Increased Plasma Glucagon-like Peptide-1 Levels Research Articles

Medium-chain fatty acid receptor GPR84 deficiency leads to metabolic homeostasis dysfunction in mice fed high-fat diet.

Overconsumption of food, especially dietary fat, leads to metabolic disorders such as obesity and type 2 diabetes. Long-chain fatty acids, such as palmitoleate are recognized as the risk factors for these disorders owing to their high-energy content and lipotoxicity. In contrast, medium-chain fatty acids (MCFAs) metabolic benefits; however, their underlying molecular mechanisms remain unclear. GPR84 is an MCFA receptor, particularly for C10:0. Although evidence from invitro experiments and oral administration of C10:0 in mice suggests that GPR84 is related to the metabolic benefits of MCFAs via glucose metabolism, its precise roles invivo remain unclear. Therefore, the present study investigated whether GPR84 affects glucose metabolism and metabolic function using Gpr84-deficient mice. Although Gpr84-deficient mice were lean and had increased endogenous MCFAs under high-fat diet feeding conditions, they exhibited hyperglycemia and hyperlipidemia along with lower plasma insulin and glucagon-like peptide-1 (GLP-1) levels compared with wild-type mice. Medium-chain triglyceride (C10:0) intake suppressed obesity, and improved plasma glucose and lipid levels, and increased plasma GLP-1 levels in wild-type mice; however, these effects were partially attenuated in Gpr84-deficient mice. Our results indicate that long-term MCFA-mediated GPR84 activation improves the dysfunction of glucose and lipid homeostasis. Our findings may be instrumental for future studies on drug development with GPR84 as a potential target, thereby offering new avenues for the treatment of metabolic disorders like obesity and type 2 diabetes.

Glucagon receptor antagonism promotes the production of gut proglucagon-derived peptides in diabetic mice

Glucagon is an essential regulator of glucose homeostasis, particularly in type 2 diabetes (T2D). Blocking the glucagon receptor (GCGR) in diabetic animals and humans has been shown to alleviate hyperglycemia and increase circulating glucagon-like peptide-1 (GLP-1) levels. However, the origin of the upregulated GLP-1 remains to be clarified. Here, we administered high-fat diet + streptozotocin-induced T2D mice and diabetic db/db mice with REMD 2.59, a fully competitive antagonistic human GCGR monoclonal antibody (mAb) for 12 weeks. GCGR mAb treatment decreased fasting blood glucose levels and increased plasma GLP-1 levels in the T2D mice. In addition, GCGR mAb upregulated preproglucagon gene expression and the contents of gut proglucagon-derived peptides, particularly GLP-1, in the small intestine and colon. Notably, T2D mice treated with GCGR mAb displayed a higher L-cell density in the small intestine and colon, which was associated with increased numbers of LK-cells coexpressing GLP-1 and glucose-dependent insulinotropic polypeptide and reduced L-cell apoptosis. Furthermore, GCGR mAb treatment upregulated GLP-1 production in the pancreas, which was detected at lower levels than in the intestine. Collectively, these results suggest that GCGR mAb can increase intestinal GLP-1 production and L-cell number by enhancing LK-cell expansion and inhibiting L-cell apoptosis in T2D.

The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids

The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.

Thymoquinone activates imidazoline receptor to enhance glucagon-like peptide-1 secretion in diabetic rats.

Thymoquinone (TQ) is one of the principal bioactive ingredients proven to exhibit anti-diabetic effects. Recently, glucagon-like peptide-1 (GLP-1) has been found to be involved in antidiabetic effects in rats. The aim of this study was to evaluate the mediation of GLP-1 in the antidiabetic effect of TQ and to understand the possible mechanisms. NCI-H716 cells and CHO-K1 cells were used to investigate the effects of TQ on GLP-1 secretion in vitro. In type 1 diabetic rats, the changes in plasma glucose and GLP-1 levels were evaluated with TQ treatment. The direct effect of TQ on imidazoline receptors (I-Rs) was identified in CHO-K1 cells overexpressing I-Rs. Additionally, in the intestinal NCI-H716 cells that may secrete GLP-1, TQ treatment enhanced GLP-1 secretion in a dose-dependent manner. However, these effects of TQ were reduced by ablation of I-Rs with siRNA in NCI-H716 cells. Moreover, these effects were inhibited by BU224, the imidazoline I2 receptor (I-2R) antagonist. In diabetic rats, TQ increased plasma GLP-1 levels, which were inhibited by BU-224 treatment. Functionally, TQ-attenuated hyperglycemia is also evidenced through GLP-1 using pharmacological manipulations. This report demonstrates that TQ may promote GLP-1 secretion through I-R activation to reduce hyperglycemia in type-1 diabetic rats.

GLP-1 mediates the modulating effect of thymoquinone on feeding behaviors in diabetic rats.

Background: Thymoquinone (TQ) is a safe nutrient isolated from the seeds or volatile oil extract of Nigella sativa. In addition to its benefits in glucose regulation, TQ improves feeding disorders in diabetic animals. Glucagon-like peptide-1 (GLP-1) analogs improve glycemic control and ameliorate obesity or hyperphagia. Therefore, the present study aimed to investigate the role of GLP-1 in TQ-induced anorexia.Method: Type 2 diabetes was induced in rats by nicotinamide and streptozotocin injection. TQ was orally administered to diabetic rats at different doses for 45 days. Following TQ treatment, changes in serum glucose levels, GLP-1 concentration, body weight, food intake, and water intake were determined. To further explore the interaction between GLP-1 and TQ, the inhibitor of dipeptidyl peptidase 4, sitagliptin and the GLP-1 receptor antagonist exendin 9–39 (Ex 9–39) were separately administered to TQ- or vehicle-treated diabetic rats.Results: TQ treatment attenuated hyperglycemia and reduced hyperphagy and water intake in streptozotocin-induced diabetic rats in a dose-dependent manner. Moreover, TQ treatment elevated plasma GLP-1 levels compared to those in control rats. The effects of TQ were enhanced by treatment with sitagliptin and reduced by the injection of Ex 9–39 into the brain. In contrast, similar treatment with another antioxidant (either ascorbic acid or N-acetylcysteine) produced the same anorexic effect as TQ without changing the plasma GLP-1 levels in diabetic rats. Therefore, TQ attenuated hyperphagy while increasing plasma GLP-1 levels and had antioxidant-like effects.Conclusion: TQ increased endogenous GLP-1 levels to reduce hyperphagy in diabetic rats.

The intestine responds to heart failure by enhanced mitochondrial fusion through glucagon-like peptide-1 signalling.

Glucagon-like peptide-1 (GLP-1) is a neuroendocrine hormone secreted by the intestine. Its receptor (GLP-1R) is expressed in various organs, including the heart. However, the dynamics and function of the GLP-1 signal in heart failure remains unclear. We investigated the impact of the cardio-intestinal association on hypertensive heart failure using miglitol, an α-glucosidase inhibitor known to stimulate intestinal GLP-1 production. Dahl salt-sensitive (DS) rats fed a high-salt diet were assigned to miglitol, exendin (9-39) (GLP-1R blocker) and untreated control groups and treated for 11 weeks. Control DS rats showed marked hypertension and cardiac dysfunction with left ventricular dilatation accompanied by elevated plasma GLP-1 levels and increased cardiac GLP-1R expression as compared with age-matched Dahl salt-resistant (DR) rats. Miglitol further increased plasma GLP-1 levels, suppressed adverse cardiac remodelling, and mitigated cardiac dysfunction. In cardiomyocytes from miglitol-treated DS hearts, mitochondrial size was significantly larger with denser cristae than in cardiomyocytes from control DS hearts. The change in mitochondrial morphology reflected enhanced mitochondrial fusion mediated by protein kinase A activation leading to phosphorylation of dynamin-related protein 1, expression of mitofusin-1 and OPA-1, and increased myocardial adenosine triphosphate (ATP) content. GLP-1R blockade with exendin (9-39) exacerbated cardiac dysfunction and led to fragmented mitochondria with disarrayed cristae in cardiomyocytes and reduction of myocardial ATP content. In cultured cardiomyocytes, GLP-1 increased expression of mitochondrial fusion-related proteins and ATP content. When GLP-1 and exendin (9-39) were administered together, their effects cancelled out. Increased intestinal GLP-1 secretion is an adaptive response to heart failure that is enhanced by miglitol. This could be an effective strategy for treating heart failure through regulation of mitochondrial dynamics.

Increased Plasma GLP-1 Levels after Resistant Starch Type 3 From Cassava Starch (Manihot Esculanta Crantz) Diet on Diabetic Rat

Diabetes mellitus (DM) occur when human body is unable to produce enough insulin and/or unable to use insulin effectively, resulting in an increase of blood sugar levels (hyperglycemia). Indonesia has ranks fourth after United States, China and India in the prevalence of DM. Controling blood sugar and insulin levels can be done through the stimulation effect of Glucagon- like peptide-1 (GLP-1). The goal of this study was to determine the effects of resistant starch type 3 (RS3) from cassava starch in increasing plasma GLP-1 levels. This reasearch use male mouse (Ratttus novergicus) as a diabetic model by providing a high-fat diet (HFD) for one mounth than combine with intraoperitonel injection of low dose streptozotocin (STZ). The mouse then grouped into 4 groups randomly (1) normal or negative control, (2) cassava starch diet, (3) RS3 diet, (4) positive control. Blood sugar levels were measured before and after STZ injection to determine the diabetic conditions (blood sugar > 200 mg /dL). After 4 weeks of dietary administration blood sugar and plasma GLP-1 levels were examined using ELISA. Statistical analysis showed decreased in blood sugar levels and increased in plasma GLP-1 levels after one mounth of RS3 diet. This research shows that RS3 from cassava starch has a potential role as a nutritional therapy on diabetes mellitus condition.
 Keywords: Resistant starch type 3, cassava starch, GLP-1, Blood Sugar, Diabetes Mellitus

Abscisic Acid Stimulates Glucagon-Like Peptide-1 Secretion from L-Cells and Its Oral Administration Increases Plasma Glucagon-Like Peptide-1 Levels in Rats.

In recent years, Abscisic Acid (ABA) has been demonstrated to be involved in the regulation of glucose homeostasis in mammals as an endogenous hormone, by stimulating both insulin release and peripheral glucose uptake. In addition, ABA is released by glucose- or GLP-1-stimulated β-pancreatic cells. Here we investigated whether ABA can stimulate GLP-1 release. The human enteroendocrine L cell line hNCI-H716 was used to explore whether ABA stimulates in vitro GLP-1 secretion and/or transcription. ABA induced GLP-1 release in hNCI-H716 cells, through a cAMP/PKA-dependent mechanism. ABA also enhanced GLP-1 transcription. In addition, oral administration of ABA significantly increased plasma GLP-1 and insulin levels in rats. In conclusion, ABA can stimulate GLP-1 release: this result and the previous observation that GLP-1 stimulates ABA release from β -cells, suggest a positive feed-back mechanism between ABA and GLP-1, regulating glucose homeostasis. Type 2 diabetes treatments targeting the GLP-1 axis by either inhibiting its rapid clearance by dipeptidyl-peptidase IV or using GLP-1 mimetics are currently used. Moreover, the development of treatments aimed at stimulating GLP-1 release from L cells has been considered as an alternative approach. Accordingly, our finding that ABA increases GLP-1 release in vitro and in vivo may suggest ABA and/or ABA analogs as potential anti-diabetic treatments.

Sardine protein diet increases plasma glucagon-like peptide-1 levels and prevents tissue oxidative stress in rats fed a high-fructose diet.

The current study investigated whether sardine protein mitigates the adverse effects of fructose on plasma glucagon‑like peptide-1 (GLP-1) and oxidative stress in rats. Rats were fed casein (C) or sardine protein (S) with or without high‑fructose (HF) for 2 months. Plasma glucose, insulin, GLP‑1, lipid and protein oxidation and antioxidant enzymes were assayed. HF rats developed obesity, hyperglycemia, hyperinsulinemia, insulin resistance and oxidative stress despite reduced energy and food intakes. High plasma creatinine and uric acid levels, in addition to albuminuria were observed in the HF groups. The S‑HF diet reduced plasma glucose, insulin, creatinine, uric acid and homeostasis model assessment‑insulin resistance index levels, however increased GLP‑1 levels compared with the C‑HF diet. Hydroperoxides were reduced in the liver, kidney, heart and muscle of S‑HF fed rats compared with C‑HF fed rats. A reduction in liver, kidney and heart carbonyls was observed in S‑HF fed rats compared with C‑HF fed rats. Reduced levels of nitric oxide (NO) were detected in the liver, kidney and heart of the S‑HF fed rats compared with C‑HF fed rats. The S diet compared with the C diet reduced levels of liver hydroperoxides, heart carbonyls and kidney NO. The S‑HF diet compared with the C‑HF diet increased the levels of liver and kidney superoxide dismutase, liver and muscle catalase, liver, heart and muscle glutathione peroxidase and liver ascorbic acid. The S diet prevented and reversed insulin resistance and oxidative stress, and may have benefits in patients with metabolic syndrome.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor in overweight or obese, but otherwise healthy human subjects.

Pradigastat is a potent and selective inhibitor of diacylglycerol acyltransferase 1, an enzyme highly expressed in the small intestine that plays a key role in postprandial triglyceride synthesis. This first-in-human study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat administered at single and multiple doses in overweight or obese healthy subjects. In single-dose cohorts (n = 72), subjects were randomized sequentially to receive single doses of pradigastat (1, 3, 10, 30, 100, or 300 mg) or placebo under fasted condition and prior to breakfast. In multiple-dose cohorts (n = 106), subjects were randomized to receive pradigastat (1, 5, 10, or 25 mg) or placebo prior to breakfast for 14 days. Following a single oral dosing, pradigastat was absorbed slowly, with a median tmax of ∼10 hours and eliminated slowly with a long half-life. With multiple oral doses, a 10- to 17-fold higher systemic exposure was observed. Pradigastat treatment (single and multiple doses) led to dose-dependent suppression of postprandial triglyceride excursions over 9 hours following a high-fat meal test. In addition, pradigastat suppressed postprandial glucose and insulin and increased plasma glucagon-like peptide-1 levels. Overall, pradigastat was safe and tolerated at single and multiple doses in healthy subjects.

Resistant maltodextrin promotes fasting glucagon-like peptide-1 secretion and production together with glucose tolerance in rats.

Glucagon-like peptide-1 (GLP-1), which is produced and released from enteroendocrine L cells, plays pivotal roles in postprandial glycaemia. The ingestion of resistant maltodextrin (RMD), a water-soluble non-digestible saccharide, improves the glycaemic response. In the present study, we examined whether the continuous feeding of RMD to rats affected GLP-1 levels and glycaemic control. Male Sprague-Dawley rats (6 weeks of age) were fed an American Institute of Nutrition (AIN)-93G-based diet containing either cellulose (5 %) as a control, RMD (2.5 or 5 %), or fructo-oligosaccharides (FOS, 2.5 or 5 %) for 7 weeks. During the test period, an intraperitoneal glucose tolerance test (IPGTT) was performed after 6 weeks. Fasting GLP-1 levels were significantly higher in the 5 % RMD group than in the control group after 6 weeks. The IPGTT results showed that the glycaemic response was lower in the 5 % RMD group than in the control group. Lower caecal pH, higher caecal tissue and content weights were observed in the RMD and FOS groups. Proglucagon mRNA levels were increased in the caecum and colon of both RMD and FOS groups, whereas caecal GLP-1 content was increased in the 5 % RMD group. In addition, a 1 h RMD exposure induced GLP-1 secretion in an enteroendocrine L-cell model, and single oral administration of RMD increased plasma GLP-1 levels in conscious rats. The present study demonstrates that continuous ingestion of RMD increased GLP-1 secretion and production in normal rats, which could be stimulated by its direct and indirect (enhanced gut fermentation) effects on GLP-1-producing cells, and contribute to improving glucose tolerance.

Postprandial effects of polydextrose on satiety hormone responses and subjective feelings of appetite in obese participants.

BackgroundDietary fibers are associated with enhanced satiety. However, the mechanism of different dietary fibers contributing to satiety-related gastrointestinal (GI) peptide release, especially in an obese population, is still poorly understood. Polydextrose (PDX), a water-soluble glucose polymer, has demonstrated its ability to reduce energy intake at a subsequent meal, but its mechanism of action requires further research. Also, there is limited evidence on its capacity to regulate subjective feelings of appetite. This study examines the effects of PDX on postprandial secretion of satiety-related GI peptides, short chain fatty acids (SCFAs), lactic acid, and subjective appetite ratings in obese participants.Methods18 non-diabetic, obese participants (42.0 y, 33.6 kg/m2) consumed a high-fat meal (4293 kJ, 36% from fat) with or without PDX (15 g) in an acute, multicenter, randomized, double-blind, placebo-controlled and crossover trial. Postprandial plasma concentrations of satiety-related peptides, namely ghrelin, cholecystokinin (CCK), glucagon-like peptide 1 (GLP-1), and peptide YY (PYY), as well as SCFAs and lactic acid were assessed. GI peptide, SCFA and lactate concentrations were then modeled using a linear mixed-effects model.The subjective feelings of hunger, satisfaction, and desire to eat were evaluated using visual analogue scales (VAS), which were analyzed as incremental areas under the curve (iAUC) during the satiation and satiety periods.ResultsWe found that PDX supplementation increased plasma GLP-1 levels more than the placebo treatment (P = 0.02). In the whole group, GLP-1 concentrations found in participants older than 40 years old were significantly lower (P = 0.01) as compared to those aged 40 years or less. There were no statistically significant differences in postprandial ghrelin, CCK, or PYY responses. The lactic acid concentrations were significantly (P = 0.01) decreased in the PDX group, while no significant changes in SCFAs were found. PDX reduced iAUC for hunger by 40% (P = 0.03) and marginally increased satisfaction by 22.5% (P = 0.08) during the post-meal satiety period.ConclusionPolydextrose increased the postprandial secretion of the satiety hormone GLP-1 and reduced hunger after a high-fat meal. PDX also reduced the elevated postprandial lactic acid levels in plasma. Therefore, PDX may offer an additional means to regulate inter-meal satiety and improve postprandial metabolism in obese participants.

Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes

Inflammation and endothelial dysfunction are increasingly being recognized as key etiological factors in the development of atherosclerosis and subsequent cardiovascular disease. These pro-atherogenic factors are strongly correlated and are often found to co-segregate in patients with type 2 diabetes. The impact of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4, on inflammation and markers of endothelial function remains to be fully characterized. ObjectiveThe objective of the present study was to examine the effects of treatment with sitagliptin on the plasma levels of various markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Methods and resultsThirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1±6.4years and a body mass index of 30.7±4.9kg/m2) were recruited into this double-blind, cross-over study using sitagliptin (100mg/d) or placebo, each for a 6-week period, including a 4-week washout period between the two phases. Blood samples were taken at the end of each phase of treatment. Compared with placebo, treatment with sitagliptin significantly reduced the plasma levels of C-reactive protein (CRP) (44.9%, P=0.006), interleukin (IL)-6 (24.7%, P=0.04), IL-18 (7.3%, P=0.004), secreted phospholipase-A2 (sPLA2) (12.9%, P=0.04), soluble intercellular adhesion molecule-1 (5.3%, P=0.002), and E-selectin (5.9%, P=0.005). A significant inverse correlation was found between changes in glucagon-like peptide-1 (GLP-1) and changes in CRP levels (r=0.41, P=0.01) following sitagliptin therapy. Sitagliptin therapy had more pronounced effects in subjects with higher levels of inflammatory markers and cell adhesion molecules compared with subjects with lower levels. ConclusionsTreatment with sitagliptin for 6weeks reduced plasma markers of low-grade inflammation and cell adhesion molecules, most likely by increasing plasma GLP-1 levels and improving glucose-insulin homeostasis. These beneficial effects of sitagliptin might represent a further advantage in the management of diabetes and its proatherogenic comorbidities.

Activation of cAMP Signaling Attenuates Impaired Hepatic Glucose Disposal in Aged Male p21-Activated Protein Kinase-1 Knockout Mice

p21-activated protein kinase-1 (Pak1) plays a role in insulin secretion and glucagon-like peptide-1 (GLP-1) production. Pak1(-/-) mice were found to carry a defect in ip pyruvate tolerance test (IPPTT), leading us to speculate whether Pak1 represses hepatic gluconeogenesis. We show here that the defect in IPPTT became more severe in aged Pak1(-/-) mice. In primary hepatocytes, 2,2'-dihydroxy-1,1'-dinaphthyldisulfide, a potent inhibitor of group I Paks, reduced basal glucose production (GP), attenuated forskolin- or glucagon-stimulated GP, and attenuated the stimulation of forskolin on the expression of Pck1 and G6pc. In addition, the capacity of primary hepatocytes isolated from Pak1(-/-) mice in GP at the basal level is significantly lower than that of the control littermates. These in vitro observations imply that the direct effect of Paks in hepatocytes is the stimulation of gluconeogenesis and that the impairment in IPPTT in Pak1(-/-) mice is due to the lack of Pak1 elsewhere. Consecutive ip injection of forskolin for 2 weeks increased gut proglucagon expression, associated with improved IPPTT in aged Pak1(-/-) mice and wild-type controls. In addition, administration of the DPP-IV (dipeptidyl peptidase-4) inhibitor sitagliptin for 1 week reversed the defect in IPPTT in aged Pak1(-/-) mice, associated with increased plasma GLP-1 levels. Our observations indicate a potential role of Pak1 in the gut/pancreas/liver axis in controlling glucose disposal and affirmed the therapeutic application of GLP-1 and DPP-IV inhibitors in attenuating hepatic gluconeogenesis.

Effect of linagliptin, alone and in combination with voglibose or exendin-4, on glucose control in male ZDF rats

The effects of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, alone and in combination with voglibose or exendin-4, on glycaemic control and body weight were assessed in an animal model of type 2 diabetes. Voglibose is an α-glucosidase inhibitor but also increases glucagon-like peptide 1 (GLP-1). Exendin-4 is a GLP-1 receptor agonist. Male Zucker Diabetic Fatty (ZDF) rats were dosed for 3 days, fasted overnight and a sucrose/glucose tolerance test was performed. Linagliptin (1mg/kg po) improved glucose tolerance by increasing plasma GLP-1 (active) and insulin secretion, whilst having no effect on body weight. Voglibose (1 and 10mg/kg po) reduced body weight, improved glycaemic control, reduced plasma insulin and increased total but not active GLP-1. The combination of linagliptin and voglibose significantly reduced body weight, improved glycaemic control and reduced plasma insulin compared to linagliptin alone. Furthermore, linagliptin plus voglibose produced a marked increase in GLP-1 (active) at 5min post-sucrose, compared to linagliptin, possibly because linagliptin prevented the degradation of GLP-1 secreted in response to voglibose. Exendin-4 (10μg/kg sc) significantly reduced body weight, improved glucose tolerance but reduced GLP-1 (active). The combination of linagliptin and exendin-4 significantly reduced body weight and improved glycaemic control but had no effect on plasma GLP-1. Overall it did not markedly improve glycaemic control compared to the individual drugs. The improved glucose control, reduced body weight and markedly increased plasma GLP-1 levels in animals given linagliptin with voglibose, suggests that this combination may be particularly beneficial in the treatment of type 2 diabetes.

Dipeptidyl-peptidase IV inhibition improves pathophysiology of heart failure and increases survival rate in pressure-overloaded mice

Incretin hormones, including glucagon-like peptide-1 (GLP-1), a target for diabetes mellitus (DM) treatment, are associated with cardioprotection. As dipeptidyl-peptidase IV (DPP-IV) inhibition increases plasma GLP-1 levels in vivo, we investigated the cardioprotective effects of the DPP-IV inhibitor vildagliptin in a murine heart failure (HF) model. We induced transverse aortic constriction (TAC) in C57BL/6J mice, simulating pressure-overloaded cardiac hypertrophy and HF. TAC or sham-operated mice were treated with or without vildagliptin. An intraperitoneal glucose tolerance test revealed that blood glucose levels were higher in the TAC than in sham-operated mice, and these levels improved with vildagliptin administration in both groups. Vildagliptin increased plasma GLP-1 levels in the TAC mice and ameliorated TAC-induced left ventricular enlargement and dysfunction. Vildagliptin palliated both myocardial apoptosis and fibrosis in TAC mice, demonstrated by histological, gene and protein expression analyses, and improved survival rate on day 28 (TAC with vildagliptin, 67.5%; TAC without vildagliptin, 41.5%; P < 0.05). Vildagliptin improved cardiac dysfunction and overall survival in the TAC mice, both by improving impaired glucose tolerance and by increasing GLP-1 levels. DPP-IV inhibitors represent a candidate treatment for HF patients with or without DM.

Transient Receptor Potential Vanilloid 1 Activation Enhances Gut Glucagon-Like Peptide-1 Secretion and Improves Glucose Homeostasis

Type 2 diabetes mellitus (T2DM) is rapidly prevailing as a serious global health problem. Current treatments for T2DM may cause side effects, thus highlighting the need for newer and safer therapies. We tested the hypothesis that dietary capsaicin regulates glucose homeostasis through the activation of transient receptor potential vanilloid 1 (TRPV1)-mediated glucagon-like peptide-1 (GLP-1) secretion in the intestinal cells and tissues. Wild-type (WT) and TRPV1 knockout (TRPV1−/−) mice were fed dietary capsaicin for 24 weeks. TRPV1 was localized in secretin tumor cell-1 (STC-1) cells and ileum. Capsaicin stimulated GLP-1 secretion from STC-1 cells in a calcium-dependent manner through TRPV1 activation. Acute capsaicin administration by gastric gavage increased GLP-1 and insulin secretion in vivo in WT but not in TRPV1−/− mice. Furthermore, chronic dietary capsaicin not only improved glucose tolerance and increased insulin levels but also lowered daily blood glucose profiles and increased plasma GLP-1 levels in WT mice. However, this effect was absent in TRPV1−/− mice. In db/db mice, TRPV1 activation by dietary capsaicin ameliorated abnormal glucose homeostasis and increased GLP-1 levels in the plasma and ileum. The present findings suggest that TRPV1 activation–stimulated GLP-1 secretion could be a promising approach for the intervention of diabetes.

Effects of DPP-4 Inhibitors on the Heart in a Rat Model of Uremic Cardiomyopathy

BackgroundUremic cardiomyopathy contributes substantially to mortality in chronic kidney disease (CKD) patients. Glucagon-like peptide-1 (GLP-1) may improve cardiac function, but is mainly degraded by dipeptidyl peptidase-4 (DPP-4).Methodology/Principal FindingsIn a rat model of chronic renal failure, 5/6-nephrectomized [5/6N] rats were treated orally with DPP-4 inhibitors (linagliptin, sitagliptin, alogliptin) or placebo once daily for 4 days from 8 weeks after surgery, to identify the most appropriate treatment for cardiac dysfunction associated with CKD. Linagliptin showed no significant change in blood level AUC(0-∞) in 5/6N rats, but sitagliptin and alogliptin had significantly higher AUC(0-∞) values; 41% and 28% (p = 0.0001 and p = 0.0324), respectively. No correlation of markers of renal tubular and glomerular function with AUC was observed for linagliptin, which required no dose adjustment in uremic rats. Linagliptin 7 µmol/kg caused a 2-fold increase in GLP-1 (AUC 201.0 ng/l*h) in 5/6N rats compared with sham-treated rats (AUC 108.6 ng/l*h) (p = 0.01). The mRNA levels of heart tissue fibrosis markers were all significantly increased in 5/6N vs control rats and reduced/normalized by linagliptin.Conclusions/SignificanceDPP-4 inhibition increases plasma GLP-1 levels, particularly in uremia, and reduces expression of cardiac mRNA levels of matrix proteins and B-type natriuretic peptides (BNP). Linagliptin may offer a unique approach for treating uremic cardiomyopathy in CKD patients, with no need for dose-adjustment.

Stimulating β-Cell Replication and Improving Islet Graft Function by AR231453, A gpr119 Agonist

Objective G protein-coupled receptor 119 (GPR119) is predominantly expressed in β cells and intestinal L cells. AR231453 is a selective small-molecular GPR119 agonist that enhances glucose-dependent insulin secretion and glucagon-like peptide 1 (GLP-1) release. We investigated whether AR231453 can directly stimulate β-cell replication and improve islet graft function in diabetic mice. Methods A total of 100 syngenic C57BL/6 mouse islets were transplanted under the left kidney of each chemically induced diabetic C57BL/6 mouse. Starting from the day of transplantation, these recipients were given bromodeoxyuridine (BrdU) daily with or without AR231453 at 10 mg/kg/d. Islet graft function was monitored by measuring blood glucose levels. At 4 weeks, left nephrectomy was performed to remove the kidney bearing the islet grafts to determine β-cell replication in the islet grafts. Insulin and BrdU immunofluorescence staining was performed to detect replicated β cells. Insulin + and BrdU + β cells in islet grafts were counted using a confocal microscope. To determine whether AR231453 increases plasma GLP-1 levels, we collected plasma from AR231453 treated mice at 30 minutes after treatment and measured plasma active GLP-1 by enzyme-linked immunosorbent assay. Results Although all recipient mice achieved normoglycemia at 28 days with or without treatment, normoglycemia was achieved in significantly fewer days in AR231453-treated mice. The vehicle-treated mice achieved normoglycemia in 16 ± 6 days, while AR231453-treated mice only required only 8 ± 3 days ( P < .01). The percentage of insulin + and BrdU + β cells in islet grafts was significantly higher in AR231453-treated mice than in vehicle-treated mice. The mean percentage of insulin + and BrdU + β cells in islet grafts was 21.5% ± 6.9% in AR231453-treated mice and 5.6% ± 3.7% in vehicle-treated mice ( P < .01). The plasma active GLP-1 levels were also significantly higher in AR231453-treated mice than in vehicle-treated mice ( P < .05). Conclusion Our data demonstrate that AR231453, a GPR119 agonist, can stimulate β-cell replication and improve islet graft function.