Glucagon-like peptide-1 (GLP-1), released from gut endocrine L cells in response to glucose, regulates appetite, insulin secretion, and gut motility. How glucose given orally, but not systemically, induces GLP-1 secretion is unknown. We show that human duodenal L cells express sweet taste receptors, the taste G protein gustducin, and several ...

OBJECTIVE: Dipeptidyl peptidase-4 (DPP4) inhibitors lower blood glucose in diabetic subjects; however, the mechanism of action through which these agents improve glucose homeostasis remains incompletely understood. Although glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) represent important targets for DPP4 activity, whether additional substrates are important for the glucose-lowering actions ...

Sulfonylureas (SU) with glucagon-like peptide-1 (GLP-1)-based therapy are an emerging therapeutic combination for type 2 diabetes. Prior human studies have hinted at endothelial effects of GLP-1 and SU. To study the endothelial effects of GLP-1 per se and to evaluate the modulatory effects, if any, of SU agents on GLP-1-induced ...

In France, prevalence of drug-treated diabetes reached 3.60% in 2005, with 92% of type 2 diabetic patients. In 2007, there are probably nearly 3000 000 diagnosed or undiagnosed diabetic patients. Ageing of the population and increase in obesity are the main causes of this "diabetes epidemic". Type 2 diabetes is ...

Glucose-dependent insulinotropic polypeptide (GIP) and peptide YY (PYY) are secreted from the intestinal K- and L-cells, respectively, following a meal. Both peptides are believed to play a key role in glucose homeostasis and energy expenditure. This study investigated the effects of daily administration of the stable and specific GIP-R antagonist, ...

BACKGROUND/AIMS: Inhibition of dipeptidyl peptidase 4 by vildagliptin enhances the concentrations of the active form of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The present study asked whether vildagliptin accentuates glibenclamide-induced hypoglycemia or affects endogenous secretion of GLP-1 and GIP after an oral glucose tolerance ...

After a meal, glucagon-like peptide-1 (GLP-1) levels in the hepatic portal vein are elevated and are twice those in peripheral blood. The aim of this study was to determine whether any of GLP-1's acute metabolic effects are initiated within the hepatic portal vein. Experiments consisted of a 40-min basal period, ...

Dipeptidyl peptidase IV (DPP-IV) deactivates the incretin hormones GLP-1 and GIP by cleaving the penultimate proline or alanine from the N-terminal (P1-position) of the peptide. Inhibition of this enzyme will prevent the degradation of the incretin hormones and maintain glucose homeostasis; this makes it an attractive target for the development ...

Peptide oral delivery is still a significant challenge because of two major impediments, low absorption efficiency and instability in gastrointestinal tract. The aim of this study was to design, prepare, and evaluate an intestine enzyme-resistant, superior intestine absorptive, and biologically preserved glucagon-like peptide-1 (GLP-1) derivative using the site-specific modification of ...

PURPOSE OF REVIEW: To review data from clinical trials of incretin mimetics in patients with type 2 diabetes. RECENT FINDINGS: Incretin mimetics are a new class of antidiabetic medication that mimic the actions of the hormone glucagon-like peptide-1. They exhibit several properties, including glucose-dependent stimulation of insulin secretion, suppression of ...

Dipeptidyl peptidase 4 (DPP-4) inhibition prevents the rapid degradation of the incretins, glucagon-like peptide 1 and glucose-dependent insulinotropic peptide. Incretins have beneficial effects on glycaemic control in patients with type 2 diabetes through their effects on both alpha- and beta-cells in the pancreas and possibly through additional non-pancreatic effects. Vildagliptin ...

Glucagon-like peptide-1 (7-36) amide (GLP-1) is an insulin secretagogue. Recently, many studies have shown GLP-1 can improve insulin resistance in peripheral tissues. In the present study, we investigated glucose uptake in 3T3-L1 adipocytes in either basal or insulin resistant state and dissected insulin signaling pathway in order to elucidate the ...

As understanding of type 2 diabetes mellitus pathophysiology expands, treatments continue to evolve and new pharmacologic targets emerge. Patients with type 2 diabetes exhibit deficiencies of the incretin system; thus, methods for increasing insulinotropic hormones have become a popular target for therapy. A new class of oral antidiabetics has emerged-the ...

BACKGROUND: The antidiabetic effect of bariatric surgery has been interpreted as a conceivable result of surgically induced weight loss and decreased caloric intake. However, glycemic control often occurs within days, before significant weight loss has been reached. The aim of our work was to investigate the hormones that control glycemic ...

The protective effect of Pycnogenol against cardiovascular diseases was clearly demonstrated. Nevertheless, little is known about its antithrombotic effect, especially in diabetes associated with enhanced thromboxane synthesis leading to severe vascular complications. Therefore, the main purpose of our study was to evaluate the effect of long-term Pycnogenol intake on synthesis ...

AIMS/HYPOTHESIS: Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes and reduced insulin secretion. The transcription factor TCF7L2 is an essential factor for glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells. We studied whether a defect in the enteroinsular axis contributes to impaired insulin ...

AIMS/HYPOTHESIS: We examined the effect of glucagon-like peptide-1 (GLP-1) on the development of diabetes and islet morphology in NOD mice by administering GLP-1 to prediabetic mice. METHODS: Eight-week-old female NOD mice were infused subcutaneously with human GLP-1 via a mini-osmotic pump for 4 or 8 weeks. In mice treated with ...

BACKGROUND: The incretin effect is reduced and the insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is abolished in patients with type 2 diabetes mellitus (T2DM). OBJECTIVE AND DESIGN: To evaluate the causality of this deficiency we investigated 8 patients with chronic pancreatitis (CP) and normal glucose tolerance ...

The physiological incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), lower blood glucose levels through multiple mechanisms, including enhancement of glucose-stimulated insulin secretion. Although of demonstrated benefit to glycemic control in patients with type 2 diabetes, particularly for GLP-1, the half-lives of these peptides are too short for practical ...

Changes in hepatic insulin clearance can occur after oral glucose or meal ingestion. This has been attributed to the secretion and action of gastric inhibitory polypeptide (GIP) and glucagon-like peptide (GLP)-1. Given the recent availability of drugs based on incretin hormones, such clearance effects may be important for the future ...

Gastric emptying is a major determinant of glycemia, gastrointestinal hormone release, and appetite. We determined the effects of different intraduodenal glucose loads on glycemia, insulinemia, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin (CCK), antropyloroduodenal motility, and energy intake in healthy subjects. Blood glucose, plasma hormone, and antropyloroduodenal motor ...

Type 2 diabetes is an endocrine/metabolic disease characterized by hyperglycemia. It is now well established that insulin resistance and pancreatic beta-cell dysfunction/failure are the two major components of the physiopathology of the disease. Current available therapies do not successfully enable patients with type 2 diabetes to reach glycemic goals. Even ...

INTRODUCTION: Alterations in entero-endocrine signaling may play a role in improvements in satiety and glucose tolerance after Roux-en-Y gastric bypass (RYGB). We report our findings of gut hormone secretion in a cohort of diabetic and nondiabetic morbidly obese patients. MATERIALS AND METHODS: Ten morbidly obese subjects who underwent uncomplicated RYGB ...

BACKGROUND: It has been hypothesized that glucagon-like peptide-1 (GLP-1), secreted by ileal L cells, plays a key-role in the resolution of type 2 diabetes after bariatric operations whose common feature is an expedite nutrient delivery to the hindgut. Ileal transposition (IT), an operation that permits L-cell stimulation by undigested food, ...

The incretin mimetics are an emerging class of agents for the treatment of diabetes. So far, exenatide is licensed for use in the US and also became available in the UK in May 2007. Within development and Phase III trials, liraglutide may also be made available within the next 2 ...

PURPOSE OF REVIEW: Past studies in humans and animals have shown that low blood glucose concentrations due to fasting negatively interfere with the ability to mount a hypothalamus-pituitary-adrenal (HPA) axis response to psychological stress or to pharmacological activation, respectively. This contradicts the classical view of the proposed primary glucocorticoid function ...

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins secreted in response to oral glucose ingestion by intestinal L and K cells, respectively. The molecular mechanisms responsible for intestinal cell glucose sensing are unknown but could be related to those described for beta-cells, brain and hepatoportal sensors. We determined ...

Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that is secreted during meal absorption and is essential for normal glucose homeostasis. However, the relatively low plasma levels and rapid metabolism of GLP-1 raise questions as to whether direct endocrine action on target organs, such as islet cells, account for all of ...

Acylated and unacylated ghrelin (AG and UAG) are gut hormones that exert pleiotropic actions, including regulation of insulin secretion and glucose metabolism. In this study, we investigated whether AG and UAG differentially regulate portal and systemic insulin levels after a glucose load. We studied the effects of the administration of ...

AIMS/HYPOTHESIS: Gastric inhibitory polypeptide (GIP) receptor antagonism with (Pro(3))GIP improves glucose tolerance and ameliorates insulin resistance and abnormalities of islet structure/function in ob/ob mice. This study examined the ability of (Pro(3))GIP to counter the development of obesity, insulin resistance and diabetes in mice fed high-fat and cafeteria diets. MATERIALS AND ...

Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells, can effectively lower blood glucose levels in patients with diabetes. A fusion gene, consisting of 10 tandem repeated GLP-1 analog genes, was expressed at a high level in the yeast Pichia pastoris. SDS polyacrylamide gel electrophoresis (SDS-PAGE), and Western Blotting results ...

Roux-en-Y bypass surgery is increasingly used for treatment of gross obesity due to the general inability of lifestyle change and existing drug treatments to counter the obesity epidemic. This common form of bariatric surgery involves bypass of the small intestine with significant reduction of body of weight that is independent ...

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the two key incretin hormones released from the gastrointestinal tract that regulate blood glucose homeostasis through potent insulin secretion. The rapid degradation of GIP and GLP-1 by the ubiquitous enzyme dipeptidyl peptidase IV (DPP IV) renders both peptides noninsulinotropic. However, DPP ...

A role of GLP-1 (glucagon-like peptide-1) in the recovery of the metabolic conditions of morbidly obese patients after bariatric surgery has been proposed. Exendin 4 (Ex-4) and exendin 9 (Ex-9) both have GLP-1-like effects upon glucose metabolism in human myocytes. We investigated in normal human adipocytes the effect of GLP-1, ...

OBJECTIVE: The ATP-dependent K+-channel (K(ATP)) is critical for glucose sensing and normal glucagon and insulin secretion from pancreatic endocrine alpha- and beta-cells. Gastrointestinal endocrine L- and K-cells are also glucose-sensing cells secreting glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) respectively. The aims of this study were to 1) investigate ...

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and role in therapy of vildagliptin for the treatment of type 2 diabetes mellitus were reviewed. SUMMARY: Vildagliptin is an agent in a new class of medications called dipeptidyl peptidase IV (DPP4) inhibitors. By inhibiting DPP4, vildagliptin causes an increase ...

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that has a potent stimulatory effect on insulin release under conditions of normal glucose tolerance. However, its insulinotropic effect is reduced or even absent entirely in type 2 diabetic patients. In this study, we addressed the role of glucose concentration in the ...

Dipeptidyl peptidase IV (DPP IV) is the primary inactivator of glucoregulatory incretin hormones. This has lead to development of DPP IV inhibitors as a new class of agents for the treatment of type 2 diabetes. Recent reports indicate that other antidiabetic drugs, such as metformin, may also have inhibitory effects ...

Insulin is an extensively studied peptide hormone in mammals. However, insulin is not restricted to vertebrates, but has also been identified in invertebrates, among whom several insect species. These insulin-like peptides (ILPs) show structural and-at least some-functional homology with mammalian insulin and act through a conserved pathway. Yet many aspects ...

OBJECTIVE: To study the relationships between glucagon-like peptide-1 (GLP-1), weight status, insulin, and insulin resistance in the fasting state. PATIENTS AND METHODS: Fasting GLP-1, glucose and insulin concentrations, insulin resistance index as homeostasis model assessment (HOMA), body mass index (BMI), and percentage body fat based on skinfold thickness measurements were ...

Many patients with type 2 diabetes mellitus (T2DM) are unable to achieve adequate glycemic control. Of the approximately 19 million individuals with T2DM in the United States, only about a third achieve the hemoglobin A(1c) (HbA(1c)0 goal set forth by the American Diabetes Association (HbA(1c) <7% [6% if it can ...

This review focuses on the mechanisms regulating the synthesis, secretion, biological actions, and therapeutic relevance of the incretin peptides glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The published literature was reviewed, with emphasis on recent advances in our understanding of the biology of GIP and GLP-1. GIP and GLP-1 ...

Approximately two thirds of patients with type 2 diabetes mellitus (T2DM) are unable to reach the hemoglobin A(1c) target set by the American Diabetes Association (HbA(1c) <7.0%). Therefore, T2DM continues to be a major public health concern. Incretin mimetics and dipeptidyl peptidase IV inhibitors are medications that have the potential ...

OBJECTIVE: To highlight the role of incretin hormones in the management of type 2 diabetes mellitus with a focus on vildagliptin, a dipeptidyl peptidase IV (DPP IV) inhibitor currently in development. DATA SOURCES: Searches were conducted in MEDLINE (1950-April 2007) and International Pharmaceutical Abstracts (1970-April 2007) using the key words ...

Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in ...

Limited data on patients undergoing Roux-en-Y gastric bypass surgery (RY-GBP) suggest that an improvement in insulin secretion after surgery occurs rapidly and thus may not be wholly accounted for by weight loss. We hypothesized that in obese patients with type 2 diabetes the impaired levels and effect of incretins changed ...

Glucagon-like peptide 1 (GLP-1) and its analogue exendin-4 (Ex4) have displayed potent glucose homeostasis-modulating characteristics in type 2 diabetes (T2D). However, there are few reports of effectiveness in type 1 diabetes (T1D) therapy, where there is massive loss of beta cells. We previously described a novel GLP-1 analogue consisting of ...

BACKGROUND: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are hormones secreted by the enteroendocrine cells of the gut in response to the ingestion of nutrients. These incretin hormones, so called because they increase insulin secretion, are key modulators of pancreatic islet hormone secretion and, thus, glucose homeostasis. The glucoregulatory ...

BACKGROUND: Insulin resistance alone does not result in the development of type 2 diabetes; progressive dysfunction of pancreatic islet alpha and beta cells, which results in inadequate control of hyperglycemia, must be present for the disease to develop. Because of these defects, meal-stimulated insulin secretion from beta cells is reduced ...

Glucose-dependent insulinotropic polypeptide (GIP) is an important gastrointestinal hormone, which regulates insulin release and glucose homeostasis, but is rapidly inactivated by enzymatic N-terminal truncation. Here we report the enzyme resistance and biological activity of several Glu(3)-substituted analogues of GIP namely; (Ala(3))GIP, (Lys(3))GIP, (Phe(3))GIP, (Trp(3))GIP and (Tyr(3))GIP. Only (Lys(3))GIP demonstrated moderately ...