Intact GLP-1 Research Articles

Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test.

DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Sitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). This pilot study confirmed that sitagliptin (100 mg) decreased the area under the curve for glucose during an OGTT (p = 0.0003). Furthermore, sitagliptin promoted insulin secretion during the early portion of the OGTT as reflected by an increase in the ratio of plasma insulin at 30 min divided by plasma insulin at 60 min (T30:T60) from mean ± SEM 0.87 ± 0.05 to 1.62 ± 0.36 mU/L (p = 0.04). The magnitude of sitagliptin's effect on insulin secretion (as judged by the increase in the T30:T60 ratio for insulin) was correlated with the magnitude of sitagliptin-induced increase in the area under the curve for intact plasma GLP1 levels during the first hour of the OGTT. This study confirmed previously reported sex differences in glucose and insulin levels during an OGTT. Specifically, females exhibited higher levels of glucose and insulin at the 90-180 min time points. However, we did not detect significant sex-associated differences in the magnitude of sitagliptin-induced changes in T30:T60 ratios for either glucose or insulin. In conclusion, T30:T60 ratios for insulin and glucose during an OGTT provide useful indices to assess pharmacodynamic responses to DPP4 inhibitors.

Insulin clearance and incretin hormones following oral and \u201cisoglycemic\u201d intravenous glucose in type 2 diabetes patients under different antidiabetic treatments

It has not been elucidated whether incretins affect insulin clearance in type 2 diabetes (T2D). We aimed exploring possible associations between insulin clearance and endogenously secreted or exogenously administered incretins in T2D patients. Twenty T2D patients were studied (16 males/4 females, 59 ± 2 years (mean ± standard error), BMI = 31 ± 1 kg/m2, HbA1c = 7.0 ± 0.1%). Patients were treated with metformin, sitagliptin, metformin/sitagliptin combination, and placebo (randomized order). On each treatment period, oral and isoglycemic intravenous glucose infusion tests were performed (OGTT, IIGI, respectively). We also studied twelve T2D patients (9 males/3 females, 61 ± 3 years, BMI = 30 ± 1 kg/m2, HbA1c = 7.3 ± 0.4%) that underwent infusion of GLP-1(7–36)-amide, GIP, GLP-1/GIP combination, and placebo. Plasma glucose, insulin, C-peptide, and incretins were measured. Insulin clearance was assessed as insulin secretion to insulin concentration ratio. In the first study, we found OGTT/IIGI insulin clearance ratio weakly inversely related to OGTT/IIGI total GIP and intact GLP-1 (R2 = 0.13, p < 0.02). However, insulin clearance showed some differences between sitagliptin and metformin treatment (p < 0.02). In the second study we found no difference in insulin clearance following GLP-1 and/or GIP infusion (p > 0.5). Thus, our data suggest that in T2D there are no relevant incretin effects on insulin clearance. Conversely, different antidiabetic treatments may determine insulin clearance variations.

37-LB: Very-Low-Dose Premeal Whey Protein Microgels Reduce Postprandial (PP) Glucose in Type 2 Diabetes: A Randomized, Placebo-Controlled Crossover Study

Whey protein (WP), found in dairy products, is rich in branched chain amino acids and bioactive peptides that stimulate the secretion of incretin hormones and insulin, but has typically required relatively high caloric doses. Technologies enhancing absorption could enable use of a lower WP-dose. This single-intervention study in type 2 diabetes (drug-naïve or on metformin), evaluated the effects of 10g WP (40 Cal) prepared with novel micelle-technology [WPM], or placebo (PBO, 0 Cal), taken as a 125 mL shot 15 min ahead of a pizza meal (622 Cal). PP glucose (0-4h) and intact GLP-1 (0-2h) responses were assessed in blood. Twenty-six individuals (mean age 62 years, baseline HbA1c 7,5%, BMI 29.1 kg/m2) completed both sequences. Compared to PBO, pre-meal WPM significantly altered the early PP glucose trajectory (Fig), reducing the 2h incremental area under the curve (iAUC) by 22% (mean [95% CI] difference iAUC-30-120min -29.43 [-55.45, -3.40] mg/dLxh, p=0.0283). The iAUC-30-180min was similar (-31.58 [-68.43, 5.26], p=0.0896). A 66.1% increase in GLP-1 iAUC-30-120min was observed (4.80 [2.19, 7.40], p=0.0009). Compared to PBO, 10g WPM taken 15 min before a pizza meal, significantly reduced the early glycemic burden and significantly augmented the GLP-1 response, suggesting its use as a convenient pre-meal shot to improve PP metabolic profile in type 2 diabetes.View largeDownload slideView largeDownload slide DisclosureL. H. De gregorio: Research Support; Self; Nestlé, Novartis Pharmaceuticals Corporation. O. E. Johansen: Employee; Self; Boehringer Ingelheim International GmbH, Nestlé. I. Neeland: Consultant; Self; Merck & Co., Inc. R. Zagury: Board Member; Self; Abbott, Consultant; Self; Nestlé, Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Danone Nutricia, Novo Nordisk Pharma Ltd., Sanofi, Servier Laboratories. B. Ahrén: Stock/Shareholder; Self; AstraZeneca, Novo Nordisk Inc. J. M. Neutel: None. K. Reyes: Employee; Self; Nestlé. E. Perrin: Other Relationship; Self; Nestlé. E. Berk: Employee; Self; Nestle Health Science. M. Von eynatten: Employee; Self; Nestlé.FundingNestlé Health Science

1002-P: Sacubitril/Valsartan Increases Postprandial Glucagon-Like Peptide-1 Concentrations and Has Synergistic Effects when Combined with Sitagliptin

Diabetes is an independent risk factor for heart failure. Treatment with a neprilysin inhibitor-angiotensin receptor blocker (sacubitril/valsartan) was demonstrated to improve glycemia and reduce time to initiation of insulin therapy but the underlying mechanism(s) are unknown. We hypothesized that sacubitril/valsartan attenuates neprilysin-dependent degradation of GLP-1, and that combined inhibition of the other enzyme cleaving intact GLP-1, dipeptidyl peptidase 4 (DPP-4), would have synergistic effects on levels of intact GLP-1. In two open-labeled clinical trials, a total of 16 healthy men received a standardized meal (34% carbohydrates, 45% fat, 21% protein) combined with a prior single dose of sacubitril (194mg)/valsartan(206mg), sitagliptin (2x100mg), sacubitril(194mg)/valsartan(206mg) and sitagliptin (2x100mg), or control. Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% and had synergistic effects on intact GLP-1 when combined with sitagliptin. Concentrations of glucose, insulin, and GIP were not significantly changed upon sacubitril/valsartan treatment. Sacubitril/valsartan synergistically protects intact GLP-1 when combined with a DPP-4 inhibitor pointing to a therapeutic potential for the combination in patients with cardiovascular disease and diabetes. Disclosure N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp &amp; Dohme Corp. P.D. Mark: None. L.H. Hansen: None. U.Ø. Andersen: None. B. Hartmann: None. R.D. Carr: Employee; Self; Merck &amp; Co., Inc. Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, Merck &amp; Co., Inc. F. Gustafsson: Advisory Panel; Self; Abbott, Corvia Medical, Inc. Consultant; Self; Bayer AG. Employee; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation. Speaker's Bureau; Self; Novartis AG, Novo Nordisk A/S. C.F. Deacon: Employee; Spouse/Partner; Merck Sharp &amp; Dohme Corp. Stock/Shareholder; Spouse/Partner; Merck &amp; Co., Inc. Other Relationship; Self; Eli Lilly and Company, Merck Sharp &amp; Dohme Corp. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. J.P. Gøtze: None. P. Plomgaard: None. Funding Rigshopitalet

1326-P: Metformin Increases GLP-1 Concentrations and Improves Glycemia in Youth with Type 2 Diabetes

Metformin is the only approved oral agent for youth with type 2 diabetes (T2D), but its mechanism of action remains controversial. Recent data suggests a primary role for the entero-insular instead of the gluconeogenic pathway, but there is no data in youth, in whom metformin efficacy is ∼50%. Our objectives were to: (1) compare incretin concentrations, glucagon-like 1 peptide (GLP-1) and gastric inhibitory polypeptide (GIP) in 12 youth with T2D not on metformin to 10 healthy age and BMI-matched controls, and (2) determine the change in incretins and gluconeogenesis (GNG) after 3 months of metformin in 8 youth with T2D. Intact GLP-1 and total GIP were measured at 0 and 2-hour during a 75g OGTT and basal GNG (2H20) and glucose production (6,62H2glucose) measured after an overnight fast. Compared to controls, youth with T2D before metformin had higher HbA1c and glucose levels and lower fasting and 2-hour GLP-1 (P&amp;lt;0.05 Table). After metformin, HbA1c decreased and fasting GLP-1 increased but there was no change in BMI, GNG or glucose production (P&amp;gt;0.1 Table). Post-metformin GLP-1 was comparable to levels in controls (P&amp;gt;0.1). There was no difference in GIP between youth with and without T2D and no change with metformin. Overall, improved glycemic control with short-term metformin in youth was associated with increased GLP-1 concentrations independent of changes in BMI and GNG supporting an entero-insular mechanistic pathway. Disclosure C.K. Cravalho: None. A.G. Meyers: None. L. Mabundo: None. A.B. Courville: None. S. Bernstein: None. Y. Dai: None. M. Walter: None. S. Chacko: None. M.W. Haymond: Advisory Panel; Self; Daiichi Sankyo Company, Limited, Zealand Pharma A/S. Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca. S.T. Chung: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases

The effect of DPP-4-protected GLP-1 (7–36) on coronary microvascular function in obese adults

ObjectiveGlucagon-like-peptide-1 (GLP-1) receptor analogues have been shown to reduce cardiovascular events in patients with type 2 diabetes. However, the mechanism behind is still unknown. The aim of the study was to investigate the effect of intact GLP-1 (7–36) on coronary microcirculation in overweight adults. Design and methodsA double-blinded randomized cross-over study was performed, with 12 overweight participants. Effects of intact GLP-1 (7-36) infusion were compared with a saline infusion on separate days. A DPP-4 inhibitor was administered to block degradation of intact GLP-1 (7–36) to the GLP-1 metabolite (9–36). Coronary microcirculation was assessed by Doppler coronary flow velocity reserve (CFVR) before and after 2 h of infusion. Peripheral endothelial function was assessed by flow mediated dilation (FMD) before and after one hour of infusion. ResultsCFVR was 3.77 ± 1.25 during GLP-1 infusion and 3.85 ± 1.32 during saline infusion, endothelial function was 16.3 ± 15.5 % during GLP-1 infusion and 7.85 ± 7.76 % during saline infusion. When adjusting for baseline values no significant differences in CFVR (ΔCFVR 0.38 ± 0.92 vs. ΔCFVR 0.71 ± 1.03, p = 0.43) and no difference in peripheral endothelial function (ΔFMD 7.34 ± 11.5 % vs. ΔFMD –1.25 ± 9.23%, p = 0.14) was found. ConclusionsWe found no effect of intact GLP-1 (7–36), protected from DPP4 mediated degradation on coronary microcirculation in overweight adults.

2003 Mixed meal effects of neprilysin inhibition

OBJECTIVES/SPECIFIC AIMS: Test the hypothesis that neprilysin inhibition with sacubitril/valsartan will increase endogenous intact GLP-1 after a mixed meal compared with valsartan. METHODS/STUDY POPULATION: Adults 18–80 years with pre-diabetes or type 2 diabetes and elevated blood pressure. RESULTS/ANTICIPATED RESULTS: We anticipate higher intact GLP-1 area under the cure after the meal when subjects receive sacubitril/valsartan compared with valsartan. DISCUSSION/SIGNIFICANCE OF IMPACT: Neprilysin inhibition may be a target for anti-diabetes therapy by decreasing degradation of GLP-1.

Clinical Pharmacokinetics and Pharmacodynamics of Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor.

Saxagliptin is an orally active, highly potent, selective and competitive dipeptidyl peptidase (DPP)-4 inhibitor used in the treatment of type2 diabetes mellitus at doses of 2.5 or 5mg once daily. DPP-4 is responsible for degrading the intestinally derived hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP). Inhibition of DPP-4 increases intact plasma GLP-1 and GIP concentrations, augmenting glucose-dependent insulin secretion. Both saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, demonstrate high degrees of selectivity for DPP-4 compared with other DPP enzymes. Saxagliptin is orally absorbed and can be administered with or without food. The half-life of plasma DPP-4 inhibition with saxagliptin 5mg is ~27 h, which supports a once-daily dosing regimen. Saxagliptin is metabolized by cytochrome P450 (CYP) 3A4/5 and is eliminated by a combination of renal and hepatic clearance. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with hepatic impairment. No clinically meaningful differences in saxagliptin or 5-hydroxy saxagliptin pharmacokinetics have been detected in patients with mild renal impairment, whereas dose reduction is recommended in patients with moderate or severe renal impairment because of greater systemic exposure [the area under the plasma concentration-time curve (AUC)] to saxagliptin total active moieties. Clinically relevant drug-drug interactions have not been detected; however, limiting the dose to 2.5mg once daily is recommended in the USA when saxagliptin is coadministered with strong CYP inhibitors, because of increased saxagliptin exposure. In summary, saxagliptin has a predictable pharmacokinetic and pharmacodynamic profile.

Evidence for neural contribution to islet effects of DPP-4 inhibition in mice

It has been suggested that neural mechanisms may contribute to effects of the incretin hormones, and, therefore, also to the effects of dipeptidyl peptidase (DPP-4) inhibition. We therefore examined whether muscarinic mechanisms are involved in the stimulation of insulin secretion by DPP-4 inhibition. Fasted, anesthetized mice were given intraperitoneal saline or the muscarinic antagonist atropine (5mg/kg) before duodenal glucose (75mg/mouse), with or without the DPP-4 inhibitor NVPDPP728 (0.095mg/mouse), or before intravenous glucose (0.35g/kg) with or without co-administration with GLP-1 or glucose-dependent insulinotropic polypeptide (GIP) (both 3nmol/kg). Furthermore, isolated islets were incubated (1h) in 2.8 and 11.1mM glucose, with or without GIP or GLP-1 (both 100nM), in the presence or absence of atropine (100µM). Duodenal glucose increased circulating insulin and this effect was potentiated by DPP-4 inhibition. The increase in insulin achieved by DPP-4 inhibition was reduced by atropine by approximately 35%. Duodenal glucose also elicited an increase in circulating intact GLP-1 and GIP and this was augmented by DPP-4 inhibition, but these effects were not affected by atropine. Atropine did also not affect the augmentation by GLP-1 and GIP on glucose-stimulated insulin secretion from isolated islets. Based on these findings, we suggest that muscarinic mechanisms contribute to the stimulation of insulin secretion by DPP-4 inhibition through neural effects induced by GLP-1 and GIP whereas neural effects do not affect the levels of GLP-1 or GIP or the islet effects of the two incretin hormones.

A Protein Preload Enhances the Glucose-Lowering Efficacy of Vildagliptin in Type 2 Diabetes.

Nutrient "preloads" given before meals can attenuate postprandial glycemic excursions, at least partly by slowing gastric emptying and stimulating secretion of the incretins (i.e., glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]). This study was designed to evaluate whether a protein preload could improve the efficacy of the dipeptidyl peptidase-4 (DPP-4) inhibitor vildagliptin to increase incretin concentrations, slow gastric emptying, and lower postprandial glycemia in type 2 diabetes. Twenty-two patients with type 2 diabetes treated with metformin were studied on four occasions, receiving either 50 mg vildagliptin (VILD) or placebo (PLBO) on both the evening before and the morning of each study day. The latter dose was followed after 60 min by a preload drink containing either 25 g whey protein (WHEY) or control flavoring (CTRL), and after another 30 min by a (13)C-octanoate-labeled mashed potato meal. Plasma glucose and hormones, and gastric emptying, were evaluated. Compared with PLBO/CTRL, PLBO/WHEY reduced postprandial peak glycemia, increased plasma insulin, glucagon, and incretin hormones (total and intact), and slowed gastric emptying, whereas VILD/CTRL reduced both the peak and area under the curve for glucose, increased plasma intact incretins, and slowed gastric emptying but suppressed plasma glucagon and total incretins (P < 0.05 each). Compared with both PLBO/WHEY and VILD/CTRL, VILD/WHEY was associated with higher plasma intact GLP-1 and GIP, slower gastric emptying, and lower postprandial glycemia (P < 0.05 each). In metformin-treated type 2 diabetes, a protein preload has the capacity to enhance the efficacy of vildagliptin to slow gastric emptying, increase plasma intact incretins, and reduce postprandial glycemia.

Important species differences regarding lymph contribution to gut hormone responses

IntroductionGLP-1 is secreted from the gut upon nutrient intake and stimulates insulin secretion. The lymph draining the intestine may transport high levels of GLP-1 to the systemic circulation before it is metabolized by DPP-4. The aims of this study were to investigate to what extent the lymphatic system might contribute to the final level(s) of systemic circulating intact GLP-1 and, in addition, whether secretory profiles in intestinal lymph might reflect lamina propria levels of GLP-1 i.e. before capillary uptake and degradation by endothelial dipeptidyl peptidase-4 (DPP-4). Method7 pigs of the YDL-strain were catheterized in the portal vein, carotid artery and cisterna chyli (lymph). Neuromedin C (NC) was infused through an ear vein catheter, before and after injection of a selective DPP-4 inhibitor (vildagliptin). Total and intact GLP-1 levels were measured throughout the 150min experiments using specific sandwich ELISAs. DPP-4 activity was measured spectrophotometrically. ResultsConcentrations of both total and intact GLP-1 were markedly lower in lymph compared to plasma samples, and did not increase significantly in response to stimulation with NC in the absence/presence of vildagliptin. In contrast, total and intact GLP-1 levels increased significantly in the portal vein and carotid artery. DPP-4 activity was lower in lymph than plasma, and was reduced further by vildagliptin. ConclusionOur observations indicate that the lymphatic system does not transport high levels of intact GLP-1 to the systemic circulation, and that GLP-1 levels in cisternal lymph do not reflect the hormone levels in the intestinal lamina propria.

Rice protein hydrolysates stimulate GLP-1 secretion, reduce GLP-1 degradation, and lower the glycemic response in rats.

Rice has historically been consumed in Asia as a major source of carbohydrates, however, little is known regarding the functional roles of rice proteins as dietary factors. In the present study, we investigated whether peptides derived from rice proteins could stimulate GLP-1 secretion, which results in reducing glycemia via the incretin effect in normal rats. Hydrolysates were prepared from the protein fraction of rice endosperm or rice bran, and the effects of these hydrolysates on GLP-1 secretion were examined in a murine enteroendocrine cell line GLUTag. Plasma was collected after oral administration of the rice protein hydrolysates, under anesthesia, or during glucose tolerance tests in rats. In anesthetized rats, plasma dipeptidyl peptidase-IV (DPP-IV) activity was measured after ileal administration of the rice protein hydrolysates. GLP-1 secretion from GLUTag cells was potently stimulated by the rice protein hydrolysates, especially by the peptic digest of rice endosperm protein (REPH) and that of rice bran protein (RBPH). Oral administration of REPH or RBPH elevated plasma GLP-1 concentrations, which resulted in the reduction of glycemia under the intraperitoneal glucose tolerance test. In addition, the plasma DPP-IV activity was attenuated after ileal administration of REPH or RBPH, which resulted in a higher ratio of intact (active) GLP-1 to total GLP-1 in the plasma. These results demonstrate that rice proteins exert potent stimulatory effects on GLP-1 secretion, which could contribute to the reduction of postprandial glycemia. The inhibitory effect of these peptides on the plasma DPP-IV activity may potentiate the incretin effect of GLP-1.

Pleiotropic mechanisms for the glucose-lowering action of DPP-4 inhibitors.

Dipeptidyl peptidase (DPP)-4 inhibition is a glucose-lowering treatment for type 2 diabetes. The classical mechanism for DPP-4 inhibitors is that they inhibit DPP-4 activity in peripheral plasma, which prevents the inactivation of the incretin hormone glucagon-like peptide (GLP)-1 in the peripheral circulation. This in turn increases circulating intact GLP-1, which results in stimulated insulin secretion and inhibited glucagon secretion, in turn increasing glucose utilization and diminishing hepatic glucose production, which, through reduction in postprandial and fasting glucose, reduces HbA1c. However, recent experimental studies in mainly rodents but also to a limited degree in humans have found additional mechanisms for DPP-4 inhibitors that may contribute to their glucose-lowering action. These nonclassical mechanisms include 1) inhibition of gut DPP-4 activity, which prevents inactivation of newly released GLP-1, which in turn augments GLP-1-induced activations of autonomic nerves and results in high portal GLP-1 levels, resulting in inhibited glucose production through portal GLP-1 receptors; 2) inhibition of islet DPP-4 activity, which prevents inactivation of locally produced intact GLP-1 in the islets, thereby augmenting insulin secretion and inhibiting glucagon secretion and possibly preventing islet inflammation; and 3) prevention of the inactivation of other bioactive peptides apart from GLP-1, such as glucose-dependent insulinotropic polypeptide, stromal-derived factor-1α, and pituitary adenylate cyclase-activating polypeptide, which may improve islet function. These pleiotropic effects may contribute to the effects of DPP-4 inhibition. This Perspectives in Diabetes outlines and discusses these nonclassical mechanisms of DPP-4 inhibition.

Cardiovascular actions of incretin-based therapies.

Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors represent 2 distinct classes of incretin-based therapies used for the treatment of type 2 diabetes mellitus. Activation of GLP-1R signaling or inhibition of DPP-4 activity produces a broad range of overlapping and unique cardiovascular actions. Native GLP-1 regulates cardiovascular biology via activation of the classical GLP-1R, or through GLP-1(9-36), a cardioactive metabolite generated by DPP-4-mediated cleavage. In contrast, clinically approved GLP-1R agonists are not cleaved to GLP-1(9-36) and produce the majority of their actions through the classical GLP-1R. The cardiovascular mechanisms engaged by DPP-4 inhibition are more complex, encompassing increased levels of intact GLP-1, reduced levels of GLP-1(9-36), and changes in levels of numerous cardioactive peptides. Herein we review recent experimental and clinical advances that reveal how GLP-1R agonists and DPP-4 inhibitors affect the normal and diabetic heart and coronary vasculature, often independent of changes in blood glucose. Improved understanding of the complex science of incretin-based therapies is required to optimize the selection of these therapeutic agents for the treatment of diabetic patients with cardiovascular disease.

Effects of Sitagliptin and Metformin Treatment on Incretin Hormone and Insulin Secretory Responses to Oral and “Isoglycemic” Intravenous Glucose

Dipeptidyl peptidase-4 (DPP-4) inhibitors prevent degradation of incretin hormones (glucagon-like peptide 1 [GLP-1] and glucose-dependent insulinotropic polypeptide [GIP]), whereas metformin may increase GLP-1 levels. We examined, in a four-period crossover trial, the influence of metformin (2,000 mg/day), sitagliptin (100 mg/day), or their combination, on GLP-1 responses and on the incretin effect in 20 patients with type 2 diabetes, comparing an oral glucose challenge (75 g, day 5) and an "isoglycemic" intravenous glucose infusion (day 6). Fasting total GLP-1 was significantly increased by metformin and not changed by sitagliptin. After oral glucose, metformin increased and sitagliptin significantly decreased (by 53%) total GLP-1. Fasting and postload intact GLP-1 increased with sitagliptin but not with metformin. After oral glucose, only sitagliptin, but not metformin, significantly augmented insulin secretion, in monotherapy and as an add-on to metformin. The incretin effect was not changed numerically with any of the treatments. In conclusion, sitagliptin increased intact GLP-1 and GIP through DPP-4 inhibition but reduced total GLP-1 and GIP (feedback inhibition) without affecting the numerical contribution of the incretin effect. Insulin secretion with sitagliptin treatment was similarly stimulated with oral and "isoglycemic" intravenous glucose. This points to an important contribution of small changes in incretin concentrations within the basal range or to additional insulinotropic agents besides GLP mediating the antidiabetic effects of DPP-4 inhibition.

Characterisation of oral and i.v. glucose handling in truncally vagotomised subjects with pyloroplasty

ObjectiveGlucagon-like peptide 1 (GLP1) is rapidly inactivated by dipeptidyl peptidase 4 (DPP4), but may interact with vagal neurons at its site of secretion. We investigated the role of vagal innervation for handling of oral and i.v. glucose.Design and methodsTruncally vagotomised subjects (n=16) and matched controls (n=10) underwent 50 g-oral glucose tolerance test (OGTT)±vildagliptin, a DPP4 inhibitor (DPP4i) and isoglycaemic i.v. glucose infusion (IIGI), copying the OGTT without DPP4i.ResultsIsoglycaemia was obtained with 25±2 g glucose in vagotomised subjects and 18±2 g in controls (P<0.03); thus, gastrointestinal-mediated glucose disposal (GIGD) – a measure of glucose handling (100%×(glucoseOGTT−glucoseIIGI/glucoseOGTT)) – was reduced in the vagotomised compared with the control group. Peak intact GLP1 concentrations were higher in the vagotomised group. Gastric emptying was faster in vagotomised subjects after OGTT and was unaffected by DPP4i. The early glucose-dependent insulinotropic polypeptide response was higher in vagotomised subjects. Despite this, the incretin effect was equal in both groups. DPP4i enhanced insulin secretion in controls, but had no effect in the vagotomised subjects. Controls suppressed glucagon concentrations similarly, irrespective of the route of glucose administration, whereas vagotomised subjects showed suppression only during IIGI and exhibited hyperglucagonaemia following OGTT. DPP4i further suppressed glucagon secretion in controls and tended to normalise glucagon responses in vagotomised subjects.ConclusionsGIGD is diminished, but the incretin effect is unaffected in vagotomised subjects despite higher GLP1 levels. This, together with the small effect of DPP4i, is compatible with the notion that part of the physiological effects of GLP1 involves vagal transmission.

Linagliptin Increases Incretin Levels, Lowers Glucagon, and Improves Glycemic Control in Type 2 Diabetes Mellitus

IntroductionLinagliptin is a xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor that is now available in numerous countries worldwide for the treatment of type 2 diabetes mellitus (T2DM). The aim of this study was to evaluate further the mechanisms underlying the improvements in glycemic control observed with linagliptin. The effects of linagliptin on DPP-4, pharmacodynamic parameters, and glycemic control versus placebo were assessed in patients with inadequately controlled T2DM.MethodsPatients in this phase 2a, multicenter, randomized, double-blind, placebo-controlled study received placebo (n = 40) or linagliptin 5 mg (n = 40). Sitagliptin 100 mg (n = 41) once daily for 4 weeks was included for exploratory purposes. Primary endpoints for linagliptin versus placebo: change from baseline to day 28 in 24-h weighted mean glucose (WMG) and intact glucagon-like peptide (GLP)-1 area under the time–effect curve between 0 and 2 h (AUEC0–2h) following meal tolerance test on day 28.ResultsLinagliptin increased intact GLP-1 AUEC0–2h (+18.1 pmol/h/L) and lowered 24-h WMG (−1.1 mmol/L) versus placebo (both P < 0.0001) after 28 days. Intact glucose-dependent insulinotropic polypeptide increased in line with GLP-1 (+91.4 pmol/h/L increase vs. placebo; P < 0.0001). Glycated hemoglobin (−0.22%; P = 0.0021), fasting plasma glucose (−0.6 mmol/L; P = 0.0283), and glucose (AUEC0–3h) (−5.9 mmol/h/L; P < 0.0001) improved significantly with linagliptin versus placebo. Most adverse events were mild; hypoglycemia or serious adverse events were not reported. Sustained DPP-4 inhibition (≥80%) throughout the treatment period was accompanied by significant reductions in glucagon starting at day 1 of linagliptin administration.ConclusionLinagliptin was well tolerated and effectively inhibited plasma DPP-4 activity in patients with T2DM, producing immediate improvements in incretin levels, glucagon suppression, and glycemic control that were maintained throughout the study period.

GLP-1 Receptor Antagonist Exendin-(9-39) Elevates Fasting Blood Glucose Levels in Congenital Hyperinsulinism Owing to Inactivating Mutations in the ATP-Sensitive K+ Channel

Infants with congenital hyperinsulinism owing to inactivating mutations in the KATP channel (KATPHI) who are unresponsive to medical therapy will require pancreatectomy to control the hypoglycemia. In preclinical studies, we showed that the GLP-1 receptor antagonist exendin-(9-39) suppresses insulin secretion and corrects fasting hypoglycemia in SUR-1−/− mice. The aim of this study was to examine the effects of exendin-(9-39) on fasting blood glucose in subjects with KATPHI. This was a randomized, open-label, two-period crossover pilot clinical study. Nine subjects with KATPHI received either exendin-(9-39) or vehicle on two different days. The primary outcome was blood glucose; secondary outcomes were insulin, glucagon, and GLP-1. In all subjects, mean nadir blood glucose and glucose area under the curve were significantly increased by exendin-(9-39). Insulin-to-glucose ratios were significantly lower during exendin-(9-39) infusion compared with vehicle. Fasting glucagon and intact GLP-1 were not affected by treatment. In addition, exendin-(9-39) significantly inhibited amino acid–stimulated insulin secretion in pancreatic islets isolated from neonates with KATPHI. Our findings have two important implications: 1) GLP-1 and its receptor play a role in the regulation of fasting glycemia in KATPHI; and 2) the GLP-1 receptor may be a therapeutic target for the treatment of children with KATPHI.

Vildagliptin: a DPP-4 inhibitor for the treatment of Type 2 diabetes

SUMMARY The key defect in Type 2 diabetes is islet dysfunction, which includes impaired insulin secretion, augmented glucagon secretion and reduced β-cell mass. The incretin hormone GLP-1 targets this islet dysfunction. GLP-1 is inactivated by DPP-4 and, consequently, DPP-4 inhibition has evolved as an efficient treatment of hyperglycemia in Type 2 diabetes since it increases the concentrations of intact GLP-1. Several DPP-4 inhibitors have been developed and all of them have been shown to be efficient in improving glycemia with a low risk for adverse events. This article reviews basic and clinical studies on one of the DPP-4 inhibitors, vildagliptin. It is a specific inhibitor of DPP-4 and improves glycemia both when used in monotherapy and when used as an add-on to metformin, sulfonylurea, thioazolidinedione or insulin in subjects with Type 2 diabetes. Clinical studies have shown that vildagliptin reduces HbA1c in association with a low risk of adverse events, including hypoglycemia, and no weight gain....

16,17-Dihydro-17b-hydroxy isomitraphylline alkaloid as an inhibitor of DPP-IV, and its effect on incretin hormone and β-cell proliferation in diabetic rat

Reduces levels of intact GLP-1 and inhibition of DPPIV augments levels of intact GLP-1 improves glycemic control in type 2 diabetes patients and diabetic animal model. Although, GLP-1 is known to stimulate insulin secretion, insulin biosynthesis and dose insulin gene transcription, augmented supplies of insulin for secretion. DHIM is an indole alkaloid, isolated from Mitragyna parvifolia. In the present in vitro study, we investigated the inhibitor activity of novel alkaloid on DPP IV. DHIM produced marked inhibition of DPP IV. Accordingly, we used 5, 10 and 20μg DHIM alkaloids in DPPIV assay, and then found 18%, 56%, and 68% inhibition activity.In the present in vivo study, we examined the 16,17-dihydro-17b-hydroxy (DHIM) effect on neonatal Wistar albino rats treated with streptozotocin, an established model of type 2 diabetes. Diabetic rats, 8weeks chronic administered with DHIM (100mg/kg) markedly reduced plasma glucose concentration, increased glucose tolerance in response to glucose loading. Consequently, GLP-1and IL-10 levels were also significantly increased in treated diabetic rats. Despite, body weight was not found changed significantly; the insulin content and β-cell mass at 2months were significantly increased by DHIM.Immunostaining and Confocal image of TUNEL assay showed that DHIM stimulates β-cell proliferation and reduced pancreatic cell apoptosis in diabetic treated rats. These results suggest that DHIM induces proliferation of pancreatic cells and increases the formation of β-cells.