Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To clarify the cytoprotective effect of glucagon-like peptide-1 receptor (GLP-1R) signaling in conditions of glucose toxicity in vivo, we performed murine isogenic islet transplantation with and without exendin-4 treatment. When a suboptimal number of islets (150) were transplanted into streptozotocin-induced diabetic mice, exendin-4 treatment contributed to the restoration of normoglycemia. When 50 islets expressing enhanced green fluorescent protein (EGFP) were transplanted, exendin-4 treatment reversed loss of both the number and mass of islet grafts one and 3 days after transplantation. TUNEL staining revealed that exendin-4 treatment reduced the number of apoptotic beta cells during the early posttransplant phase, indicating that GLP-1R signaling exerts its cytoprotective effect on pancreatic beta cells by inhibiting their apoptosis. This beneficial effect might be used both to ameliorate type 2 diabetes and to improve engraftment rates in clinical islet transplantation.
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PMID:GLP-1 receptor signaling protects pancreatic beta cells in intraportal islet transplant by inhibiting apoptosis. 1821 28

The glucagon-like peptide-1 receptor (GLP-1R) belongs to Family B1 of the seven-transmembrane G protein-coupled receptors, and its natural agonist ligand is the peptide hormone glucagon-like peptide-1 (GLP-1). GLP-1 is involved in glucose homeostasis, and activation of GLP-1R in the plasma membrane of pancreatic beta-cells potentiates glucose-dependent insulin secretion. The N-terminal extracellular domain (nGLP-1R) is an important ligand binding domain that binds GLP-1 and the homologous peptide Exendin-4 with differential affinity. Exendin-4 has a C-terminal extension of nine amino acid residues known as the "Trp cage", which is absent in GLP-1. The Trp cage was believed to interact with nGLP-1R and thereby explain the superior affinity of Exendin-4. However, the molecular details that govern ligand binding and specificity of nGLP-1R remain undefined. Here we report the crystal structure of human nGLP-1R in complex with the antagonist Exendin-4(9-39) solved by the multiwavelength anomalous dispersion method to 2.2A resolution. The structure reveals that Exendin-4(9-39) is an amphipathic alpha-helix forming both hydrophobic and hydrophilic interactions with nGLP-1R. The Trp cage of Exendin-4 is not involved in binding to nGLP-1R. The hydrophobic binding site of nGLP-1R is defined by discontinuous segments including primarily a well defined alpha-helix in the N terminus of nGLP-1R and a loop between two antiparallel beta-strands. The structure provides for the first time detailed molecular insight into ligand binding of the human GLP-1 receptor, an established target for treatment of type 2 diabetes.
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PMID:Crystal structure of the ligand-bound glucagon-like peptide-1 receptor extracellular domain. 1828 2

Type 2 diabetes mellitus is associated with progressive decreases in pancreatic beta-cell function. Most patients thus require increasingly intensive treatment, including oral combination therapies followed by insulin. Fear of hypoglycemia is a potential barrier to treatment adherence and glycemic control, while weight gain can exacerbate hyperglycemia or insulin resistance. Administration of insulin can roughly mimic physiologic insulin secretion but does not address underlying pathophysiology. Glucagon-like peptide 1 (GLP-1) is an incretin hormone released by the gut in response to meal intake that helps to maintain glucose homeostasis through coordinated effects on islet alpha- and beta-cells, inhibiting glucagon output, and stimulating insulin secretion in a glucose-dependent manner. Biological effects of GLP-1 include slowing gastric emptying and decreasing appetite. Incretin mimetics (GLP-1 receptor agonists with more suitable pharmacokinetic properties versus GLP-1) significantly lower hemoglobin A1c, body weight, and postprandial glucose excursions in humans and significantly improve beta-cell function in vivo (animal data). These novel incretin-based therapies offer the potential to reduce body weight or prevent weight gain, although the durability of these effects and their potential long-term benefits need to be studied further. This article reviews recent clinical trials comparing therapy with the incretin mimetic exenatide to insulin in patients with oral treatment failure, identifies factors consistent with the use of each treatment, and delineates areas for future research.
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PMID:Exploiting the antidiabetic properties of incretins to treat type 2 diabetes mellitus: glucagon-like peptide 1 receptor agonists or insulin for patients with inadequate glycemic control? 1832 2

Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone with the potential to change diabetes. The physiological effects of GLP-1 are multiple, and many seem to ameliorate the different conditions defining the diverse physiopathology seen in type 2 diabetes. In animal studies, GLP-1 stimulates beta-cell proliferation and neogenesis and inhibits beta-cell apoptosis. In humans, GLP-1 stimulates insulin secretion and inhibits glucagon and gastrointestinal secretions and motility. It enhances satiety and reduces food intake and has beneficial effects on cardiovascular function and endothelial dysfunction. Enhancing incretin action for therapeutic use includes GLP-1 receptor agonists resistant to degradation (incretin mimetics) and dipeptidyl peptidase (DPP)-4 inhibitors. In clinical trials with type 2 diabetic patients on various oral antidiabetic regimes, both treatment modalities efficaciously improve glycaemic control and beta-cell function. Whereas the incretin mimetics induce weight loss, the DPP-4 inhibitors are considered weight neutral. In type 1 diabetes, treatment with GLP-1 shows promising effects. However, several areas need clinical confirmation: the durability of the weight loss, the ability to preserve functional beta-cell mass and the applicability in other than type 2 diabetes. As such, long-term studies and studies with cardiovascular end-points are needed to confirm the true benefits of these new classes of antidiabetic drugs in the treatment of diabetes mellitus.
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PMID:GLP-1: physiological effects and potential therapeutic applications. 1843 75

The obesity epidemic in the developed and developing world is being followed by an epidemic of type 2 diabetes. In type 2 diabetes, subjects cannot manage glucose properly because they do not produce enough insulin, and the peripheral tissues have become resistant to insulin. Glucagon-like peptide 1 (GLP-1) is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. One of the actions of GLP-1 is to stimulate insulin secretion. In subjects with type 2 diabetes, intravenous or subcutaneous GLP-1 stimulated insulin production and decreased blood glucose levels. However, as GLP-1 is rapidly metabolised, it is not suitable for use in most subjects with type 2 diabetes. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the GLP-1 receptor. After subcutaneous administration, synthetic exendin-4 (exenatide) decreased postprandial concentrations of glucose and insulin, and fasting glucose levels in subjects with type 2 diabetes, and the effects lasted several hours. Subsequently, exenatide was been trialled in subjects taking metformin only, a sulfonylurea only, or metformin and a sulfonylurea, and shown to improve glycemic control with few adverse events, initially over 30 weeks, and then extended to 82 weeks. Exenatide may also be as effective as insulin glargine in subjects with type 2 diabetes not adequately controlled with the oral agents. In conclusion, exenatide represents a new and beneficial addition to the medicines used to treat type 2 diabetes.
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PMID:Is exenatide improving the treatment of type 2 diabetes? Analysis of the individual clinical trials with exenatide. 1847 91

Current strategies to treat type 2 diabetes (DMT2) include reducing insulin resistance using glitazones, supplementing with exogenous insulin, increasing endogenous insulin production with sulfonylureas and meglitinides, reducing hepatic glucose production through biguanides, and limiting postprandial glucose absorption with alpha-glucosidase inhibitors. In all of these areas, new generations of molecules with improved efficacy and safety profiles, are being investigated. Promising biological targets are rapidly emerging such as the role of lipotoxicity as a cause of glucometabolic insulin resistance, leading to a host of new molecular drug targets such as AMP-activated protein kinase (AMPK) activators, recombinant adiponectin derivatives, and fatty acid synthase (FAS) inhibitors. Insulin action can be enhanced in muscle, liver and fat, with small-molecule activators of the insulin receptor or inhibitors of protein tyrosine phosphatase (FTP)-IB. Defective glucose-stimulated insulin secretion by pancreatic B-cells could be alleviated with recombinant glucagon-like peptide (GLP-1) or agonists to the GLP-1 receptor. This review presents a new approach for obesity and DMT2 drug discovery through pharmacogenomics. Several compounds have already been validated through genetic engineering in animal models or the preliminary use of therapeutic compounds in humans.
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PMID:[Molecular targets for new drug discovery to treat type 2 diabetes and obesity]. 1848 61

Exenatide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic used in the treatment of type 2 diabetes. There is increasing evidence that GLP-1 can influence glycemia not only via pancreatic (insulinotropic and glucagon suppression) and gastric-emptying effects, but also via an independent mechanism mediated by portal vein receptors. The aim of our study was to investigate whether exenatide has an islet- and gastric-independent glycemia-reducing effect, similar to GLP-1. First, we administered mixed meals, with or without exenatide (20 microg sc) to dogs. Second, to determine whether exenatide-induced reduction in glycemia is independent of slower gastric emptying, in the same animals we infused glucose intraportally (to simulate meal test glucose appearance) with exenatide, exenatide + the intraportal GLP-1 receptor antagonist exendin-(9-39), or saline. Exenatide markedly decreased postprandial glucose: net 0- to 135-min area under the curve = +526 +/- 315 and -536 +/- 197 mg.dl(-1).min(-1) with saline and exenatide, respectively (P < 0.05). Importantly, the decrease in plasma glucose occurred without a corresponding increase in postprandial insulin but was accompanied by delayed gastric emptying and lower glucagon. Significantly lower glycemia was induced by intraportal glucose infusion with exenatide than with saline (92 +/- 1 vs. 97 +/- 1 mg/dl, P < 0.001) in the absence of hyperinsulinemia or glucagon suppression. The exenatide-induced lower glycemia was partly reversed by intraportal exendin-(9-39): 95 +/- 3 and 92 +/- 3 mg/dl with exenatide + antagonist and exenatide, respectively (P < 0.01). Our results suggest that, similar to GLP-1, exenatide lowers glycemia via a novel mechanism independent of islet hormones and slowing of gastric emptying. We hypothesize that receptors in the portal vein, via a neural mechanism, increase glucose clearance independent of islet hormones.
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PMID:Exenatide can reduce glucose independent of islet hormones or gastric emptying. 1849 81

The improved understanding of glucoregulatory hormones has driven the development of new pharmacologic agents to treat type 2 diabetes. One new class of antihyperglycemic medication is incretin mimetics (IMs). Incretin hormones potentiate insulin secretion following meal ingestion, a process that is impaired in patients with type 2 diabetes. GLP-1, a 30-amino acid peptide incretin hormone, is produced in the L cells of the ileum and colon. Studies have shown that a 6-week continuous GLP-1 infusion in patients with type 2 diabetes improved glycemic control and beta-cell function and delayed gastric emptying. Despite the rapid degradation and inactivation of GLP-1 by the enzyme dipeptidyl peptidase IV (DPP-IV), agents that mimic the actions of GLP-1 are of great clinical interest. First-in-class IM exenatide, a GLP-1 receptor agonist resistant to DPP-IV inactivation, mimics many beneficial glucoregulatory effects of GLP-1, such as suppressing glucagon secretion, regulating gastric emptying and satiety, and increasing glucose-dependent insulin secretion. Exenatide is an adjunctive therapy for patients who take metformin, a sulfonylurea, a thiazolidinedione, or a combination of these oral medications but have not achieved glycemic control. An 82-week, open-label extension trial has shown that exenatide is well tolerated and that the benefits, including improved glycemic control, weight loss, and mitigation of cardiovascular risk factors, are sustained.
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PMID:Beyond glycemic control: the effects of incretin hormones in type 2 diabetes. 1852 67

Type 2 diabetes mellitus and obesity share a pathogenic relationship, and both have rapidly increased in prevalence over the past decade. This review evaluates the effects of antidiabetes therapies on weight and glycemic control in the type 2 diabetes mellitus population. A PubMed search was conducted to identify randomized controlled trials that reported the weight effects of antidiabetes treatments. The search focused on the newer incretin-based therapies, including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists. Antiobesity drugs and treatment options potentially available to patients with type 2 diabetes mellitus, including bariatric surgery, were also examined. Most of the established antidiabetes therapies (eg, sulfonylureas, thiazolidinediones) promote weight gain, thereby exacerbating insulin resistance and glucose intolerance. Dipeptidyl peptidase-4 inhibitors exhibit a weight-neutral profile, however, and GLP-1 receptor agonists (eg, exenatide, liraglutide) have achieved significant body weight reductions in spite of improved glycemic control, which is often accompanied by weight gain. Antiobesity drugs, such as orlistat and sibutramine, are effective weight-lowering agents in patients with type 2 diabetes mellitus, but safety and tolerability concerns may limit their use. Bariatric surgery in obese patients is associated with improved glycemic values and decreased mortality. Clinical evidence substantiating the weight-neutral effects of DPP-4 inhibitors and the weight-loss effects of GLP-1 agonists is promising, offering an expansion of therapeutic options for overweight and obese patients with type 2 diabetes mellitus. Evidence on the clinical utility of antiobesity drugs is more equivocal, and more data are needed to evaluate the safety and tolerability of these agents.
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PMID:The effects of pharmacologic agents for type 2 diabetes mellitus on body weight. 1865 64

More than 20 million people in the United States, or 7% of the population, have diabetes, with health care and work-related costs estimated to be $174 billion in 2007. Obesity constitutes one of the major driving factors behind this epidemic. Most drugs currently used to treat diabetes address the primary metabolic defects in type 2 diabetes mellitus, which are insulin resistance and pancreatic islet dysfunction. Incretin augmentation therapies, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase IV inhibitors, restore glucose homeostasis by addressing some of the unmet needs in diabetes therapies related to alpha-cell dysfunction and chronic beta-cell dysfunction. This new group of drugs offers certain advantages because its use is characterized by a low incidence of hypoglycemia and the absence of weight gain. Moreover, the use of fixed-dose combinations of dipeptidyl peptidase IV inhibitors with other oral antidiabetic agents seems very attractive to patients because of their reduced pill intake and minimized financial burden, which may improve adherence. An efficient strategy to slow down the epidemic of diabetes must include these emerging therapies and regimens, coupled with intensive patient education that includes information on treatment benefits and adverse effects, medication costs, and medication regimen complexity.
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PMID:Multidisciplinary interventions: mapping new horizons in diabetes care. 1866 11


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