Extrapancreatic Effects Research Articles

Use of Glucagon-Like Peptide-1 Receptor Agonists Does Not Increase the Risk of Cancer in Patients with Type 2 Diabetes Mellitus.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are increasingly used for the treatment of type 2 diabetes mellitus (T2DM) given their extra-pancreatic effects. However, there are concerns about carcinogenesis in the pancreas and thyroid gland. We aimed to evaluate the site-specific incidence of cancer in patients with T2DM-treated GLP-1 RAs using a nationwide cohort. This study included data obtained from the Korean National Health Insurance Service (between 2004 and 2021). The primary outcome was newly diagnosed cancer, and the median follow-up duration for all participants was 8 years. After propensity score matching, 7,827 participants were analyzed; 2,609 individuals each were included in the GLP-1 RA, diabetes mellitus (DM) control, and non-DM control groups. The incidence rate ratio (IRR) of subsequent cancer in patients with T2DM was 1.73, which was higher than that of individuals without DM, and it increased in both men and women. Analysis of patients with T2DM showed no increased cancer risk associated with the use of GLP-1 RA, and similar results were observed in both men and women. The IRRs of pancreatic cancer (0.74), thyroid cancer (1.32), and medullary thyroid cancer (0.34) did not significantly increase in the GLP-1 RA group compared with those in the DM control group. There was a 73% higher risk of cancer in patients with T2DM compared with the general population. However, among patients with T2DM, there was no association between the use of GLP-1 RAs and new-onset cancers, including pancreatic and medullary thyroid cancers.

Sulfonylureas exert antidiabetic action on adipocytes by inhibition of PPARγ serine 273 phosphorylation

ObjectiveSulfonylureas (SUs) are still among the mostly prescribed antidiabetic drugs with an established mode of action: release of insulin from pancreatic β-cells. In addition, effects of SUs on adipocytes by activation of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) have been described, which might explain their insulin-sensitizing potential observed in patients. However, there is a discrepancy between the impact of SUs on antidiabetic action and their rather moderate in vitro effect on PPARγ transcriptional activity. Recent studies have shown that some PPARγ ligands can improve insulin sensitivity by blocking PPARγ Ser-273 phosphorylation without having full agonist activity. It is unknown if SUs elicit their antidiabetic effects on adipocytes by inhibition of PPARγ phosphorylation. Here, we investigated if binding of SUs to PPARγ can interfere with PPARγ Ser-273 phosphorylation and determined their antidiabetic actions in vitro in primary human white adipocytes and in vivo in high-fat diet (HFD) obese mice. MethodsPrimary human white preadipocytes were differentiated in the presence of glibenclamide, glimepiride and PPARγ ligands rosiglitazone and SR1664 to compare PPARγ Ser-273 phosphorylation, glucose uptake and adipokine expression. Transcriptional activity at PPARγ was determined by luciferase assays, quantification of PPARγ Ser-273 phosphorylation was determined by Western blotting and CDK5 kinase assays. In silico modelling was performed to gain insight into the binding characteristics of SUs to PPARγ. HFD mice were administered SUs and rosiglitazone for 6 days. PPARγ Ser-273 phosphorylation in white adipose tissue (WAT), body composition, glucose tolerance, adipocyte morphology and expression levels of genes involved in PPARγ activity in WAT and brown adipose tissue (BAT) were evaluated. ResultsSUs inhibit phosphorylation of PPARγ at Ser-273 in primary human white adipocytes and exhibit a positive antidiabetic expression profile, which is characterized by up regulation of insulin-sensitizing and down regulation of insulin resistance-inducing adipokines. We demonstrate that SUs directly bind to PPARγ by in silico modelling and inhibit phosphorylation in kinase assays to a similar extend as rosiglitazone and SR1664. In HFD mice SUs reduce PPARγ phosphorylation in WAT and have comparable effects on gene expression to rosiglitazone. In BAT SUs increase UCP1 expression and reduce lipid droplets sizes. ConclusionsOur findings indicate that a part of SUs extra-pancreatic effects on adipocytes in vitro and in vivo is probably mediated via their interference with PPARγ phosphorylation rather than via classical agonistic activity at clinical concentrations.

1853-PUB: Extrapancreatic Effects of GIP on Bone

Glucose-dependent insulinotropic polypeptide (GIP) exhibits extrapancreatic effects through the receptor for GIP (GIPR). In this study, we used Ni-Ti Closed Coil Spring (Ni-Ti) in GIPR-deficient mice (GIPRKO) and wild-type mice (WT) to investigate the effect of GIP on force-induced bone remodeling due to orthodontic tooth movement. It was investigated. Ni-Ti was attached between the maxillary bone and the maxillary left first molar (M1) of GIPRKO and WT, and mechanical load was applied by pulling the M1 in the mesial direction. Remaining amount and bone quality were measured. A histological examination of the maxilla was also performed. As a result, compared to WT, GIPRKO showed a significant increase in tooth movement distance and a significant decrease in residual alveolar bone mass. TRAP staining showed an increase in osteoclasts in GIPRKO compared to WT on the tooth moving side. We also found that GIPRKO reduced osteoblasts in the steady state and suppressed osteoblasts after tooth movement. These results suggest that GIPRK impairs bone remodeling through increased bone resorption due to mechanical load, and that GIP plays an important role in bone remodeling. Disclosure T.Yamauchi: None. S.Goto: None. K.Naruse: None. N.Nakamura: None. M.Miyabe: None. M.Ito: None. R.Hoshino: None. S.Kanada: None. T.Sekiya: None. T.Matsubara: None. K.Miyazawa: None.

Impacts of Glucose-Dependent Insulinotropic Polypeptide on Orthodontic Tooth Movement-Induced Bone Remodeling.

Glucose-dependent insulinotropic polypeptide (GIP) exerts extra-pancreatic effects via the GIP receptor (GIPR). Herein, we investigated the effects of GIP on force-induced bone remodeling by orthodontic tooth movement using a closed-coil spring in GIPR-lacking mice (GIPRKO) and wild-type mice (WT). Orthodontic tooth movements were performed by attaching a 10-gf nickel titanium closed-coil spring between the maxillary incisors and the left first molar. Two weeks after orthodontic tooth movement, the distance of tooth movement by coil load was significantly increased in GIPRKO by 2.0-fold compared with that in the WT. The alveolar bone in the inter-root septum from the root bifurcation to the apex of M1 decreased in both the GIPRKO and WT following orthodontic tooth movement, which was significantly lower in the GIPRKO than in the WT. The GIPRKO exhibited a significantly decreased number of trabeculae and increased trabecular separation by orthodontic tooth movement compared with the corresponding changes in the WT. Histological analyses revealed a decreased number of steady-state osteoblasts in the GIPRKO. The orthodontic tooth movement induced bone remodeling, which was demonstrated by an increase in osteoblasts and osteoclasts around the forced tooth in the WT. The GIPRKO exhibited no increase in the number of osteoblasts; however, the number of osteoclasts on the coil-loaded side was significantly increased in the GIPRKO compared with in the WT. In conclusion, our results demonstrate the impacts of GIP on the dynamics of bone remodeling. We revealed that GIP exhibits the formation of osteoblasts and the suppression of osteoclasts in force-induced bone remodeling.

Antidiabetic Activities of Extracts of Ficus bengalensis Linn

Abstract: Various extracts of diverse parts of medicinal plants have been shown to possess antidiabetic and hypoglycemic effect. Most of them look to act directly on pancreas (pancreatic effect) and stimulate insulin level in blood. Some have extra pancreatic effect by acting directly on tissues like liver, muscle, etc and alter favorably, the activities of the regulatory enzymes of glycolysis, gluconeogenesis and other pathways. The research work embodied in the thesis deals with the scientific exploration of indigenous plants viz., Ficus bengalensis Linn for their possible anti-diabetic and hypoglycemic activity. The present investigations concluded that the ethanolic and aqueous extracts of aerial parts of Ficus bengalensis Linn endowed with potential antidiabetic activity which could be attributed by their possible multiple effects on both pancreatic and extra-pancreatic site by influencing either the metabolism and/or absorption of glucose, which in turn also influence the lipid metabolism. Keywords: hypoglycemic, Ficus bengalensis Linn, Diabetic, Lipid metabolism

Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the GIPR Region.

There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs1800437 (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PPcoloc] > 0.97; PP explained by the candidate variant [PPexplained] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 ∼770 Kb; R2 with E354 = 0.004; PPcoloc > 0.99; PPexplained = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354’s association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272 (R2 with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials.

Gliquidone ameliorates hepatic insulin resistance in streptozotocin-induced diabetic Sur1−/− rats

Gliquidone was suggested to exert hypoglycemic effect through enhancing hepatic insulin sensitivity. However, inadequate in vivo evidences make this statement controversial. The aim of the present study was to clarify the insulin-sensitizer role of gliquidone in liver and muscle, so as to confirm its extra-pancreatic effects in vivo. TALEN technique was used to create Sur1 knockout (Sur1−/−) rats. Diabetic Sur1−/− rat models were established by high-fat diet combined with streptozotocin, and which were randomly divided into three groups: gliquidone, metformin and saline, treated for 8 weeks. Fasting blood glucose (FBG) and body mass were tested each week. IPGTT, IPITT and hyperinsulinemic-euglycemic clamp tests were used to evaluate glucose tolerance and insulin sensitivity, respectively. Key mediators of glucose metabolism in liver and skeletal muscle and the activity of AKT and AMPK in these tissues were further analyzed. We found that gliquidone decreased FBG and increased insulin sensitivity without increasing insulin secretion in diabetic Sur1−/− rats. Further exploration implied that gliquidone mainly increased hepatic glycogen storage and decreased gluconeogenesis, which were accompanied with activation of AKT, but not enhanced muscle GLUT4 expression. However, both these effects were still weaker than that of metformin. These results suggested that gliquidone could exerts an extra-pancreatic hypoglycemic effect by improving insulin sensitivity, which might be largely attributes to its additional insulin sensitizer role in hepatic glucose metabolism.

Emerging Role of Caveolin-1 in GLP-1 Action.

Glucagon-like peptide-1 (GLP-1) is a gut hormone mainly produced in the intestinal epithelial endocrine L cells, involved in maintaining glucose homeostasis. The use of GLP-1 analogous and dipeptidyl peptidase-IV (DPP-IV) inhibitors is well-established in Type 2 Diabetes. The efficacy of these therapies is related to the activation of GLP-1 receptor (GLP-1R), which is widely expressed in several tissues. Therefore, GLP-1 is of great clinical interest not only for its actions at the level of the beta cells, but also for the extra-pancreatic effects. Activation of GLP-1R results in intracellular signaling that is regulated by availability of downstream molecules and receptor internalization. It has been shown that GLP-1R co-localizes with caveolin-1, the main component of caveolae, small invagination of the plasma membrane, which are involved in controlling receptor activity by assembling signaling complexes and regulating receptor trafficking. The aim of this review is to outline the important role of caveolin-1 in mediating biological effects of GLP-1 and its analogous.

Irisin and Incretin Hormones: Similarities, Differences, and Implications in Type 2 Diabetes and Obesity.

Incretins are gut hormones that potentiate glucose-stimulated insulin secretion (GSIS) after meals. Glucagon-like peptide-1 (GLP-1) is the most investigated incretin hormone, synthesized mainly by L cells in the lower gut tract. GLP-1 promotes β-cell function and survival and exerts beneficial effects in different organs and tissues. Irisin, a myokine released in response to a high-fat diet and exercise, enhances GSIS. Similar to GLP-1, irisin augments insulin biosynthesis and promotes accrual of β-cell functional mass. In addition, irisin and GLP-1 share comparable pleiotropic effects and activate similar intracellular pathways. The insulinotropic and extra-pancreatic effects of GLP-1 are reduced in type 2 diabetes (T2D) patients but preserved at pharmacological doses. GLP-1 receptor agonists (GLP-1RAs) are therefore among the most widely used antidiabetes drugs, also considered for their cardiovascular benefits and ability to promote weight loss. Irisin levels are lower in T2D patients, and in diabetic and/or obese animal models irisin administration improves glycemic control and promotes weight loss. Interestingly, recent evidence suggests that both GLP-1 and irisin are also synthesized within the pancreatic islets, in α- and β-cells, respectively. This review aims to describe the similarities between GLP-1 and irisin and to propose a new potential axis–involving the gut, muscle, and endocrine pancreas that controls energy homeostasis.

Current data on the effectiveness of gliclazide and molecular mechanisms of action of the drug

With the growing prevalence of type 2 diabetes mellitus (T2DM) the possibility of treating it with available drugs is one of the main issues. Although glycemic control and reduction of micro- and macrovascular outcomes remain important aspects of treatment, the main limiting factors are the availability and cost of oral hypoglycemic agents. Although newer agents, such as sodium -glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide 1 receptor agonists, potentially being valuable for patients with insulin resistance and cardiovascular complications, they are relatively expensive and have limited availability. Second-generation sulfonylureas effectively reduce glycated hemoglobin and contribute to the prevention of micro- and macrovascular complications of T2DM The review substantiates the role of Gliclazide MR as a more affordable drug for the treatment of T2DM, the safety of which has been confirmed by many studies; cardio-and nephroprotective effects are shown, as well as mechanisms for influencing в-cells of the pancreas and extrapancreatic effects through activation of phospholipase C and the G-protein-сoupled-receptors (GPCR) are analyzed. The latest data on the assessment of adverse events of Gliclazide MR are presented in comparison with both other sulfonylureas and glucose-lowering drugs of other classes.

Statins and Higher Diabetes Mellitus Risk: Incidence, Proposed Mechanisms, and Clinical Implications.

3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are ubiquitously prescribed for cardiovascular disease (CVD) prevention and treatment. However, the use of statins has been linked to the development of new-onset diabetes mellitus (NODM), which could possibly increase future CVD risk. This phenomenon necessitates a clear discussion of the possible etiologies of this relationship and its broader clinical consequences. We discuss the reported incidence of NODM in statin users through a rigorous review of data from metaanalyses of randomized control trials examining this association. We also highlight the various possible mechanisms responsible for the development of statin-induced diabetes mellitus. Finally, we examine the clinical implications of this effect on future CVD risk and identify specific patient factors that can be used for risk-stratification strategies. Data from 14 randomized control trials metaanalyses suggest a 9-33% higher risk of NODM with statin use. Several cellular, molecular, and genetic mechanisms, as well as lifestyle habits, have been identified as potential underlying factors responsible for this elevated risk. The principle mode of the diabetogenic action of statins is still unclear, though it is likely the result of a complex interplay of pancreatic and extrapancreatic effects. It is understood that patient populations with a greater predisposition to diabetes mellitus, and those with thicker epicardial adiposity are more at risk for the development of statin-induced NODM. Despite these observations, robust data from a variety of investigations suggest that the CVD preventative benefits of statin treatment significantly outweigh the risks associated with the development of NODM. Nevertheless, further study must better identify the causative mechanisms involved in this process, its natural history, and the unique factors that will help clinicians risk stratify and appropriately monitor patients on statin therapy.

The effect of glimepiride on glycemic control and fasting insulin levels

Glimepiride is a new once-daily sulfonylurea. Animal studies have shown that it lowers blood glucose through extrapancreatic process. The aim of our study is to observe the effect of glimepiride on glycemic control, body weight change and insulin levels during fasting. Thirty two Type 2 diabetic patients, whose blood glucose levels cannot be controlled adequately with diet and exercise alone, received a 12-week course of glimepiride treatment. They were followed up after 2 weeks, 4 weeks, 8 weeks and 12 weeks. Their fasting, two-hour postprandial blood glucose and body weight were recorded during each visit. Hemoglobulin A1c (HbA1c) and fasting insulin levels were measured at the beginning and end of the study. Fasting plasma glucose (FPG), two-hour postprandial plasma glucose (PPG) and HbA1c values decreased significantly after treatment. The paired mean FPG decreased from 237 ± 66.58 mg/dL to 149 ± 41.31 mg/dL (P ≤ 0.001), PPG from 352 ± 112.44 mg/dL to 159 ± 22.86 mg/dL (P ≤ 0.001) and HbA1c from 11.04 ± 2.91% to 6.98 ± 1.52% (P ≤ 0.001). In contrast, fasting insulin levels and body weight did not have meaningful differences at 0 week and 12 weeks. The paired mean fasting insulin level increased from 13.19 ± 1.52 μIU/mL to 16.76 ± 9.48 μIU/mL (P = 0.594). The paired mean body weight increased from 65.01 ± 8.94 kg at baseline to 68.25 ± 9.80 kg at endpoint (P = 0.023). Glimepiride lowers blood glucose effectively without much effect on fasting insulin levels and body weight gain. These results suggested that glimepiride lowers blood glucose not only by stimulating insulin secretion but also by its extrapancreatic effects. This metabolic effect is desirable because hyperinsulinemia increases body weight, atherosclerosis and risk of hypoglycemia in diabetic patients.

1052-P: Investigation of the Extrapancreatic Effects of the DPP-4 Inhibitor Sitagliptin: A Randomized, Double-Blinded, Placebo-Controlled Crossover Trial in Totally Pancreatectomized Patients

Dipeptidyl peptidase 4 (DPP-4) inhibitors increase circulating concentrations of the insulinotropic and glucagon-modulating gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). The multiorgan distribution of GIP and GLP-1 receptors suggests pleiotropic extrapancreatic effects of these hormones (and thus DPP-4 inhibition), but these have been difficult to disentangle from their potent effects on the endocrine pancreas. Here, we investigated postprandial effects of the DPP-4 inhibitor sitagliptin in totally pancreatectomized (PX) patients as compared to matched healthy controls (CTRLs). In a randomized, double-blinded, placebo-controlled crossover study, 10 PX patients (age 65.7±6.4 [mean±SD] years; BMI 23.8±4.3 kg/m2) and 10 CTRLs (age 65±7.8 years; BMI 24.3±3.5 kg/m2) underwent a 3-hour liquid mixed meal test (MMT) after two doses of 150 mg sitagliptin (administered the night before and on the morning of the MMT) and placebo, respectively. Basal insulin was administered as usual; no bolus insulin was administered during study days. Blood samples were drawn throughout the experimental days. Sitagliptin did not affect fasting plasma glucose compared to placebo in CTRLs (5.4±0.2 vs. 5.5±0.1 mmol/l, P=0.6) nor in PX patients (7.7±1.0 vs. 7.9±0.9 mmol/l, P=0.88). Also, sitagliptin did not affect postprandial plasma glucose excursions as assessed by peak values, time to peak values or area under the curve in any of the groups. In conclusion, the DPP-4 inhibitor sitagliptin has no effect on fasting plasma glucose or postprandial plasma glucose excursions in PX patients; suggesting that no or little extrapancreatic effects of GIP and GLP-1 are involved in the glucose-lowering action of DPP-4 inhibition in patients with diabetes. Disclosure M. Baekdal: None. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. S.W. Nielsen: None. C. Hansen: None. J.H. Storkholm: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.

GLP-1-induced renal vasodilation in rodents depends exclusively on the known GLP-1 receptor and is lost in prehypertensive rats.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone known to stimulate postprandial insulin release. However, GLP-1 also exerts extrapancreatic effects, including renal effects. Some of these renal effects are attenuated in hypertensive rats, where renal expression of GLP-1 receptors is reduced. Here, we assessed the expression and vascular function of GLP-1 receptors in kidneys from young prehypertensive rats. We also examined GLP-1-induced vasodilation in the renal vasculature in wild-type (WT) and GLP-1 receptor knockout mice using wire and pressure myography and the isolated perfused juxtamedullary nephron preparation. We investigated whether GLP-1 and the metabolite GLP-1(9-36)amide had renal vascular effects independent of the known GLP-1 receptor. We hypothesized that hypertension decreased expression of renal GLP-1 receptors. We also hypothesized that GLP-1-induced renal vasodilatation depended on expression of the known GLP-1 receptor. In contrast to normotensive rats, no immunohistochemical staining or vasodilatory function of GLP-1 receptors was found in kidneys from prehypertensive rats. In WT mice, GLP-1 induced renal vasodilation and reduced the renal autoregulatory response. The GLP-1 receptor antagonist exendin 9-39 inhibited relaxation, and GLP-1(9-36)amide had no vasodilatory effect. In GLP-1 receptor knockout mice, no relaxation induced by GLP-1 or GLP-1(9-36)amide was found, the autoregulatory response in afferent arterioles was normal, and no GLP-1-induced reduction of autoregulation was found. We conclude that in prehypertensive kidneys, expression and function of GLP-1 receptors is lost. The renal vasodilatory effect of GLP-1 is mediated exclusively by the known GLP-1 receptor. GLP-1(9-36)amide has no renal vasodilatory effect. GLP-1 attenuates renal autoregulation by reducing the myogenic response.

Potential linkage between dipeptidyl peptidase-4 inhibitor use and the risk of pancreatitis/pancreatic cancer.

Dipeptidyl peptidase (DPP)-4 inhibitors, a class of oral hypoglycemic agents, are widely used, especially in Asian populations, as they have been shown to be well-tolerated and to cause relatively few hypoglycemic events despite exerting a potent glucose-lowering effect by promoting endogenous insulin secretion, besides also having extra-pancreatic effects. Meanwhile, use of DPP-4 inhibitors has been reported to be associated with the development of bullous pemphigoid (BP), a rare autoimmune blistering skin disease1 , even though the absolute increase in the risk of development of BP is relatively low.

Incretin Hormones: The Link between Glycemic Index and Cardiometabolic Diseases.

This review aimed to describe the potential mechanisms by which incretin hormones could mediate the relationship between glycemic index and cardiometabolic diseases. A body of evidence from many studies suggests that low glycemic index (GI) diets reduces the risk for type 2 diabetes and coronary heart disease. In fact, despite the extensive literature on this topic, the mechanisms underlying unfavorable effects of high GI foods on health remain not well defined. The postprandial and hormonal milieu could play a key role in the relationship between GI and cardiovascular risk. Incretin hormones, glucagon-like peptide1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are important regulators of postprandial homeostasis by amplifying insulin secretory responses. Response of GIP and GLP-1 to GI have been studied more in depth, also by several studies on isomaltulose, which have been taken as an ideal model to investigate the kinetics of incretin secretion in response to foods’ GI. In addition, extrapancreatic effects of these incretin hormones were also recently observed. Emerging from this have been exciting effects on several targets, such as body weight regulation, lipid metabolism, white adipose tissue, cardiovascular system, kidney, and liver, which may importantly affect the health status.

943-P: Improvement in Glycemic Variability with Dulaglutide Therapy Evaluated by Continuous Glucose Monitoring System: A Real-World Experience of Indian Patients with Type 2 DM

Dulaglutide-based therapy may potentiate improved glycemic variability (GV) in patients with type 2 diabetes (T2D) owing to their several pancreatic and extra-pancreatic effects. This study assessed the effects of dulaglutide on GV using continuous glucose monitoring system (CGMS) in patients with T2D. Patients (N = 27) from a CGMS specialty center in India received dulaglutide as add-on to oral antidiabetics (OADs) with or without insulin and were subsequently monitored for continuous glucose data using CGMS (FreeStyle Libre Pro) for ≤15 days considering 70-140 mg/dL as target. CGMS data revealed a significant reduction (P<.05) in overall within-patient mean CGM glucose on Day 5 relative to Day 1 which further reduced at Day 15 (Figure), warranting titration of doses of OADs and/or insulin. Interestingly, the coefficient of variation for overall within-patient mean glucose on Day 15 (21.99%) was less compared to Day 1 (31.56%). Through Day 1 to Day 15, overall within-patient mean % time of glucose in target significantly (P<.05) increased (25.19% to 66.42%) along with reduced mean % time above target (68.96% to 17.42%). A non-significant increase in overall mean % time below target (5.86% to 16.16%) was observed with no events of severe hypoglycemia. Dulaglutide improved GV and is well tolerated in patients with T2D. Disclosure S.A. Patange: None.

Evaluation of Pancreatic and Extra Pancreatic Effects of Branched Amino Acids

Abstract Background and aims: Leucine, Isoleucine, and Valine collectively known as Branched-chain amino acids (BCAAs), can be closely associated with metabolic dysregulates and with insulin resistance. We aimed to explore the role of BCAAs as potential treatment option for diabetes. Material and method: Bioassay the effect of BCAAs on MIN6 cell line on insulin secretion and pancreatic beta cells expansion, then were checked for inhibitory potential of pancreatic amylase, glucosidase and lipase as alternative approach for diabetes treatment. Results: BCAAs significantly enhance insulin secretion parallel to L-alanine efficacy. Furthermore, BCAAs obtain a dose dependent β-cell proliferation similar to glucagon-like peptide-1. Moreover, these acids could restore the secretory function of MIN6 β-cell despite stressful gluco-lipo-toxicity; separately or combined. Moreover, BCAAs exerted a dose dependent dual inhibition of amylase, glucosidase and lipase. Conclusions: Our current findings suggest that BCAAs supplementation may have a potential therapeutic effect against diabetes as insulin releasing agent and as specific inhibitors for both-amylase/α-amyloglucoside and lipase

Emerging incretin hormones actions: focus on bone metabolism.

Incretin hormones, namely glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gastro-intestinal hormones released from different enteroendocrine cells after nutrient intake. Incretins exert their actions though binding to and activation of specific GIP and GLP-1 receptors which are present in several target tissues. Incretin receptor activation in the pancreas leads to the incretin effect and other significant non-insulinotropic effects. Extra-pancreatic effects of incretin hormones in several other target tissues, such as their role in the pathophysiology of obesity and their potential relation with cardiovascular function, cognitive function, triglyceride storage in adipose tissue and bone metabolism, have attracted scientific interest. In the current review we intend to summarize existing knowledge on specific effects of GIP and GLP-1 in bone cells and bone metabolism. Starting from the identification of GIP receptor and GLP-1 receptor in animal and human bone cells, continuing with the skeletal effects of incretin deficiency or overexpression in animals, ending to the latest data on incretin and incretin agonists administration in cells, animals and humans, incretins play a significant yet complex role in the pathophysiology of bone metabolism affecting both formation and resorption. Although existing evidence seem strong and concrete, there is still a long way to go until their possible therapeutic or adjuvant use as bone modulating drugs can be considered.

Exploring the influence of extrapancreatic effect of sulphonylureas on clinical outcomes in patients with type 2 diabetes

Recent studies revealed a number of interesting extrapancreatic actions of sulfonylureas (SUs), and there existed various mechanisms and targets of extrapancreatic effects among different SUs. We try to explore the impact of extrapancreatic effects on the clinical outcome of patients with type 2 diabetes mellitus(T2DM) based on the data from basic and clinical researches, including the effects of SUs on atherosclerosis, cognitive impairment, risk factors associated with abnormal bone metabolism, as well as the safety of treatment. All together, extrapancreatic effects of novel sulphonylureas (e.g. glimepiride) are associated with the improved clinical outcomes and less adverse effects in patients with T2DM. Key words: Diabetes mellitus, type 2; Sulfonylureas; Extrapancreatic effect; Clinical outcome