Effect of single‐dose DPP‐4 inhibitor sitagliptin on β‐cell function and incretin hormone secretion after meal ingestion in healthy volunteers and drug‐naïve,well‐controlled type 2 diabetes subjects

To explore the effects of a single dose of the DPP‐4 inhibitor sitagliptin on glucose‐standardized insulin secretion and β‐cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug‐naïve, well‐controlled type 2 diabetes (T2D) subjects (mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100 mg) or placebo before a meal (525 kcal). β‐cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β‐cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion, in both healthy and T2D subjects, compared to placebo, but without increasing β‐cell glucose sensitivity. Sitagliptin also increased active glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) and reduced total (reflecting the secretion) GIP, but not total GLP‐1 levels. We conclude that a single dose of DPP‐4 inhibition induces dissociated effects on different aspects of β‐cell function and incretin hormones after meal ingestion in both healthy and well‐controlled T2D subjects.     

Plasma gastric inhibitory polypeptide and glucagon‐like peptide‐1 levels after glucose loading are associated with different factors in Japanese subjects

Aims/Introduction: Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are major incretins that potentiate insulin secretion from pancreatic β‐cells. The factors responsible for incretin secretion have been reported in Caucasian subjects, but have not been thoroughly evaluated in Japanese subjects. We evaluated the factors associated with incretin secretion during oral glucose tolerance test (OGTT) in Japanese subjects with normal glucose tolerance (NGT). Materials and Methods: We measured plasma GIP and GLP‐1 levels during OGTT in 17 Japanese NGT subjects and evaluated the factors associated with GIP and GLP‐1 secretion using simple and multiple regression analyses. Results: GIP secretion (AUC‐GIP) was positively associated with body mass index (P < 0.05), and area under the curve (AUC) of C‐peptide (P < 0.05) and glucagon (P < 0.01), whereas GLP‐1 secretion (AUC‐GLP‐1) was negatively associated with AUC of plasma glucose (P < 0.05). The insulinogenic index was most strongly associated with GIP secretion (P < 0.05); homeostasis model assessment β‐cell was the most the strongly associated factor in GLP‐1 secretion (P < 0.05) among the four indices of insulin secretion and insulin sensitivity. Conclusions: Several distinct factors might be associated with GIP and GLP‐1 secretion during OGTT in Japanese subjects. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00078.x, 2011)     

Reactive hypoglycaemia following GLP‐1 infusion in pancreas transplant recipients

The aim of the study was to determine whether reactive hypoglycaemia in pancreas transplant recipients that followed administration of glucagon‐like peptide‐1 (GLP‐1) was associated with excessive insulin, insufficient glucagon, or both. Methodology involved six portally drained pancreas recipients who received GLP‐1 (1.5 pmol/kg/min) or placebo infusion on randomized occasions during glucose‐potentiated arginine testing. The second subject developed symptomatic hypoglycaemia [plasma glucose (PG) 42 mg/dl] 1 h after GLP‐1 administration; subsequent subjects received intravenous glucose following GLP‐1, but not placebo, infusion for PG levels <65 mg/dl. Following GLP‐1 vs. placebo infusion, PG was lower (58 ± 4 vs. 76 ± 5 mg/dl; p < 0.05) despite administration of intravenous glucose. During hypoglycaemia, insulin levels and the insulin‐to‐glucagon ratio were greater after GLP‐1 vs. placebo infusion (p < 0.05), while glucagon did not vary. It can be concluded from the study that GLP‐1 can induce reactive hypoglycaemia in pancreas transplant recipients through excessive insulin secretion associated with an increased insulin‐to‐glucagon ratio.     

Combining GLP‐1 receptor agonists with insulin: therapeutic rationales and clinical findings

Due to the increasing prevalence of type 2 diabetes mellitus (T2DM), the emergent trend towards diagnosis in younger patients and the progressive nature of this disease, many more patients than before now require insulin to maintain glycaemic control. However, there is a degree of inertia among physicians and patients regarding the initiation and intensification of insulin therapy, in part due to concerns about the associated weight gain and increased risk of hypoglycaemia. Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) increase insulin release and suppress glucagon secretion in a glucose‐dependent manner, thus conferring glycaemic control with a low incidence of hypoglycaemia. GLP‐1RAs also promote weight loss, and have beneficial effects on markers of β cell function, lipid levels, blood pressure and cardiovascular risk markers. However, the durability of their effectiveness is unknown and, compared with insulin, the antihyperglycaemic efficacy of GLP‐1RAs is limited. The combination of a GLP‐1RA and insulin might thus be highly effective for optimal glucose control, ameliorating the adverse effects typically associated with insulin. Data from clinical studies support the therapeutic potential of GLP‐1RA–insulin combination therapy, typically showing beneficial effects on glycaemic control and body weight, with a low incidence of hypoglycaemia and, in established insulin therapy, facilitating reductions in insulin dose. In this review, the physiological and pharmacological rationale for using GLP‐1RA and insulin therapies in combination is discussed, and data from clinical studies that have assessed the efficacy and safety of this treatment strategy are outlined.     

Weight loss and incretin responsiveness improve glucose control independently after gastric bypass surgery

Background: The aim of the present study was to determine the mechanisms underlying Type 2 diabetes remission after gastric bypass (GBP) surgery by characterizing the short‐ and long‐term changes in hormonal determinants of blood glucose. Methods: Eleven morbidly obese women with diabetes were studied before and 1, 6, and 12 months after GBP; eight non‐diabetic morbidly obese women were used as controls. The incretin effect was measured as the difference in insulin levels in response to oral glucose and to an isoglycemic intravenous challenge. Outcome measures were glucose, insulin, C‐peptide, proinsulin, amylin, glucagon, glucose‐dependent insulinotropic polypeptide (GIP), glucagon‐like peptide‐1 (GLP‐1) levels and the incretin effect on insulin secretion. Results: The decrease in fasting glucose (r = 0.724) and insulin (r = 0.576) was associated with weight loss up to 12 months after GBP. In contrast, the blunted incretin effect (calculated at 22%) that improved at 1 month remained unchanged with further weight loss at 6 (52%) and 12 (52%) months. The blunted incretin (GLP‐1 and GIP) levels, early phase insulin secretion, and other parameters of β‐cell function (amylin, proinsulin/insulin) followed the same pattern, with rapid improvement at 1 month that remained unchanged at 1 year. Conclusions: The data suggest that weight loss and incretins may contribute independently to improved glucose levels in the first year after GBP surgery.     

Taspoglutide,a novel human once‐weekly analogue of glucagon‐like peptide‐1, improves glucose homeostasis and body weight in the Zucker diabetic fatty rat

Aim: Glucagon‐like peptide‐1 (GLP‐1) receptor agonists are a novel class of pharmacotherapy for type 2 diabetes. We investigated the effects of a novel, long‐acting human GLP‐1 analogue, taspoglutide, in the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. Methods: Blood glucose and plasma levels of insulin, peptide YY (PYY), glucose‐dependent insulinotropic polypeptide (GIP) and triglycerides were measured during oral glucose tolerance tests (oGTT) conducted in ZDF rats treated acutely or chronically with a single long‐acting dose of taspoglutide. Pioglitazone was used as a positive control in the chronic study. Postprandial glucose, body weight, glycaemic control and insulin sensitivity were assessed over 21 days in chronically treated animals. Results: Acute treatment with taspoglutide reduced glucose excursion and increased insulin response during oGTT. In chronically treated rats, glucose excursion and levels of GIP, PYY and triglycerides during oGTT on day 21 were significantly reduced. Postprandial glucose levels were significantly lower than vehicle controls by day 15. A significant reduction in body weight gain was noticed by day 8, and continued until the end of the study when body weight was approximately 7% lower in rats treated with taspoglutide compared to vehicle. Glycaemic control (increased levels of 1,5‐anhydroglucitol) and insulin sensitivity (Matsuda index) were improved by taspoglutide treatment. Conclusions: Taspoglutide showed typical effects of native GLP‐1, with improvement in glucose tolerance, postprandial glucose, body weight, glycaemic control and insulin sensitivity.     

Combination treatment with alogliptin and voglibose increases active GLP‐1 circulation,prevents the development of diabetes and preserves pancreatic beta‐cells in prediabetic db/db mice

Aim: Alogliptin, a dipeptidyl peptidase‐4 (DPP‐4) inhibitor, and voglibose, an alpha‐glucosidase inhibitor, have different but complementary mechanisms of action on glucagon‐like peptide‐1 (GLP‐1) regulation and glucose‐lowering effects. The present study evaluated the chronic effects of combination treatment with alogliptin and voglibose in prediabetic db/db mice. Methods: Alogliptin (0.03%) and voglibose (0.001%) alone or in combination were administered in the diet to prediabetic db/db mice. Results: After 3 weeks, voglibose treatment increased GLP‐1 secretion (voglibose alone, 1.6‐fold; alogliptin plus voglibose, 1.5‐fold), while it decreased plasma glucose‐dependent insulinotropic polypeptide (GIP) (voglibose alone, ?30%; alogliptin plus voglibose, ?29%). Alogliptin, voglibose and combination treatment decreased plasma DPP‐4 activity by 72, 15 and additively by 80%, respectively, and increased plasma active GLP‐1 levels by 4.5‐, 1.8‐ and synergistically by 9.1‐fold respectively. Combination treatment increased plasma insulin by 3.6‐fold (alogliptin alone, 1.3‐fold; voglibose alone, 1.8‐fold), decreased plasma glucagon by 30% (alogliptin alone, 11%; voglibose alone, 8%), and prevented the development of diabetes, much more effectively than either agent alone. After 4 weeks, alogliptin, voglibose and combination treatment increased pancreatic insulin content by 1.6‐, 3.4‐ and synergistically by 8.5‐fold respectively. Furthermore, combination treatment resulted in an increased expression of insulin, pancreatic and duodenal homeobox 1 (PDX1) and glucose transporter 2 (GLUT2), and maintenance of normal beta/alpha‐cell distribution in the pancreatic islet. Conclusions: Chronic treatment with alogliptin in combination with voglibose concurrently increased active GLP‐1 circulation, increased insulin secretion, decreased glucagon secretion, prevented the onset of the disease, and preserved pancreatic beta‐cells and islet structure in prediabetic db/db mice.     

Diabetes and obesity treatment based on dual incretin receptor activation: ‘twincretins’

The gut incretin hormones glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion and regulate glucagon secretion. GLP‐1 also slows gastric emptying and suppresses appetite, whereas GIP seems to affect lipid metabolism. The introduction of selective GLP‐1 receptor (GLP‐1R) agonists for the treatment of type 2 diabetes and obesity has increased the scientific and clinical interest in incretins. Combining the body weight‐lowering and glucose‐lowering effects of GLP‐1 with a more potent improvement of β cell function through additional GIP action could potentially offer a more effective treatment of diabetes and obesity, with fewer adverse effects than selective GLP‐1R agonists; therefore, new drugs designed to co‐activate both the GIP receptor (GIPR) and the GLP‐1R simultaneously are under development. In the present review, we address advances in the field of GIPR and GLP‐1R co‐agonism and review in vitro studies, animal studies and human trials involving co‐administration of the two incretins, as well as results from a recently developed GIPR/GLP‐1R co‐agonist, and highlight promising areas and challenges within the field of incretin dual agonists.     

Chronic administration of DSP‐7238, a novel,potent, specific and substrate‐selective DPP IV inhibitor,improves glycaemic control and β‐cell damage in diabetic mice

Aims: The purpose of this study is to assess the in vitro enzyme inhibition profile of DSP‐7238, a novel non‐cyanopyrrolidine dipeptidyl peptidase (DPP) IV inhibitor and to evaluate the acute and chronic effects of this compound on glucose metabolism in two different mouse models of type 2 diabetes. Methods: The in vitro enzyme inhibition profile of DSP‐7238 was assessed using plasma and recombinant enzymes including DPP IV, DPP II, DPP8, DPP9 and fibroblast activation protein α (FAPα) with fluorogenic substrates. The inhibition type was evaluated based on the Lineweaver–Burk plot. Substrate selectivity of DSP‐7238 and comparator DPP IV inhibitors (vildagliptin, sitagliptin, saxagliptin and linagliptin) was evaluated by mass spectrometry based on the changes in molecular weight of peptide substrates caused by release of N‐terminal dipeptides. In the in vivo experiments, high‐fat diet‐induced obese (DIO) mice were subjected to oral glucose tolerance test (OGTT) following a single oral administration of DSP‐7238. To assess the chronic effects of DSP‐7238 on glycaemic control and pancreatic β‐cell damage, DSP‐7238 was administered for 11 weeks to mice made diabetic by a combination of high‐fat diet (HFD) and a low‐dose of streptozotocin (STZ). After the dosing period, HbA1c was measured and pancreatic damage was evaluated by biological and histological analyses. Results: DSP‐7238 and sitagliptin both competitively inhibited recombinant human DPP IV (rhDPP IV) with K_i values of 0.60 and 2.1 nM respectively. Neither vildagliptin nor saxagliptin exhibited competitive inhibition of rhDPP IV. DSP‐7238 did not inhibit DPP IV‐related enzymes including DPP8, DPP9, DPP II and FAPα, whereas vildagliptin and saxagliptin showed inhibition of DPP8 and DPP9. Inhibition of glucagon‐like peptide‐1 (GLP‐1) degradation by DSP‐7238 was apparently more potent than its inhibition of chemokine (C‐X‐C motif) ligand 10 (IP‐10) or chemokine (C‐X‐C motif) ligand 12 (SDF‐1α) degradation. In contrast, vildagliptin and saxagliptin showed similar degree of inhibition of degradation for all the substrates tested. Compared to treatment with the vehicle, single oral administration of DSP‐7238 dose‐dependently decreased plasma DPP IV activity and improved glucose tolerance in DIO mice. In addition, DSP‐7238 significantly decreased HbA1c and ameliorated pancreatic damage following 11 weeks of chronic treatment in HFD/STZ mice. Conclusions: We have shown in this study that DSP‐7238 is a potent DPP IV inhibitor that has high specificity for DPP IV and substrate selectivity against GLP‐1. We have also found that chronic treatment with DSP‐7238 improves glycaemic control and ameliorates β‐cell damage in a mouse model with impaired insulin sensitivity and secretion. These findings indicate that DSP‐7238 may be a new therapeutic agent for the treatment of type 2 diabetes.     

Metformin reduces the rate of small intestinal glucose absorption in type 2 diabetes

In rodents, metformin slows intestinal glucose absorption, potentially increasing exposure of the distal gut to glucose to enhance postprandial glucagon‐like peptide‐1 (GLP‐1) secretion. We evaluated the effects of metformin on serum 3‐O‐methylglucose (3‐OMG; a marker of glucose absorption) and plasma total GLP‐1 concentrations during a standardized intraduodenal infusion of glucose and 3‐OMG in patients with type 2 diabetes. A total of 12 patients, treated with metformin 850 mg twice daily or placebo for 7 days each in a double‐blind, randomized, crossover design (14 days’ washout between treatments), were evaluated on days 5 or 8 of each treatment (6 subjects each). On each study day, 30 minutes after ingesting 850 mg metformin or placebo, patients received an infusion of glucose (60 g + 5 g 3‐OMG, dissolved in water to 240 mL) via an intraduodenal catheter over the course of 120 minutes. Compared with placebo, metformin was associated with lower serum 3‐OMG ( P < .001) and higher plasma total GLP‐1 ( P = .003) concentrations. The increment in plasma GLP‐1 after metformin vs placebo was related to the reduction in serum 3‐OMG concentrations ( P = .019). Accordingly, metformin inhibits small intestinal glucose absorption, which may contribute to augmented GLP‐1 secretion in type 2 diabetes.     

Glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1: Incretin actions beyond the pancreas

Glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the two primary incretin hormones secreted from the intestine on ingestion of various nutrients to stimulate insulin secretion from pancreatic β‐cells glucose‐dependently. GIP and GLP‐1 undergo degradation by dipeptidyl peptidase‐4 (DPP‐4), and rapidly lose their biological activities. The actions of GIP and GLP‐1 are mediated by their specific receptors, the GIP receptor (GIPR) and the GLP‐1 receptor (GLP‐1R), which are expressed in pancreatic β‐cells, as well as in various tissues and organs. A series of investigations using mice lacking GIPR and/or GLP‐1R, as well as mice lacking DPP‐4, showed involvement of GIP and GLP‐1 in divergent biological activities, some of which could have implications for preventing diabetes‐related microvascular complications (e.g., retinopathy, nephropathy and neuropathy) and macrovascular complications (e.g., coronary artery disease, peripheral artery disease and cerebrovascular disease), as well as diabetes‐related comorbidity (e.g., obesity, non‐alcoholic fatty liver disease, bone fracture and cognitive dysfunction). Furthermore, recent studies using incretin‐based drugs, such as GLP‐1 receptor agonists, which stably activate GLP‐1R signaling, and DPP‐4 inhibitors, which enhance both GLP‐1R and GIPR signaling, showed that GLP‐1 and GIP exert effects possibly linked to prevention or treatment of diabetes‐related complications and comorbidities independently of hyperglycemia. We review recent findings on the extrapancreatic effects of GIP and GLP‐1 on the heart, brain, kidney, eye and nerves, as well as in the liver, fat and several organs from the perspective of diabetes‐related complications and comorbidities.     

Effects of glucose and meal ingestion on incretin secretion in Japanese subjects with normal glucose tolerance

Aims/Introduction: Gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) are the major incretins; their secretion after various nutrient loads are well‐evaluated in Caucasians. However, little is known of the relationship between incretin secretion and differing nutritional loading in Japanese subjects. In the present study, we evaluated GIP and GLP‐1 secretion in Japanese subjects with normal glucose tolerance (NGT) after glucose loading (75 g glucose and 17 g glucose) and meal ingestion. Materials and Methods: A total of 10 Japanese NGT subjects participated in 75 g oral glucose tolerance test (OGTT), 17 g OGTT and meal tolerance test (MTT). Plasma glucose (PG), serum insulin (IRI), serum C‐peptide (CPR), plasma total GIP, and plasma total GLP‐1 levels during OGTT and MTT were determined. Results: Area under the curve (AUC)‐GIP was increased in proportion to the amount of glucose, and was highest in MTT, showing that GIP secretion is also stimulated by nutrients other than glucose, such as lipid. In contrast, although the larger glucose load tended to induce a larger GLP‐1 release, AUC‐GLP‐1 was not significantly different among the three loading tests (75 g OGTT, 17 g OGTT, MTT) irrespective of the kind or amount of nutrition load. Conclusions: Our results suggest that nutritional composition might have a greater effect on GIP secretion than that on GLP‐1 secretion in Japanese NGT subjects . (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00143.x, 2012)     

Improved glycaemic control with minimal hypoglycaemia and no weight change with the once‐daily human glucagon‐like peptide‐1 analogue liraglutide as add‐on to sulphonylurea in Japanese patients with type 2 diabetes

Aim: Sulphonylureas (SUs) are often used as first‐line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. Methods: The efficacy and safety of the once‐daily human glucagon‐like peptide‐1 (GLP‐1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m²; mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24‐week, double‐blind, parallel‐group trial. Results: The mean change in HBA1c from baseline to week 24 (LOCF) was ?1.56 (s.d. 0.84) and ?1.46 (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and ?0.40 (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < 0.0001 for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference ?1.47 mmol/l and ?1.80 mmol/l with 0.6 and 0.9 mg vs. placebo; p < 0.0001). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: ?0.37 kg), while mean body weight decreased in subjects receiving placebo (?1.12 kg). Conclusions: The addition of liraglutide to SU treatment for 24 weeks dose‐dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss.     

Engineering and characterization of the long‐acting glucagon‐like peptide‐1 analogue LY2189265, an Fc fusion protein

Background

Glucagon‐like peptide‐1 (GLP‐1) receptor agonists are novel agents for type 2 diabetes treatment, offering glucose‐dependent insulinotropic effects, reduced glucagonemia and a neutral bodyweight or weight‐reducing profile. However, a short half‐life (minutes), secondary to rapid inactivation by dipeptidyl peptidase‐IV (DPP‐IV) and excretion, limits the therapeutic potential of the native GLP‐1 hormone. Recently, the GLP‐1 receptor agonist exenatide injected subcutaneously twice daily established a novel therapy class. Developing long‐acting and efficacious GLP‐1 analogues represents a pivotal research goal. We developed a GLP‐1 immunoglobulin G (IgG4) Fc fusion protein (LY2189265) with extended pharmacokinetics and activity.

Methods

In vitro and in vivo activity of LY2189265 was characterized in rodent and primate cell systems and animal models.

Results

LY2189265 retained full receptor activity in vitro and elicited insulinotropic activity in islets similar to native peptide. Half‐life in rats and cynomolgus monkeys was 1.5–2 days, and serum immunoreactivity representing active compound persisted > 6 days. In rats, LY2189265 enhanced insulin responses during graded glucose infusion 24 h after one dose. LY2189265 increased glucose tolerance in diabetic mice after one dose and lowered weight and delayed hyperglycaemia when administered twice weekly for 4 weeks. In monkeys, LY2189265 significantly increased glucose‐dependent insulin secretion for up to a week after one dose, retained efficacy when administered subchronically (once weekly for 4 weeks) and was well tolerated.

Conclusions

LY2189265 retains the effects of GLP‐1 with increased half‐life and efficacy, supporting further evaluation as a once‐weekly treatment of type 2 diabetes. Copyright © 2010 John Wiley & Sons, Ltd.     

Dual modulation of GIP and glucagon action by the low molecular weight compound 4-hydroxybenzoic acid 2-bromobenzylidene hydrazide

Aim: The presence of functional gastric inhibitory polypeptide (GIP) receptors on adipocytes and knowledge that GIP plays a key role in fat deposition suggests a beneficial effect of GIP receptor antagonism in obesity and insulin resistance. GIP receptor antagonists studied to date are peptidic GIP analogues that must be administered by injection. Methods: The present study has examined in vitro and in vivo metabolic actions of a low molecular weight GIP receptor modulator 4‐hydroxybenzoic acid 2‐bromobenzylidene hydrazide (4H2BH), suitable for oral administration. Results: 4H2BH alone had no significant effect on cAMP production or insulin secretion from BRIN‐BD11 cells. However, 4H2BH significantly inhibited GIP‐mediated cAMP production and insulin secretion in vitro. 4H2BH also suppressed (p < 0.05 to p < 0.001) glucagon‐induced elevations of cAMP generation and insulin secretion in BRIN‐BD11 cells. However, 4H2BH had no effect on glucagon‐like peptide‐1 (GLP‐1) mediated insulinotropic actions. Administration of 4H2BH to mice in combination with glucose and GIP significantly annulled the glucose‐lowering actions of GIP. In agreement with this, 4H2BH completely annulled GIP‐mediated insulin secretion. Combined injection of 4H2BH with glucagon also partially (p < 0.05 to p < 0.001) impaired glucagon‐induced elevations in blood glucose and plasma insulin. 4H2BH had no effect on blood glucose or insulin levels when administered alone. Conclusion: These results indicate that 4H2BH has a dual effect of inhibiting GIP and glucagon‐mediated biological actions. Given that hyperglucagonaemia is also a cardinal feature of type 2 diabetes, 4H2BH and related low molecular weight compounds appear worthy of further evaluation for therapeutic potential in obesity diabetes.     

Ingestion of a moderate high‐sucrose diet results in glucose intolerance with reduced liver glucokinase activity and impaired glucagon‐like peptide‐1 secretion

Aims/Introduction: Excessive intake of sucrose can cause severe health issues, such as diabetes mellitus. In animal studies, consumption of a high‐sucrose diet (SUC) has been shown to cause obesity, insulin resistance and glucose intolerance. However, several in vivo experiments have been carried out using diets with much higher sucrose contents (50–70% of the total calories) than are typically ingested by humans. In the present study, we examined the effects of a moderate SUC on glucose metabolism and the underlying mechanism. Materials and Methods: C57BL/6J mice received a SUC (38.5% sucrose), a high‐starch diet (ST) or a control diet for 5 weeks. We assessed glucose tolerance, incretin secretion and liver glucose metabolism. Results: An oral glucose tolerance test (OGTT) showed that plasma glucose levels in the early phase were significantly higher in SUC‐fed mice than in ST‐fed or control mice, with no change in plasma insulin levels at any stage. SUC‐fed mice showed a significant improvement in insulin sensitivity. Glucagon‐like peptide‐1 (GLP‐1) secretion 15 min after oral glucose administration was significantly lower in SUC‐fed mice than in ST‐fed or control mice. Hepatic glucokinase (GCK) activity was significantly reduced in SUC‐fed mice. During the OGTT, the accumulation of glycogen in the liver was suppressed in SUC‐fed mice in a time‐dependent manner. Conclusions: These results indicate that mice that consume a moderate SUC show glucose intolerance with a reduction in hepatic GCK activity and impairment in GLP‐1 secretion. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00208.x , 2012)     

Incretin therapies: highlighting common features and differences in the modes of action of glucagon‐like peptide‐1 receptor agonists and dipeptidyl peptidase‐4 inhibitors

Over the last few years, incretin‐based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon‐like peptide 1 (GLP‐1), which is partly responsible for augmenting glucose‐dependent insulin secretion in response to nutrient intake (the ‘incretin effect’). In patients with T2D, pharmacological doses/concentrations of GLP‐1 can compensate for the inability of diabetic β cells to respond to the main incretin hormone glucose‐dependent insulinotropic polypeptide, and this is therefore a suitable parent compound for incretin‐based glucose‐lowering medications. Two classes of incretin‐based therapies are available: GLP‐1 receptor agonists (GLP‐1RAs) and dipeptidyl peptidase‐4 (DPP‐4) inhibitors. GLP‐1RAs promote GLP‐1 receptor (GLP‐1R) signalling by providing GLP‐1R stimulation through ‘incretin mimetics’ circulating at pharmacological concentrations, whereas DPP‐4 inhibitors prevent the degradation of endogenously released GLP‐1. Both agents produce reductions in plasma glucose and, as a result of their glucose‐dependent mode of action, this is associated with low rates of hypoglycaemia; however, there are distinct modes of action resulting in differing efficacy and tolerability profiles. Furthermore, as their actions are not restricted to stimulating insulin secretion, these agents have also been associated with additional non‐glycaemic benefits such as weight loss, improvements in β‐cell function and cardiovascular risk markers. These attributes have made incretin therapies attractive treatments for the management of T2D and have presented physicians with an opportunity to tailor treatment plans. This review endeavours to outline the commonalities and differences among incretin‐based therapies and to provide guidance regarding agents most suitable for treating T2D in individual patients.     

Glucagon‐like peptide‐1 secretion by direct stimulation of L cells with luminal sugar vs non‐nutritive sweetener

Aims/Introduction: Oral ingestion of carbohydrate triggers secretion of glucagon‐like peptide (GLP)‐1, which inhibits the postprandial rise in blood glucose levels. However, the mechanism of carbohydrate‐induced GLP‐1 secretion from enteroendocrine L cells remains unclear. In the present study, GLP‐1 secretion was examined by meal tolerance tests of healthy Japanese volunteers. Materials and Methods: Twenty‐one healthy Japanese men participated in the study. The meal tolerance test was performed with modified nutrient compositions, with or without pretreatment with the α‐glucosidase inhibitor acarbose, or with substitution of sucrose with an equivalent dose of sweeteners in the meal. Blood concentrations of glucose, insulin, GLP‐1, and apolipoprotein (Apo) B‐48 were measured. Results: GLP‐1 secretion started concomitant with the increase in blood glucose levels 10 min after meal ingestion. Insulin secretion started at 5 min, before the increase in blood glucose levels, reflecting the contribution of direct nutrient stimulation on the former parameter and neural regulation in the latter. Carbohydrate retention in the gut lumen induced by acarbose pretreatment extended postprandial GLP‐1 secretion and negated the increase in serum ApoB‐48 levels. GLP‐1 secretion was markedly decreased by a reduction in the amount of sucrose in the meal and was not restored by an equivalent dose of sweeteners used to compensate for the sweet taste. Conclusions: The results indicate that direct stimulation of L cells with sugar, but not sweetener, is required for carbohydrate‐induced GLP‐1 secretion. In addition, inhibition of digestion of dietary carbohydrate by α‐glucosidase inhibitors may prevent postprandial hyperglycemia by increasing GLP‐1 secretion and by inhibiting glucose absorption. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00163.x, 2011)     

The effect of glucagon‐like peptide‐1 and glucagon‐like peptide‐2 on microcirculation: A systematic review

GLP‐1 and GLP‐2 are gut‐derived hormones used in the treatment of diabetes type‐2 and short bowel syndrome, respectively. GLP‐1 attenuates insulin resistance and GLP‐2 reduces enterocyte apoptosis and enhances crypt cell proliferation in the small intestine. In addition, both hormones have vasoactive effects and may be useful in situations with impaired microcirculation. The aim of this systematic review was to provide an overview of the potential effects of GLP‐1 and GLP‐2 on microcirculation. A systematic search was performed independently by two authors in the following databases: PubMed, EMBASE, Cochrane library, Scopus, and Web of Science. Of 1111 screened papers, 20 studies were included in this review: 16 studies in animals, three in humans, and one in humans and rats. The studies were few and heterogeneous and had a high risk of bias. However, it seems that GLP‐1 regulates the pancreatic, skeletal, and cardiac muscle flow, indicating a role in the glucose homeostasis, while GLP‐2 acts primarily in the regulation of the microcirculation of the mid‐intestine. These findings may be useful in gastrointestinal surgery and in situations with impaired microcirculation of the gut.