innate immunity. However, recent studies have shown that this system is involved in metabolic events [13]. The majority of complement components are synthesized mainly by hepatocytes, but also can be produced by other cells such as macrophages and adipocytes [14]. Recently, it was demonstrated that serum complement factor 3 (C3) synthesis can be up-regulated by pro-inflammatory cytokines IL-6 and interleukin- 1 beta (IL-1β), while serum complement factor 4 (C4) can be influenced by gamma interferon (IFN-γ) [15,16]. This study aimed to detect the association between complement system, inflammatory cytokines and glucose control in obese subjects.

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Patients and Methods

Subjects

Seventy-nine volunteers obese subjects were interviewed, only 68 of them met eligibility criteria, signed the consent form to participate in the study at the Internal Medicine Department at King Abdul Aziz University Hospital. Participants were enrolled between January 2017 and April 2017. Scientific research ethical committee of the Faculty of Applied Medical Sciences, King Abdulaziz University approved this study. Their age ranged from 26-43 years and their body mass index (BMI) ranged from 30 to 37kg/m2. While, the exclusion criteria were pregnant women, smoking, patients with body mass index ≥40kg/m2, subjects taking any medications or herbal supplements, respiratory infection, liver, cardiovascular, renal, endocrine and thyroid diseases. In the other hand sixty lean subjects (BMI ≤25kg/m2) were participated in the study as a control group, the mean age was 36.18±5.84 year and body mass index (BMI) was ≤25kg/ m2. All participants who were enrolled into two groups, group (A) consisted of 68 obese subjects and group (B) consisted of 60 lean subjects.

Measurements

For all subjects, independent assessors who were blinded to group assignment and not involved in the routine treatment of the patients performed clinical evaluations and laboratory analysis. Body mass index (BMI) was calculated on the basis of weight (kilograms) and height (meters), and subjects were classified as normal weight (BMI 18.5-24.9kg/m2), overweight (BMI 25-29.9kg/m2), and obese (BMI ≥30kg/m2).

Measurement of inflammatory cytokines: Venous blood samples after a 12-hours fasting were centrifuged at +4 °C (1000=g for 10min). Interleukin-6 (IL-6) levels were analyzed by “Immulite 2000” immunassay analyzer (Siemens Healthcare Diagnostics, Deerfield, USA). However, tumor necrosis factoralpha (TNF-α) and C-reactive protein (CRP) levels were measured by ELISA kits (ELX 50) in addition to ELISA microplate reader (ELX 808; BioTek Instruments, USA).

Serum glucose, insulin and insulin resistance tests: Plasma glucose concentration and insulin were determined (Roche Diagnostics GmbH, Mannheim, Germany) using commercially available assay kits. Insulin resistance was assessed by homeostasis model assessment (HOMA-IR). HOMAIR = [fasting blood glucose (mmol/l) fasting insulin (mIU/ ml)]/22.5 [17]. However, insulin sensitivity was assessed by The quantitative insulin-sensitivity check index (QUICKI) using the formula: QUICKI=1/[log(insulin) + log(glucose)] [18]. All serum samples were analyzed in duplicates.

Measurement of complement system function: Biomarkers of C3 and C4 concentrations were measured from frozen serum samples stored at -80 °C by the immunochemiluminometric method (Advia Centaur XP, Siemens, Berlin, Germany).

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Statistical Analysis

SPSS (Chicago, IL, USA) version 21 was used for statistical analysis of data. Quantitative variables were described as mean±SD. An independent t-test was used to compare mean values of each parameter among the groups. To observe possible relationships between C3, C4, HBA1c, HOMA-IR, QUICKI, TNF-α, Il-6, CRP, Pearson’s correlation coefficient (r) was used. All assumptions were carefully appreciated in each model we followed. All variables with p- value less than 0.05 were considered as statistical significance.

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Results

Detailed baseline characteristics of the obese group and the lean group presented in Table 1. Comparison between both groups regarding baseline variables showed that there was no statistically significant difference between the both groups as regards age and gender, while the rest of variables the obese group showed significant differences (Table 1).

BMI: Body Mass Index; HDL-c: High-density Lipoprotein Cholesterol; LDL-c: Low-Density Lipoprotein Cholesterol; (*) indicates a significant difference between groups, P < 0.05.

C3: Serum Complement Factor 3; C4: Serum Complement Factor 4; HBA1c: Glycosylated Hemoglobin; HOMA-IR: Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) Index; QUICKI: The Quantitative Insulin-Sensitivity Check Index; TNF-α: Tumor Necrosis Factor -Alpha; IL-6: Interleukin-6; CRP: C-reactive Protein; (*) indicates a significant difference between groups, P<0.05.The mean values of HBA1c, HOMA-IR, C3, C4, TNF-α, Il-6, CRP were significantly higher in the obese group than in the lean control group. In the other hand, the mean value of QUICKI was significantly lower in the obese group than in the lean control group (Table 2). However, HBA1c and HOMA-IR showed a strong direct relationship with C3, C4, TNF-α ,Il-6 and CRP, while QUICKI showed a strong inverse relationship with C3, C4, TNF-α, Il-6 and CRP in the obese group (Table 3) (P < 0.05).

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Discussion

Obesity is usually associated with systemic low-grade inflammation which is responsible for complement system and macrophage infiltration [19,20]. which are linked with insulin resistance, T2DM and metabolic syndrome [21]. The complement system is mainly associated with innate immunity in addition to be involved in metabolic events [22]. Certainly, complement components C3 and C4 are associated with diabetes cardiovascular risk and the metabolic syndrome [23-25].

Concerning inflammatory markers, the results of the present study showed significantly higher values of TNF-α, IL-6 and CRP in obese than the lean control group. Researchers have found that plasma levels of CRP, TNF-α, IL-6 and other inflammatory mediators are elevated in subjects with obesity [26-28]. In correlation analysis, HBA1c and HOMA-IR showed a strong direct relationship with TNF-α, Il-6 and CRP, while QUICKI showed a strong inverse relationship with TNF-α, Il-6 and CRP in the obese group. Our findings are similar to many case-controlled researches demonstrated a direct association between HbA1c and inflammatory cytokines [29-36].

Regarding the values of C3 and C4, the present study showed significantly higher values of C3 and C4 in the obese group than the lean group. Our findings agreed with Wlazlo & colleagues [37] enrolled 532 individuals in their cohort study and reported that there was an association between the degree of body fat and the C3 level [37]. However, several studies reported that C3 and C4 correlated with CRP and other inflammatory markers [38,39]. However, in correlation analysis, HBA1c and HOMA-IR showed a strong direct relationship with C3 and C4, while QUICKI showed a strong inverse relationship with C3 and C4 in the obese group. Our findings agreed with Phillips et al. [40] reported that among 1754 with metabolic syndrome, they found an association between C3 and insulin resistance, abdominal obesity, low HDL and smoking [40]. Similarly, Koistinen et al. [41] reported that C3 level was associated with insulin resistance in in obese nondiabetic subjects and type 2 diabetics [41]. In addition, Onat & colleagues [42] conducted a cohort study on 1220 adult subjects of general population and they reported that C3 level was associated significantly with waist circumference, triglycerides, CRP, smoking and insulin resistance [42]. Moreover, Wlazlo et al. [43] conducted a 7-year prospective analysis on type 2 diabetes mellitus and found an independent association between C3 level and insulin resistance [43]. In the other hand, Bratti & colleagues [44] reported that C3 and C4 were significantly higher with positive correlation with HOMA-IR in morbidly obese patients than lean subjects, while following bariatric surgery there was reduction in triacylglycerol and increase in HDL and insulin sensitivity 6months following surgery [44].

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Conclusion

The present study suggests that in obese subjects there is an association between complement system, inflammatory cytokines and glucose control.

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Acknowledgment

The author thanks Prof. Mohammed Tayeb for his skillful assistance in selection of participants, laboratory analysis and during clamp procedures of this study. In addition, author is grateful for the cooperation and support of all patients who participated in this study.

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Optimal Management Site of Hospitalization for Patients with Diabetic Ketoacidosis

Authored by Leonid Barski

Abstract

Management of patients with DKA involves rehydration, administration of insulin, correction of electrolyte derangements, correction of metabolic acidosis, and treatment of precipitant factors. To date there are no randomized prospective studies that have evaluated the optimal hospital site for the management of patients with DKA. The decision where to care for patients with DKA must be based on known clinical prognostic indicators and on the local availability of hospital resources. The response to initial therapy in the emergency department can be used as a guideline for choosing the most appropriate hospital site for further care.

The current mainstay of insulin therapy in DKA is continuous intravenous infusion. Recent studies have demonstrated the therapeutic feasibility and cost-effectiveness of the treatment of mild uncomplicated DKA with subcutaneous insulin analogs outside of the ICU setting. Optimal place of hospitalization must be based on the severity of DKA, possibility of route of administration of insulin, quality and education of medical team and medical word for appropriate monitoring and laboratory analyzes. We recommend that all patients with severe DKA, requiring intravenous insulin treatment, must be hospitalized in an ICU unit. Patients with mild to moderate DKA can be hospitalized in a medical word if it has trained staff and conditions suitable for adequate management and monitoring of these patients.

Keywords:Diabetic ketoacidosis; Diabetes mellitus; Site of care; Intensive care unit; General medical wardDiabetic ketoacidosis; Diabetes mellitus; Site of care; Intensive care unit; General medical ward

Abbrevations:DKA- Diabetic Ketoacidosis; ICU: Intensive Care Unit

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Introduction

In the last decade there has been significant improvement of survival among DKA patients in most developed countries with a mortality of <1% [1-3]. However, DKA is associated with mortality rates as high as 5-9% in the elderly and in patients with severe comorbidities [4,5]. Though mortality from DKA is more often attributable to severe underlying illness and comorbidities [4], DKA itself is a hypercoagulable state resulting in potentially fatal complications including stroke, myocardial infarction, and disseminated intravascular coagulation [6,7]. Management involves rehydration, administration of insulin, correction of electrolyte derangements; particularly hypokalemia, correction of metabolic acidosis, and treatment of precipitant factors such as infection, pancreatitis, trauma, and myocardial infarction [8-10]. Complications of DKA management include pulmonary venous congestion and severe electrolyte imbalance. Cerebral edema represents a major potential complication, although this has been documented mostly in children.

The optimal hospital site for the management of patients with DKA (intensive care unit, general medical ward or emergency department) is an important issue. To date there are no randomized prospective studies that have evaluated this question. Given the lack of such studies, the decision where to care for patients with DKA must be based on known clinical prognostic indicators and on the local availability of hospital resources [11-13]. The response to initial therapy in the emergency department can be used as a guideline for choosing the most appropriate hospital site for further care [10,11]. Admission to ICU should be considered for patients with hypotension or oliguria refractory to initial rehydration and for patients with mental obtundation or coma [11]. Patients who are mildly ketotic and without severe systemic manifestations can be effectively managed in a general medical ward [11].

Different routes of insulin treatment patients with DKA and it’s influence on the site of hospitalization

Regular insulin is favored over insulin analogues. The current mainstay of insulin therapy in DKA is continuous intravenous infusion due to its rapid onset and ease of dose titration [4,14]. Some institutions require intravenous insulin infusions to be managed in the intensive care setting and thus some advocate for the use of subcutaneous or intramuscular injections in order to avoid an intensive care admission [4,15-17].

Insulin analogs glulisine, aspart and lispro have been reported to have equal efficacy and potency compared to regular insulin, attributable to their similar receptor binding affinity and receptor mediated clearance [3,18,19], however only studies comparing the role of intravenous glulisine infusion as an alternative to intravenous infusion of regular human insulin has been performed [20]. In spite of their more rapid onset, studies comparing the pharmacokinetics and pharmacodynamics of intravenous glulisine (an ultrashort-acting insulin analogue) to intravenous regular insulin (short-acting insulin) have found thatglulisine demonstrates equivalent glucose utilisation and disposal; and a similar distribution and elimination profile to regular insulin [3,20].

The benefits of administering subcutaneous insulin injections hourly outside of the intensive care setting must also be weighed against the increased demands on nursing staff in medical wards, increased variability with dose administration times, time to onset of action, peak effect, and duration of effect [23].

Recent studies have demonstrated the therapeutic feasibility and cost-effectiveness of the treatment of mild uncomplicated DKA with insulin analogs outside of the ICU setting; however, the proposed subcutaneous insulin protocols have yet to find widespread support from hospital administrations and treating physicians [10]. Lack of nursing and medical staff training, presence of multiple comorbidities in diabetes patients, insufficient resources with which to conduct frequent bedside glucose testing in hospital wards, and the absence of financial incentives to treat DKA outside of ICUs are some of the factors that diminish the enthusiasm of providers to take on this important issue of health care resource utilization without compromising patient care [10]. Future trials testing less complex subcutaneous insulin delivery protocols should be considered in an attempt to

The use of constant intravenous insulin infusions is now generally considered to be the standard of care in most hospitals [24]. But in a large part the choice of route insulin therapy for patients with DKA is institution dependent [24].

Severity of DKA and it influence on the site of hospitalization

Diagnostic criteria for DKA include presence of blood glucose >250mg/dL, arterial pH of ≤7.30, bicarbonate level of ≤18m Eq/L, and adjusted for albumin anion gap of >10-12 [4]. The Joint British Diabetes Societies suggest that the presence of one or more of the following may indicate severe diabetic ketoacidosis and admission to a Level 2 ⁄ high-dependency unit environment and insertion of a central line and immediate senior review should be considered: blood ketones over 6mmol/l; bicarbonate level below 5mmol/l; venous⁄arterialpHbelow7.1; hypokalemia on admission (under 3.5mmol/l); Glasgow Coma Scale (GCS) less than 12 or abnormal AVPU (Alert, Voice, Pain, Unresponsive) scale; oxygen saturation below 92% on air (assuming normal baseline respiratory function); systolic blood pressure below 90mmHg; pulse over 100 or below 60 b min; anion gap above [25].

Significance of standardized protocols for DKA management and medical staff education

Several guidelines for the management of DKA have been suggested [4,25-27]. One approach to delivering best clinical practices is development of inpatient standardized protocols for DKA management. Studies have shown that protocol-directed care of patients with DKA is both safe and efficient, as highlighted by significant decreases in length of stay without increases in the rate of iatrogenic complications [10,28,29].

Patients treated under these protocols expe¬rienced a decrease in time to resolution of ∼10 hours without increased rates of iatrogenic hypoglycemia or hypokalemia [9]. Other studies have also demonstrated suboptimal care as a result of low adherence stemming from discontinuity of medical care, understaffing, and low experience in the care of DKA patients [30,31].

Therefore, there is a need for ongoing medical staff education and training in order to increase protocol adherence in patients with DKA. The care of patients with DKA should be a collaborative effort that includes the expertise of endocrinology, intensive care, medical pharmacy, and nursing specialists [10]. Recent studies showing clinical benefits and safety of subcutane¬ous insulin administration in patients with mild DKA and utility of protocol-driven care offer new pathways to reducing the cost of DKA care while maintaining quality of clinical outcomes. Also, resources should be directed toward the education of primary care providers and patients and their families so that they can identify signs and symptoms of uncontrolled diabetes earlier [3].

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Summary and Outlook

Optimal place of hospitalization must be based on the severity of DKA, possibility of route of administration of insulin, quality and education of medical team and medical word for appropriate monitoring and laboratory analyzes.

The current available guidelines state that the most effective means of insulin delivery during DKA is a continuous infusion of regular insulin, usually referred to as continuous lowdose insulin infusion [4,25,27]. Therefore, all patients with severe DKA requiring intravenous insulin treatment must be hospitalized in an ICU unit. Patients with mild to moderate DKA can be hospitalized in a medical word if it has trained staff and conditions suitable for adequate management and monitoring of these patients.

The issue of cost effectiveness in the treatment of DKA is also very important as treatment with continuous intravenous insulin infusion in ICU unit is more resource intensive as compared to hourly subcutaneous insulin injection or even intravenous insulin infusion in the medical ward. Adhering to the existing protocols in the treatment of DKA including rehydration, correction of electrolyte derangements, administration of insulin, correction of metabolic acidosis, and treatment of precipitants must be performed in all institutions and wards managing patients with DKA.

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Effect of Arginase-1 Inhibition on the Incidence of Autoimmune Diabetes in NOD Mice

Authored by Peter Buchwald

Abstract

Metabolism of the amino acid L-arginine is implicated in many physiological and pathophysiological processes including autoimmune conditions such as type 1 diabetes (T1D). Alternate arginine metabolism through the citrulline-nitric oxide (NO) or the ornithine pathways can lead to proinflammatory or immune regulatory effects, respectively. In this report, we blocked the arginine-ornithine metabolic pathway by inhibiting the enzyme arginase-1 with Nω-hydroxy-nor-arginine (nor-NOHA) to make arginine more available to the alternate citrulline pathway for augmented NO production and increased incidence of autoimmune T1D in female non-obese diabetic (NOD) mice. Unexpectedly, mice receiving nor-NOHA did not develop diabetes although increased NO production is proinflammatory and expected to increase diabetes incidence. These results warrant further studies of the mechanism of action of nor-NOHA, and highlight its potential as a therapeutic agent for the treatment or prevention of T1D.

Keywords: nor-NOHA; T1D; NOD; Incidence rate; Arginine; Metabolism; Ornithine; Nitric oxide; Inflammation; Macrophages

Abbrevations:nor-NOHA: Nω-hydroxy-nor-arginine; T1D: Type 1 Diabetes; NOD: Non-Obese-Diabetic; D-NOD: Diabetic NOD; ND-NOD: Non-Diabetic NOD; NO: Nitric Oxide; iNOS: Induced Nitric Oxide Synthase; Arg-1: Arginase-1; ODC: Ornithinedecarboxylase; DFMO: Di-fluoromethyl-ornithine

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Introduction

The role of L-arginine metabolism in autoimmune diseases has recently become of interest. Specifically, metabolic products of two alternate arginine metabolism pathways (Figure 1) are implicated in both proinflammatory/autoimmune and immune regulatory/tolerogenic immune responses. The argininecitrulline- nitric oxide (NO) pathway favors proinflammatory polarization of innate (M1-like) and adaptive (Th1/Th17) immune cells. For example, when enough arginine substrate is available and the enzyme NO synthase (NOS or iNOS) is upregulated, NO production increases in pro-inflammatory M1 macrophages. Depending on its level, NO can be either pro- and or anti-inflammatory. Whereas, high levels of NO are proinflammatory and cytotoxic, and promote both apoptosis and necrosis in target cells [1,2], low levels have been shown to have anti-inflammatory effects [3-5]. On the other hand, the alternate ornithine pathway of arginine metabolism favors polarization towards immunoregulatory function in immune cells such as regulatory T cells (Tregs) and M2 macrophages, which are essential during resolution of inflammation, tissue healing, and immune tolerance induction/maintenance. When the enzyme arginase-1 is overexpressed, arginine is metabolized to urea, ornithine, and downstream polyamines that are crucial building blocks during cell proliferation and maintenance of tissue homeostasis. Therefore, we hypothesized that administration of an arginase-1 inhibitor should block the urea-ornithine pathway making arginine more available for the alternate citrulline- NO pathway for increased production of NO and associated tissue inflammation and, ultimately, increased incidence of autoimmune diabetes (Figure 1).

Nor-omega-hydroxide-L-arginine (nor-NOHA) is a competitive inhibitor of arginase-1 that should increase arginine availability to the NO pathway, whereby, increasing the production of NO [6]. To our knowledge there are no available reports on the effect of nor-NOHA on the autoimmune process in animal models of type 1 diabetes (T1D). The non-obesediabetic (NOD) mouse is a widely used model of human T1D and provides an attractive opportunity to investigate the effect of nor-NOHA on the incidence of autoimmune diabetes [7,8]. The diagram shown in Figure 1 illustrates a working model of the effect arginine metabolism and nor-NOHA treatment on diabetes incidence in diabetes-prone female NOD mice. In the current study, we investigated arginine metabolism and the spontaneous incidence of autoimmune diabetes as a function of age in female NOD mice, and evaluated the effect of nor-NOHA treatment on diabetes incidence.

Simplified scheme/model of alternate arginine metabolism either through the urea-ornithine or the citrulline-nitric oxide (NO) pathways leading to anti-or pro-inflammatory effects, respectively, and associated decrease or increase in diabetes incidence. The scheme also illustrates the effect of nor-NOHA on arginase-1 (Arg-1) and the production of ornithine and downstream polyamines by ornithinedecarboxylase (ODC). The citrulline-NO pathway is catalyzed by induced nitric oxide synthase (iNOS). Citrulline is also produced from carbamoylphosphate and ornithine. When ornithine is reduced through Arg-1 inhibition by nor-NOHA, homocitrulline is produced from carbamoylphosphate and lysine.

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Materials and Methods

Animals and treatments

Female NOD mice of around 8 weeks of age were purchased from Taconic Biosciences (USA) and Jackson Laboratories (USA) and housed in groups of five with access to food and water ad libitum. The room temperature was kept at 23°Celsius and the light-dark cycle was 12/12 hours. All animal procedures were approved by the IACUC of the University of Miami. Nor-NOHA was obtained from Cayman Chemicals (USA). It was dissolved in PBS (phosphate buffered saline), and injected intraperitoneally at the dose of 30mg/kg every other day until 12 doses were completed. Blood sugar measurements were obtained using Contour Next® glucometer and strips (Bayer). A drop of blood was obtained by pricking the distal end of the tail with a 25G hypodermic needle and the drop was applied to the blood glucose strip. Non-fasting blood sugar levels were measured every two days before and during the treatment period (with nor-NOHA or PBS), and then once in the week after, and once 172 days after the beginning of the treatment. Mice were considered diabetic after 3 consecutive readings of hyperglycemia (>300mg/dL) [7].

Metabolomics analysis

Blood concentration data for arginine, its derivatives, and other metabolites used here were obtained in an untargeted metabolomics study by LC–MS as described previously in detail [9]. In brief, repeated blood samples were collected prospectively from NOD mice at 6, 11, 16, 21, and 26 weeks of age. Blood glucose was also measured at least twice weekly to monitor diabetes incidence in the same mice. Data from blood samples obtained in mice that developed diabetes by 26 weeks of age were pooled into the diabetic (progressor) group, and those from mice remained normoglycemic by the same age were considered as non-diabetic controls (non-progressors) in the analysis. We did not conduct analysis in mice older than 26 weeks of age to avoid potential confounding issues related to long-standing diabetes and the insulin therapy in the diabetic mice. The metabolomics data in the diabetic mice (up to 26 weeks of age) were expressed as fold increase relative to nondiabetic controls. See reference [9] for complete details.

Statistical analysis

Data were plotted and analyzed using Prism 6 version 6.07 (GraphPad Software, Inc; La Jolla California USA). Kaplan-Meyer survival curves were used to calculate the median age (in weeks) of spontaneous onset of diabetes in the total pooled populations of female NOD mice obtained from the different vendors. Additional analysis of the median age of diabetes onset was also performed based on the cumulative percent of diabetic mice over time assuming a Hill-type sigmoidal dependence. Estimations of the incidence rate of diabetes was done with onset data binned per week and obtained using the slope values of linear regression analysis of the cumulative percent of diabetic mice in two different regimes using a rate-change point identified by a linearized biexponential model as previously described in detail [10,11]. Segmental linear regression analysis was carried out using the minimum sum of squared errors method to identify the change in inflection of the data (i.e., transition points between the linear regimes). The diabetes incidence rate or probability in each regime (i.e., the estimated number of mice developing diabetes during a specified age-range) was calculated based on the slope value multiplied by the age-range (in weeks) and divided by the total number of mice remaining normoglycemic at the beginning of the chosen age range. Comparisons of the slopes of the linear regressions was done by F-test. Pair-wise comparisons of the treatment groups were by Student t-test or ANOVA followed by post hoc tests (e.g., Holm-Sidak method). Data are presented as means±SEM. Asterisks indicate significant difference at p <0.05 level.

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Results

Changes in arginine metabolism in diabetic progressor vs. non-progressor female NOD mice

We assessed the metabolism of arginine and other amino acids as part of an untargeted longitudinal metabolomics study [9] in repeated blood samples obtained from female NOD mice that did or did not progress to autoimmune diabetes during a follow up period between 6 and 26 weeks of age. The overall results showed relatively similar metabolic profiles between the groups before onset of diabetes (i.e., between 6 and 16 weeks) (Figure 2). However, differences in arginine metabolites and other amino acids became evident between 21 and 26 weeks coincident with diabetes onset. At week 26, ornithine was reduced by ~30% and citrulline was elevated by ~20% in diabetic mice (D-NOD) compared to non-diabetic controls (ND-NOD) (Figure 2A). Lysine was also reduced by ~50% while homocitrulline was significantly increased at weeks 21 (50%) and 26 (110%) in diabetic mice compared to non-diabetic counterparts (Figure 2B).

Incidence of autoimmune diabetes in NOD mouse population as a function of age

We tracked the spontaneous incidence of autoimmune diabetes in a total pooled population of young female NOD mice (n=126) starting around 8 weeks of age. Mice that received no treatment started to develop diabetes around 10 weeks of age. By 38 weeks, approximately 80% of the mice became diabetic and the remaining 20% maintained normoglycemia up to ~43 weeks of age (Figure 3A). According to Kaplan-Meyer survival curve analysis, in this cohort the median age of diabetes onset was 19.9 weeks in the total population of female NOD mice aged up to 43 weeks. Further analysis of diabetes incidence based on the cumulative percentage of diabetic mice during the same age range using nonlinear regression analysis (fit with a Hill curve) showed a median age of diabetes onset of 17.8 weeks (Figure 3B). While these analyses yielded estimates of the age of diabetes onset in the total population between 8 and 43 weeks of age, they could not provide estimates of the likelihood of diabetes development in the remaining ~20% fraction of mice that maintained normoglycemia up to this age. Data indicate that, at least in these NODs, the rate of diabetes onset is not completely flattened out (i.e., zero), and there is a decreasing, but non-zero chance of still developing diabetes in older female NOD mice. Therefore, we adopted a multi-linear model to fit the data along two distinct linear regimes from 10 to 23 and 24 to 43 weeks of age with a rate-of-change point selected as to give the best fit of the data (Figure 3C) also see Methods). The slopes of the first and second regimes obtained this way (6.2 and 0.62, respectively) were significantly different (p<0.00001), which indicated varying diabetes incidence rates before and after 23 weeks of age in this pooled NOD mouse population.

The effect of nor-NOHA on the incidence of autoimmune diabetes in old NOD mice

Normoglycemic old female NOD mice were treated with nor-NOHA (30mg/kg, i.p.) or PBS as control every other day for 24 days starting around 45 weeks of age. During the treatment period, the non-fasting blood glucose levels in both treatment groups fluctuated but remained within “normal” glycemia range (<300mg/dL). During a 6-week follow up period, the mean non fasting glycemia (measured every 2 days) in the PBS-treated mice was higher on 8 occasions and lower on 7 occasions than in the nor-NOHA group (Figure 4A). While all mice remained normoglycemic during and after the treatment period, there was a tendency toward lower mean non-fasting glycemia in the nor- NOHA-treated mice compared to the PBS controls as indicated, for example, by the blood glucose AUC data (Figure 4B) and the median values of non-fasting blood glucose at selected time-points with marginally significant difference (Figure 4C). Moreover, further follow up of the mice up to 25 weeks after treatment initiation showed that 50% of the PBS-treated mice became diabetic, while 100% of the nor-NOHA-treated mice remained normoglycemic (Figure 4D).

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Discussion

Female NOD mice are used extensively as a model for human autoimmune T1D [12-17]. Numerous studies have shown that under specific-pathogen-free conditions typically 70-90% of female NOD mice develop diabetes spontaneously by 45 weeks of age [9,11]. Consistent with this, we found an 80% diabetes incidence rate in a population of 126 female NOD mice aged up to 43 weeks (Figure 1). While most studies are conducted in NOD mice that develop diabetes before this advanced age, the remaining 10–30% of NOD mice that maintain normoglycemia by age 45 weeks are typically discarded from studies because of their reduced incidence of diabetes. Histological analysis of the pancreas from these older non-diabetic female NOD mice have shown evident mononuclear cell infiltrate around relatively intact islets [11]. This observation, also known as peri-insulitis, raises the possibility for local immune regulatory processes that may slow down the autoimmune attack against the insulinproducing beta cells, leading to reduced diabetes incidence. It is unclear however what specific diabetes incidence rate old female NOD mice have because long-term follow up beyond 45 weeks of age is rarely done, likely due to experimental and other logistical considerations. We reasoned that old non-diabetic female NOD mice provide a useful model to investigate the effects of different interventions aimed at changing the incidence of autoimmune diabetes beyond the age range where the probability of diabetes onset is significantly higher due to more aggressive autoimmune responses against the beta cells. Studies in older non-diabetic NOD mice may also be more representative of immune processes in adults, and may be particularly pertinent to the investigation of immune regulatory function and immune tolerance.

Arginine metabolism has been implicated in both proinflammatory and immune regulatory processes. Consequently, alternate arginine metabolism through the ornithine or citrulline pathways may lead, respectively, to decreased or increased incidence of autoimmune diabetes (Figure 1). Proinflammatory Th1/Th17 cytokines activate iNOS which produces nitric oxide (NO) from L-arginine through the citrulline- NO metabolic pathway in proinflammatory immune cells. NOproducing immune cells such as M1 macrophages can damage the pancreatic islets during diabetes development (McDaniel et al., 1996). Citrulline is also produced from carbamoylphosphate and ornithine; however, when ornithine is less abundant homocitrulline is produced from carbamoylphosphate and lysine. While no significant variations of citrulline and ornithine levels in the blood have been reported in association with aging [18], homocitrulline has been shown to increase progressively with age and has been suggested as a biomarker of aging-associated inflammation [19,20]. Homocitrulline has also been implicated in the pathogenesis of autoimmune arthritis [21,22], but little is known about its involvement in T1D. Our current findings, however, showing significantly elevated homocitrulline levels in diabetic NOD mice (Figure 2B) suggest its possible involvement, in addition to arginine metabolism, in the inflammation during the pathogenesis of T1D, and this involvement is likely to have persisted in the mice aged beyond 26 weeks old. Alternatively, Th2 cytokines induce arginase-1, which hydrolyses arginine into urea and ornithine, and in turn drives immune cell polarization towards regulatory function. Ornithine is also a precursor for polyamines that are required for cell proliferation and maintenance (Classen et al., 2009). Consistently, our current findings showed increased levels of citrulline and reduced levels of ornithine in diabetic female NOD mice compared to nondiabetic counterparts (Figure 2A). Therefore, we investigated whether reducing ornithine through arginase-1 inhibition by nor-NOHA treatment and promoting the alternate argininecitrulline- nitric oxide (NO) pathway will influence the incidence of autoimmune diabetes in >45 weeks old female NOD mice.

Based on our analysis of the incidence of diabetes in female NOD mouse population, we estimated incidence rates of approximately 64% and 43% in mice aged 10 to 23 and 24 to 43 weeks, respectively. These predicted rates were consistent with those observed in the total NOD population for each of the age ranges (66% and 31%; Figure 3A). Using the same approach and by extrapolating the data in the second linear regime up to 68 weeks of age, we estimated that ~50% of the NOD mice remaining normoglycemic by age 43 weeks (i.e., 45 out of 126) will become diabetic by 68 weeks. Consistent with this predicted rate, our experimental data showed that half of the control PBS-treated mice became diabetic by 68 weeks of age (Figure 4D); whereas, unexpectedly, all the nor-NOHAtreated mice remained normoglycemic during the same follow up period. This was surprising because blocking the arginineornithine pathway makes arginine more available for the alternate arginine-citrulline-NO pathway, and was expected to increase NO production and associated pro-inflammatory effects causing increased diabetes incidence. Contrary to this, our current findings suggested that nor-NOHA treatment seemingly protected the mice from autoimmune diabetes. While more studies are needed to further explain these findings, and while we did not measure citrulline and other arginine metabolites and polyamines in the >45 weeks old mice, the current results are consistent with other studies using nor-NOHA in animal models of inflammatory conditions other than T1D. For instance, nor-NOHA was reported to ameliorate inflammation in (i) the adipose tissues of mice on a high-fat-diet [23], (ii) the bronchi in an animal model of bronchial asthma [24], and (iii) the arteries of another model of arthritis [25]. Therefore, while we speculate that arginase-1 inhibition in our study likely resulted in increased production of NO, the relatively short nor-NOHA treatment regimen we used may have resulted in moderate increase in NO levels, which has been shown to have anti-inflammatory rather than proinflammatory effects [3-5]. Moreover, nor-NOHA could have interfered with the production of the proinflammatory eukaryotic translation initiation factor 5A (eIF5A) to prevent the autoimmune response, as blocking eIF5a with siRNA was recently shown to reduce mouse mortality by LPS [26], and its knockdown increased resistance to streptozotocin-induced diabetes in mice [27]. Moreover, treatment with di-fluoromethyl-ornithine (DFMO; a blocker of ornithine decarboxylase which transforms ornithine into putrescine/hypusine) or with N1-guanyl-1,7-diaminoheptane (an inhibitor of the enzyme desoxyhypusine which is critical for the activation of eIF5A) was also shown to reduce insulitis and the incidence of autoimmune diabetes in young NOD mice [28,29]. Interestingly, the eIF5A inhibitor DFMO is currently in clinical trials to evaluate its effect on halting the progression of autoimmune diabetes in children with new onset T1D (Clinical Trials.gov; study identifier NCT02384889).

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Conclusion

In summary, our current study showed that arginine metabolism is altered in diabetes-prone NOD mice; the arginine-citrulline-NO pathway was upregulated, whereas the alternate arginine-ornithine pathway was downregulated in diabetic female NOD mice as compared to their non-diabetic counterparts. A 24-day treatment with the arginase-1 inhibitor nor-NOHA aimed to further upregulate the citrulline-NO pathway unexpectedly reduced the incidence of autoimmune diabetes in older diabetes-prone female NOD mice. These findings warrant further investigation of the mechanism of action of nor-NOHA on the autoimmune process in diabetes, and highlight its potential as a therapeutic agent for the treatment or prevention of T1D.

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Exercise Effects on Gutdysbiosis, Intestinal Permeability and Systemic Inflammation in Patients with Type 2 Diabetes: A Pilot Study

Authored by Evasio Pasini

Abstract

Exercise plays a significant role in the prevention of the diabetes. Recent data propose that dysbiosis of intestinal microbiota composition contributes to development of Type 2 diabetes (T2D). Moreover, dysbiosis alters intestinal endothelium permeability causing the “Leaky gut syndrome” (LGS). We measured in 15 selected patients with standard medical cures for sable T2D the effects of 6 months of endurance, resistance and flexibility training on the gut microbiota composition and intestinal permeability. At baseline, T2D patients had high biochemical parameters (glycaemia, HOMA index, HbA1c, C-Reactive Protein [CRP]) with dysbiosis (elevated concentration of Mycetes) and altered intestinal impermeability (Measured by faecal Zonulin). Alter chronic exercise, glycaemia, HOMA index, HbA1c and CPR were reduced as well as faecal presence of Mycetesspp and Zonulin. This pilot study showed that selected patients with T2D had intestinal dysbiosis with overgrow of Mycetes, presence of LGS and low grade inflammation. Interestingly, chronic exercise significantly reduced all these parameters.

Keywords: Exercise; Diabetes; Microbiota; Dysbiosis; Zonulin; Leaky gut syndrome

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Introduction

Evidences show that exercise plays a significant role in the prevention of the diabetes and control of glycaemia as well as in the diabetes-related organ complications [1]. Furthermore, recent data propose microbiota composition as possible potential environmental contributor to development of T2D [2]. Indeed, gut dysbiosis influences fundamental intestinal functions as epithelium permeability, causing the “Leaky gut syndrome” (LGS) [3]. As consequence, LGS heavily influences gut functions including digestive, absorptive and endocrine activities that, in turns, may influence glucose metabolism. Moreover, LGS activates inflammation allowing translocation of microorganisms from the intestinal lumen to the blood circulation. Interestingly, recent papers show that physical activities could modify gut microbiota [4,5]. Recent evidences suggest that a useful method for assessing the alteration of intestinal permeability is the dosage of Zonulin in the patient’s stools [6]. Thus, the aim of this study was to evaluate the role of chronic exercise on the gut flora composition and intestinal permeability in patients with stable T2D.

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Materials and Methods

This research was a controlled open-label trial. Research protocol was approved by the Ethics Committee of Spedali Civili di Brescia, and performed in accordance with the Declaration of Helsinki. We selected non-smokers 15 males patients with mean age of 69±1.3 years with a controlled diet of 7949kJ (1900 kcal) derived from 40-60% carbohydrates, 30% fat and 10-20% protein. About 20g/1000kcal of fibre were present.

Patients had diagnosis of T2D for at least 2 years, no need for insulin therapy, arterial hypertension and dyslipidemia controlled by statins and either ACE-inhibitors or angiotensin receptor blockers, absence of diabetes-specific complications and/or ischemic heart disease and ability to perform physical activities. Patients with endocrine disorders and inflammatory or malabsoptive intestinal diseases were not included in the study. Patients studied did not used antibiotic, steroid, laxative, antidiarrheal and/or probiotic treatment over the previous 3 months and during the study. Biochemical measurements and gut flora was determined as we described before [7]. Measurements of biochemical variables, including C-reactive protein (CRP) as marker of systemic inflammation, were performed in peripheral venous sample after 12-h overnight fast.

Gut Flora were determined in stool sample collected with strikers and inserted in a hermetic vials with a specific medium. Then, microbiota were counted after 48h of incubation at proper condition with a selective agar. A further proof of the isolation was performed with bacterial metabolic tests performed on isolated organisms through “BBL Crystal Identification System” (Becton Dickinson NJ USA). The results are expressed in CFU (Colony Forming Units)/ml of stool. The test was performed by laboratory of clinical and virology Functional Point (Bergamo. Italy) which follows international standard of quality control and it is accredited with the national health system. The tests reproducibly was <9%. LIS was measured as faecal Zonulin concentration (ng/ml) using a commercial ELISA kits (Immunodiagnostic AG, Bensheim, Germany).

T2D patients were treated with standard medical care. They have optimal glycaemic, lipid, blood pressure and body weight targets according to the international guidelines. The training program was of six months of endurance, resistance and flexibility training, following the most recent guidelines of the Italian Society of Diabetology and Medical Diabetology Association as described in details elsewhere [8]. Breathy, endurance training involved cycling on mechanically braked cycle ergometers while wearing heart rate monitors, at the intensity individually prescribed according to the baseline results of the exercise test. Time of exercise has been increased progressively in the first 3 months, starting from 15 minutes and reaching the target of 35 minutes.

Resistance training was of 40 to 50 minutes of different exercises which involved the major muscle groups (upper limb, lower limb, chest, back and core). Exercises included both calisthenics and repetitions with ankle weights, dumbbells and elastic bands. Patients started with 3 sets of 8 repetitions, then progressively improved to 3 sets of 12-15 repetitions. Flexibility training was of static stretching exercises that involved upper and lower body, performed before and after the resistance training exercise. All training sessions were performed in a hospital-based setting and under the supervision of specialized personal. Exercises was performed 3-time a week of about 90 minutes each section. To assess the statistical significance of differences between the variables measured before starting the excise programs (baseline =T0) and after 6 months of exercise training (T1), we used Student’s t-test for paired samples. A value of p <0.05 was considered statistically significant.

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Results

As expected, at baseline (TO), T2D patients showed altered biochemical parameters (glycaemia, HOMA index, HbA1c, CRP) (Table 1). In addition, these patients had dysbiosis with little reduction of Lactobacillus and presence of pathogenic gut flora as documented by the high concentration of Mycetes spp. In addition, T2D patients showed higher Zonulin concentration in the stool suggesting altered intestinal impermeability (Table 2). Six mounts of exercise training (T1) improved glycaemia, HOMA index and HbA1c in T2D patients. Interestingly, exercise attenuated systemic inflammation measured as CRP also (Table 1). Furthermore, chronic exercise increased the intestinal concentration of Lactobacillus and significantly reduced Mycetesspp and Zonulin concentration (Table 2).

nv= Normal Value

nv = Normal Value

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Discussion

This pilot study showed that selected patients with T2D had intestinal dysbiosis with overgrow of mycetes, presence of “Leaky gut syndrome” and chronic inflammation. Interestingly, chronic exercise significantly reduced all these parameters. Previous studies show that dysbiosis is present in T2D patients [9,10]. In line with these data, we found a massive presence of mycetes and candida in T2D patients, and inflammatory index. It is well known that gut mycetes stimulate systemic inflammation. Indeed, mycetes activates the innate immune receptor C-Type Lection Dectin-1. In detail, Dectin-1 is a cell receptor which reacts with B-1,3-glucans which is presents in the fungi wall. In turns, Dection-1 stimulates intracellular caspase recruitments domain-containing protein 9 with consequent local and generalised activation of inflammation due to inflammatory cytokine production and consequent stimulation of T helper 17 [11]. Notably, systemic inflammation is present in diabetic patients and it is consider one of the possible pathophysiological cause of this metabolic syndrome [2]. In addition, local intestinal inflammation could induce altered intestinal importability with consequent loss of gut fundamental functions. Indeed, for the first time in these patients, we found increased Zonulin’s faecal concentration suggesting the presence of “Leak gut syndrome”. Indeed, Zonilin is the proteins that physiologically modulates the intracellular intestinal cells tight junctions [6]. Traditionally, the functions of intestinal tract is the digestion and abortions of the ingested nutrients. However, recent evidences show that intestine regulates the immune and endocrine system by producing specific inflammatory molecules and/or hormones. In addition, it regulates the trafficking of macromolecules and/or microorganism between intestinal lumen and blood influencing systemic inflammation. It is intuitive that maintenance of intestinal impermeability and functions is crucial to maintain global metabolic body homeostasis avoiding the presence of “Leak gut syndrome” and the consequence malfunction.

It is known that exercise controls glycaemia and inflammation but here, for the first time, we showed that exercise decreases gut mycetes colonisation and the presence of “Leak gut syndrome” in T2D patients, likely improving important intestinal functions. The mechanisms by which exercise modified gut flora and reduced is not known yet. Recent data shows that exercise influences microbiota by several mechanisms. Indeed, exercise may modify bile acids profiles [12] and/or faecal short chain fatty acids (SCFAs) as butyrate [13]. Exercise may also interact with gut immunological function increasing intestinal immunoglobulin A (IgA), decreasing number of lymphocytes-B and CD4+T cells, and influencing gene expression of cytokines as IL-6, Il-4, IL-10 and TGF-B [14]. Exercise can also modify microbiota because is able to reduce intestinal transit time [15].

We think that our data, although preliminary, could have important clinical implications. Indeed, for the first time, we showed that patients with T2D have heavy intestinal mycetes colonisation and LIS, and chronic exercise can reduced these alteration. This likely could improving intestinal function which influence nutrients metabolism, hormonal production and absorption of oral drug-administered. So, exercise, with or without a specific therapies able to cure of intestinal microbiota, could be an important step for tailored therapy allowing traditional therapy and patients metabolism to function more properly.

This study has some limitations. We used a selective culture medium to identify bacteria and mycetes instead of molecular biology techniques. Indeed, we don’t want to provide a “faecal finger print” of patients. We won’t identify saprophytes and some minor intestinal pathological and mycetes species capable of stimulating inflammation without gastrointestinal symptoms [7]. This is a pilot study with a limited number of selected patients. We have in progress a large scale study to confirm these results.

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What Next After Metformin? Guidelines and Indian Context

Authored by H B Chandalia

Go toPrevalence of T2DM in IndiaUnique challenges in managing T2DM in IndiaPathophysiological challenges of Indian T2DM patientsDietary differences in India and western countriesMetformin monotherapy- first line drugLimitations of current OADsSulfonylureas (SUs)Thiazolidinediones (TZDs)Incretin based therapiesInsulin therapySodium-glucose co-transporter 2 (SGLT2) inhibitors: novel therapy independent of InsulinDapagliflozinGlycemic efficacyNon-glycemic benefits of dapagliflozinWeight lossBlood pressureSafety profile of dapagliflozin

SGLT 2 inhibitors added on to metforminInternational guidelines for T2DMGo toStudy design

Abstract

There is a rapidly increasing epidemic of type 2 diabetes in India and other Asian countries due to rapid urbanization and lifestyle changes occurring in the country. India faces several challenges in diabetes management, including a rising prevalence in urban and rural areas, lack of disease awareness among the public, limited health care facilities, high cost of treatment, and rising prevalence of diabetic complications. Current antidiabetic agents fail to address disease progression and are often associated with weight gain and risk of hypoglycemia. SGLT2 represents a novel target for the treatment of diabetes. The mechanism of SGLT2 inhibition is independent of circulating insulin levels or insulin sensitivity; therefore, these agents can be combined in type 2 diabetes with all other antidiabetic classes, including exogenous insulin. Dapagliflozin is the first in class SGLT2 inhibitor that is associated with substantial improvements in glycemic control, reduction in weight especially fat mass, modest reduction in blood pressure and low risk of hypoglycemia. Besides this, there are indications that dapagliflozin is capable of improving β cell function and reduction in albuminuria. Although the long-term efficacy and safety of SGLT2 inhibitors remain under study, the class represents a novel therapeutic approach in the treatment of type 2 diabetes.

Keywords: Dapagliflozin; Metformin; SGLT2 inhibitors; Type 2 diabetes mellitus

Introduction

The prevalence of Type 2 diabetes is rising globally. A recent report by International Diabetes Federation (IDF) on the global scenario shows that the prevalence of diabetes in 2014 was 382 million and estimated to increase to an alarming 592 million by 2035.Nearly 80% of the diabetic population lives in the developing countries [1] and greater than 60% of world diabetes population will be in Asia [2]. Diabetes is fast gaining the status of a potential epidemic in India with more than 62 million diabetic individuals currently diagnosed with the disease [1]. It is predicted that by 2030 diabetes mellitus may afflict up to 79.4 million individuals in India, while China (42.3 million) and United States (30.3 million) will also see significant increases in the disease [1].

The etiology of diabetes in India is multifactorial and includes genetic factors along with environmental influences. Some of the major factors which pose unique challenges in managing T2DM in India are presented in Table 1. The prevalence estimates are escalating both in the urban and rural regions of India. Although the prevalence of diabetes is lower in low socioeconomic group versus the high-income groups living in urban areas, the former group has higher prevalence of complications. This is because they tend to neglect the disease due to lack of awareness and also due to economic barriers [3]. Low disease awareness among the population is also one of the major causes for diabetes epidemic [3]. Cost of diabetes care is very high and it increases many-fold in case of complications which require admission to hospital, surgery or insulin treatment. Many patients suffer from vascular complications at the time of diagnosis due to the fact that the person is asymptomatic and has low awareness about the disease. Early diagnosis of diabetes (at pre-diabetes stage) will make early initiation of treatment possible and thus avoid occurrence of vascular complications. Early intervention could also help to preserve the beta cell function [4]. Because of progressive nature of diabetes, patients fail to achieve target with multiple anti-diabetic agents. With early diagnosis and proper management, it may be possible to prevent T2DM along with its long term complications. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) representation pre-diabetic state which is also highly prevalent in India. Current estimates show that India has nearly 3.0% of adults with prediabetes [4].

The pathophysiology of T2DM is progressive, characterized by decreased insulin sensitivity, deteriorating beta cell function [5], and decreased incretin function [6]. Decreased insulin function leads to chronic hyperglycemia (during fasting and postprandial periods) and acute glycemic fluctuations. These may be associated with microvascular and macrovascular complications caused by excessive protein glycation and activation of oxidative stress [7-9].

As compared to western countries, India has a higher prevalence of diabetes despite having lower overweight and obesity rates, suggesting that diabetes may occur at a much lower body mass index (BMI) in Indians compared with Europeans [10]. Therefore, lean Indian adults with a lower BMI may be at equal risk as those who are obese [11]. Further, South Asian population has several unique characteristics like onset of diabetes at young age, a relatively lower BMI at the time of diagnosis with accompanying insulin resistance and reduced insulin secretory capacity. This body type is termed as thin-fat phenotype (thin muscle but increased body fat) and is associated with an increased risk of developing diabetes [10]. Indians develop T2DM at a younger age than the western populations and also develop diabetes with minor weight gain [12]. The development of the disease at a young age predisposes the patients to develop chronic long-term complications at a relatively young age with severe morbidity and early mortality in the most productive years of life [12]. Further, Indians are genetically predisposed to the development of coronary artery disease due to dyslipidaemia and low levels of high density lipoproteins; these determinants make Indians more prone to development of the complications of diabetes. Due to high ethnic and genetic susceptibility for the disease, Indians have lower threshold limits for the environmental risk factors and indicate that diabetes must be carefully screened and monitored regardless of patient’s age in India [13,14]. Under-nutrition during intrauterine development causes permanent changes in the structure and function of the developing systems of the fetus. This increases susceptibility to disease in later life. Asians mothers (especially in rural India) thought to be chronically undernourished because of their low BMI with iron and other nutrient deficiencies. One-third of Indian babies are born with low birth weight (LBW<2.5kg) [15]. It is thus possible that maternal and fetal under nutrition contribute to the diabetes epidemic in the Asian countries [15].

Studies have shown that in all parts of India, T2DM patients consume high total and complex carbohydrate (CHO) in their diet when compared with dietary recommendations. An earlier study has shown that 64.1±8.3% (95% CI 63.27 to 64.93) of total calories come from CHO in the T2DM group which has a direct effect on postprandial blood glucose and insulin response [16]. This suggests that CHO consumption by T2DM patients in India is higher than that recommended by the guidelines [16]. This unique feature in Indian dietary habit makes Indians more prone to T2DM as compared to western countries.

Metformin stands out not only for its antihyperglycemic properties but also for its effects beyond glycemic control such as improvements in endothelial dysfunction, oxidative stress, insulin resistance, lipid profiles and fat redistribution [17]. Negligible risk of hypoglycaemia when used in monotherapy and few drug interactions of clinical relevance give this drug a high safety profile and most preferred choice as first line therapy.

Current guidelines from ADA/EASD and AACE/ACE recommend early initiation of metformin as a first-line drug for monotherapy and combination therapy for patients with T2DM. This recommendation is based primarily on metformin’s glucose-lowering effects, relatively low cost, and generally low level of side effects, including the absence of weight gain [18]. The optimal second-line drug when metformin monotherapy fails is not clear.

T2DM is typically managed with rigorous medical therapy and a stepwise approach which includes lifestyle modifications, addition of oral antidiabetic drugs (OADs) and addition of insulin. OADs are normally introduced when lifestyle modifications fail to adequately controlglycemia. They are very useful for managing hyperglycemia, especially in the early stages of disease. Insulin and other antihyperglycemic agents like sulfonylureas (SUs), biguanides, thiazolidinediones (TZDs) and incretin based therapies are the drugs routinely used in the treatment of T2DM.However, there are several limitations that prevent antihyperglycemic agents from reaching their potential (Table 2).

SUs are as effective in lowering HbA1c, but their use is associated with hypoglycaemia and weight gain up to 2kg [17]. It has also been found that though they are effective in lowering the blood glucose rapidly in the initial phase of therapy, this effect is not sustained over time. SU therapy was implicated as a potential cause of increased cardiovascular disease mortality in the University Group Diabetes Program study [17].

TZDs, well known as insulin sensitizers, appear to have a more durable effect on glycemic control, particularly in comparison with SUs [19]. However, TZDs lead to weight gain, fluid retention, peripheral oedema, and a two-fold increased risk for congestive cardiac failure, potential for increased fracture risk [19].

Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors offer analtered way of reducing hyperglycaemia by targeting the incretin system. GLP-1- based therapies have a beneficial effect on weight, because of their inhibitory effect on appetite via the gut-brain axis [20]. However, use of GLP-1 RA is associated with dose-dependent gastrointestinal side effects including nausea, vomiting and diarrhoea, and also two potential safety issues are pancreatitis and medullary carcinoma of the thyroid [21]. DPP 4 inhibitors are less potent to reduce hyperglycaemia compared to GLP 1 RA and besides that they are weight neutral [21].

Insulin therapy is often accompanied by hypoglycemia and weight gain which have been identified by patients and health care providers as common concerns prior to insulin initiation. These are key factors responsible for patients reluctance to insulin intensification [22]. Interestingly, the weight gain associated with insulin therapy is mainly seen in patients who had experienced significant weight loss prior to institution of insulin therapy [23]. Further, traditional vial and syringe method of insulin administration is associated with needle stick injury, social stigma, lack of convenience, difficulty with accurate dosing and therefore decreased adherence to the prescribed insulin regimen. New insulin analogs are effective in reducing HbA1c levels with a lower risk of overall and nocturnal hypoglycemia compared with conventional insulins [24]. They have also been shown to induce less weight gain than either NPH or insulin glargine [24].

Of immense therapeutic importance, intra subject coefficient of variation of insulin response has been shown to be 20-40%, 20% for human regular and rapid acting analogues and 40% for Neutral Protamine Hagedorn (NPH) and glargine insulin. All the above pharmacological drugs focus on reducing hyperglycemia and improving insulin sensitivity. These drugs target the primary defects associated with T2DM. However, despite the wide choice of treatment options available, glycemic control declines over time and eventually combination of other antihyperglycemic agents is required [25].

SGLT2 inhibitors are a new class of oral antidiabetic drugs, which reduce hyperglycemia by increasing urinary glucose excretion independent of insulin action [26]. SGLT2, located in the renal proximal tubule, reabsorbs90% of the filtered glucose [27] and its inhibition represents a new form of pharmacotherapy for the treatment of type 2 diabetes. The mechanism of action of SGLT2 inhibitors is unique and does not depend upon beta-cell function or tissue insulin sensitivity [26]. Through SGLT2 inhibition, reabsorption of tubular glucose is reduced and urinary glucose excretion increased [27] SGLT2 inhibitor induced glucose excretion is proportional to the amount of glucose filtered by the kidneys, which is a function of the glomerular filtration rate (GFR) and plasma glucose concentration [28]. Increased plasma glucose concentration (as observed in DM) leads to increased glucose filtration (dependent on the GFR) and may allow greater excretion of glucose with SGLT2 inhibition. The effect of SGLT2 inhibitors diminishes as patients plasma glucose concentrations decrease, the intrinsic risk of hypoglycemia with this drug class is low [28].

Dapagliflozin, a potent and selective SGLT2 inhibitor, has been shown to improve glycemic control in patients with type 2 diabetes when used as monotherapy [29-31] or in combination with metformin [32,33], sulfonylureas [34-36], thiazolidinedione [37], DPP4 inhibitors [38], or insulin [39].

Multiple trials have examined the efficacy of dapagliflozin versus placebo in lowering the HbA1c in drug-naive T2DM individuals. In a 24-week multicenter study [31], decrease in dapagliflozin treated subjects HbA1c was 0.5-0.6% (from a baseline HbA1c of 7.8-8.0%) and FPG decrease by ~25mg/dl (from a baseline FPG of 160mg/dl). In a subgroup of subjects with baseline HbA1c of 10.1-12.0%, dapagliflozin (5 and 10mg/ day) reduced the HbA1c by 2.88 and 2.66%, respectively. In another 24-week study [29,30], Dapagliflozin lowered the HbA1c by 0.7-0.8% from a baseline HbA1c of 7.8-8.1%. The efficacy of dapagliflozin in lowering the plasma glucose concentration as add-on therapy has been examined in poorly controlled T2DM treated with metformin, sulfonylureas and pioglitazone. Dapagliflozin effectively reduced the HbA1c in poorly controlled diabetic individuals independent of the background therapy. In a 24-week study [32], metformin-treated individuals with HbA1c 7-10% were randomized to receive different doses of dapagliflozin or placebo. The placebo-subtracted reduction in HbA1c at 24 weeks was -0.37 to -0.54%. Dapagliflozin also produced a dose-dependent decrease in FPG. 71% of subjects in this study participated in a 102-week extension study and the decrease in HbA1c was maintained at 102 weeks [33].

As add-on therapy, dapagliflozin has been shown to have similar potency to sulfonylureas in lowering the HbA1c in poorly controlled metformin-treated diabetic subjects. In a 52-week head-to-head study [34], meformin-treated subjects (HbA1c >6.5%) were randomized to receive dapagliflozin or glipizide. After an 8-week lead in period, dapagliflozin and glipizide were up-titrated over 18 weeks to 10 and 20 mg, respectively. The decrease in HbA1c at 52 weeks was identical in both groups (0.52%) [34], and the decrease in HbA1c in dapagliflozin-treated subjects was maintained at 102 weeks [35]. In a 24-week study [36], sulfonylurea treated subjects with poor glycemic control (HbA1c 7-10%) were randomized to receive different doses of dapagliflozin or placebo. The placebo-subtracted decrease in HbA1c was -0.44 to -0.68%, respectively. Dapagliflozin (5 and 10mg) has also been examined in a 24-week study [37] in poorly controlled (mean HbA1c 8.4%), pioglitazone-treated T2DM subjects. The placebo-subtracted decrease in HbA1c was -0.40 and -0.55%, respectively, and the decrease in HbA1c was maintained at 48 weeks. Dapagliflozin equally reduced the fasting and the postprandial plasma glucose concentration by ~ 25mg/dl.

In a larger study (n =800), [39] the addition of dapagliflozin (2.5, 5 and 10mg/day) to insulin-treated T2DM individuals (receiving ~70-80 units/day for a mean of ~6 years) caused a dose-dependent decrease in HbA1c (-0.40, -0.49 and -0.57%, respectively) compared with placebo over 24 weeks and the decrease in HbA1c was maintained at 48 weeks [39].

Other factors which play important role in the pathophysiology of T2DM were also improved by dapagliflozin alone or in combination with other diabetic drugs. Hypertension and albuminuria are risk factors for cardiovascular (CV) and renal disease in patients with T2DM [40]. Control of glycemia, blood pressure (BP) and albuminuria are critical for reducing CV and renal risk. Dapagliflozin reduces HbA1c and BP in patients with T2DM and also reduces urinaryalbumin:creatinine ratio in T2DM patients with hypertension using renninangiotensin system blockade without increasing any renal AEs [40]. Further, dapagliflozin improved glycemia in T2D patients with CVD, and improved insulin sensitivity in patients with T2D for up to 52 weeks. [41] Dapagliflozin alone and in combination with saxagliptin was shown to improve ßcell function and increased insulin clearance [42].

In addition to the beneficial effects related to improved glycemic control, dapagliflozin exerts additional non-glycemic benefits in T2DM patients that make the drug desirable as monotherapy and as combination therapy.

The urinary loss of 60-80g of glucose per day equates to a negative energy balance of 240 - 320 cal/day or an equivalent body weight of 2-3pounds/month if this caloric deficit is not offset by an increase in caloric intake. Consistent with this, weight loss was observed in diabetic subjects treated with dapagliflozin at all doses and at all stages of the disease [43]. Reduction in body weight was 2.26kg to 5.43kg as monotherapy [44], second add on therapy or add on to Insulin [44]. The weight loss primarily was due to a decrease in fat mass which is 2/3rd [44] while lean tissue mass reduction was 1/3rd as measured by dual-energy X-ray absorptiometry (DXA). Reduction in waist circumference was 2.5cm [44].

A consistent finding in all dapagliflozin studies has been a reduction in systolic/diastolic blood pressure of 4-5/2-3mmHg respectively [45]. This has been attributed to the diuretic effect that occurs during the initial days of dapagliflozin treatment [46]. Since uric acid and sodium reabsorption in the proximal tubule are coupled, decrease in serum uric acid concentration consistently has been observed in diabetic patients treated with dapagliflozin [47].

A major safety concern for anti-diabetic agents is the potential for patients to develop hypoglycaemia. Indeed, thus far, clinical trials have revealed virtually no instances of major hypoglycemic events, despite some increased risk of mild or moderate hypoglycemic events, which mostly occurred when they are superimposed with the background SU and Insulin therapy [34,39]. Clinical trials have consistently shown the early SGLT2 inhibitor dapagliflozin to be a safe agent for diabetic patients. Following an initial safety trial in healthy subjects showing that dapagliflozin was safe and well tolerated and did not induce hypoglycemia or produce any other adverse events [47], its safety was examined in type 2 diabetic patients, confirming that multiple oral doses of dapagliflozin rarely caused major hypoglycemia or other adverse events [29].

An increased incidence of mycotic vulvo-vaginal infections in women and mycotic balanitis in males has been observed. Rates of balanitis in men are several-fold less than rates of vulvovaginitis in women, and both infections are easily resolved by standard therapies [29]. SGLT2 inhibitors also possess a diuretic effect, hence symptoms related to volume depletion may occur [48]. Consequently, these agents should be used cautiously in elderly, any patient already on a diuretic, and patient with tenuous intravascular volume status.

Studies with dapagliflozin have demonstrated that treatment with an SGLT2 inhibitor has no deleterious effect on renal function [49]. Moreover, because the majority of drug’s clearance is by the liver, no dose adjustment is necessary in patients with renal impairment [49]. Because of its mechanism of action, the efficacy of dapagliflozin to reduce plasma glucose concentrations is highly dependent on the level of renal function. As the GFR declines, there is a decrease in the filtered glucose load and a progressive decrease in the glucose lowering ability of the drug. Thus dapagliflozin is not recommended if eGFR is <45 mi/min/1.73m2 [48].

It is possible that SGLT2 inhibitor therapy may prevent diabetic nephropathy. Enhanced sodium-glucose reabsorption in the proximal tubule has been shown to play an important role in the development of diabetic nephropathy [49]. SGLT2 inhibitors may prevent diabetic nephropathy not only by reducing the plasma glucose concentration but also by increasing sodium delivery to the distal nephron, thereby inhibiting the glomerulotubular feedback reflex [49]. Type 2 diabetes is a major risk factor for cardiovascular (CV) disease, and the presence of both Type 2 diabetes and cardiovascular disease increases the risk of death [50]. There is concern that intensive glucose lowering or the use of specific glucose-lowering drugs may be associated with adverse cardiovascular outcomes. Therefore, it is necessary to establish the cardiovascular safety benefits of glucose-lowering agents [51]. Since the mode of action of SGLT2 inhibitors is independent of insulin secretion; these agents are associated with a low risk of hypoglycemia, which has been linked to increased CV events. In addition, the drug has been demonstrated to ameliorate a variety of CV risk factors and potential pathways as described in Figure 1 [52]. Dapagliflozin has an acceptable CV profile. Meta-analyses have been performed analyzing the cardiovascular safety of dapagliflozin [53].

Meta-analysis did not show an increased CV risk for dapagliflozin-treated patients, with no evidence for an increased risk of major CV events and with hazard ratios <1 consistently across various composite CV endpoints and across different subgroups [53]. Also, EMPA-REG study with Empagliflozin, another SGLT2, showed that T2DM patients with high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care [54]. In CVD REAL, A large multinational study, treatment with SGLT-2i versus oGLDs was associated with a lower risk of HHF and death, suggesting that the benefits seen with empagliflozin in a randomized trial may be a class effect applicable to a broad population of T2D patients in real-world practice [55]. In CVD REAL Nordic study a total of 40,908 patients with T2D were identified as new users of dapagliflozin (n=10227) ora DPP 4 inhibitor (n=30681). Dapagliflozin was associated with a lower risk of MACE, HHF and all-cause mortality compared with DPP-4 inhibitors: HRs 0.79 (95%confi-dence interval [CI] 0.67-0.94), 0.62(95% CI 0.50- 0.77), and 0.59(95% CI 0.49-0.72), respectively [56].

Recently, the U.S. Food and Drug Administration (FDA) issued a Drug Safety Communication that warns of an increased risk of diabetic ketoacidosis (DKA) with surprisingly mild to moderate glucose elevations (euglycemic DKA [euDKA]) associated with the use of all the approved sodium-glucose cotransporter 2 (SGLT2) inhibitors [57]. In the randomized controlled T2D study program, more than 18,000 patients exposed to dapagliflozin and the frequency of reported events suggestive of DKA (blinded and unblinded events) was less than 0.1% [56]. Similarly in DECLARE study 17,150 patients randomized todapagliflozin or placebo, the total number of reported blinded events of potential DKAs is less than 0.1% [58]. In a retrospective analysis of randomized phase 2 and 3 empagliflozin trials (13,000 T2D participants), there were eight events consistent with DKA with no imbalance observed between patients treated with empagliflozin 10mg (two events), empagliflozin 25mg (one event), and placebo (five events) [59]. The canagliflozin (another SGLT2 inhibitor) data reported by Erondu et al. [60] appeared to have a greater incidence of DKA, but 6 out of the 12 cases had evidence of latent autoimmune diabetes in adults or T1D or tested positive for GAD65 antibodies. Thus the evidence so far suggests that the risk of euDKA (and not simple ketosis) in T2DM related to the use of SGLT2 inhibitors will probably turn out to be very low with an acceptable frequency. Still, physicians and patients need to be made aware that such risk may be increased in long-standing T2DM patients with marked beta-cell insufficiency or in latent autoimmune diabetes. This potential complication related to SGLT2 inhibition is predictable, detectable, and preventable so that the balance of benefits and risks favors the use of SGLT2 inhibitors in the T2DM population [58].

Numerous preclinical and clinical studies indicate that SGLT2 inhibitors are efficacious but still they may not be the first choice for T2DM therapy. Currently, the standard first line therapy is metformin, due to its low cost and favourable safety profile. SGLT2 inhibitors could quickly become a second-line therapy, and may possibly replace metformin as the first-line therapy in the future [61]. SGLT2 inhibitors may be a particularly good choice for T2DM patients who do not achieve adequate glycaemic control with metformin or other anti-diabetic drugs. In two clinical studies, dapagliflozin as an add-on to metformin decreased HbA1c levels significantly without any serious adverse effects [32].

ADA guidelines recommend weight loss for all overweight or obese individuals who have /are at risk for diabetes. Weight reduction is especially important in Asians who have lower cut-offs for overweight and obesity and hence are highly predisposed to development of diabetes and worsening of diabetes [59]. Shantha et al. [60], in 2012 demonstrated that intentional weight loss of 10% in obese individuals with T2DM could potentially decrease percentage HbA1c by 0.81%. WHO recommends lowered cut-off points for overweight/obesity for Asians in the Asia Pacific region (overweight: BMI =23 kg/m² in comparison with 25kg/m² for western populations) [10].

The major change in treatment options since the publication of the 2012 position statement has been the availability of a new class of glucose-lowering drugs, the sodium-glucose cotransporter 2 (SGLT2) inhibitors. These agents reduce HbA1c by 0.5-1.0% (5.5-11mmol/mol) versus placebo [61]. When compared with most standard anti-diabetic agents in headto- head trials, they appear to be roughly similarly efficacious with regard to initial HbA1c lowering [62]. Additional potential advantages include modest weight loss and consistent lowering of systolic and diastolic blood pressure along with reductions in plasma uric acid levels and albuminuria [63]. Current treatment guidelines approved SGLT2 inhibitors as monotherapy, they are mainly used in combination with metformin and/or other agents. Given their demonstrated efficacy and clinical experience to date, they are reasonable options as second-line or third-line agents [61].

All major organizations (American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD)/ American Association of Clinical Endocrinologists (AACE)) recommend metformin as first-line therapy in individuals with new-onset diabetes and also recommend as a combination therapy with other anti-diabetic agent in case of disease progression. Dapagliflozin is an effective novel strategy to reduce the plasma glucose concentration in type 2 diabetic subjects. The drug’s unique mechanism of action, which is independent of insulin sensitivity and beta cell function, allows the use of dapagliflozin in combination with all other antidiabetic agents and at all stages of the disease. However, because metformin does not improve beta cell function, metformin-treated individuals experience a progressive increase in HbA1c after the first year of therapy. Dapagliflozin can provide an effective therapeutic option in metformin-failing diabetic individuals. An increase in the plasma glucagon-like peptide-1 (GLP-1) concentration has been observed in some clinical studies following initiation of dapagliflozin therapy. This observation makes the double combination of dapagliflozin plus a dipeptidyl peptidase IV (DPP-IV) inhibitor an attractive therapeutic option in metformin-failing individuals. In newly diagnosed T2DM individuals with a very high HbA1c (e.g., >9.0%), metformin alone will not lower the HbA1c to the treatment goal (<7.0%). Dapagliflozin plus metformin have an additive effect to lower the HbA1c. Dapagliflozin monotherapy produces a profound decrease in HbA1c in patients with a high initial HbA1c (>9.0%). The combination of dapagliflozin plus metformin is an attractive therapeutic option in newly diagnosed diabetic individuals with a high initial HbA1c. Dapagliflozin can provide an effective therapeutic option in metformin-failing diabetic individuals. Metformin cannot be started in about 10- 20% of subjects with new-onset diabetes due to either gastrointestinal (GI) side effects or due to renal failure. Thus, dapagliflozin, as monotherapy or in combination with a DPP-IV inhibitor, can provide an effective initial therapy in metformin-intolerant individuals. Because dapagliflozin is effective in lowering the HbA1c at all stages of diabetes, it can be added in subjects who fail on multiple oral agent therapy or in insulin-treated individuals who do not reach the target glycemic control. Progressive beta-cell failure is the principle factor responsible for the progression of T2DM. Thus, preservation of β-cell function can be expected to produce a durable reduction in HbA1c. More data will be required before making definitive conclusions about the durability of dapagliflozin. To the extent that glucotoxicity contributes to the decline in beta-cell function in subjects with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG), these drugs also may prove useful in the treatment of ‘prediabetes’. Lastly, unlike most currently available antidiabetic agents, SGLT 2 inhibitors promote weight loss and reduces blood pressure which would be expected to have potential cardiovascular benefit [64,65].

Conclusion

The pathogenesis of type 2 diabetes involves numerous defects and no single anti-diabetic agent can correct all these metabolic disturbances. An effective anti-diabetic therapy will require multiple drugs used in combination. Based on expert commentsinhibition of SGLT2 represents a highly promising therapeutic approach for T2DM treatment. With a unique mechanism of action-increased urinary glucose excretionthe SGLT2 inhibitors can be used as monotherapy as well as in combination with currently available anti-diabetic agents. Their distinct, targeted mechanism of action makes SGLT2 inhibitors good candidates for combination therapies with other anti-diabetic agents as well as insulin. Moreover, due to their high potential to control hyperglycemia, effect on visceral fat and improvement in insulin sensitivity, SGLT2 inhibitors are expected to have protective effects against micro and macrovascular complications. With these properties, the SGLT2 inhibitors have potential for use throughout the continuum of diabetes treatment in Indian populationas Indian patient’s needs are unique due to environmental, social and genetic facts. Considering International glycemic control guidelines, mechanism of action, substantial improvements with respect to glycemic and extragycemic parameters and safety profile associated with Dapagliflozin, it could be excellent choice for managing T2DM after metformin in Indian patients.

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Health-Related Quality of Life Measurement

Authored by Zeinab Jannoo

Introduction

Health-Related Quality of Life (HRQoL) assesses the impact of illnesses on the physical, mental and social well-being of individuals and its importance is increasingly recognized [1]. Some instruments are intended for general use, irrespective of illness and the condition of the patient. The generic instruments may often be applicable to healthy people too. Some of the earliest ones were developed initially with population surveys in mind, but later was extended to include clinical trial settings. These instruments are commonly described as Quality of Life (QoL) scales and they are measures of health status since the focus is mainly on physical symptoms. Whilst the generic QoL instruments measure QoL generally and assess the various health domains, the diabetes-specific QoL is more sensitive to changes and is specific to the disease per se [2]. There are many instruments that have been developed nowadays for survey studies as well as clinical trials [3]. The aim of this paper is to present a short review on QoL and Health-Related Quality of Life (HRQoL).

During the past few decades, the application of HRQoL measures has gained a rapid importance since there was a need to develop brief, self-administered and reliable questionnaires to capture the patients’ view of their health [4-6]. This led to the development of two types of HRQoL questionnaires. The first type is the generic HRQoL instruments such as “Sickness Impact Profile (SIP)” [7], “36 item Short Form Health Survey (SF-36)” [6], and the “Nottingham Health Profile (NHP)” [7] which are used to assess various health conditions in a general population and the second type the disease-specific instruments, for instance “Problem Areas in Diabetes Scale (PAID)” [8], “Dialysis Quality of Life (DIA-QOL)”, multiple sclerosis quality of life instrument [9] pertain to a specific illness or health condition. Since the generic instruments fail to focus on issues of particular concern to patients with disease, and may often lack the sensitivity to detect differences, this has led to the extensive use of disease-specific instruments.

Generally the generic HRQoL measures, such as the SF-36, contains the essential elements of HRQoL and it is also easily cross-culturally validated [10]. In contrast to the generic scales instrument allows HRQoL comparisons across several populations with different diseases to be made, the disease-specific instrument is precisely related to a specific disease [10,11]. Furthermore, using only one disease-specific instrument, it is more difficult to assess the HRQoL for patients having multiple diseases. Hence the choice of a HRQoL instrument is based on the specific health condition of a patient. Therefore, a combination of generic and disease-specific instruments may be more appropriate in measuring the patient’s health status [10]. The majority of these HRQoL measures that have been developed are used predominantly in English-speaking countries such as USA and European countries. Healthcare professionals and researchers have evaluated different HRQoL measures in different countries across various cultural groups [4,12]. Because of the wide spectrum of cultural diversity involved in the evaluation process, therefore, great care need to be given in translation of the original HRQoL instruments, especially in Asian communities which need extensive psychometric analysis to test the translated instruments [12,13]. Cross-cultural comparisons, on the other hand, can lead to effective health intervention and facilitate the exploration of results in different countries [14].

In view of the discussion on QoL and HRQoL measures, it has become an important issue to be able to decide upon which measure is more appropriate especially in clinical trials. Therefore, the various factors associated with a certain illness should be well documented prior to the choice of any instrument to be administered to the patient.

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Can Diabetes Mellitus Type-1 be A Transmissible Disease? Revisit to an Earlier Premise

Authored by Khaled K Al-Qattan

Commentary

To some diabetalogists/diabeticians, and certainly the majority of the general public, the title of this commentary might come a bit as a surprise. What is known about diabetes mellitus (DM), as a medical condition, that it is a group of linked biochemical-physiological disorders initiated by pathological rise in the circulating blood glucose concentration. This hyperglycemia develops mostly as a consequence to either hypoinsulinemia (DM type-1) or cellular insensitivity to insulin (DM type-2). In extreme cases both causative factors transpire and therefore act together on the body leading to the induction and progression of an aggressive form of the disease. For the time being, DM is unequivocally regarded as an inherent condition since its causes’ are innate to the affected person and provoked primarily by life-style and genetics. Although this self-origin manifestation of the condition is certainly true as evident in the multitude of scientific studies and reports, nonetheless other unorthodox cofounders may exist and yet to be revealed and ascertained.

One such further and elusive causative factor of DM could be its possible transmissibility from a diabetic patient to a biochemically-physiologically-genetically susceptible non-diabetic individual. In an article titled “Is Diabetes of Infectious Origin?” published as early as 1927 in The Journal of Infectious Diseases, Eduard Gunderson proposed that DM may be transmissible via blood transfer and/or anomalous contents in consumed meat. For a moment, this assumption might be thought of as a tad farfetched as no scientific evidence exists to support what could be regarded as a bold claim. Nevertheless, in a fairly recent study led by Claudio Soto and published in the Journal of Experimental Medicine it was reported that DM type-2 might be caused by the formation of toxic aggregates of misfolding of islet amyloid polypeptide protein which could result from transmissible proteins.

This commentary proposes that it is highly probable that DM type-1 might also be a transmissible disease, however via bacterial agents. This assumption is supported by an ample and compelling, although be it circumstantial, evidence provided by the findings and observations of considerable and recent related studies. Interest in the transformation of the body, and in particular the gut, microbiota as a cause to the development of numerous human diseases began to attract growing attention and formed the bases for many scientific studies. Examples of such diseases include metabolic, liver, gastrointestinal, respiratory, mental and autoimmune abnormalities, in addition to DM. As far as DM is concerned, human diabetics were shown to possess transformed gut microbiota and, vice versa, chemical induction of DM type-1 distorted the microbiota of rats’ gastrointestinal system. The question, among many, that presents itself at this juncture: Can such a transformation in the microbiota of the body, and in particular that of the gut, becomes an intermediary in the transmissibility of DM type-1? To answer this question, first it must be stated that such a hypothesis is sound as it is established that microbial agents are the foremost propagators of infectious diseases. Additionally, and as concluded from the observations of recent studies, if infection and gut microbiota transformation do occur, then it is highly probable that an aggressive attack on the intestinal apical wall will develop leading to epithelial lesions, inflammations and consequently drastic autoimmune responses. Formed erratic antibodies may translocate and even attack neighboring cells and those could be the insulin producing beta-cells due to the close proximity of the pancreas to the most susceptible part of the intestine; the duodenum.

With the lack of direct scientific evidence, is the assumption that DM type-1 be an infectious disease lacks ground? The answer is simply YES. Nonetheless, if bodily material contaminated with pathogens were to transfer between a diabetic and non-diabetic, and the latter subject was prone to such infections, due for example to compromised immune responses, such a possibility may materialize. This aforementioned suggestion is based on the scientific fact that pathogens, and certainly those that dwell in the gut of patients, can make a healthy individual become sick. Thus, the premise that non-classical live biological agents that exist in the gut of a diabetic might be an additional factor that leads to the development of DM type-1 in the most vulnerable of individuals is highly plausible under the ‘right’ circumstances. In an attempt to address such an interesting objective we carried out a small and limited pilot study in which we co-habituated healthy and streptozotocin-induced diabetic Sprague-Dawley rats for more than 16 weeks and on biweekly bases monitored their blood glucose. No change was observed in the blood glucose of the normal rats although the streptozotocininjected rats showed progressively the classical symptoms of diabetes. Although this study yielded negative data, still the high rate at which DM type-1 is spreading world-wide, which almost exceeds the international curve for any other epidemic, warrants consideration of every possible etiology of this disease. Accordingly, more focused studies testing versatile combinations of external and internal variables are recommended to test this proposed hypothesis.

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Physical Activity, Exercise, Weight Reduction and Oxidative DNA Damage in Colorectal Cancer Risk Groups. Is there a Hormesis Relationship Between Risk Biomarkers and Lifestyle Factors?

Authored by H Allgayer

Abstract

Patients with obesity and/or type 2 diabetes have an increased tumor risk including colorectal cancer. Physical acrtivity (PA), exercise (EX) and weight reduction (WR) are effective strategies to decrease this risk. Highly sensitive tumor risk biomarkers such as oxidative DNA damage products (8-oxo-2’deoxyguanosine [8-oxo-dG]) increasingly are used in epidemiological and clinical (intervention) studies to better quantify this risk and to investigate potential effects of PA/EX/WR on this biomarker with the aim to further improve prevention and patient management programs. Based on the available data a U-shaped relationship between urinary 8-oxo-dG excretion and the level of PA/EX intensity is assumed, on the other hand, the relationship with BMI seems to be less clear. In this minireview this data will be discussed with regard to clinical and epidemiologic aspects.

Keywords: Type 2 diabetes; Obesity; Colorectal cancer; Weight reduction physical activity; Exercise; Oxidative DNA damage; 8-oxo-dG

Abbreviations: T2D: Type 2 Diabetes; CRC: Colorectal Cancer; BMI: Body Mass Index; PA/EX: Physical Activity/Exercise; 8-oxo-dG: 8-oxo-2’-Deoxy-Guanosine; ROS: Reactive Oxygen Species; ROM: Reactive Oxygen Metabolites; TTL: Total Thiol

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Introduction

Epidemiologic and clinical studies in the last three decades have convincingly demonstrated that patients with type 2 diabetes (T2D) have a higher tumor risk including colorectal cancer (CRC) and that CRC-patients with T2D have an elevated risk of a more aggressive disease course compared to non-diabetic individuals [1,2]. In addition, there is convincing evidence that elevated body mass index (BMI [kg/m2]) particularly visceral fat mass may also contribute to an increased tumor risk including CRC, whereas on the other side weight reduction was found to decrease this risk [3-5]. Physical activity/exercise (PA/EX) was shown to be associated in a dose-dependent and inverse relationship with a 30 to 50 percent lower decrease of tumor risk in the most active individuals [6]. To further improve prevention strategies and therapeutic management in risk groups more clinical and epidemiological studies with quantitative data using highly sensitive risk biomarkers and their modification by lifestyle factors are urgently needed.

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Disease, Oxidative DNA Damage Products and Risk Prediction Models

To quantify tumor risks (including CRC) a series of compounds modifiable by lifestyle factors (diet, PA/EX) have been proposed, among them 8-oxo-2’-deoxy-guanosine (8-oxo-dG) which was shown to reflect (mutagenic) oxidative DNA damage deriving from interactions with reactive oxygen species (ROS) produced in excess as a consequence of increased endogenous and exogenous oxidative stress [7,8]. Elevated levels of 8-oxo-dG have been found in many conditions and diseases with an increased cancer risk including T2D [9-14]. In a recently published clinical crosssectional study comparing urinary 8-oxo-dG in individuals with different CRC-risks we found that urinary excretion in patients with T2D (having a moderately elevated CRC risk) was in between those with curatively treated CRC (high risk for recurrence) and non-diabetic controls (average risk) [15]. Urinary excretion of 8-oxo-dG was significantly correlated with BMI (p=0.04) in all study participants, but not with the smoking status, age, alcohol consumption or gender. One clinically important application would be the implementation of stress biomarkers into predefined CRCprediction models to further improve accuracy with inclusion into appropriate prevention programs. Thus, in a recently published meta-analysis compiling the data of two large scale populationbased studies with >4000 individuals (ESTHER and Tromsö study) it was shown that the inclusion of reactive oxygen metabolites (ROM) assessed as total thiol (TTL) and hydrogen peroxide levels (d-ROM) into already existing models significantly improved their accuracy (C-statistics) [16]. Another study from the same group could show that CRC patients in the presence of elevated blood TTL and d-ROM levels had a poorer prognosis compared to those without these parameters [17]. Similar population-based trials with implementation of additional risk biomarkers such as urinary excretion levels of 8-oxo-dG into those prediction models presently are not available but are likely to further improve our prevention programs particularly in patients at an increased CRCrisk.

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Physical Activity/Exercise and Oxidative DNA Damage (8-oxo-dG)

Quantitative data concerning beneficial effects of PA/EX on the individual tumor risk in terms of risk biomarkers are clinically important, but not widely available and not entirely consistent. The great majority of clinical and experimental intervention studies in healthy volunteers as well as in patients belonging to risk groups such as T2D or curatively treated CRC have shown decreased systemic and urinary 8-oxo-dG levels (and other risk biomarkers) in the range of 20–30 percent following moderate intensity of EX, whereas at higher intensity levels oxidative DNA damage increased suggesting a U-shaped (hormesis) relationship. [18-25]. One possible explanation for this effect may be that cellular and humoral compensatory mechanisms such as exerciseinduced activation of antioxidant defenses (e.g., superoxide dismutase, DNA repair systems) would be exhausted at higher EX intensities with a shift to more prooxidant compounds [26-28]. In our recently published study [15] we found that urinary 8-oxo-dG excretion was independent of the individual level of PA in all study participants, an observation being somewhat surprising and in contrast to data from interventional studies mostly showing clear beneficial effects of regular exercise on genome stability and DNA damage in risk groups such as patients with T2D [19,20]. A possible explanation of this discrepancy may be that exercise-induced changes of 8-oxo-dG levels are closely linked to rapid changes of humoral and cellular redox systems [26,27] and that these rather short lived effects may have been missed in non-interventional settings such as our study, a view based on a closer look into the time protocols of these studies e.g times at which biomarkers had been assessed in relation to previous PA/ EX [15]. Despite these limitations further biomarker-guided longterm prospective interventional trials with individually tailored exercise programs are urgently needed to improve patient management particularly in those at increased CRC-risk such as obesity and T2D with particular emphasis on moderate intensity protocols to obtain optimal individual benefit.

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Body Mass Index and 8-oxo-dG

In contrast to PA/EX the relationship of BMI oxidative DNA damage seems to be less clear as there are studies reporting inverse (negative) as well as positive correlations [29-32]. In a longitudinal study investigating a cohort of 179 healthy office workers Mizoue et al. found a negative correlation up to BMI 27 kg/m2 [31], in morbidly obese patients undergoing bariatric surgery, however, a positive correlation was observed with a highly significant decrease 6 months after surgery [32]. Based on these data the authors of both groups suggested that there may possibly be a similar relationship of BMI with urinary 8-oxodG excretion as seen for PA/EX.; a negative correlation being observed at low/normal BMI (<27 kg/m2) turning positive above this value [31,32]. When the participants in our recently published study (T2D, CRC, non-diabetic controls) were analyzed separately according to their diagnosis the observed positive correlation (p=0.04) was no longer significant. Additional BMI-models with multiple adjustments for the cofactors gender, age, BMI, alcohol consumption and smoking status yielded similar results (no correlation) [15]. In line with this data are results of our earlier study showing no significant correlation of BMI with urinary 8-oxodG excretion in CRC-patients [21]. It is, therefore, important to adjust for multiple confounding factors, when correlations of BMI with 8-oxo-dG in clinical and/or epidemilogical studies are investigated. Despite these limitations oxidative DNA damage biomarkers should be included into weight reduction programs particularly for the obese/morbidly obese individuals and those in whom bariatric surgery is planned [32]. Our finding of a positive correlation of BMI with urinary 8-oxo-dG excretion (in the nondiabetic controls) may further support the view that long-term (beneficial) effects of PA (or energy expenditure during EX) on risk biomarkers may be mediated at least partially by the weight loss (BMI reduction) as observed during appropriate exercise programs.

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Gestational Diabetes and Insulin Use in Pregnancy

Authored by Sinisa Franjic

Abstract

Diabetes in pregnancy can significantly endanger the health of a pregnant woman, especially the vulnerable population and her child, and it is extremely important to talk about this disease. Diabetes mellitus or diabetes is a metabolic disease in which there is a chronic condition of elevated blood sugar levels (hyperglycemia) due to insufficient action of insulin, a hormone secreted by the pancreas. In some cases of the disease, insulin is not produced or is produced very little, and in other cases it is produced even in increased amounts, but the cells are resistant to its action, which is called insulin resistance. Sugar, or glucose, is the fuel that the human body needs to function properly. It is a source of energy for all the cells in our body and is created by the breakdown of carbohydrates in the digestive system. In order for our cells to be able to use the obtained glucose, they need insulin - a hormone that serves to transfer glucose to the cells. Precisely because of this, if the action of insulin is disturbed, the cells, but also the whole human body, do not function in a normal way. Because glucose cannot enter cells due to the ineffective action of insulin, it accumulates in the blood. High blood glucose levels damage small blood vessels in the kidneys, eyes, heart and nervous system. If diabetes is not treated, severe irreversible organ damage can occur. There are three main types of diabetes: type 1, type 2 and gestational diabetes. Pregnancy exacerbates existing type 1 and 2 diabetes, but also in some women, the disease may first appear in pregnancy, which is called gestational diabetes.

Keywords: Diabetes; Gestational diabetes; Insulin; Pregnancy; Health

Abbreviations: HPL: Human Placental Lactogen; DM: Diabetes Melitus; GDM: Gestational Diabetes Mellitus; ADA: American Diabetes Association; PCOS: Polycystic Ovary Syndrome; SHBG: Sex Hormone-Binding Globulin; WHO: World Health Organization

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Introduction

Insulin is a pancreatic hormone that’s essential for the regulation of glucose [1]. Lack of insulin and also the inability to adequately reply to insulin are primary causes of diabetes. Insulin contains a similar function in males and females. However, insulin’s ability to control blood sugar is significantly more challenging in females than in males due to the influence of female hormones on blood sugar.

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Insulin

a) Regulates the body’s use of glucose [1]

b) Controls blood sugar levels

c) Regulates fat storage

d) Provides the signals required by the liver, muscles, and fat to take in glucose from the blood

e) Signals the liver to take in glucose and store it as glycogen

Maternal metabolism is directed toward supplying adequate nutrition for the fetus [2]. In pregnancy, placental hormones cause insulin resistance at tier that tends to parallel the expansion of the fetoplacental unit. because the placenta grows, more placental hormones are secreted. Human placental lactogen (HPL) and hormone (somatotropin) increase in direct correlation with the expansion of placental tissue, rising throughout the last 20 weeks of pregnancy and causing insulin resistance. Subsequently, insulin secretion increases to beat the resistance of those two hormones. within the nondiabetic pregnant woman, the pancreas can answer the demands for increased insulin production to keep up normal glucose levels throughout the pregnancy. However, the woman with glucose intolerance or diabetes during pregnancy cannot cope with changes in metabolism resulting from insufficient insulin to fulfill the needs during gestation.

Over the course of pregnancy, insulin resistance changes. It peaks within the last trimester to produce more nutrients to the fetus. The insulin resistance typically leads to postprandial hyperglycemia, although some women even have an elevated fasting blood glucose level. With this increased demand on the pancreas in late pregnancy, women with diabetes or glucose intolerance cannot accommodate the increased insulin demand; glucose levels rise as a results of insulin deficiency, leading to hyperglycemia. Subsequently, the mother and her fetus can experience major problems.

In general, pregnancy increases medication requirements for adequate glucose control within the second and third trimesters [3]. Women with type 1 diabetes may become more brittle within the first trimester and thus prone to hypoglycemia. additionally, hyperemesis may complicate oral intake for diabetic pregnant women. Management of diabetic women having surgical abortions depends partly on plans for pain management. No changes in diet or medication are required for those having abortions under local anaesthesia. When deeper sedation requires preprocedure fasting, a common approach is to have the patient inject half her usual long-acting insulin dose the evening before and skip the morning dose. Ideally, a woman with diabetes is scheduled to have one in every of the first procedures of the day, in order that are going to be able to eat and take her usual dose of morning insulin afterwards; morning NPH will be active within the afternoon. Glucose is monitored frequently by finger stick before, during, and after the procedure, with insulin given as required until the patient resumes eating. Although sliding scales of insulin doses associated with blood glucose levels are used in hospitals for many years, little evidence supports this approach.

When advising women regarding medications and diet, providers should keep in mind that modest hyperglycemia poses no acute risk to women undergoing an abortion. “Loose” control of diabetes round the time of the procedure is preferred to “tight” control. as an example, a transient blood glucose concentration of 180 to 200mg/dL during an abortion isn’t worrisome, whereas a blood glucose level of 30mg/dL is. Hence, providers should have food, intravenous glucose solutions, or glucagon available. After the procedure, the patient’s medication requirements may decrease substantially. Coordination of care along with her medical provider is usually recommended, especially during this transitional time.

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Effects

Any elevated blood glucose concentration within the maternal blood (hyperglycemia), as in diabetes (described within the discussion on the pancreas and diabetes mellitus), is harmful to the developing fetus [4]. In early pregnancy when the organ systems are developing, the hyperglycemia may cause congenital malformations or maybe result in fetal death. Later within the pregnancy, the additional glucose crossing the placenta into the fetal bloodstream causes the fetal pancreas to release more insulin, and also the extra glucose is metabolized to promote fetal growth. As a result, the fetus becomes larger than average size; the larger fetal kidneys secrete more urine, which contributes to the quantity of amnionic fluid and causes its volume to increase. Delivery of the oversized fetus is also tougher, possibly requiring a cesarean section. After delivery, the infant’s blood glucose may fall precipitously (hypoglycemia) because the newborn infant’s pancreas has been at home with handling a much higher intrauterine blood glucose concentration and has not had time to compensate for the lower postdelivery blood glucose. The infant also faces neonatal respiratory distress problems caused by inadequate surfactant, as described within the discussion on the respiratory system. For these reasons, recognition and treatment of hyperglycemia in pregnancy are within the best interest of both the mother and her baby.

Pregnant women should be evaluated on their initial visit for any risk factors— like obesity, gestational diabetes in a previous pregnancy, a family history of diabetes, and the other factors that may predispose her to gestational diabetes—and some form of screening test should be performed. the usual screening test consists of 50g of glucose solution given orally without relation to fasting status, followed by determining the concentration of glucose within the patient’s blood one hour later. If the result exceeds a predetermined concentration, more comprehensive studies are performed to confirm the diagnosis of gestational diabetes, and a course of treatment is begun.

Pregnant women are routinely screened for gestational diabetes in many developed countries, during the second half of the second trimester, because it is related to adverse perinatal outcomes [5]. Treatment usually commences with dietary and exercise changes, with insulin common because the first-line medical treatment. However, only if critical illness is related to altered carbohydrate metabolism, screening for gestational diabetes while a pregnant woman is in ICU (intensive care unit) wouldn’t be indicated. Rather, assessing blood glucose levels as one normally would during critical illness is required, keeping in mind that maternal hyperglycemia should be actively avoided.

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GDM

According to the National Diabetes Data Group Classification, there are four sorts of diabetes [6]. they’re type 1 Diabetes Melitus (DM), called insulin-dependent diabetes; type 2 DM, called insulin-resistant diabetes; diabetes dependent on other specific conditions like infection or drug induced; and gestational diabetes mellitus (GDM). GDM is defined as carbohydrate intolerance that’s first recognized during pregnancy. There’s a 50% risk of GDM turning to chronic DM within 5 yr after diagnosis if no lifestyle changes are made. Diabetes poses significant risks to maternal/fetal morbidity and mortality. Incidence of diabetes in pregnancy has increased because more women are delaying pregnancy until relatively late into their reproductive years. Currently the incidence is 4%-14% with GDM accounting for nearly 90%.

At the first prenatal visit all women are screened for clinical risk factors when obtaining a history. If risk factors are identified like previous history of GDM, known impaired glucose metabolism, previous macrosomic baby (greater than 4000 g), and obesity (BMI greater than 30), early screening is usually recommended. An early screen that’s negative is repeated for these high-risk women at 24-28 wk. Between 24 and 28 wk gestation, it’s recommended that each one pregnant women be screened for GDM. A two-step screening process is currently supported by ACOG (American Congress of Obstetricians and Gynecologists). The approach begins with administration of 50 g of oral glucose solution with a 1-hr serum glucose measurement because the initial screening. Screening is suggested even for patients with low risk factors (age younger than 25 yr, not a member of an ethnic group at risk for developing type 2 DM, BMI but 25, no previous history of abnormal glucose tolerance, no previous history of adverse obstetric outcomes that are usually related to GDM, and no known diabetes during a first-degree relative [mother, father, siblings]).

For all women with type 1 DM, four to 5 daily insulin injections or an insulin pump are going to be required [7]. For women not on an insulin pump, insulin should lean as a part of a basal - bolus regimen with a long - acting basal insulin, usually given at night, and rapid or short - acting insulin boluses loving each meal. There’s some evidence that the chance of hypoglycaemia for women with type 1 DM in early pregnancy is lessened with the use of an insulin pump and suitable patients should be considered for an insulin pump prior to pregnancy.

For women with type 2 DM, a basal - bolus regimen is additionally recommended because it offers the foremost flexibility around food timing and exercise and lessens the chance of hypoglycaemia in early pregnancy. For some women who have had type 2 DM for only a short time and are well controlled on diet and metformin alone, adequate glycaemic control could also be achievable prior to and early in pregnancy with either a twice - daily mixture (of a brief - and medium- acting insulin) or with just a rapid - acting insulin with meals. However, by the second trimester most women would require a basal - bolus regimen.

Continuing with the oral agent metformin for girls with type 2 DM before pregnancy is usually recommended by the United Kingdom clinical guidelines, although this is often not endorsed by other national guidelines. While there’s no evidence that the sulphonylureas are teratogenic in early pregnancy, these agents are related to less good glycaemic control in pregnancy than insulin and less favourable pregnancy outcomes.

Gestational diabetes mellitus (GDM) is one in every of the foremost common obstetric complications, with incidence starting from 3 to 10% in developed countries [8]. There’s currently an absence of consensus within the medical literature regarding screening for GDM because data fail to indicate that universal screening for GDM benefits the population.

Selective screening exempts women considered at low risk for GDM. ACOG states that although universal screening is that the most sensitive means of detection, certain low risk women may have the benefit of selective screening (SOR C). The American Diabetes Association (ADA) also endorses selective screening, generally performed at 24 to 28weeks’ gestation with a 1-hour test (blood glucose measured 1 hour after oral ingestion of 50g glucose in 150mL fluid). The test is performed either fasting or non-fasting, although fasting may increase the probabilities of a false-positive screen. Women at higher risk for GDM may be screened at the initial prenatal visit, with follow-up testing done at 24 to 28weeks if the first test is normal.

If the 1-hour test is abnormal, a 3-hour glucose challenge test should be administered. The test is performed after an overnight fast. A 100-g glucose load is given orally, with blood drawn before ingestion and hourly for 3 consecutive samples. A diet containing a minimum of 150g of carbohydrates must be consumed for 3 days before testing. Carbohydrate depletion causes spuriously high glucose levels on the glucose challenge test. A diagnosis of GDM is created when elevation occurs with either the fasting glucose alone or with two or more of the 3- hour measurements.

Specific treatment including dietary advice and insulin for GDM reduces the danger of maternal preeclampsia and perinatal morbidity (composite outcome of death, shoulder dystocia, bone fracture, and nerve palsy). However, it’s related to higher risk of labor induction. Intensive insulin therapy is related to lower rates of macrosomia and wish for cesarean, but increased risks for both maternal and neonatal hypoglycemia. Sulfonylureas (glipizide and glyburide) and metformin (Glucophage) are being used in women with preexisting type 2 diabetes, especially when polycystic ovarian disease is present.

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PCOS

PCOS (polycystic ovary syndrome) could be a complex syndrome involving both a genetic and an environmental component with many possible presentations both physically and hormonally [9]. The core problem for all PCOS patients is increased intraovarian androgens. However, the pathway to the present increase is extremely complex and, in many cases, undefined. PCOS doesn’t have one easily definable cause. People with PCOS have a genetic makeup that puts them at risk. The genetic background is complex, involving many areas of the genetic code. A number of the problem areas include heredity (so there is also a case history of PCOS, obesity, or adult-onset diabetes) but often the genetic abnormalities arise anew during the genetic formation of the person with PCOS. However, having the genetic background doesn’t mean that an individual will automatically have PCOS. There has to make certain environmental factors that trigger the problem. There’s no agreement on what environmental factors exist or how important are known factors. One environmental factor which may trigger PCOS is overweight/obesity and therefore the insulin resistance which frequently accompanies these conditions. PCOS is related to certain metabolic disorders which are a part of the metabolic syndrome. These include dyslipidemia and glucose intolerance. The prevalence of metabolic syndrome in adolescents has been estimated to be between 12% and 44%. amenorrhea as a presenting symptom in PCOS is unusual since the usual history is one among amenorrhea. However, both presentations have similarities like insulin resistance and increased intraovarian androgens. Obesity is present in 35– 50% of adolescents with PCOS and in some patients seems to be a risk factor for PCOS with the link being insulin resistance. The increased androgen production increases the incidence of hirsutism and acne. Included within the diagnosis is hormonal testing to eliminate other causes of the clinical picture of PCOS like 17-0H progesterone for nonclassic adrenal hyperplasia and androgen profiles to eliminate the diagnosis of adrenal or ovarian tumors.

Although 50–70% of PCOS patients have insulin resistance [10], it’s not one in all the diagnostic criteria of PCOS. the subject deservedly receives much attention, as many of the clinical signs and symptoms of PCOS is also attributed to excess insulin exposure. The precise molecular basis for insulin resistance is unknown, but it appears to be a postreceptor defect. There’s tissue specificity of insulin resistance in PCOS: muscle and adipose tissue are resistant, while the ovaries, adrenals, liver, skin, and hair remain sensitive. The resistance to insulin in skeletal muscle and adipose tissue leads to a metabolic compromise of insulin function and glucose homeostasis, but there’s preservation of the mitogenic and steroidogenic function in other tissues. The effect of hyperinsulinemia on the sensitive organs leads to downstream effects seen in PCOS, like hirsutism, acanthosis nigricans, obesity, stimulation of androgen synthesis, increase in bioavailable androgens via decreased sex hormonebinding globulin (SHBG), and, potentially, modulation of LH secretion.

Insulin resistance may be a component of the World Health Organization (WHO) definition of the metabolic syndrome, which may be a cluster of risk factors for cardiovascular disease. The WHO defines the metabolic syndrome because the presence of glucose intolerance or insulin resistance, with a minimum of two of the following: hypertension, dyslipidemia, obesity, and microalbuminuria. Women with PCOS are 4.4 times more likely to have the metabolic syndrome, so it becomes prudent to screen these patients, especially in those with insulin resistance.

Lipid abnormalities are more prevalent in PCOS patients. There may be a big increase in total cholesterol, ldl cholesterol, and triglycerides, and a decrease in hdl cholesterol compared to weight-matched controls. The dyslipidemia, impaired glucose intolerance, central obesity, hyperandrogenism, and hypertension seen in PCOS patients greatly increase the chance for cardiovascular disease. based on this risk profile, women with PCOS have a sevenfold increased risk of myocardial infarction.

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Management

Prevention of hyperglycemia through rigorous control of blood sugar level is that the mainstay of treatment within the pregnant woman with pregestational diabetes [11]. This is often best accomplished by careful preconceptional counseling and achievement of normal HbA1c levels before pregnancy in pregestational diabetics, frequent (usually 4–5 times per day) home glucose level monitoring, adjustment of diet, and regular exercise.

Non–weight-bearing or low-impact exercise may be initiated or continued. Even short episodes of exercise will sensitize the patient’s response to insulin for approximately 24 hours. All care providers should stress the importance of diet. Soluble fiber provides satiety and improves both the quantity of insulin receptors and their sensitivity. Carbohydrate restriction improves glycemic control and will enable a patient to realize her glycemic goals using diet and activity. Calories are prescribed at 25–35kcal/kg of actual weight, generally 1800–2400kcal/d. Diet should be approximately 40% carbohydrate, 40% fat, and a pair of 0% protein usually divided into 3 meals and 2 or 3 snacks per day. A bedtime snack is especially important to prevent nocturnal hypoglycemia. When postprandial values exceed the targets, it’s important to review all recent food intake and to adjust food choice, preparation, and portion size.

Self-monitoring of fasting, 1- or 2-hour postprandial, and nighttime blood glucose levels using a glucose meter provides instant feedback to assess the patient’s diet and behavior. When the glycemic goals are met, the feedback may be a powerful motivator. Diet and/or activity errors are identified and corrected as needed. Optimal glucose levels during pregnancy are fasting levels of 70–95mg/dL and 1-hour postprandial values <130–140mg/dL or 2-hour postprandial values <120mg/dL.

A minimum of two visits to a dietitian improves education and active participation regarding diet. Food records are useful. The dietitian reviews content and calories and suggests the way to include favorite ethnic foods to improve compliance. Other family members should be encouraged to participate within the dietary education because their understanding and support increase the prospect for a successful diet. Often, the other family members will benefit from the healthful diet changes. Additional follow-up visits between patient and dietitian are important when glycemic goals don’t seem to be reached, weight change is simply too great or too small, or the patient has difficulty maintaining the diet .

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Conclusion

Gestational diabetes is diabetes that is first diagnosed in pregnancy. It most often occurs in the second trimester of pregnancy, primarily due to insulin resistance, which is potentiated by hormones produced by the placenta. Insulin resistance is a disorder of glucose metabolism when there is a weakening of the peripheral effect of insulin whose main task is to facilitate the transfer of glucose from the blood to target tissues (liver, muscle, fat tissue). The consequence of the insufficient peripheral effect of insulin is manifested in enhanced pancreatic function and increased secretion of insulin from the beta cell with the aim of maintaining the balance of blood glucose levels. Gestational diabetes occurs during pregnancy in women whose pancreatic function is insufficient to overcome pregnancyrelated insulin resistance. Among the main consequences are increased risks of preeclampsia, macrosomia and cesarean delivery and their associated morbidities.

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Diabetic Foot Ulcer: An Overview, Risk Factors, Pathophysiology, And Treatment

Authored by Gudisa Bereda

Abstract

Diabetic foot ulcer is one of the major health challenges that can decrease the quality of life, lengthen hospitalization and entails more cost to the patient. Diabetic foot disease outcome fifteen percent of the diabetic patients and person with diabetes are fifteen times more probably to undergo lower extremity amputation than their non-diabetic counterpart. Risk factors for ulceration are specific or systemic contributions such as uncontrolled hyperglycemia, duration of diabetes, peripheral vascular disease, blindness or visual loss, chronic renal disease, advanced age and local issues such as peripheral neuropathy, structural foot deformity, trauma and incorrectly suited shoes, callus, history of prior ulcer amputation, delayed elevated pressures, limited joint mobility. The initial goals of treatment for diabetic foot ulcer are to acquire wound closure as expeditiously as possible. Debridement includes remove of dead, injured, or exposed tissue, which improves the healing potential of the remaining healthy tissues. The principle of antibiotic management is depending on evidence provided by reports on bacteriological culture and sensitivity from distinctive centers worldwide. Use of anti-infective/antibiotics must be guided by proper cultures.

Keywords: Diabetic foot ulcer; Overview, Pathogenesis; Risk factors; Treatment

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Introduction

Diabetes mellitus is a severe, chronic metabolic disorders that described by elevated sugar level either when the pancreas does not secrete sufficient insulin, or when the body cannot effectively use insulin [1]. Infection is an often complication of diabetic foot ulcers (DFUs), with up to fifty eight percent of ulcers being exposed at primary presentation at a diabetic foot clinic, elevating to eight two percent in patients hospitalized for a DFU. These diabetic foot infections are correlated with poor clinical consequences for the patient and most expenses for both the patient and the health care system. Patients with DFIs have a fifty times accelerated risk of hospitalization and one hundred fifty times elevated risk of lower extremity amputation compared with patients with diabetes and no foot infection. Among patients with DFIs, five percent will undergo a major amputation and twenty thirty percent a minor amputation, with the availability of peripheral arterial disease (PAD) highly elevating amputation risk [2-5]. DFU notifies to a cover in the continuity of the skin epithelium enclosing its full thickness or beyond, distal to the ankle joints, in a people living with DM [6,7]. DFU is one of the major health challenges that can rupture the QOL, lengthen hospitalization and entails more cost to the patient. Diabetic foot disease outcome fifteen percent of the diabetic patients and person with diabetes are fifteen times further probably to undergo lower extremity amputation than their non-diabetic counterpart [8-10]. The challenge and features of diabetic foot are infection, ulceration, or gangrene. Neuropathy, poor circulation, and vulnerability to infection are the three major contributors to the development of diabetic foot; which when available, foot abnormalities or mild trauma can readily influence to ulceration and infection [11, 12].

Ulceration is the most common precursor of amputation and has been distinguished as a component in greater than 2/3 of lower-limb amputations. The availability or absence of infection and/or ischemia, footwear and pressure relief, and overall glycemic control lead the healing of ulcers. The depth of an ulcer is other significant factor that influences the consequence of DFUs [13]. Wounds on the feet, known as DFUs, are a major complication of diabetes. DFUs can become exposed, influencing to amputation of the foot or lower limb [14]. Limb amputation has a major impact on the individual, not solely in distorting body image, but also with respective to loss of productivity, elevating dependency, and costs of managing foot ulcers if patients necessitates inpatient care [15,16]. Lower limb amputation in diabetic patients is correlated with important excess mortality. Foot ulceration is also believed to be correlated with enhanced deaths due to related cardiovascular disease. Furthermore, patients with foot ulceration frequently have developed diabetes complications [17- 19]. 15% of those with diabetes will advance at least one DFU during their lifetime [20]. Foot challenges responsible for up to fifteen percent of healthcare resources in developed countries and 40% in developing countries. Among Ethiopian diabetic patients foot ulcer is a major health challenge. Foot ulcer correlated with sepsis sequences in twelve percent of death. Low follow-up and poor glycemic control are preponderance contributing factors. Understanding of the influential factors of foot ulcer in diabetics will enable great risk patients to be recognized early [21-25].

The main risk factors for DFUs involve sensory neuropathy, lower limb ischemia, and trauma [26]. Risk factors for ulceration are specific or systemic contributions such as uncontrolled hyperglycemia, duration of diabetes, peripheral vascular disease, blindness or visual loss, chronic renal disease, advanced age and local issues such as peripheral neuropathy, structural foot deformity, trauma and incorrectly suited shoes, callus, history of prior ulcer amputation, delayed elevated pressures, limited joint mobility [20,21,24]. The grades of the University of Texas (UT) system are as follows: grade zero (pre- or post-ulcerative site that has cured), grade one (superficial wound not involving tendon, capsule, or bone), grade two (wound penetrating to tendon or capsule), and grade three (wound penetrating bone or joint). Within each wound grade there are 4 stages: clean wounds (stage A), non-ischemic infected wounds (stage B), ischemic noninfected wounds (stage C), and ischemic infected wounds (stage D) [15]. DFUs can be medically categorized in several ways but all of them define the ulcer in terms of its depth and the availability of osteomyelitis or gangrene. As an example, the categorization according to Wagner’s system is depending on the following grades: grade zero (no ulcer in a foot with a high-pitfall factor of complication); grade one (partial/full thickness ulcer); grade two (deep ulcer, penetrating down to ligaments and muscle, but no bone involvement); grade three (deep ulcer with cellulitis or abscess formation); grade four (localized gangrene); and grade five (extensive whole foot gangrene). The classification of diabetic foot ulcers is significant as it perhaps facilitate the choice of suitable dressing based on the wound type and on its phase [27- 30] (Figure 1).

Pathophysiology

The most common contributing factors in creating DFU are neuropathy, peripheral artery disease (PAD), abnormality and minor trauma. Additionally contributing factors are necrosis, gangrene, infection, PAD, advancing age of the patient and other co-morbidities such as end ESRD, and heart failure. The DFU patients are ordinarily older males with a history of delayed DM combined with poor health situation. They ordinarily based on assistance of other to work their daily activities. The average age of these patients is sixty-five years and they are ordinarily presented with the disease for at least ten years. The majority of them has a history of uncontrolled diabetes additionally elevated degree of HbA1c, and in 1/3 of the cases other co morbidities are available. Neuropathy sequences in insensitivity and occasionally causes abnormalities in the foot. In these patients, even a minor trauma perhaps influences to a chronic ulcer. Additionally, the persistent walking on the influenced foot, which is insensitive to pressure sense, changes the healing procedure. In the availability of peripheral vascular disease (PVD), the wound becomes ischemic and a non-healing ulcer advance. In patients with neuro ischemic ulcer, unfortunately, the classic signs of infection such as pain, warmth and tenderness are masked. Decrease in pain and tenderness is owing to neuropathy and the warmth and redness declines indispensably because of ischemia. These alters perhaps confuse the physician and sequences in misdiagnosing for wound infection [31-33].

Diagnostic criteria

In recent clinical practices, the evaluation of DFU comprises of several important works in early diagnosis, keeping track of advancement and number of lengthy actions received in the management and treatment of DFU for each case: 1) the medical history of the patient is evaluated; 2) a wound or diabetic foot specialist examines the DFU thoroughly; 3) additional tests like CT scans, MRI, X-Ray perhaps helpful to support advance a management plan. The patients with DFU specifically have a challenge of a swollen leg, although it can be itchy and painful based on each case. Ordinarily, the DFUs have aberrant structures and unusual outer boundaries. The visual appearance of DFU and its enveloping skin based upon the several stages i.e. redness, callus formation, blisters, and significant tissues types like granulation, slough, and bleeding, scaly skin. Thereby, the ulcer evaluation with the support of computer vision algorithms would be depending on the exact assessment of these visual signs as color descriptors and texture features [34].

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Treatment

The objectives of management are: (1) to create and maintain a plantigrade, stable foot; (2) to heal an ulcerated wound; (3) to heal fractures; (4) to suppress abnormalities. The initial goals of treatment for DFU are to acquire wound closure as expeditiously as possible [35]. Not all diabetic foots are preventable, but proper preventive measures can dramatically minimize their occurrences. Managing a DFI necessitates correct wound care and proper antibiotic therapy. Multiple factors involving assessment of the wound, its categorization, and the require for debridement involving sharp surgical, mechanical, chemical etc., have to be received onto consideration before proceeding with the correct selection of topical regimen [36]. The preventive measures and treatment of diabetic complications consists of the following: Lifestyle modification; BP control (the best indicator of glucose control over a period of time is HbA1C level. This test measures the average BS concentration over a ninety-d span of the average RBC in peripheral circulation. The higher the HbA1C level, the greater glycosylation of Hg in RBCs will happen. Surveys have reveal that BG levels > 11.1 mmol/L (equivalent to > 310mg/mL or an HbA1C level of > 12) is correlated with decreased neutrophil work, involving leukocyte chemotaxis [37]); lipid management; glycemic control; smoking cessation, BP control (ACE inhibitors or angiotensin receptor blockers were recommended for all patients with HTN, previous cardiovascular disease, and/or microalbuminuria, unless there was known renovascular disease. Beta-blockers were recommended for all patients with existing cardiovascular disease or in whom BP was still uncontrolled despite ACE inhibition.

Education

Patients’ training plays an indispensable function in suppression of DFU. The goal of training is to motivate the patient and create adequate skills in order to maximize the use of preventive methods. It is also crucial to make sure that the patient has understood all the instructions. Recently, a broad range and combinations of patient educational interventions have been evaluated for the prevention of DFU that different from brief education to intensive education involving observation and hands on teaching. Patients with DFU should be educated about risk factors and the necessity of foot care, involving require for self-inspection, monitoring foot temperature, proper daily foot hygiene, usage of correct footwear, and blood sugar control. Debridement: Debridement includes remove of dead, injured, or exposed tissue, which improves the healing potential of the remaining healthy tissues. Based on the wound tissue type, other debridement techniques are recommended: (1) Surgical debridement or sharp debridement-recommended for necrotic and exposed wounds. The terms surgical debridement and sharp debridement are frequently used intercalate, certain clinicians refer to surgical debridement as being settled in an operating room, whereas sharp debridement is settled in a clinic setting. Sharp surgical debridement is the most effective and quickest method of debridement; (2) Autolytic debridement-a selective procedure in which the necrotic tissue is liquefied. A wound filled in with an occlusive dressing permits concentration of tissue fluids containing macrophages, neutrophils, and enzymes, which remove bacteria and digest necrotic tissues. This is reached by a moist wound curing environment. Autolytic debridement is not advisable for the treatment of exposed pressure ulcers; (3) Mechanical debridement-includes remove of unhealthy tissue using a dressing, which is altered regularly by wound irrigation (pressure: 4-15psi), without injuring healthy/new tissues. Scrubbing the wound aids in remove of exudates and devitalized tissues, however this influences to bleeding as well as pain resulting from wound trauma. This technique is used in the treatment of surgical wounds and venous leg ulcers. The shortcomings of the method are that it is time consuming and high cost; (4) enzymatic debridement-a method of debriding devitalized tissue by topical enzymes such as collagenase, fibrinolysin, or papain. Recommended for sloughy, exposed, necrotic wounds where surgical debridement is contraindicated; and (5) Maggot debridement-a procedure in which maggots or fly larva that are accelerated in a sterile environment are used. The most frequently used fly is Lucilia sericata, which is used for human wound management when conventional managements fail. Maggots are placed on the wound pursued by wrapping with 2ndry dressing. The larvae feed on the necrotic (dead) tissue and bacteria available at the wound site and produce antimicrobial enzymes, which support in the wound healing procedure [38-40].

Wound dressings for diabetic foot ulcer treatment

Natural skin is thought-out the perfect wound dressing and thereupon an ideal wound dressing should try to duplicate its properties. Historically, wound dressings were primary thoughtout to play only a passive and protective function in the healing procedure. Although in current decades wound management has been revolutionized by the innovator that moist dressings can assist wounds heal quicker. In addition, a moist wound environment is also an indispensable factor to initiate the proliferation and migration of fibroblasts and keratinocytes as well as to accelerate collagen generation, influencing to decreased scar formation [41-43].

Antibiotic selection

The principle of antibiotic management is depending on evidence provided by reports on bacteriological culture and sensitivity from other centers worldwide. Usage of anti-infective/ antibiotics must be guided by proper cultures. Improper usage of antibiotics could influence to resistance and adverse drug reactions. Oral and parenteral antibiotics are prescribed for mild soft tissue infections and moderate to severe infections, respectively [44].

Antibacterial agents

Used only or in combination for each class except dry necrotic wounds. Topical antibiotics have wide spectrum antibacterial coverage which lasts for twelve hour and are less toxic. Metronidazole gel has excellent anaerobic coverage and supports in maintaining a moist wound healing environment. By weight, gels are highly liquid, yet they behave like solids owing to a 3-dimensional cross-linked network within the liquid. It is the crosslinking within the fluid that bestows a gel its structure (hardness) and contributes to its adhesion [45]. Off-loading: Total contact casts and therapeutic shoes are appropriate alternatives for remove of pressure from the wound. The further effective offloading technique for the treatment of neuropathic DFU is total contact casts (TCC). TCC is minimally padded and molded carefully to the shape of the foot with a heel for walking.

Surgery

Diabetic foot surgery plays a crucial function in the suppression and treatment of DFU and has been on elevate over the past two decades. Although surgical interventions for patients with DFU are not without peril, the selective correction of persistent foot ulcers can improve consequences. Vascular foot surgery such as bypass grafts from femoral to pedal arteries and peripheral angioplasty to ameliorate blood flow for an ischemic foot have been currently advanced [46-48].

Advanced dressing

A major breakthrough for DFU treatment over the last decades was the observation of novel dressings. Ideally, dressings should confer moisture balance, protease sequestration, growth factors enliven, antimicrobial activity, O2 permeability, and the capacity to accelerate autolytic debridement that facilitates the secretion of granulation tissues and the re-epithelialization procedure. Furthermore, it should have a delayed time of action, high efficiency, and improved sustained drug release in the case of medicated therapies [49].

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Conclusion

Diabetic foot disease outcome fifteen percent of the diabetic patients and person with diabetes are fifteen times further probably to undergo lower extremity amputation than their non-diabetic counterpart. Risk factors for ulceration are specific or systemic contributions such as uncontrolled hyperglycemia, duration of diabetes, peripheral vascular disease, blindness or visual loss, chronic renal disease, advanced age and local issues such as peripheral neuropathy, structural foot deformity, trauma and incorrectly suited shoes, callus, history of prior ulcer amputation, delayed elevated pressures, limited joint mobility. The preventive measures and treatment of diabetic complications consists of the following: Lifestyle modification; BP control (the best indicator of glucose control over a period of time is HbA1C level. This test measures the average BS concentration over a ninety-d span of the average RBC in peripheral circulation. Historically, wound dressings were primarily considered to play solely a passive and protective function in the healing procedure.

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Clinical Application of Reduced-Carbohydrate Diets for Type 1 Diabetes Management: A Retrospective Case Series

Authored by Jessica Turton

Abstract

Background: The aim of this study was to explore the clinical application of reduced-carbohydrate (RC) diets for type 1 diabetes (T1D) management at a community-based diabetes centre.

Methods: To be included in this retrospective case series, adults with T1D must have attended at least two appointments with a Credentialled Diabetes Educator and Accredited Practising Dietitian (CDE/APD) for advice regarding: (a) advanced carbohydrate counting, (b) carbohydrate reduction, and/or (b) low-carbohydrate diet support. Data regarding specific dietary recommendations and clinical outcomes was extracted from patient records stored at the center. A semi-structured interview with the CDE/APD was conducted to collect additional information about the design and delivery of the RC diets. Thematic analysis was used to identify core components of the RC diets, and descriptive statistics were used to assess pre-post changes in clinical T1D outcomes.

Results: 26 adults with T1D were eligible and included (77% female). The RC diets represented a patient-led approach involving adjustments to energy and macronutrient intakes, glucose self-monitoring, and insulin management. 22/26 participants attended the center seeking low-carbohydrate diet support, and the average carbohydrate prescription was 63g/day (22-253g/day) which translated to a 37% reduction from baseline. HbA1c reduced from 9.0% (75mmol/mol) to 7.0% (53mmol/mol) (-5.7 to -0.1%), with an average follow-up of 55weeks (n=8). Estimated A1c reduced from 7.1% (54mmol/mol) to 6.3% (45mmol/mol) (-2.9 to+0.6%) over 21 weeks (n=19). Mean total daily insulin reduced from 44 to 31 U/day (-46 to+6 U/day), with an average follow-up of 17 weeks (n=15).

Conclusions: This study provides real-world insights into the clinical application of RC diets in the management of adults with T1D at a community-based diabetes centre. Prospective clinical trials are needed to conclusively determine the effects of RC diets on clinical T1D outcomes.

Keywords: Type 1 diabetes; Glycaemic control; Reduced carbohydrate diets; Retrospective case series.

Abbreviations: TRC: Reduced Carbohydrate; HbA1c: Hemoglobin A1c; TEI: Total Energy Intake; LC: Low-Carbohydrate; CDE: Credentialed Diabetes Educator; APD: Accredited Practicing Dietitian; EA1c: Estimated A1c; CGM: Continuous Blood Glucose Monitoring; FGM: Flash Blood Glucose Monitoring; TDI: Total Daily Insulin; BMI: Body Mass Index; ISF: Insulin Sensitivity Factor(s); VLCKD: Very Low-Carbohydrate Ketogenic; LCD: Low-Carbohydrate Diet; MCD: Moderate-Carbohydrate Diet; kcal: Kilocalories; Kilojoules

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Introduction

Type 1 Diabetes (T1D) is an autoimmune condition characterized by the destruction of pancreatic beta cells and absolute insulin deficiency. Glycemic control is the strongest predictor of diabetes-related complications with a hemoglobin A1c (HbA1c) level ≤7.0% (53mmol/mol) considered the primary target in diabetes management [1-3]. Standard treatment methods include insulin therapy, blood glucose monitoring and carbohydrate counting [4].However, dietary advice for people with T1D remains consistent with national recommendations for the general population, which is a high-carbohydrate diet (45-65% total energy intake [TEI]) [4,5]. Data from T1D registries (2010-2013) across nineteen countries in Australasia, Europe, and North America (n=324,501) reported that 84% of patients’ HbA1c was >7.0% (53 mmol/mol) [6]. Further, data from the 2006 Australian National Diabetes Audit-Australian Quality Self-Management Audit (n=3,930) reported a mean HbA1c of 8.4% (68 mmol/mol) amongst T1D patients [7]. It appears that current T1D management strategies are lacking in effect and dietary approaches specifically aimed at improving glycaemic control in T1D should be explored.

It is well established that dietary carbohydrates impose the greatest impact on post-prandial blood glucose levels. Lowcarbohydrate (LC) diets providing <130 grams of carbohydrate per day (g/day) or <26% TEI have recently been acknowledged by governing health bodies as an effective approach for type 2 diabetes management and a research priority area for T1D [8-10]. Despite very LC diets being the original method to treat diabetes prior to the discovery of insulin in the early 1900’s [11] a 2018 systematic review of diet interventions containing <45% TEI from carbohydrates highlighted a sheer lack of both observational and interventional studies investigating the feasibility and effect(s) of lower-carbohydrate diets in adults with T1D [12]. Nine studies were identified of which two were randomized controlled trials with small sample sizes (n=10), four were pre-post intervention studies, two were retrospective case series, and one was a case report [12]. Nevertheless, the collective evidence demonstrated promising results, including improvements in HbA1c, total daily insulin and frequency of severe hypoglycaemia in T1D adults [12]. A recent observational study of individuals with T1D (n=316) showed that exceptional HbA1c levels of ~5.7% (39mmol/mol) can be obtained with adherence to a very LC diet (~35g/day) [13]. Until prospective clinical trials with sufficient sample sizes are conducted to conclusively determine the effect(s) of RC diets in adults with T1D, small-scale studies exploring the use and feasibility of RC diets in real-world clinical practice settings are useful to help practitioners better understand the role of RC diets for T1D management [9,12].

Therefore, a retrospective case series of adults with T1D who have been actively managed with a RC diet delivered by a Credentialed Diabetes Educator (CDE) and Accredited Practising Dietitian (APD) (hereon referred to as CDE/APD) at a communitybased diabetes centre was conducted. The objectives of this study were to 1) describe the core components of RC diets used in realworld T1D management; and 2) determine (pre-post) change(s) in clinical T1D management outcomes for patients choosing to follow a RC diet, including HbA1c, glycaemic variability, total daily insulin use, and fasting blood glucose levels. This is a hypothesisgenerating study sought to explore the feasibility and effects of prescribing a RC diet for the management of T1D.

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Materials And Methods

Study design

This case series was a retrospective chart review of adults previously diagnosed with T1D who had chosen to follow a RC diet delivered by the CDE/APD between January 2017 and November 2019 at a community-based diabetes centre in Stirling, Western Australia. The study protocol was registered and included in the Australian New Zealand Clinical Trials Registry and allocated a registration number of ACTRN12619001538134 (http://www. ANZCTR.org.au/ ACTRN12619001538134.aspx). Ethical approval was obtained from the University of Sydney’s Human Research Ethics Committee (project no.: 2019/668).

Participants

An email was sent out to existing patients at the centre inviting them to complete an online survey and provide informed consent to share their data with researchers and be assessed for eligibility to participate in this retrospective analysis. Ethical approval was obtained for a single email invitation, and no further attempts were made to contact non-responders for consent to share their data. One researcher (JT) assessed the consenting patient records for study eligibility and to collect relevant data for analysis during a 1-week period in November2019. To be included, patients must have attended at least two appointments (≥2 weeks apart) with the CDE/APD for advice regarding a RC diet for the management of T1D and been between 18-60 years of age at the time of their first appointment. A RC diet was defined as any approach that involved; (a) advanced carbohydrate counting, (b) carbohydrate reduction, and/or (b) LC diet support. It was assumed that advanced carbohydrate counting led to a natural reduction in carbohydrate intake irrespective of any specific prescription due to greater participant awareness of the carbohydrate content in various foods. Participants must have also had at least one clinical T1D outcome measured on at least two time-points (≥2 weeks apart) that was recorded in their patient record by the CDE/APD. As the diabetes centre is a private billing allied health clinic, all participants were responsible for scheduling consultations with the CDE/APD on an as-needed basis. Researchers did not contact participants for any missing data, and only data in patient records stored at the diabetes centre or provided by participants in the online survey was assessed. All eligible participants were included in the analysis.

Study outcomes

Core components of the RC diet: Content analysis was performed on the core dietary and delivery components of the RC diets, including the prescribed amounts and types of dietary carbohydrates, proteins, and fats, in addition to total energy. Reported details on the dietary delivery method(s) and any adjustment(s) made to glucose self-monitoring or insulin management were also analysed.

Clinical outcomes: The primary clinical T1D management outcomes were HbA1c and estimated A1c (EA1c), calculated as (mean glucose mmol/L + 2.59)/1.59 using the data recorded by a continuous [CGM] or flash [FGM] blood glucose monitoring device across 7-14 days [14]. EA1c has been used to assess glycaemic control in previous studies [15,16] rather than actual HbA1c, likely due to reduced need for blood collections and clinic visits [14]. Secondary clinical outcomes were time spent in blood glucose target ranges and low glucose events (<3.9mmol/L) recorded by a CGM or FGM device across 7-14 days. Additional clinical outcomes were total daily insulin (TDI) and fasting glucose levels, as measured by participants using their own devices. For each outcome, the earliest and last recorded value reported in patient records was considered the ‘pre’ and ‘post’ value, respectively.

Data collection

Patient records: Data were collected from patient records stored at the centre. Patient records included clinical notes and medical correspondence written by the CDE/APD. Specialist letters, pathology reports, and blood glucose monitoring reports were also assessed, if available. Patient records were assessed by one researcher (JT) to extract the following data for each participant: Body Mass Index (BMI) as assessed by the CDE/APD; use of CGM/FGM device; use of Insulin Sensitivity Factors (ISF) or insulin pump; use of carbohydrate counting; dietary intake at baseline as assessed by the CDE/APD (including macronutrient and energy intakes); details on the prescribed LC dietary approach; details on any specific delivery techniques used; details on any insulin and blood glucose monitoring adjustments; length of follow-up (i.e., time from first appointment to last appointment); and, all recorded clinical T1D outcome values. Due to the retrospective nature of this study, it was anticipated that not all participants would have complete data available in their patient records. Data analysis was completed on available data with no imputations made for missing data.

Participant survey: Participants completed a short online questionnaire at the time of consent to provide demographic data and general health information that may not have been available from their patient records. This data included: date of birth (for age calculation); ethnicity; religion; gender; highest level of education completed; height; body weight; year of type 1 diabetes diagnosis; and co-morbidities.

Practitioner interview: One researcher (JT) interviewed the centre’s CDE/APD and Chief Executive Officer (C.E.O.) to collect and clarify information on the RC diets delivered, in addition to information about the non-clinical social, community and educational services offered at the centre. The interview was semi-structured, and questions are included in the supplementary files (Supplementary Table 8). Answers were recorded verbatim.

Data synthesis & analysis: Thematic analysis was used to assess the dietary prescription details extracted from patient records and the semi-structured interview to identify core components of the RC diets. All investigators reviewed the initial themes identified in the collaborative data until consensus was reached on the core components and general methodologies used amongst included participants. Clinical T1D management outcome values were presented in tabular format for each participant (case-by-case) and pre-post means and mean differences were calculated using descriptive statistics. Mean changes in HbA1c, EA1c, time in target range, low glucose events, TDI and fasting glucose levels were compared using the first recorded value (pre) and the last recorded value (post) available for each participant.

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Results

Participants and characteristics

† Survey data was used for these participants and may not reflect true baseline BMI at time of initial appointment.

§ Refers to category: Black / African / Caribbean / Black British.

‡ 1, University or college degree (related to health, medical or nutritional sciences); 2, University or college degree (unrelated to health, medical or nutritional sciences); 3, University or college credit (no degree); 4, Trade/technical or vocational training; 5, High school (or equivalent secondary level).

NR: Not Reported; y: Years; m: Months; Coeliac: Coeliac disease; CGM: Continuous Blood Glucose Monitoring Device; FGM: Flash Blood Glucose Monitoring Device; ISF: Insulin Sensitivity Factor(s); Pump: Insulin Pump; Carb: Carbohydrate; S: Sometimes; G: Grams

Email invitations were sent out to all existing patients at the centre (n=240). Of these, n=38 completed the online survey and provided informed consent to share their patient records with the researchers for assessment. Twenty-six participants were eligible and included in the study, while n=12 were not eligible with reasons provided (Supplementary Table 10). Baseline participant characteristics of included participants (n=26) are presented in Table 1. 77% (20/26) of participants were female with a mean age of 35 years (18-58years). The average duration of T1D was 12.4 years (2 months to 42 years), with 54% (14/26) of participants having lived with T1D for 10 years or longer. 65% (17/26) of participants were overweight or obese and 31% (8/26) were of normal weight according to BMI [17].

Baseline dietary intake

Baseline energy and macronutrient intake data is presented in Supplementary Table 1. Of the 16 participants (16/26) who reported to be following a particular diet at baseline; 75% reported to be following a LC diet, of which one was a vegetarian LC diet; and 19% were following a vegan diet. Nineteen participants (19/26) had baseline carbohydrate intake data in g/day available, with a mean of 100g/day, ranging from 20-283 g/day. According to the suggested definitions by Feinman et al. [18], 37% of participants were following a very LC ketogenic diet (VLCKD) (20-50g/day),26% were following a LC diet (LCD) (<130g/day), and 32% were following a moderate-carbohydrate diet (MCD) (130-225g/day). Thirteen participants (13/26) had baseline energy intake data, with a mean TEI of 1,662 kcal/day 250 (6,848kJ/day), ranging from 728-2,546kcal/day (3,000-10,489kJ/day).

Core components of RC diets

Participants received personalised advice and support regarding a RC diet by the centre’s CDE/APD at various timepoints between January 2017 and November 2019, and the average follow-up duration was 41 weeks (2-127 weeks) (Table 2). The RC diet represented a patient-led approach that included advice and education on the topics of dietary carbohydrates, proteins, and fats; glucose self-monitoring; and insulin management (Table 2 & Supplementary Table 9). The CDE/APD reported that the majority of patients who attend the diabetes centre are actively seeking LC diet support. Actual data from patient records indicated that 85% of participants (22/26) were seeking LC diet support. Prior to implementing any carbohydrate reduction, participants were first educated on how to dose insulin for their absolute carbohydrate intake, including proper use of insulin to carbohydrate ratios and correction factors. If participants were not properly counting carbohydrates in all foods and fluids, then advanced carbohydrate counting education was provided to ensure all digestible carbohydrates were accounted for including carbohydrates in non-starchy vegetables, low-sugar fruits, nuts, and seeds. The CDE/APD typically referred patients to an online nutrient database (Calorie King (19)), and the centre offered a carbohydrate counting course. Data extracted from patient records indicated that 65% of participants (17/26) required advanced carbohydrate counting education (Table 2).

F: Female; M: Male; Appts: Appointments; FU: Follow Up Duration; w: Weeks; TEI: Total Energy Intake; kcal: Kilocalories; NR: Not Reported; Carb; Total Digestible Carbohydrates; g: Grams; VLCKD: Very Low-Carbohydrate Ketogenic Diet; LCD: Low-Carbohydrate Diet; MCD: Moderate- Carbohydrate Diet; HCD: High-Carbohydrate Diet; SFA: Saturated Fatty Acids; LCS: Low-Carbohydrate Diet Support; ACC: Advanced Carbohydrate Counting; Y: Yes

The CDE/APD reported that the initial recommended change in carbohydrates was generally a reduction of ~50% from baseline intake, except for those already following a VLCKD. Actual prescriptions were reported in g/day and/or TEI for 77% of participants (20/26) (Table 2). The average carbohydrate prescription of the RC diets was 63g/day (or 11% TEI) ranging from 22-253g/day (or 5-26% TEI), which translated to a 37% reduction from baseline (Table 2 & Supplementary Table 1). 68% of prescriptions were VLCKD (20-50g/day), 16% were LCD (<130g/day), and 11% were MCD (130-225g/day) [18] (Table 2). Participants were routinely provided with a CGM or FGM (if they were not already using one) to use over the initial 1-2 weeks. This was to assist them in identifying the required insulin adjustments to prevent hypoglycaemia in expectation that rapid acting insulin requirements would immediately reduce with carbohydrate reduction. Participants were advised to return for a follow-up within 2-4weeks of the initial appointment to receive further support on titrating insulin dosages in expectation that background/basal insulin requirements would also reduce with continued adherence to the RC diet. The carbohydrate prescription may have continued to be adjusted depending on participants’ goals, preferences, motivations, and outcome progress. Total energy prescriptions were calculated using the Schofield equation to help participants meet their energy demands on a RC diet [20]. Sixteen participants (16/26) had total energy prescriptions recorded in their patient records (Table 2). Of these, the average prescription was 2,085 kcal/day (8,590 kJ/ day), ranging from 1,408-3,106kcal (5,800-12,795kJ/day), which reflected a 25% increase from baseline (Table 2 & Supplementary Table 1). Dietary protein prescriptions were based on 20- 25% of participants’ total energy prescription, and protei n options and portion sizes were discussed with participants in terms of real food quantities (e.g., 100g cooked meat). Seventeen participants (17/26) had actual protein prescriptions recorded and of these, the average was 113g/day (or 23% TEI), ranging from 70-175g/day (or 14-32% TEI) (Table 2). Participants were recommended to meet their remaining energy requirements with a variety of dietary fats, and fat options and portion sizes were discussed. The types of foods recommended included minimally processed meat, fish, eggs, full-fat dairy, non-starchy vegetables, low-sugar fruits, nuts, seeds, avocado, olive oil, butter, and nut butters. Fifteen participants (15/26) had actual fat prescriptions recorded, with an average prescription of 153 g/day (or 64% TEI), ranging from 80-250g/day (or 45-75% TEI) (Table 2). Participants were given practical advice on structuring meals according to their macronutrient and energy requirements. The CDE/APD provided education to facilitate adherence to the RC diets. Topics included: effect(s) of carbohydrates on blood glucose levels and insulin requirements, role(s) of dietary fats as an energy source and in weight management/general health, effect(s) of increasing dietary fats on cholesterol levels and risk of cardiovascular disease, hypoglycaemia treatment, and ketone monitoring. The CDE/APD reported that participants following the RC diets eventually required education and advice on how to factor in protein when calculating mealtime insulin dosages (known as ‘protein bolusing’). Courses, meet-up events, and peer support/learning opportunities were also offered to participants by the community-based diabetes centre to complement the clinical services with the CDE/APD. For example, the centre has a Facebook group with 700 members and 3000 engagements per month.

Clinical outcomes

HbA1c:Eight participants had pre-post values for HbA1c that were either self-reported usual care measurements recorded by the CDE/APD (n=4), usual care measurements taken from pathology reports or specialist correspondence (n=1), a combination of both (n=2), or measured at the diabetes centre (n=1) (Supplementary Table 2). Mean HbA1c reduced from 9.0% (75mmol/mol) to 7.0% (53mmol/mol) (-2.2%; -5.7 to -0.1%), with an average follow-up duration of 55 weeks (10-114 weeks). Four (4/8) participants had a post HbA1c value within the T1D management target range of ≤7.0% (53mmol/mol), while only one (1/8) participant had a prevalue within this target. Two participants with the highest starting HbA1c values experienced the greatest reductions at follow-up (13.4 to 7.7%; -5.7% and 10.6 to 5.3%; -5.3%). No participants had an increase in HbA1c reported.

Estimated A1c:Nineteen participants had pre- and postvalues for EA1c measured using an FGM (n=14, FreeStyle Libre™), a CGM (n=1, Dexcom) or both (n=1, Libre + Dexcom; n=3, Libre + Medtronic) (Figure 1 & Supplementary Table 3). Of these participants, eight (8/19) had pre-post values over a duration of 2-10 weeks, of which five experienced a reduction, two experienced no changes, and one experienced an increase, with an average absolute change in EA1c of -0.3% (-1.6 to +0.6%). Six participants (6/19) had pre-postvalues over a duration of 10-25weeks, of which five experienced a reduction and one no change, with an average absolute change of -1.1% (-2.9 to 0.0%); and five participants (5/19) had pre-post values for durations greater than 25weeks of which all experienced a reduction and average absolute change of -1.0% (-2.4 to -0.2%). Across all 19 participants, the average follow-up for measuring changes in EA1c was 21 weeks (2-55weeks), with an overall mean pre-post change of -0.7% (-2.9 to+0.6%), with mean EA1c values reducing from 7.1% (54mmol/mol) (4.6 to 11.4%) to 6.3% (45mmol/mol) (4.6 to 9.0%).

Time in target range: Twelve participants had pre-post values for time in target range that were measured using a FGM (n=7), CGM (n=2) or both (n=3) (Supplementary Table 4). Three participants (3/12) used non-standard blood glucose target ranges within 3.9-8.5mmol/L. Of these, all participants (3/3) experienced an increase in time in target, from an average of 58% to 65% (+7%; +3 to +13%). Nine participants (9/12) used the standard target range of 3.9-10.0 mmol/L and their overall mean time in target increased from 58% to 76% (+18%; -8 to +46%), with an average follow-up duration of 19 weeks (4-52weeks).

Low glucose events: Fourteen participants had pre-post values for low glucose events (<3.9 mmol/L) measured over a 2-week period using an FGM (n=10), CGM (n=1) or both (n=3) (Supplementary Table 5). The mean frequency increased by one event following an average duration of 17 weeks, with 50% (7/14) experiencing a decrease in low glucose events ranging from -1 to -13 events over a 2-week period. Ten participants (10/14) had pre-post minute data available (Supplementary Table 5). Of these, the mean minutes spent in the low glucose range (<3.9 mmol/L) for each event reduced from 120 to 94 over a 2-week period.

Total daily insulin: Fifteen participants had pre-post values for TDI that were either self-reported measurements recorded by the CDE/APD (n=6), taken from CGM or FGM reports (n=4), a combination of both (n=4), or taken from a combination of an insulin pump summary report and a CGM report (n=1) (Supplementary Table 6). Mean TDI reduced by 30% from 44 U/ day to 31 U/day (-13 U/day; -46 to +6 U/day), with an average follow-up duration of 17 weeks (2-65weeks). Five participants (5/15) reported reductions in TDI of >20 U/day, ranging from -24 to -46 U/day. The participant who experienced the greatest reduction in TDI (-46 U/day) had the highest reported pre-value (91 U/day), with a follow-up duration of 55weeks.

Fasting blood glucose: Five participants self-reported pre-post fasting blood glucose values at least two weeks apart (Supplementary Table 7). All five reported lower post-values with a mean reduction from 12.5mmol/L to 9.3mmol/L (-8.5 to -0.2mmol/L) following an average duration of 29weeks.

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Discussion

This retrospective case series explored the practical application and effect(s) of RC diets for T1D patients at a community-based diabetes centre. Professionally supported RC diets appear to be a feasible management option for adults with T1D and may lead to maintenance or improvements in clinical outcomes in some patients. The RC diets described in this analysis were predominantly patient-led approaches involving individuals with an a priori interest in LCD who were actively seeking professional support. In addition to dietary adjustments, the RC diets involved delivery of diet-related education and changes to blood glucose self-monitoring and insulin management practices. The main clinical findings were that RC diets led to reductions in HbA1c and EA1c, increased time spent in target ranges, reduced time spent in the hypoglycaemic range, and less insulin being required overall. However, prospective clinical trials are needed to confirm these findings and conclusively determine the effects of RC diets on clinical outcomes in T1D management.

This study provides real-world insights into the use of professionally supported RC diets, including VLCKD and LCD [18] in the management of adults with T1D. It has been previously reported that individuals with T1D following RC diets experience difficulties in seeking professional support. An online survey of 316 people with T1D self-engaging in a VLCKD reported high levels of overall health and satisfaction with their diabetes management but not with their professional diabetes care team, with only 49% of respondents agreeing or strongly agreeing that their diabetes care providers were supportive of their dietary choices [13]. In the current study, 85% of participants presented to the community-based diabetes centre specifically seeking support with a LC dietary approach for T1D management. Given the sheer dearth of available evidence investigating lowercarbohydrate diets in T1D, the present analysis is a useful contribution to the evidence base on this topic and may assist healthcare professionals in better supporting T1D patients who choose to follow a RC dietary approach.

This study highlights a patient population that is particularly interested in LCD for the management of their T1D. Although the RC diet involved a reduction in total carbohydrates, the mean carbohydrate intake at baseline was already low (100g/day or 24%TEI) relative to the estimated population average. Data from a previous study which analysed the macronutrient profiles of adults with T1D from the Australian Health Survey 2011- 13 reported that the average carbohydrate intake was 213g/ day (45%E) [21]. Nevertheless, the RC diets involved additional reductions in dietary carbohydrates alongside other dietary manipulations which may have been uniquely beneficial. The CDE/ APD recommended that dietary fats make up ‘remaining energy requirements’ after carbohydrates and proteins were accounted for. The mean dietary fat prescription was 153g/day (or 64%TEI) which was a clinically significant increase of 94% from a baseline fat intake of 79g/day (or 41%TEI). This is consistent with dietary fat prescriptions identified in previous LCD intervention studies of type 2 diabetes patients which were ‘unrestricted’ in fat (n=9 studies) or ‘high fat’ diets (>35%E) (n=9 studies) [22]. Dietary fat provides an important source of energy and fat-soluble nutrients for individuals on a RC diet, and substitution of carbohydrates with fats results in a lower glycaemic load [23,24]. With that said, minimally processed fats from meat, fish, eggs, full-fat dairy, nuts, seeds, avocado, olive oil, and butter tended to be the recommended sources of fat in the collective studies [22]. These whole foods contain a natural balance of monounsaturated, polyunsaturated, and saturated fatty acids [24]. On the other hand, ultra-processed oils containing excessively high amounts of omega-6 polyunsaturated fatty acids have been identified as drivers for obesity and cardiovascular disease (CVD) [25, 26]. Although HbA1c is a primary determinant of CVD risk in diabetes, future prospective studies investigating RC diets for T1D should measure an array of CVD risk factors, including lipid changes, to help us better understand the long-term efficacy of higher-fat LCDs in T1D.

In the present analysis, more participants had reliable data for EA1c than HbA1c given that CGM and FGM devices were recommended by the CDE/APD, and reports were available to validate the results. The 0.7% absolute reduction in EA1c shown in this study (7.1% to 6.3%) is consistent with findings from previous research in T1D. Nielsen et al. 2012 [27] showed in a 4-year intervention study (n=48) that a LCD (≤75g/ day) significantly reduced HbA1c by 0.7% (7.6% to 6.9%) in adults with T1D. Additionally, a 12-week randomised controlled trial (n=10) showed that a LCD (~100g/day) decreased HbA1c by 0.7% (7.9% to 7.2%) compared to no change with a diet higher in carbohydrates (~200g/day) [28]. A 0.7% HbA1c reduction is considered clinically relevant for patients with T1D [29], particularly if HbA1c is maintained below the recommended target of 7.0%. A large Swedish study (n=10,000) showed that T1D patients with an HbA1c between 6.5% and 6.9% had a lower risk of developing retinopathy and early kidney disease compared to patients with an HbA1c ≥7.0% [30].

RC diets may be a useful option in T1D for improving or maintaining glycaemic control with less use of insulin overall. The present analysis demonstrated a clinically significant reduction in TDI of -14 U/ day from 44 U/day to 31 U/day across 2-65weeks. Similarly, a previous case-series of 10 adults with T1D reported a reduction in TDI of -17 U/day (47 to 30U/day) across 8-61 months with a VLCKD (30g/day) [31]. Excessive long-term reliance on high doses of insulin may lead to additional complications related to hyperinsulinemia, such as obesity, type 2 diabetes [32] and hypertension [32-34]. In addition, requiring less insulin is also expected to result in significant cost-savings for people affected by T1D and the health system [35]. On the other hand, previous dietary modelling showed that comparedto a traditional highcarbohydrate, low-fat diet, a low-carbohydrate, high-fat diet may be associated with negligible, marginally higher costs ($2.06 per person per week) [36]. Hence, potential insulin cost savings, marginally higher dietary intake costs, and costs associated with changes in health outcomes should be considered collectively in determining the value of a RC diet approach for individuals with T1D.

A commonly cited concern of the use of LC diets in T1D is an increased risk of severe hypoglycaemia. However, the present data showed that the overall time spent within the target blood glucose range of 3.9-10 mmol/L increased by 18% with a RC diet, and minutes per low glucose event (<3.9mmol/L) decreased by 25%. Similarly, a 12-month study of 46 adults who self-reduced carbohydrates to ~162 g/day in combination with flexible insulin therapy reported a reduction of severe hypoglycaemia from 3.7 to 0.2 episodes per year. Nevertheless, it must be acknowledged that any diet or lifestyle change in individuals with T1D may increase the risk of hypoglycaemia in the short-term due to the consequent changes in blood glucose self-monitoring and insulin titrations that are often required. Participants in the current study were encouraged to re-appoint within two weeks of commencing dietary change to review their insulin management with the CDE/APD. Unfortunately, evidence-based guidelines for adjusting pharmaceuticals for patients with T1D wishing to follow RC diets are scant, but referring to practical guides used in type 2 diabetes may be a useful approach for practitioners [37].

This study has several limitations. The retrospective nature of this study meant there were major inconsistencies in the outcomes reported for included participants. To some extent, the available data was limited because the CDE/APD did not write clinical notes intending for them to be assessed by external researchers, and researchers did not contact participants to collect missing data. In addition, limitations in the reporting of the data meant that we were unable to assess adherence to the RC diets prescribed or determine pre-post changes in patient wellbeing, or whether any associations exist between the level of dietary carbohydrate prescribed and changes in T1D management outcomes. However, to our knowledge, the diabetes centre selected for this study is the only T1D centre in Australia actively promoting RC diets as an option for T1D management and considering the major lack of available research on this topic, the present analysis is useful and clinically relevant work. The high risk of selection bias must also be emphasised because most patients attending the centre were actively seeking LCD support, with the majority already following some form of LCD (albeit unsupported). For ethical reasons that only permitted a one-off invitation request, data from non-responders could not be examined and therefore any differences between responders and non-responders could not be determined. Finally, the lack of a control group or control period and the multi-modal nature of our exploratory study design precludes the ability to draw causality between the RC diet or other specific aspects of the approach imposed and the observed changes in clinical T1D outcomes. The authors acknowledge the need for high-quality prospective interventional studies investigating this important research area to better inform clinical practice guidelines.

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Discussion

In summary, this hypothesis-generating study provides realworld insights into the practical application of RC diets in the management of adults living with T1D. Professionally supported RC diets appear to be a feasible option for motivated T1D patients and may lead to maintenance or improvements in clinical outcomes. Prospective clinical trials are needed to conclusively determine the effects of RC diets, including LCD and VLCKD, on clinical outcomes in T1D management.

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Acknowledgements

Thank you to the participants of this study for agreeing to participate and share their data for this research. Thank you to the staff at the community-based diabetes centre in Stirling, Western Australia for assisting with administrative tasks.

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Author Contributions

Jessica Turton: Conceptualization, Methodology, Formal Analysis, Investigation, Writing – Original Draft, Writing – Editing & Review, Visualization, Project Administration. Grant Brinkworth: Conceptualization, Methodology, Writing – Editing & Review, Visualization. Helen Parker: Conceptualization, Methodology, Writing – Editing & Review, Visualization. Amy Rush: Conceptualization, Methodology, Writing – Editing & Review, Resources. Rebecca Johnson: Conceptualization, Methodology, Writing – Editing & Review, Resources. Kieron Rooney: Conceptualization, Methodology, Writing – Editing & Review, Visualization.

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Competing Interests

Ms Rush and Ms Johnson have financial involvements with the community-based diabetes centre where the research was undertaken as an employee and as the C.E.O., respectively. The centre could obtain indirect benefit from this research by receiving information on the effectiveness of their services not normally obtained if not participating in this study. However, no direct financial benefit is expected to be obtained. No other authors have any competing interests to declare.

ID: Participant ID; F: Female; M: Male; TEI: Total Energy Intake; kcal: Kilocalories; NR: Not Reported; Carb: Total Digestible Carbohydrates; g: Grams; class: Classification; VLCKD: Very Low-Carbohydrate Ketogenic Diet; LCD: Low-Carbohydrate Diet; MCD: Moderate- Carbohydrate Diet; HCD: High Carbohydrate Diet; SFA: Saturated Fatty Acids.

F: Female; M: Male; MD: Mean Difference.

F: Female; M: Male; W: Weeks; MD: Mean Difference.

F: Female; M: Male; W: Weeks; Min: Minutes; NA: Not Available; MD: Mean Difference.

F: Female; M: Male; W: Weeks; U: Units; MD: Mean Difference.

F: Female; M: Male; W: Weeks; MD: Mean Difference.

Carbs: Carbohydrates; TEI: Total Energy Intake.

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