Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incretins are gut peptides that potentiate nutrient-stimulated insulin secretion following meal ingestion. Activities of the dominant incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, include glucose-dependent stimulation of insulin secretion and, in preclinical models, improvement in islet beta-cell mass. GLP-1 additionally reduces glucagon secretion, inhibits gastric emptying and promotes satiety. Patients with type 2 diabetes mellitus (T2DM) exhibit reduced total and intact GLP-1 levels, and exogenous administration of the hormone via continuous infusion results in glucose profiles similar to those in non-diabetic subjects. Incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). Thus, strategies to enhance incretin activity have included development of GLP-1 receptor agonists resistant to the action of DPP-4 (e.g. exenatide and liraglutide) and DPP-4 inhibitors that act to increase concentrations of endogenous intact incretins (e.g. sitagliptin and vildagliptin). Clinical trials of these incretin-based therapies have shown them to be effective in improving glycaemic control in patients with T2DM.
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PMID:Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. 1787 44

Vildagliptin is a potent selective inhibitor of dipeptidyl peptidase-4 (DPP-4) that improves glycaemic control by increasing islet alpha-cell and beta-cell responsiveness to glucose. In patients with type 2 diabetes mellitus (T2DM), vildagliptin improves beta-cell function, measured as insulin secretory rate relative to glucose level, and reduces glucagon secretion and endogenous glucose production in the postprandial period, resulting in reduced glucose levels. In clinical trials in T2DM, vildagliptin 100 mg/day monotherapy is effective in reducing haemoglobin A1c (HbA1c) across the spectrum of hyperglycaemia and has maintained efficacy over long-term treatment with neutral effects on body weight and lipids. Vildagliptin is associated with a low risk of hypoglycaemia, and has an adverse event profile comparable to placebo, including a reduced rate of gastrointestinal adverse effects compared with metformin and a reduced rate of oedema compared with rosiglitazone. As add-on combination therapy, vildagliptin produces significant further reductions in HbA1c in patients receiving metformin, pioglitazone, glimepiride and insulin, and has been found to reduce frequency of hypoglycaemia as an add-on to insulin. Preliminary findings indicate that the improved islet cell function underlying the efficacy of vildagliptin in T2DM is also observed in patients with impaired glucose tolerance, with vildagliptin treatment resulting in reduced glycaemic excursions. The overall profile of vildagliptin and the preliminary evidence of beneficial effects in the prediabetic state suggest that DPP-4 inhibition could be an effective strategy to prevent or delay progression from the prediabetic state to overt T2DM.
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PMID:The DPP-4 inhibitor vildagliptin: robust glycaemic control in type 2 diabetes and beyond. 1787 45

Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted in response to a meal ingestion, which is rapidly degraded by a specific enzyme, dipeptidylpeptidase-4 (DPP-4). It enhances insulin secretion in a glucose-dependent manner, inhibits glucagon secretion, retards gastric emptying,... Two pharmacological approaches have been developed to increase the abnormally low GLP-1 levels in type 2 diabetic patients: either to subcutaneously inject an agent closed to GLP-1 (exenatide), which is partially resistant to the action of DPP-4, either to orally administer a selective DPP-4 inhibitor (sitagliptin,...). These new drugs offer improved blood glucose control of type 2 diabetic patients, without inducing hypoglycaemia and with favourable effects on body weight.
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PMID:[Incretin mimetics and incretin enhancers for the treatment of type 2 diabetes]. 1789 62

Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.
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PMID:G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. 1790 Jul

Dipeptidyl peptidase (DPP-IV) rapidly metabolizes hormones such as glucagon-like peptide-1(7-36)amide. This study evaluated circulating DPP-IV activity in type 2 diabetic patients in relation to GLP-1 degradation and metabolic control. Blood samples were collected from type 2 diabetic patients in three main categories: good glycaemic control (HbA(1c) <7%, upper limit of non-diabetic range), moderate glycaemic control (HbA(1c) 7-9%) and poor glycaemic control (HbA(1c) >9%). Age- and sex-matched non-diabetic subjects were used as controls. Circulating DPP-IV activity of healthy control subjects was 22.5+/-0.7 nmol/ml/min (n=70). In the combined groups of type 2 diabetic subjects, circulating DPP-IV activity was significantly decreased at 18.1+/-0.7 nmol/ml/min (p<0.001, n=54). DPP-IV activity was negatively correlated with both glucose (p<0.01) and HbA(1c) (p<0.01) in this population. Furthermore, DPP-IV activity was reduced 1.2-fold (p<0.01, n=25), 1.3-fold (p<0.001, n=19) and 1.3-fold (p<0.05, n=10) in good, moderate and poorly controlled diabetic groups, 18.7+/-1.0, 17.4+/-1.4 and 18.0+/-1.5 nmol/ml/min, respectively. Degradation of GLP-1 by in vitro incubation with pooled plasma samples from healthy and type 2 diabetic subjects revealed decreased degradation to the inactive metabolite, GLP-1(9-36), in the diabetic group. These data indicate decreased DPP-IV activity and GLP-1 degradation in type 2 diabetes. DPP-IV enzyme activity appears to be depressed in response to poor glycaemic control.
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PMID:Decreased dipeptidyl peptidase-IV activity and glucagon-like peptide-1(7-36)amide degradation in type 2 diabetic subjects. 1790 81

The two incretin hormones GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-dependent Insulinotropic Peptide) are released by the gut in response to nutrient ingestion. Both of them potentiate glucose-induced insulin response, enhance insulin biosynthesis and, at least in rodents, preserve beta-cell mass through reduction of apoptosis and stimulation of beta-cell proliferation. In addition to its insulinotropic action, GLP-1 (but not GIP) suppresses glucagon secretion, delays gastric emptying and promotes satiety. Since in type 2 diabetes, the secretion of GLP-1 is dramatically reduced whereas its effects are retained, a number of pharmacological strategies aiming at restoring the incretin activity of this peptide have been explored. Because GLP-1 is rapidly degraded by the ubiquitous enzyme, dipeptidyl peptidase-IV (DPP-IV) and has a very short-lived action, DPP-IV resistant mimetics have been designed. Several randomized placebo-controlled studies with DPP-IV resistant GLP-1 analogues confirmed their efficacy to improve glycemic control in type 2 diabetic patients. The first one, exenatide, has been approved by the Food and Drug Administration (FDA) in 2005 for the treatment of type 2 diabetes. Longer-acting mimetics requiring only one injection per day or even per week are currently assessed in phase 3 trials. Another successful approach has been the development of orally active DPP-IV inhibitors which reversibly and selectively block the enzymatic activity. Many small-molecule DPP-IV inhibitors, called gliptins, have been shown to be effective as antihyperglycemic agents and, up to now, devoid of major adverse events. The first drug of this new therapeutic class having received FDA approval, sitagliptin, is now available for the treatment of type 2 diabetes in U.S. However, the efficacy/safety profile of these compounds and their positioning in the therapeutic algorithm of type 2 diabetes remains to be defined.
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PMID:[The incretin effect: a new therapeutic target in type 2 diabetes]. 1795 29

Many patients with type 2 diabetes fail to achieve adequate glycaemic control with available treatments, even when used in combination, and eventually develop microvascular and macrovascular diabetic complications. Even intensive interventions to control glycaemia reduce macrovascular complications only minimally. There is, therefore, a need for new agents that more effectively treat the disease, as well as target its prevention, its progression, and its associated complications. One emerging area of interest is centred upon the actions of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which enhance meal-induced insulin secretion and have trophic effects on the beta-cell. GLP-1 also inhibits glucagon secretion, and suppresses food intake and appetite. Two new classes of agents have recently gained regulatory approval for therapy of type 2 diabetes; long-acting stable analogues of GLP-1, the so-called incretin mimetics, and inhibitors of dipeptidyl peptidase 4 (DPP-4, the enzyme responsible for the rapid degradation of the incretin hormones), the so-called incretin enhancers. This article focuses on DPP-4 inhibitors.
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PMID:DPP-4 inhibitor therapy: new directions in the treatment of type 2 diabetes. 1798 67

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 with intensive treatment type 2 diabetic patients may face spikes in blood glucose after meals, weight gain, and a loss of effectiveness of their treatments over time. The novel agents recently developed by the Pharmaceutical Industry may either provide an alternative therapeutic strategy or offer useful adjuncts to existing therapies. Glucagon-like peptide 1 (GLP-1), produced in the small intestine and amylin, produced by beta cells in the pancreas, also have glucose lowering effects. Amylin is an hormone secreted after a meal, having a complementary action to insulin. GLP-1, also released in a post-prandial manner, promotes insulin production and secretion, reduces glucagon secretion, delays gastric emptying and induces a feeling of fullness. The most promising effect of GLP-1 is its ability to increase beta-cell mass by stimulating neogenesis and reducing apoptosis in rodents. However the fact that GLP-1 is rapidly degraded by dipeptidylpeptidase IV (DPPIV) in vivo reduces its usefulness. Thus, in order to improve therapeutic efficacy, two approaches have been investigated: the development of GLP-1 analogs resistant to degradation or the development of DPP-IV inhibitors. Synthetic analogs of amylin (pramlintide), GLP-1 (exenatide) and inhibitors of the degradation of GLP-1 (sitagliptin, DPP-IV inhibitor) are now available for clinical use. Promising biological targets being investigated include those leading to insulin sensitization (11beta-HSD-1 inhibitors and antagonists of glucocorticoids receptor), reducing hepatic glucose output (antagonist of glucagon receptor, inhibitors of glycogen phosphorylase and fructose-1,6-biphosphatase) and finally increasing urinary elimination of excess glucose (SGLT inhibitors). A particular role is played by glucokinase activators (GKA) which can both increase insulin secretion and improve hepatic glucose metabolism. In this review, we present a summary of the data available on newly approved treatments (amylin and GLP-1 analogs as well as DPP-IV inhibitors) and give an overview of the targets currently being studied for the treatment of type 2 diabetes with an emphasis on the small molecule drug design.
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PMID:Newly approved and promising antidiabetic agents. 1798 55

Sitagliptin, a novel orally-active dipeptidyl-peptidase (DPP-4) inhibitor has been introduced into type 2 diabetes therapy. Sitagliptin inhibits the degradation of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), as well as that of other regulatory peptides important for glucose homeostasis. It reduces haemoglobin A1c (HbA1c), fasting and postprandial glucose by glucose- dependent stimulation of insulin secretion and inhibition of glucagon secretion. Sitagliptin is weight neutral. Indirect measures show a possible improvement of beta-cell function. Sitagliptin does not cause hypoglycemia when compared to metformin or placebo. Metformin, which has a different unique mechanism, has been used in type 2 diabetes for approximately 50 years. Metformin improves insulin resistance and is the first-line antidiabetic drug in use today. The combination of a DPP-4 inhibitor with metformin allows a broad and complementary spectrum of antidiabetic actions. This combination does not increase the risk of hypoglycaemia nor does it promote weight gain, an adverse effect of various other oral antidiabetic combinations. This article gives an overview of the data available on the combined antidiabetic effects of metformin and sitagliptin.
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PMID:Sitagliptin with metformin: profile of a combination for the treatment of type 2 diabetes. 1798 21

Inhibition of dipeptidyl peptidase 4 (DPP-4) is a novel treatment for type-2 diabetes. DPP-4 inhibition prevents the inactivation of glucagon-like peptide 1 (GLP-1), which increases levels of active GLP-1. This increases insulin secretion and reduces glucagon secretion, thereby lowering glucose levels. Several DPP-4 inhibitors are in clinical development. Most experience so far has been with sitagliptin (Merck; approved by the FDA) and vildagliptin (Novartis; filed). These are orally active compounds with a long duration, allowing once-daily administration. Both sitagliptin and vildagliptin improve metabolic control in type-2 diabetes, both in monotherapy and in combination with metformin and thiazolidinediones. A reduction in HbA(1c) of approximately 1% is seen in studies of DPP-4 inhibition of up to 52 weeks' duration. DPP-4 inhibition is safe and well tolerated, the risk of hypoglycaemia is minimal, and DPP-4 inhibition is body-weight neutral. DPP-4 inhibition is suggested to be a first-line treatment of type-2 diabetes, particularly in its early stages in combination with metformin. However, the durability and long-term safety of DPP-4 inhibition remain to be established.
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PMID:DPP-4 inhibitors. 1805 33


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