Active Glucagon-like Peptide-1 Levels Research Articles

Letter: Predictive Factors for Efficacy of Dipeptidyl Peptidase-4 Inhibitors in Patients with Type 2 Diabetes Mellitus (Diabetes Metab J 2015;39:342-7).

Dipeptidyl peptidase-4 (DPP-4) inhibitor is one of the widely used diabetic medications these days. In clinical practice, some patients respond more effectively to this drug and show better glycemic improvement. Several studies [1,2,3,4] analyzed the predictors of response to DPP-4 inhibitors, however the results were somewhat inconsistent. The discrepancy might be due to the different definition of efficacy predictors and heterogeneity of study population. In this article entitled Predictive factors for efficacy of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus, Yagi et al. [5] evaluated the predictive factors for the efficacy of DPP-4 inhibitors based on the change of glycosylated hemoglobin (HbA1c) after 12 months of treatment. They described the predictors to be a decrease in HbA1c level after 3 months of treatment, a high baseline HbA1c level, a low baseline body mass index, and no history of coronary artery disease (CAD). This article is interesting, especially in that the long-term effects of DPP-4 inhibitors on glycemic control could be predicted by the short term response, which might make it easier to identify the good responders to DPP-4 inhibitors. Although there are some clinical significances, some points need to be clarified. First, the criteria for DPP-4 inhibitor add-on therapy needs to be clarified better in this study. The study patients aged 68.3±35.8 years old, and baseline HbA1c were 7.5%±1.3%. Initially, 36.6% of patients already had HbA1c <7% when DPP-4 inhibitors are added on. Considering that the patients were relatively old with mild elevated HbA1c level, the reason for additional DPP-4 inhibitors might be helpful to understand and validate the efficacy of DPP-4 inhibitors. In addition, a majority of patients have already been treated with other anti-diabetic drugs. Forty-four percent of patients used α-glucosidase inhibitors, 32.5% for sulfonylurea, and 15.2% for biguanides. In these patients, the reason for additional DPP-4 inhibitor instead of the dose increment of baseline drugs could be informative. Second, combination therapy of other anti-diabetic drugs might affect glucose metabolism and exert confounding effects. A previous study has reported that combination treatment of alogliptin and voglibose increased plasma active glucagon-like peptide-1 (GLP-1) levels and pancreatic insulin content synergistically in db/db mice [6]. Another study showed that a combination of miglitol and sitagliptin effectively attenuate postprandial hyperglycemia with various patterns of insulin, glucagon, and GLP-1 release, suggesting that individual hormone-related glycemic responses to the DPP-4 inhibitors and α-glucosidase inhibitor are complex and multifactorial [7]. Synergistic effect of sulfonylurea and DPP-4 inhibitor has been suggested, because some patients showed dramatic glycemic improvement after this combination therapy [8]. Sulfonylurea added to DPP-4 inhibitor might potentiate insulin secretion by activating exchange protein activated by cyclic AMP 2 (Epac2) [9]. There are substantial synergistic or heterogenous responses to combination therapy of DPP-4 inhibitor with other anti-diabetic drugs. Analyzing the patients with similar baseline anti-diabetic drugs could be more appropriate to evaluate the predictive factors for the efficacy of DPP-4 inhibitors. Third, duration of diabetes is one of the substantial predictors for the response to DPP-4 inhibitors. Several studies have shown that shorter duration of diabetes is associated with greater reduction in HbA1c after DPP-4 inhibitor add-on [1,2,3]. Further information including duration of diabetes could support the interesting findings in this study. In addition, incidence rate of CAD increases with longer duration of diabetes [10]. As shown in this study, absence of CAD itself could be one of the predictors of DPP-4 inhibitor response, otherwise, shorter duration of diabetes might be the unrevealed connection link of good response for DPP-4 inhibitors. Lastly, the authors evaluated the predictive factors based on the change of HbA1c after 12 months of treatment. Baseline HbA1c, however, is an important factor that affects the change of glycemic control [4]. In this study, as baseline HbA1c was high, the change of HbA1c would also appear to be more significant. Identifying the predictive factors with reference to the baseline HbA1c could be more interesting if individual responses to DPP-4 inhibitors were considered. Based on the results of this study, short-term follow-up studies with a large patient population are warranted to investigate the predictors of DPP-4 inhibitor response.

Teneligliptin improves glycemic control with the reduction of postprandial insulin requirement in Japanese diabetic patients.

Teneligliptin is a novel peptidomimetic-chemotype prolylthiazolidine-based inhibitor of dipeptidyl peptidase-4 (DPP-4). The aim of this study was to evaluate the effects of teneligliptin on 24 h blood glucose control and gastrointestinal hormone responses to a meal tolerance test, and to investigate the glucose-lowering mechanisms of teneligliptin. Ten patients with type 2 diabetes mellitus (T2DM) were treated for 3 days with teneligliptin (20 mg/day). Postprandial profiles for glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), active glucose-dependent insulinotropic polypeptide (GIP), ghrelin, des-acyl ghrelin, and 24 h glycemic fluctuations were measured via continuous glucose monitoring for 4 days. Once daily teneligliptin administration for 3 days significantly lowered postprandial and fasting glucose levels. Significant elevations of fasting and postprandial active GLP-1 and postprandial active GIP levels were observed. Teneligliptin lowered postprandial glucose elevations, 24 h mean blood glucose levels, standard deviation of 24 h glucose levels and mean amplitude of glycemic excursions (MAGE) without hypoglycemia. Serum insulin levels in the fasting state and 30 min after a meal were similar before and after teneligliptin treatment; however significant reductions at 60 to 180 min after treatment were observed. A significant elevation in early-phase insulin secretion estimated by insulinogenic and oral disposition indices, and a significant reduction in postprandial glucagon AUC were observed. Both plasma ghrelin and des-acyl ghrelin levels were unaltered following teneligliptin treatment. Teneligliptin improved 24 h blood glucose levels by increasing active incretin levels and early-phase insulin secretion, reducing the postprandial insulin requirement, and reducing glucagon secretion. Even short-term teneligliptin treatment may offer benefits for patients with T2DM.

Procyanidins and their healthy protective effects against type 2 diabetes.

This review focuses on the role of procyanidins, the main group of flavonoids, on type 2 diabetes mellitus (T2DM) and insulin resistance. We compile the role of procyanidins on several animal models, and we evaluate their effects on target tissues and analyze the mechanisms involved. Procyanidin treatments in fructose or high-fat induced insulin resistant models were found to improve the damage induced by the diet, thus improving glycemia and insulin sensitivity. The same positive effects were also reported in models of late stage T2DM, in which pancreatic β-cells can no longer counteract hyperglycemia. More controversial results were found in genetically obese or cafeteria diet-induced insulin resistant models. Human studies, although limited, further support the hypoglycemic effect of procyanidins. Regarding their mechanisms, procyanidins have been found to target several tissues involved in glucose homeostasis, which is also discussed in the present review. In insulin-sensitive tissues, procyanidins modulate glucose uptake and lipogenesis and improve their oxidative/inflammatory state, the disruption of which is important in T2DM development. In the insulin-producing tissue, the pancreas, procyanidins modulate insulin secretion and production and β-cell mass, although the available results are divergent. Finally, the gut is another potential target for procyanidins. The available data suggest that modulation of the active glucagon-like peptide-1 (GLP-1) levels could partially explain the reported antihyperglycemic effect of these natural compounds.

Effects of miglitol, sitagliptin, and initial combination therapy with both on plasma incretin responses to a mixed meal and visceral fat in over-weight Japanese patients with type 2 diabetes. “The MASTER randomized, controlled trial”

To assess changes in circulating incretin levels and body fat compositions with initial combination therapy with α-glucosidase inhibitor and dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes (T2D). In this multicenter open-label 24-week trial, Japanese over-weight (BMI ≥ 25 kg/m(2)) patients with T2D not taking medication or taking metformin and/or sulfonylurea were randomly assigned to receive either 50mg of miglitol three times a day (M, n=14), 50mg of sitagliptin once a day (S, n=14), or a combination of both (M+S, n=13). Changes in plasma incretin levels during a meal tolerance test (MTT) and body fat composition with impedance method were evaluated. During MTT, postprandial plasma glucose levels decreased more after M+S than after M or S, and postprandial serum insulin levels decreased significantly after M and M+S whereas they increased after S. After M, active gastric inhibitory polypeptide (aGIP) decreased significantly at 30 min despite a significant increase at 120 min. After S, aGIP levels increased significantly throughout the MTT. After M+S, aGIP increased significantly at 0 and 120 min despite of significant decrease at 30 min. M+S further enhanced postprandial active glucagon-like peptide-1 levels during MTT than S did. Total body fat mass decreased significantly after M and M+S. Visceral fat mass decreased significantly only after M+S. Serum adiponectin increased significantly only after M+S. In over-weight patients with T2D, M+S may have a beneficial effect on adiposity with relation to these different effects on two incretins.

Multiple-dose pharmacokinetics and pharmacodynamics of evogliptin (DA-1229), a novel dipeptidyl peptidase IV inhibitor, in healthy volunteers.

PurposeEvogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase IV (DPP-IV) inhibitor in clinical development for the treatment of type 2 diabetes mellitus. This study aimed to investigate the pharmacokinetic and pharmacodynamic profiles and tolerability of evogliptin after repeated oral administration in healthy subjects.Patients and methodsA block-randomized, double-blind, placebo-controlled, multiple-dose, dose-escalation study was performed in a total of 30 subjects. Repeated once-daily doses of 5, 10, or 20 mg evogliptin or the same doses of placebo were orally administered to ten subjects in each dosage group for 10 days. Subjects in each group were randomized to receive evogliptin or placebo with a ratio of 8:2. Pharmacokinetics of evogliptin were evaluated, with its concentrations in serial plasma and urine samples collected following the first and last administrations. DPP-IV activity and glucagon-like peptide-1, glucose, and insulin levels were quantified to evaluate evogliptin’s pharmacodynamics on the first and last dosing days.ResultsAll participants completed the study without any serious or severe adverse event. The evogliptin plasma concentration reached its peak within 4–5 hours and decreased relatively slowly, with a terminal elimination half-life of 33–39 hours. Repeated administration resulted in a 1.4- to 1.5-fold accumulation. Evogliptin’s systemic exposure and inhibition of plasma DPP-IV activity increased in a dose-dependent manner. Inhibition of DPP-IV activity >80% was sustained over 24 hours in all evogliptin dose groups and provided an increase in postprandial active glucagon-like peptide-1 levels by 1.5- to 2.4-fold. Postprandial glucose levels in the evogliptin-treated groups were reduced 20%–35% compared to placebo, but were not accompanied by increased insulin levels.ConclusionRepeated administration of evogliptin in healthy subjects was well tolerated and exhibited linear pharmacokinetics within the 5–20 mg dose range. A once-daily regimen of 5–20 mg evogliptin effectively inhibited DPP-IV activity.

Glycemic/metabolic responses to identical meal tolerance tests at breakfast, lunch and dinner in Japanese patients with type 2 diabetes mellitus treated with a dipeptidyl peptidase-4 inhibitor and the effects of adding a mitiglinide/voglibose fixed-dose combination

Background: The effects of the mitiglinide/voglibose fixed-dose combination on postprandial glycemic/metabolic responses in patients with type 2 diabetes mellitus (T2DM) treated with dipeptidyl peptidase-4 (DPP-4) inhibitors are unknown.Methods: Twelve T2DM patients treated with a DPP-4 inhibitor underwent identical meal tolerance tests (MTTs) at breakfast, lunch and dinner, before and 2 – 3 weeks after treatment with a fixed-dose combination of mitiglinide 10 mg and voglibose 0.2 mg (combination). Patients were randomized in a cross-over fashion to administer the combination either three-times-daily before each meal or twice-daily before breakfast and dinner. Glycemic/metabolic responses were evaluated at 0, 30, 60 and 120 min in each MTT.Results: Three-times-daily administration of the combination significantly suppressed postprandial hyperglycemia after each meal, particularly after lunch and dinner. Active glucagon-like peptide-1 levels increased significantly after each meal, as did early-phase insulin secretion without excessive insulin secretion. Postprandial hyperglycemia after lunch was significantly greater after twice-daily than three-times-daily administration, but there were no clinically relevant differences in other metabolic responses.Conclusion: This study revealed that adding the mitiglinide/voglibose combination to a DPP-4 inhibitor elicited additive improvements in postprandial glycemic/metabolic responses assessed using MTTs at breakfast, lunch and dinner with identical meal compositions.

A grape seed extract increases active glucagon-like peptide-1 levels after an oral glucose load in rats.

We have previously reported that procyanidins, a class of flavonoids, improve glycemia and exert an incretin-like effect, which was linked to their proven inhibitory effect on the dipeptidyl-peptidase 4 (DPP4) activity. However, their actual effect on incretin levels has not been reported yet. Therefore, in the present study we have evaluated whether a grape seed extract enriched in procyanidins (GSPE) modulates plasma incretin levels and attempted to determine the mechanisms involved. An acute GSPE treatment in healthy Wistar female rats prior to an oral glucose load induced an increase in plasma active glucagon-like peptide-1 (GLP-1), which was accompanied by an increase in the plasma insulin/glucose ratio and a simultaneous decrease in glucose levels. In agreement with our previous studies, the intestinal DPP4 activity was inhibited by the GSPE treatment. We have also assayed in vitro whether this inhibition occurs in inner intestinal tissues close to GLP-1-producing cells, such as the endothelium of the capillaries. We have found that the main compounds absorbed by intestinal CaCo-2 cells after an acute treatment with GSPE are catechin, epicatechin, B2 dimer and gallic acid, and that they inhibit the DPP4 activity in endothelial HUVEC cells in an additive way. Moreover, an increase in plasma total GLP-1 levels was found, suggesting an increase in GLP-1 secretion. In conclusion, our results show that GSPE improves glycemia through its action on GLP-1 secretion and on the inhibition of the inner intestinal DPP4 activity, leading to an increase in active GLP-1 levels, which, in turn, may affect the insulin release.

Dipeptidyl Peptidase IV Inhibitor Protects Against Tacrolimus-Induced Pancreatic and Renal Injury.

Background: Dipeptidyl peptidase IV (DPP IV) inhibitors had a protective effect in various disease models. This study was performed to evaluate whether sitagliptin, a DPP IV inhibitor, is effective against tacrolimus-induced pancreatic and renal injury. Method: Tacrolimus (TAC, 1.5mg/kg/day, s.c.) with or without sitagliptin (10, 20 mg/kg/day, gavage) were administered to rats for 4 weeks. We evaluated the effect of sitagliptin on DPP IV activity and GLP-1 level in tacrolimus-treated rats, and assessed the protective effect of sitagliptin in an experimental model of chronic tacrolimus-induced nephropathy and pancreatic injury. Oxidative stress and oxidative resistance were evaluated by measuring 8-hydroxy-2'-deoxyguanosine (8-OHdG) and heme oxygenase-1 (HO-1). The protective mechanism of sitagliptin was also tested based on the glucagon like peptide-1 (GLP-1)/ (forkhead box O) FoxO pathway. Results: Tacrolimus treatment for 4 weeks caused a 2-fold increase in plasma DPP4 activity and a 5-fold decrease in serum active GLP-1 levels; however, concomitant treatment with sitagliptin reversed these effects. Sitagliptin treatment attenuated tacrolimus-induced pancreatic islet and renal dysfunction, with improvement of islet size and renal tubulointerstitial fibrosis. Tacrolimus treatment increased oxidative stress marker, 8-OHdG and decreased oxidative resistance gene (reduced HO-1), and its underlying pathways (FoxO1 activation and FoxO3 deactivation), whereas sitagliptin treatment reversed these changes. Treatment of primary rat islet and HK-2 cells with GLP-1 also decreased the oxidative injury caused by tacrolimus. Consequently, sitagliptin upregulated antioxidant enzymes e.g. manganese superoxide dismutase, and downregulated proapoptotic proteins e.g. B-cell lymphoma 2-interacting mediator of cell death and apoptotic cell death assessed by the number of TDT-mediated dUTP-biotin nick end labeling-positive cells. Conclusion:DPP IV inhibition by sitagliptin attenuated TAC-induced pancreatic islet and renal dysfunction and enhanced the GLP-1 signaling pathway, which may be associated with a decrease in oxidative injury and apoptotic cell death. These beneficial effects of the DPP IV inhibitor may be helpful in delaying the onset of TAC-induced diabetes and nephropathy in renal transplant patients.

Dipeptidyl peptidase IV inhibitor MK-0626 attenuates pancreatic islet injury in tacrolimus-induced diabetic rats.

BackgroundTacrolimus (TAC)-induced pancreatic islet injury is one of the important causes of new-onset diabetes in transplant recipients. This study was performed to evaluate whether a dipeptidyl peptidase IV (DPP IV) inhibitor is effective in improving TAC-induced diabetes mellitus by reducing pancreatic islet injury.MethodsRats were treated with TAC (1.5 mg/kg, subcutaneously) and the DPP IV inhibitor MK-0626 (10 or 20 mg/kg, oral gavage) for 4 weeks. The effect of MK-0626 on TAC-induced diabetes was evaluated by assessing pancreatic islet function, histopathology. TAC-induced incretin dysfunction was also examined based on active glucagon-like peptide-1 (GLP-1) levels in the serum after glucose loading. The protective effect of MK-0626 was evaluated by measuring markers of oxidative stress, oxidative resistance, and apoptosis. To determine whether enhanced GLP-1 signaling is associated with these protective effects, we measured the expression of the GLP-1 receptor (GLP-1R) and the effect of the GLP-1 analog exendin-4 on cell viability and oxidative stress in isolated islets.ResultsMK-0626 treatment attenuated TAC-induced pancreatic islet dysfunction and islet morphology. TAC treatment led to a defect in active GLP-1 secretion; however, MK-0626 reversed these effects. TAC treatment increased the level of 8-hydroxy-2′-deoxyguanosine (8-OHdG), the number of apoptotic death, and the level of active caspase-3, and decreased the level of manganese superoxide dismutase and heme oxygenase-1; MK-0626 treatment reversed these changes. MK-0626 treatment restored the expression of GLP-1R, and direct administration of exendin-4 to isolated islets reduced TAC-induced cell death and 8-OHdG expression.ConclusionsThe DPP IV inhibitor MK-0626wasan effective antidiabetic agent that exerted antioxidative and antiapoptotic effects via enhanced GLP-1 signaling in TAC-induced diabetics.

Circulating Glucagon-like Peptide-1 (GLP-1) Inhibits Eating in Male Rats by Acting in the Hindbrain and Without Inducing Avoidance

To address the neural mediation of the eating-inhibitory effect of circulating glucagon-like peptide-1 (GLP-1), we investigated the effects of 1) intra-fourth ventricular infusion of the GLP-1 receptor antagonist exendin-9 or 2) area postrema lesion on the eating-inhibitory effect of intrameal hepatic portal vein (HPV) GLP-1 infusion in adult male rats. To evaluate the physiological relevance of the observed effect we examined 3) the influence of GLP-1 on flavor acceptance in a 2-bottle conditioned flavor avoidance test, and 4) measured active GLP-1 in the HPV and vena cava (VC) in relation to a meal and in the VC after HPV GLP-1 infusion. Intrameal HPV GLP-1 infusion (1 nmol/kg body weight-5 min) specifically reduced ongoing meal size by almost 40% (P < .05). Intra-fourth ventricular exendin-9 (10 μg/rat) itself did not affect eating, but attenuated (P < .05) the satiating effect of HPV GLP-1. Area postrema lesion also blocked (P < .05) the eating-inhibitory effect of HPV GLP-1. Pairing consumption of flavored saccharin solutions with HPV GLP-1 infusion did not alter flavor acceptance, indicating that HPV GLP-1 can inhibit eating without inducing malaise. A regular chow meal transiently increased (P < .05) HPV, but not VC, plasma active GLP-1 levels, whereas HPV GLP-1 infusion caused a transient supraphysiological increase (P < .01) in VC GLP-1 concentration 3 minutes after infusion onset. The results implicate hindbrain GLP-1 receptors and the area postrema in the eating-inhibitory effect of circulating GLP-1, but question the physiological relevance of the eating-inhibitory effect of iv infused GLP-1 under our conditions.

Effects of Exenatide in a Morbidly Obese Patient with Type 2 Diabetes

IntroductionThe effect of exenatide in weight loss has been reported. Presented here is a case of a morbidly obese patient with type 2 diabetes using exenatide who dramatically lost her body weight in a year and experienced improved glycemic control.Case reportExenatide therapy was initiated for a 59-year-old morbidly obese Japanese woman with type 2 diabetes. To examine the effects of the exenatide treatment, continuous glucose monitoring was performed, and blood was drawn at 0, 30, 60, 120, and 180 min after breakfast to measure insulin, glucagon, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) levels. After 1 year of exenatide therapy, the patient lost 37.5 kg, her glycemic control improved, and her insulin sensitivity recovered. The patient’s levels of insulin, glucagon, active GLP-1, and total GIP also decreased after 1 year of exenatide treatment.ConclusionThe exenatide treatment was effective for reducing body weight and improving glycemic control. After 1 year of exenatide treatment, decreased glucagon, active GLP-1, and total GIP levels were observed following a meal, suggesting that exenatide might affect these hormonal reactions.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-014-0050-6) contains supplementary material, which is available to authorized users.

Cotreatment with the α-glucosidase inhibitor miglitol and DPP-4 inhibitor sitagliptin improves glycemic control and reduces the expressions of CVD risk factors in type 2 diabetic Japanese patients

ObjectiveIn this study, we examined whether inhibition of postprandial hyperglycemia by combination therapy with two drugs for reducing postprandial hyperglycemia, i.e., α-glucosidase inhibitor miglitol and dipeptidyl peptidase (DPP)-4 inhibitor sitagliptin, improves glycemic control and reduces the risk of cardiovascular disease (CVD) development. Materials/MethodsWe enrolled 32 type 2 diabetic Japanese patients with hemoglobin A1c (HbA1c) levels ranging from 6.9% to 10.5%, who had been treated for at least 2 months with 50mg miglitol (t.i.d.) or 50mg sitagliptin (q.d.). Following a monotherapy period with either miglitol (Group-M) or sitagliptin (Group-S) for 1 month, the patients were subjected to combination therapy with sitagliptin and miglitol for 3 months. Meal tolerance tests were performed at the end of the monotherapy and combination therapy. ResultsCombination therapy for 3 months after monotherapy reduced HbA1c (changes: Group-M: −1.3%±0.7%, P<0.001; Group-S: −0.6%±0.5%, P<0.001) and glycoalbumin levels and increased 1,5-anhydroglucitol concentrations in the blood. In the meal tolerance tests, circulating active glucagon-like peptide-1 levels were elevated in both groups, while active glucose-dependent insulinotropic polypeptide levels were reduced by combination therapy in the group with add-on miglitol therapy. The plasma protein concentrations of interleukin (IL)-8 and adhesion molecules (sE-selectin and sVCAM-1) were reduced by switching to the combination therapy, in particular with the add-on miglitol therapy. ConclusionsOur results suggest that combination therapy with miglitol and sitagliptin improves glycemic control and reduces the circulating protein concentrations of IL-8, sE-selectin, and sVCAM-1 in type 2 diabetic Japanese patients.

Effects of miglitol, vildagliptin, or their combination on serum insulin and peptide YY levels and plasma glucose, cholecystokinin, ghrelin, and obestatin levels

We previously reported that combination therapy with an α-glucosidase inhibitor (αGI) and a dipeptidyl peptidase-4 (DPP-4) inhibitor increased active glucagon-like peptide-1 (GLP-1) levels and decreased total glucose-dependent insulinotropic polypeptide (GIP) levels, compared with monotherapy, in non-diabetic men. However, the peptide YY (PYY), cholecystokinin (CCK), ghrelin, and obestatin levels in patients receiving a combination of αGIs and DPP-4 inhibitors have not been previously reported. We evaluated the effect of miglitol, vildagliptin, or their combination on these parameters. Miglitol and/or vildagliptin were administered according to four different intake schedules in eleven non-diabetic men (C: no drug, M: miglitol; V: vildagliptin, M+V: miglitol+vildagliptin). Blood samples were collected at 0, 30, 60, and 120 min after the start of breakfast. The plasma glucose, serum insulin, serum total PYY (PYY1-36 and PYY3-36), plasma CCK, plasma active ghrelin, and plasma obestatin levels were measured. The area under the curve (AUC) of the serum total PYY level in the M group was significantly greater than that in the C group, and the AUC of the serum total PYY level in the M+V group was significantly lower than that in the M group. The combination therapy did not change the AUC of the plasma CCK, plasma active ghrelin, plasma obestatin, and ghrelin/obestatin levels, compared with the control. The results of our study suggested that combination therapy with miglitol and vildagliptin had no effect on appetite regulation hormones, such as total PYY, CCK, active ghrelin, and obestatin, compared with the levels in the control group.

Liraglutide suppresses obesity and hyperglycemia associated with increases in hepatic fibroblast growth factor 21 production in KKAy mice.

Social isolation contributes to the development of obesity and insulin-independent diabetes in KKAy mice. Here we show that systemic administration of liraglutide, a long-acting human glucagon-like peptide-1 (GLP-1) analog, significantly decreased food intake, body weight, and blood glucose levels at 24 h after its administration while having no significant effects on plasma insulin and glucagon levels in individually housed KKAy mice. In addition, the systemic administration of liraglutide significantly increased plasma fibroblast growth factor (Fgf) 21 levels (1.8-fold increase) associated with increases in the expression of hepatic Fgf21 (1.9-fold increase) and Pparγ (1.8-fold increase), while having no effects on the expression of hepatic Pparα and Fgf21 in white adipose tissue. Moreover, systemic administration of liraglutide over 3 days significantly suppressed food intake, body weight gain, and hyperglycemia in KKAy mice. On the other hand, despite remarkably increased plasma active GLP-1 levels (4.2-fold increase), the ingestion of alogliptin, a selective dipeptidyl peptidase-4 inhibitor, over 3 days had no effects on food intake, body weight, blood glucose levels, and plasma Fgf21 levels in KKAy mice. These findings suggest that systemic administration of liraglutide induces hepatic Fgf21 production and suppresses the social isolation-induced obesity and diabetes independently of insulin, glucagon, and active GLP-1 in KKAy mice.

The glycemic/metabolic responses to meal tolerance tests at breakfast, lunch and dinner, and effects of the mitiglinide/voglibose fixed-dose combination on postprandial profiles in Japanese patients with type 2 diabetes mellitus

Background: Meal tolerance tests (MTTs) are usually conducted at breakfast after overnight fasting in type 2 diabetes mellitus (T2DM) patients, but differences in postprandial glycemic responses between meals have been reported.Objective: We conducted MTTs at breakfast, lunch, and dinner to examine the effects of a fixed combination of 10 mg mitiglinide/0.2 mg voglibose (the combination) on glycemic/metabolic responses to meals during the day in T2DM patients. MTTs with unified meals were conducted in 11 T2DM patients before and after 4 weeks of treatment with the combination administered thrice daily before meals. Glycemic/metabolic profiles measured before and at 30, 60, and 120 min after each meal were compared between each meal and between the baseline and treatment periods.Results and conclusion: The combination significantly reduced postprandial hyperglycemia after each meal. Postprandial AUC0 – 120 min for insulin significantly decreased after lunch and dinner compared with after breakfast, while insulin levels significantly increased at only 30 min after breakfast and dinner. The combination also significantly increased postprandial C-peptide and active glucagon-like peptide-1 levels, and reduced free fatty acid and triglyceride levels, but did not significantly affect glucagon levels compared with baseline, confirming that treatment with the combination improves postprandial responses in Japanese T2DM patients.

Beneficial effects of vildagliptin combined with miglitol on glucose tolerance and islet morphology in diet-controlled db/db mice

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes primarily by increasing plasma active glucagon-like peptide-1 (GLP-1) levels. While various combination therapies based on DPP-4 inhibitors have been proposed for treatment of type 2 diabetes, the effects of combination therapy of DPP-4 inhibitors and alpha-glucosidase inhibitors on β-cell function are less characterized. We evaluated the effects of long-term treatment with vildagliptin, a DPP-4 inhibitor, on metabolic parameters and β-cell function, in combination with miglitol, an alpha-glucosidase inhibitor, in diet-controlled db/db mice. In this study, 6-week-old male db/db mice were provided with standard chow twice a day for 6weeks. Meal tolerance tests and glucose tolerance tests showed that the combination therapy of vildagliptin with miglitol, but not each alone, suppressed postprandial glycemic excursion, enhanced postprandial active GLP-1 levels and prevented deterioration of glucose tolerance in the db/db mice. The combination treatment did not alter β-cell mass, but resulted in preserved expression of glucose transporter 2, Zinc transporter 8 and MafA and reduced the number of α cells. These results suggest that the combination of vildagliptin and miglitol prevents the development of overt diabetes in diet-controlled pre-diabetic db/db mice by normalizing postprandial glucose and incretin response, and by preserving β-cell structure and the expression of factors essential for β-cell function.

A molecular connection of Pterocarpus marsupium, Eugenia jambolana and Gymnema sylvestre with dipeptidyl peptidase-4 in the treatment of diabetes

Context: Pterocarpus marsupium (PM) (Leguminosae), Eugenia jambolana (EJ) (Myrtaceae) and Gymnema sylvestre (GS) (Asclepiadaceae) are the most important medicinal plants in the Indian system of traditional medicine for the treatment of hyperglycemia.Objectives: Dipeptidyl peptidase-4 (DPP-4) inhibitors are the emerging class of anti-diabetic agents. However, only few compounds are commercially available. Therefore, in the present study we tried to explore the naturally occurring PM, EJ and GS semi-standardized extracts for their potential DPP-4 inhibition in vitro and in vivo.Materials and methods: DPP-4 inhibition was evaluated by in vitro inhibitory assay, and enzyme kinetics were calculated using one-phase exponential decay equation. Glucose load (2 g/kg) was administered to control and diabetic rats 30 min following extract administration (100, 200 and 400 mg/kg) orally once, and blood samples were withdrawn at 0, 0.5, 1, 1.5, 2 and 3 h to measure plasma active glucagon-like peptide-1 (GLP-1) levels.Results: PM and EJ inhibit DPP-4 potently with IC50 values of 273.73 ± 2.96 and 278.94 ± 6.73 µg/mL, respectively, compared to GS (773.22 ± 9.21 µg/mL). PM, EJ and GS exhibit long duration of action with enzyme inhibitory half-lives of 462.3, 317.2 and 153.8 min, respectively. Extracts significantly increase GLP-1 levels compared to negative control groups and peak GLP-1 level was observed at 2 h for PM and EJ, whereas for GS it was at 1.5 hDiscussion and conclusion: Taken together, results suggest the extracts may have potent DPP-4 inhibitory action, and their hypoglycemic action attributed through an increase in plasma active GLP-1 levels.

Differential Effects of Laparoscopic Sleeve Gastrectomy and Laparoscopic Gastric Bypass on Appetite, Circulating Acyl-ghrelin, Peptide YY3-36 and Active GLP-1 Levels in Non-diabetic Humans

Laparoscopic Roux-en-Y gastric bypass (LRYGBP) reduces appetite and induces significant and sustainable weight loss. Circulating gut hormones changes engendered by LRYGBP are implicated in mediating these beneficial effects. Laparoscopic sleeve gastrectomy (LSG) is advocated as an alternative to LRYGBP, with comparable short-term weight loss and metabolic outcomes. LRYGBP and LSG are anatomically distinct procedures causing differential entero-endocrine cell nutrient exposure and thus potentially different gut hormone changes. Studies reporting the comparative effects of LRYGBP and LSG on appetite and circulating gut hormones are controversial, with no data to date on the effects of LSG on circulating peptide YY3-36 (PYY3-36) levels, the specific PYY anorectic isoform. In this study, we prospectively investigated appetite and gut hormone changes in response to LRYGBP and LSG in adiposity-matched non-diabetic patients. Anthropometric indices, leptin, fasted and nutrient-stimulated acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), PYY3-36 levels and appetite were determined pre-operatively and at 6 and 12 weeks post-operatively in obese, non-diabetic females, with ten undergoing LRYGBP and eight adiposity-matched females undergoing LSG. LRYGBP and LSG comparably reduced adiposity. LSG decreased fasting and post-prandial plasma acyl-ghrelin compared to pre-surgery and to LRYGBP. Nutrient-stimulated PYY3-36 and active GLP-1 concentrations increased post-operatively in both groups. However, LRYGBP induced greater, more sustained PYY3-36 and active GLP-1 increments compared to LSG. LRYGBP suppressed fasting hunger compared to LSG. A similar increase in post-prandial fullness was observed post-surgery following both procedures. LRYGBP and LSG produced comparable enhanced satiety and weight loss. However, LSG and LRYGBP differentially altered gut hormone profiles.

The Relationship between Anagliptin Concentration Showing Over 80% Inhibition of Plasma Dipeptidyl Peptidase-4 Activity and its Protective Effect against Glucagon-like Peptide-1 Degradation

In dipeptidyl peptidase-4 (DPP-4) inhibitors, the inhibition of plasma DPP-4 activity by 80% is considered sufficient to have an effect on glycemic control improvement through the elevation of intact glucagon-like peptide-1 (GLP-1). To clarify whether or not the 80% inhibition is sufficient to protect against GLP-1 degradation, we investigated rats with a continuous infusion of exogenous GLP-1. When GLP-1 was infused into the femoral or portal vein, the steady state active GLP-1 levels in plasma significantly increased (P<0.05) at the 80% inhibitory concentration (IC80) of anagliptin (a highly selective DPP-4 inhibitor) against plasma DPP-4 activity, compared with control. In addition, the peptide levels increased in a concentration-dependent manner at drug concentrations from IC80 to 10-fold IC80, and the levels at the 10-fold IC80 were significantly higher (P<0.05) than those at IC80. The concentration dependency on GLP-1 increment was also confirmed based on the experiment in which the endogenous active GLP-1 levels were measured after an oral carbohydrate load. These findings suggest that an almost complete inhibition (80%) of plasma DPP-4 activity was insufficient to protect GLP-1 degradation, and much higher drug concentrations such as 10-fold IC80 are necessary to potently protect GLP-1 from degradation by DPP-4 commonly present in blood and tissues.

Liraglutide Suppresses the Plasma Levels of Active and Des-Acyl Ghrelin Independently of Active Glucagon-Like Peptide-1 Levels in Mice

Glucagon-like peptide-1 (GLP-1), an insulinotropic gastrointestinal peptide that is primarily produced by intestinal endocrine L-cells, stimulates satiety. Ghrelin, a hormone that is produced predominantly by the stomach stimulates hunger. There are two forms of ghrelin: active ghrelin and inactive des-acyl ghrelin. After depriving mice of food for 24 h, we demonstrated that the systemic administration of liraglutide (100 μg/kg), a human GLP-1 analog that binds to the GLP-1 receptor, increased (1.4-fold) the plasma levels of active GLP-1 and suppressed the plasma levels of active and des-acyl ghrelin after 1 h. Despite the elevated plasma levels of active GLP-1 (11-fold), liraglutide had no effect on the plasma levels of active or des-acyl ghrelin after 12 h. These findings demonstrated that liraglutide suppresses the plasma levels of active and des-acyl ghrelin independently of active GLP-1 levels in fasted mice, suggesting a novel in vivo biological effect of liraglutide beyond regulating plasma GLP-1.