Twelve weeks treatment with the DPP‐4 inhibitor,sitagliptin, prevents degradation of peptide YY and improves glucose and non‐glucose induced insulin secretion in patients with type 2 diabetes mellitus

Aim: To examine the effects of 12 weeks of treatment with the DPP‐4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non‐glucose induced insulin secretion during a hyperglycaemic clamp, in patients with type 2 diabetes. Method: A double‐blinded, placebo‐controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add‐on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90‐min 20 mM hyperglycaemic clamp with 5 g of l ‐arginine infusion. Main outcome measure was postprandial total glucagon‐like peptide 1 (GLP‐1) concentration. Additional measures were insulin and C‐peptide, glycaemic control, intact and total peptide YY (PYY) and glucose‐dependent insulinotropic polypeptide (GIP), and intact glucagon‐like peptide 2 (GLP‐2) and GLP‐1. Results: All patients [sitagliptin n = 12, age: 59.5 (39–64) years, HbA1c: 8.0 (7.3–10.0)%, BMI: 33.2 (29.3–39.4); placebo n = 12, age: 60 (31–72) years, HbA1c: 7.7 (7.1–9.8)%, BMI: 30.7 (25.7–40.5)] [median (range)] completed the trial. Sitagliptin treatment improved glycaemic control, had no effect on total GLP‐1, GIP or intact GLP‐2, but reduced total PYY and PYY_{3‐ 36}, and increased PYY_{1‐ 36} and intact incretin hormones. Sitagliptin improved first and second phases of beta cell secretion and maximal secretory capacity. All effects were achieved after 1 week. No significant changes occurred in the placebo group. Conclusion: The postprandial responses of total GLP‐1 and GIP and intact GLP‐2 were unaltered. PYY degradation was prevented. Glucose and non‐glucose induced beta cell secretion was improved. There was no difference in responses to sitagliptin between 1 and 12 weeks of treatment.     

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)     

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)     

Incretin concept revised: The origin of the insulinotropic function of glucagon‐like peptide‐1 – the gut,the islets or both?

Incretins comprise a pair of gut hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1), which are secreted in response to food ingestion and enhance glucose‐dependent insulin secretion from pancreatic β‐cells. Immediately after secretion, GLP‐1 is degraded by dipeptidyl peptidase‐4 more rapidly than GIP, and circulating levels of biologically intact GLP‐1 are substantially lower than those of biologically intact GIP. Therefore, there has been a debate on how the gut‐derived GLP‐1 exerts insulinotropic actions. Recent publications have revealed two novel mechanisms by which GLP‐1 exerts insulinotropic actions: (i) the gut‐derived GLP‐1 activates receptors expressed in nodose ganglions, thereby potentiating glucose‐dependent insulin secretion through the vagus nerves; and (ii) the pancreatic α‐cell‐derived GLP‐1 activates receptors expressed in β‐cells in a paracrine manner. While the relative contributions of the two mechanisms under normal and pathological conditions remain unknown and mechanisms regulating GLP‐1 secretion from α‐cells need to be investigated, the available data strongly indicate that the effects of GLP‐1 on insulin secretion are far more complex than previously believed, and the classical incretin concept regarding GLP‐1 should be revised.     

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.     

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.     

Effect of sitagliptin on glucose control in type 2 diabetes mellitus after Roux‐en‐Y gastric bypass surgery

The present study was a 4‐week randomized trial to assess the efficacy and safety of sitagliptin, a dipeptidyl‐peptidase‐4 inhibitor, in persistent or recurring type 2 diabetes after Roux‐en‐Y gastric bypass surgery (RYGB). Participants (n = 32) completed a mixed meal test (MMT) and self‐monitoring of plasma glucose (SMPG) before and 4 weeks after randomization to either sitagliptin 100 mg daily or placebo daily. Questionnaires were administered to assess gastrointestinal discomfort. Outcome variables were glucose, active glucagon‐like peptide‐1 and β‐cell function during the MMT, and glucose levels during SMPG. Age (56.3 ± 8.2 years), body mass index (34.4 ± 6.7 kg/m²), glycated haemoglobin (7.21 ± 0.77%), diabetes duration (12.9 ± 10.0 years), years since RYGB (5.6 ± 3.3 years) and β‐cell function did not differ between the placebo and sitagliptin groups at pre‐intervention. Sitagliptin was well tolerated, decreased postprandial glucose levels during the MMT (from 8.31 ± 1.92 mmol/L to 7.67 ± 1.59 mmol/L, P = 0.03) and mean SMPG levels, but had no effect on β‐cell function. In patients with diabetes and mild hyperglycemia after RYGB, a short course of sitagliptin provided a small but significant glucose‐lowering effect, with no identified improvement in β‐cell function.     

Establishment of new clonal pancreatic β‐cell lines (MIN6‐K) useful for study of incretin/cyclic adenosine monophosphate signaling

Incretin/cyclic adenosine monophosphate (cAMP) signaling is critical for potentiation of insulin secretion. Although several cell lines of pancreatic β‐cells are currently available, there are no cell lines suitable for investigation of incretin/cAMP signaling. In the present study, we have newly established pancreatic β‐cell lines (named MIN6‐K) from the IT6 mouse, which develops insulinoma. MIN6‐K8 cells respond to both glucose and incretins, such as glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP), as is the case in pancreatic islets, whereas MIN6‐K20 cells respond to glucose, but not to incretins. Despite the difference in incretin‐potentiated insulin secretion between these two cell lines, the accumulation of cAMP after stimulation of GLP‐1 is comparable in these cells. Interestingly, we also found that incretin responsiveness is drastically induced by the formation of pseudoislets from MIN6‐K20 cells to a level comparable to that of pancreatic islets. Thus, these cell lines are useful for studying incretin/cAMP signaling in β‐cells. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00026.x, 2010)     

DPP‐4 inhibition and islet function

During recent years, dipeptidyl peptidase‐4 (DPP‐4) inhibition has been included in the clinical management of type 2 diabetes, both as monotherapy and as add‐on to several other therapies. DPP‐4 inhibition prevents the inactivation of the incretin hormones, glucose‐dependent insulinotropic polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1). This results in stimulation of insulin secretion and inhibition of glucagon secretion, and there is also a potential β‐cell preservation effect, as judged from rodent studies; that is, it might target the key islet dysfunction in the disease. In type 2 diabetes. This reduces 24‐h glucose levels and reduces HbA_1c by ≈ 0.8–1.1% from baseline levels of 7.7–8.5%. DPP‐4 inhibition is safe, with a very low risk for adverse events including hypoglycemia, and it prevents weight gain. The present review summarizes the studies on the influence of DPP‐4 inhibition on islet function. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00184.x, 2012)     

Effects of DPP‐4 inhibitor linagliptin and GLP‐1 receptor agonist liraglutide on physiological response to hypoglycaemia in Japanese subjects with type 2 diabetes: A randomized,open‐label, 2‐arm parallel comparative,exploratory trial

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors reduce the risk of hypoglycaemia, possibly through augmentation of glucose‐dependent insulinotropic polypeptide (GIP) action, but not that of glucagon‐like peptide‐1 (GLP‐1) on glucagon secretion. To examine this model in Japanese individuals with type 2 diabetes (T2D), the effects of the DPP‐4 inhibitor linagliptin on glucagon and other counter‐regulatory hormone responses to hypoglycaemia were evaluated and compared with those of the GLP‐1 receptor agonist liraglutide in a multi‐centre, randomized, open‐label, 2‐arm parallel comparative, exploratory trial. Three‐step hypoglycaemic clamp glucose tests preceded by meal tolerance tests were performed before and after 2‐week treatment with the drugs. Glucagon levels were increased during the hypoglycaemic clamp test at 2.5 mmol/L. This increase was similar in the linagliptin and liraglutide groups, both before and after the 2‐week treatment. Changes in other counter‐regulatory hormones (ie, growth hormone, cortisol, epinephrine and norepinephrine) were also similar between the groups, but were suppressed substantially after 2‐week treatment compared to baseline. In conclusion, we confirmed that the glucagon response to hypoglycaemia was not affected by linagliptin or liraglutide treatment in Japanese individuals with T2D.     

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)     

Combination therapy of dipeptidyl peptidase‐4 inhibitors and metformin in type 2 diabetes: rationale and evidence

The main pathogenesis of type 2 diabetes mellitus (T2DM) includes insulin resistance and pancreatic islet dysfunction. Metformin, which attenuates insulin resistance, has been recommended as the first‐line antidiabetic medication. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors are novel oral hypoglycaemic agents that protect glucagon‐like peptide‐1 (GLP‐1) from degradation, maintain the bioactivity of endogenous GLP‐1, and thus improve islet dysfunction. Results from clinical trials have shown that the combination therapy of DPP‐4 inhibitors and metformin [as an add‐on, an initial combination or a fixed‐dose combination (FDC)] provides excellent efficacy and safety in patients with T2DM. Moreover, recent studies have suggested that metformin enhances the biological effect of GLP‐1 by increasing GLP‐1 secretion, suppressing activity of DPP‐4 and upregulating the expression of GLP‐1 receptor in pancreatic β‐cells. Conversely, DPP‐4 inhibitors have a favourable effect on insulin sensitivity in patients with T2DM. Therefore, the combination of DPP‐4 inhibitors and metformin provides an additive or even synergistic effect on metabolic control in patients with T2DM. This article provides an overview of clinical evidence and discusses the rationale for the combination therapy of DPP‐4 inhibitors and metformin.     

Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones secreted in response to meal ingestion, thereby enhancing postprandial insulin secretion. Therefore, an attenuated incretin response could contribute to the impaired insulin responses in patients with diabetes mellitus. The aim of the present investigation was to investigate incretin secretion, in obesity and type 1 and type 2 diabetes mellitus, and its dependence on the magnitude of the meal stimulus. Plasma concentrations of incretin hormones (total, reflecting secretion and intact, reflecting potential action) were measured during two meal tests (260 kcal and 520 kcal) in eight type 1 diabetic patients, eight lean healthy subjects, eight obese type 2 diabetic patients, and eight obese healthy subjects. Both in diabetic patients and in healthy subjects, significant increases in GLP-1 and GIP concentrations were seen after ingestion of both meals. The incretin responses were significantly higher in all groups after the large meal, compared with the small meal, with correspondingly higher C-peptide responses. Both type 1 and type 2 diabetic patients had normal GIP responses, compared with healthy subjects, whereas decreased GLP-1 responses were seen in type 2 diabetic patients, compared with matched obese healthy subjects. Incremental GLP-1 responses were normal in type 1 diabetic patients. Increased fasting concentrations of GIP and an early enhanced postprandial GIP response were seen in obese, compared with lean healthy subjects, whereas GLP-1 responses were the same in the two groups. beta-cell sensitivity to glucose, evaluated as the slope of insulin secretion rates vs. plasma glucose concentration, tended to increase in both type 2 diabetic patients (29%, P = 0.19) and obese healthy subjects (22% P = 0.04) during the large meal, compared with the small meal, perhaps reflecting the increased incretin response. We conclude: 1) that a decreased GLP-1 secretion may contribute to impaired insulin secretion in type 2 diabetes mellitus, whereas GIP and GLP-1 secretion is normal in type 1 diabetic patients; and 2) that it is possible to modulate the beta-cell sensitivity to glucose in obese healthy subjects, and possibly also in type 2 diabetic patients, by giving them a large meal, compared with a small meal.     

Review of methods for measuring β‐cell function: Design considerations from the Restoring Insulin Secretion (RISE) Consortium

The Restoring Insulin Secretion (RISE) study was initiated to evaluate interventions to slow or reverse the progression of β‐cell failure in type 2 diabetes (T2D). To design the RISE study, we undertook an evaluation of methods for measurement of β‐cell function and changes in β‐cell function in response to interventions. In the present paper, we review approaches for measurement of β‐cell function, focusing on methodologic and feasibility considerations. Methodologic considerations included: (1) the utility of each technique for evaluating key aspects of β‐cell function (first‐ and second‐phase insulin secretion, maximum insulin secretion, glucose sensitivity, incretin effects) and (2) tactics for incorporating a measurement of insulin sensitivity in order to adjust insulin secretion measures for insulin sensitivity appropriately. Of particular concern were the capacity to measure β‐cell function accurately in those with poor function, as is seen in established T2D, and the capacity of each method for demonstrating treatment‐induced changes in β‐cell function. Feasibility considerations included: staff burden, including time and required methodological expertise; participant burden, including time and number of study visits; and ease of standardizing methods across a multicentre consortium. After this evaluation, we selected a 2‐day measurement procedure, combining a 3‐hour 75‐g oral glucose tolerance test and a 2‐stage hyperglycaemic clamp procedure, augmented with arginine.     

GLP‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence

The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas (SU), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self‐regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous. Stimulation of insulin secretion from pancreatic β‐cells by glucagon‐like peptide 1 receptor (GLP‐1R) agonists is known to be glucose‐dependent. GLP‐1R agonists potentiate glucose‐stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations. This ‘glucose‐regulated’ activity of GLP‐1R agonists makes them useful and potentially safer therapeutics for overall glucose control compared to non‐regulated therapies; hyperglycaemia can be reduced with minimal hypoglycaemia. While the inherent mechanism of action of GLP‐1R agonists mediates their glucose dependence, studies in rats suggest that SUs may uncouple this dependence. This hypothesis is supported by clinical studies showing that the majority of events of hypoglycaemia in patients treated with GLP‐1R agonists occur in patients treated with a concomitant SU. This review aims to discuss the current understanding of the mechanisms by which GLP‐1R signalling promotes insulin secretion from pancreatic β‐cells via a glucose‐dependent process.     

Synergistic effect of α‐glucosidase inhibitors and dipeptidyl peptidase 4 inhibitor treatment

Monotherapy of α‐glucosidase inhibitor (α‐GI) or dipeptidyl peptidase 4 (DPP4) inhibitor does not sufficiently minimize glucose fluctuations in the diabetic state. In the present study, we evaluated the combined effects of various of α‐GI inhibitors (acarbose, voglibose or miglitol) and sitagliptin, a DPP4 inhibitor, on blood glucose fluctuation, insulin and active glucagon‐like peptide‐1 (GLP‐1) levels after nutriment loading in mice. Miglitol and sitagliptin elicited a 47% reduction (P < 0.05) of the area under the curve of blood glucose levels for up to 2 h after maltose‐loading, a 60% reduction (P < 0.05) in the range of blood glucose fluctuation, and a 32% decrease in plasma insulin compared with the control group. All three of the combinations elicited a 2.5–4.9‐fold synergistic increase in active GLP‐1 (P < 0.05 vs control). Thus, combined treatment with the α‐GI miglitol, which more strongly inhibits the early phase of postprandial hyperglycemia, and DPP4 inhibitor yields both complementary and synergistic effects, and might represent a superior anti‐hyperglycemic therapy. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00081.x, 2011)     

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.     

Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on beta-cell function in patients with type 2 diabetes: a model-based approach

Purpose: The purpose of this exploratory analysis was to assess the effect of sitagliptin, a dipeptidyl peptidase‐4 inhibitor, on pancreatic beta‐cell function using a model‐based analysis. Methods: Data for this analysis were from three large, placebo‐controlled clinical studies that examined sitagliptin 100 mg q.d. as add‐on to metformin therapy or as monotherapy over 18 or 24 weeks. In these studies, subsets of patients consented to undergo extensive blood sampling as part of a nine‐point meal tolerance test performed at baseline and study end‐point. Blood samples were collected at ?10, 0, 10, 20, 30, 60, 90, 120 and 180 min relative to the start of a meal and subsequently were assayed for plasma glucose and serum C‐peptide concentrations. Parameters for beta‐cell function were calculated using the C‐peptide minimal model, which estimates insulin secretion rate (ISR) and partitions the ISR into basal (Φ_b; ISR at basal glucose concentrations), static (Φ_s; ISR at above basal glucose concentrations following a meal) and dynamic (Φ_d; ISR in response to the rate of increase in above basal glucose concentrations following a meal) components. The total responsivity index (Φ_total; average ISR over the average glucose concentration) is calculated as a function of Φ_s, Φ_d and Φ_b. Insulin sensitivity was assessed with a validated composite index (ISI). Disposition indices (DI), which assess insulin secretion in the context of changes in insulin sensitivity, were calculated as the product of Φand ISI. Results: When administered in combination with ongoing metformin therapy or as monotherapy, sitagliptin was associated with substantial reductions in postprandial glycaemic excursion following a meal challenge relative to placebo. Sitagliptin produced significant (p < 0.05 vs. placebo) improvements in Φ_s and Φ_total, regardless of treatment regimen (add‐on to metformin or as monotherapy). For Φ_d, there was a numerical, but not statistically significant, improvement with sitagliptin relative to placebo. Treatment with sitagliptin increased Φ_b, but the difference relative to placebo was only significant with monotherapy. ISI was not significantly different between sitagliptin and placebo. The DIs for the static, dynamic and total measures were significantly (p < 0.05) increased with sitagliptin treatment relative to placebo. Conclusions: In this model‐based analysis, sitagliptin improved beta‐cell function relative to placebo in both fasting and postprandial states in patients with type 2 diabetes.