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)

Incretin hormones are defined as intestinal hormones released in response to nutrient ingestion, which potentiate the glucose-induced insulin response. In humans, the incretin effect is mainly caused by two peptide hormones, glucose-dependent insulin releasing polypeptide GIP, and glucagon-like peptide-1 GLP-1. GIP is secreted by K cells from the upper small intestine while GLP-1 is mainly produced in the enteroendocrine L cells located in the distal intestine. Their effect is mediated through their binding with specific receptors, though part of their biological action may also involve neural modulation. GIP and GLP-1 are both rapidly degraded into inactive metabolites by the enzyme dipeptidyl-peptidase-IV (DPP-IV). In addition to its effects on insulin secretion, GLP-1 exerts other significant actions, including stimulation of insulin biosynthesis, inhibition of glucagon secretion, inhibition of gastric emptying and acid secretion, reduction of food intake, and trophic effects on the pancreas. As the insulinotropic action of GLP-1 is preserved in type 2 diabetic patients, this peptide was a candidate as a therapeutic agent for this disease. A number of pharmacological strategies have been developed to provide continuous delivery of GLP-1 and to prevent degradation of GLP-1, including continuous administration of GLP-1, DPP-IV inhibitors and DPP-IV resistant GLP-1 analogues. Recent results of the most clinically advanced incretin mimetics confirmed their efficacy to improve glycemic control in type 2 diabetic patients. Further results are expected to confirm the efficacy/safety profile of these compounds, and to find their place in the therapeutic strategy of type 2 diabetes.
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PMID:Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. 1614 14

Glucagon-like peptide-1 (GLP-1) has long-term effects on pancreatic islets by increasing the insulin secretory capacity and beta cell mass. The islet effects of GLP-1 are glucose dependent and therefore tied to glucose sensing and metabolism. We examined whether prevention of inactivation of GLP-1 by inhibiting dipeptidyl peptidase-4 (DPP-4) is sufficient to promote long-term augmentation of glucose-stimulated insulin secretion. We also explored whether a defective glucose sensing and metabolism could be overcome by DPP-4 inhibition. We administered the orally active and highly selective DPP-4 inhibitor (1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidineP-4; vildagliptin; 3 mumol/mouse daily) to normal, wildtype, mice and to mice with a beta-cell targeted dominant-negative mutant hepatocyte nuclear factor-1alpha (HNF-1alpha); these mice have a defective islet response to glucose. After eight weeks, vildagliptin augmented the insulin response after gastric glucose (75 mg) by 5-fold in male mice (7.3+/-0.8 vs. 1.3+/-0.5 nmol/l, P<0.001) and 30-fold in female mice (26.5+/-5.8 vs. 0.9+/-0.3 nmol/l, P<0.001). Furthermore, glucose-stimulated insulin secretion from isolated islets was markedly enhanced by 9 weeks treatment with vildagliptin. In contrast, in transgenic mice, the severely suppressed insulin response was only marginally improved by vildagliptin in males, and not affected at all in females. We conclude that DPP-4 inhibition improves islet function and increases beta cell secretory responses on a long-term basis and that this is dependent on intact expression of HNF-1alpha.
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PMID:Beta-cell expression of a dominant-negative HNF-1alpha compromises the ability of inhibition of dipeptidyl peptidase-4 to elicit a long-term augmentation of insulin secretion in mice. 1617 1

Glucagon-like peptide GLP-1 is an endogenous insulinotropic/glucagonostatic hormone that acts in a self-limiting mechanism. It is a multifunctional hormone that leads to insulin release stimulation, liver glucagon breakdown suppression, upregulation of islet cell proliferation, and neogenesis and retardation of gastric emptying. The short half-life and high renal clearance due to degradation via dipeptidyl peptidase-IV DPP-IV, and active glomerular filtration rate make this hormone ineffectual as an exogenous agent. More stable and long acting GLP-1 analogues and DPP-1 inhibitors have been developed with promising clinical value for the treatment of type-2 diabetes. The GLP-1 derivatives have the advantage of decreasing body weight while the DPP-IV inhibitors can be administered orally up to once daily. The mechanism of action as well as the tolerable side effect is astounding. This review article covers this new generation of anti-diabetics.
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PMID:Glucagon-like peptide-1 derivatives and dipeptidyl peptidase-IV inhibitors. New hope for the treatment of type-2 diabetes. 1622 47

Glucagon-like peptide-1 is an insulinotropic hormone with antidiabetic potential due to its spectrum of effects, which include glucose-dependent stimulation of insulin and inhibition of glucagon secretion, tropic effects on the pancreatic beta-cells, inhibition of gastric emptying and the reduction of appetite. Glucagon-like peptide-1 is, however, extremely rapidly inactivated by the serine peptidase, dipeptidyl peptidase IV, so that the native peptide is not useful clinically. A new approach to utilise the beneficial effects of glucagon-like peptide-1 in the treatment of type 2 diabetes has been the development of orally active dipeptidyl peptidase IV inhibitors. Preclinical studies have demonstrated that this approach is effective in enhancing endogenous levels of glucagon-like peptide-1, resulting in improved glucose tolerance in glucose-intolerant and diabetic animal models. In recent studies of 3-12 months duration in patients with type 2 diabetes, dipeptidyl peptidase IV inhibitors have proved efficacious, both as monotherapy and when given in combination with metformin. Fasting and postprandial glucose concentrations were reduced, leading to reductions in glycosylated haemoglobin levels, while beta-cell function was preserved. Current information suggests dipeptidyl peptidase IV inhibitors are body weight neutral and are well tolerated. A number of dipeptidyl peptidase IV inhibitors are now in the late stages of clinical development. These have different properties, in terms of their duration of action and anticipated dosing frequency, but data from protracted dosing studies is presently not available to allow comparison of their clinical efficacy.
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PMID:Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes. 1624 77

The 'incretin effect' describes the phenomenon of an enhanced insulin response following oral ingestion of glucose compared with that after intravenous administration of glucose, leading to identical postprandial plasma glucose excursions. It accounts for up to 60% of the postprandial insulin secretion, but is diminished in patients with type 2 diabetes mellitus. Gastrointestinal hormones that promote the incretin effect are called incretins. Glucagon-like peptide-1 (GLP-1) is an important incretin. Under hyperglycemic conditions in humans, it stimulates insulin secretion and normalizes blood glucose levels. GLP-1 does not stimulate insulin secretion at normal glucose levels; therefore, it does not cause hypoglycemia. Furthermore, it inhibits glucagon secretion and delays gastric emptying. In vitro and animal data have demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting the apoptosis of islet cells. The improvement of beta-cell function due to GLP-1 can be indirectly observed from the increased insulin secretory capacity of humans receiving such treatment. GLP-1 may represent an attractive therapeutic method for patients with type 2 diabetes because of its multiple effects, including the simulation of satiety in the CNS by acting as a transmitter or by crossing the blood brain barrier. Native GLP-1 is degraded rapidly upon intravenous or subcutaneous administration and is therefore not feasible for routine therapy. Long-acting GLP-1 analogs (e.g. liraglutide) and exendin-4 (exenatide) that are resistant to degradation, called 'incretin mimetics', are being investigated in clinical trials. Dipeptidyl peptidase-IV inhibitors (e.g. vildagliptin, sitagliptin, and saxagliptin) that inhibit the enzyme responsible for incretin degradation are also being studied.
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PMID:Glucagon-like peptide-1-based therapies for the treatment of type 2 diabetes mellitus. 1631 2

Type 2 diabetes is characterized by hyperglycemia resulting from insulin resistance in the setting of inadequate beta-cell compensation. Currently available therapeutic agents lower blood glucose through multiple mechanisms but do not directly reverse the decline in beta-cell mass. Glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by Exenatide (exendin-4), not only acutely lower blood glucose but also engage signaling pathways in the islet beta-cell that lead to stimulation of beta-cell replication and inhibition of beta-cell apoptosis. Similarly, glucose-dependent insulinotropic polypeptide (GIP) receptor activation stimulates insulin secretion, enhances beta-cell proliferation, and reduces apoptosis. Moreover, potentiation of the endogenous postprandial levels of GLP-1 and GIP via inhibition of dipeptidyl peptidase-IV (DPP-IV) also expands beta-cell mass via related mechanisms. The thiazolidinediones (TZDs) enhance insulin sensitivity, reduce blood glucose levels, and also preserve beta-cell mass, although it remains unclear whether TZDs affect beta-cell mass via direct mechanisms. Complementary approaches to regeneration of beta-cell mass involve combinations of factors, exemplified by epidermal growth factor and gastrin, which promote islet neogenesis and ameliorate diabetes in rodent studies. Considerable preclinical data support the concept that one or more of these therapeutic approaches, alone or in combination, may potentially reverse the decline in beta-cell mass that is characteristic of the natural history of type 2 diabetes.
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PMID:Therapeutic approaches to preserve islet mass in type 2 diabetes. 1640 49

Canalicular bile is formed by the osmotic filtration of water in response to osmotic gradients generated by active transport at the apical and basolateral plasma membrane domains of hepatocytes. We recently demonstrated that mixed plasma membrane fractions isolated from rat hepatocyte couplets contain lipid microdomains ("rafts") enriched in cholesterol and sphingolipids and AQP8 and 9. We isolated lipid microdomains from hepatocyte apical and basolateral plasma membrane domains using Triton X-100 as detergent, and characterized their lipid and protein composition. A Triton-insoluble band ("raft fraction") at the 5%/30% sucrose interface in both apical and basolateral fractions was enriched for alkaline phosphatase (apical) and Na/K ATPase (basolateral) and was negative for amino peptidase-N. This detergent-insoluble band was also positive for caveolin-1 (a "raft" associated protein) and negative for clathrin (a "raft" negative protein). Lipid analysis showed that, the Triton-insoluble fraction was highly enriched in cholesterol and sphingolipids. Immunofluorescence staining on hepatocyte couplets for both caveolin-1 and cholera toxin B showed a punctate distribution on both the apical and basolateral plasma membranes, consistent with localized membrane microdomains. Dot blot analysis showed that the "raft" associated ganglioside GM1 was enriched in the detergent-insoluble fraction both domains. Furthermore, exposure of isolated hepatocytes to glucagon, a choleretic agonist, significantly increased the expression of AQP8 associated with the apical microdomain fractions but had no effect on AQP9 expression in the basolateral microdomain fractions. In conclusion, "rafts" represent target microdomains for exocytic insertion and retrieval of "flux proteins", including AQPs, involved in canalicular bile secretion.
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PMID:Isolation and characterization of lipid microdomains from apical and basolateral plasma membranes of rat hepatocytes. 1644 Mar 38

Dipeptidyl peptidase-IV (DPP-IV) inhibitors, or glucagon-like peptide-1 (GLP-1) enhancers, are looked to as a potential new class of antidiabetic agents. In particular, potent and long-acting inhibitors might offer advantages in exploiting DPP-IV inhibition. The series of [(S)-gamma-(arylamino)prolyl]-(S)-2-cyanopyrrolidine compounds on which we reported previously has a highly potent inhibitory activity but seemed to be unstable in neutral aqueous solution. Here, we describe [(S)-gamma-(arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors. They are the thiazolidine analogs of [(S)-gamma-(arylamino)prolyl]-(S)-2-cyanopyrrolidine but with the electrophilic nitrile removed to improve chemical stability in aqueous solution. Of the compounds investigated in the present study, the [((S)-gamma-3,4-dicyanophenylamino)prolyl]thiazolidine 12 m was the most potent. The structure-activity relationship (SAR) of the gamma-substituent in the proline moiety of the thiazolidide was similar to that obtained with the (S)-2-cyanopyrrolidide. The gamma-substituent in the proline moiety of both the (S)-2-cyanopyrrolidide and the thiazolidide may engage with the S(2) binding pocket of DPP-IV and thereby achieve hydrophobic interaction in the same manner. Based on pharmacokinetic experiments in rats, the representative compound 11, which displayed high oral bioavailability (BA=83.9%) and long half-life in plasma (t(1/2)=5.27 h), was found to have an excellent pharmacokinetic profile.
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PMID:[(S)-gamma-(Arylamino)prolyl]thiazolidine compounds as a novel series of potent and stable DPP-IV inhibitors. 1646 Sep 48

Type 2 diabetes mellitus is a major and growing health problem throughout the world. Current treatment approaches include diet, exercise, and a variety of pharmacological agents including insulin, biguanides, sulfonylureas and thiazolidinediones. New therapies are still needed to control metabolic abnormalities, and also to preserve beta-cell mass and to prevent loss of beta-cell function. Glucagon-like peptide 1 (GLP-1) is a drug candidate which potentially fulfils these conditions. GLP-1 is an incretin hormone secreted by intestinal L-cells in response to meal ingestion is a novel pharmacological target with multiple antihyperglycemic actions. GLP-1 glucoregulatory actions include glucose-dependent enhancement of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying and reduction of food intake. GLP-1 is rapidly inactivated by amino peptidase, dipeptidyl peptidase IV (DPP-IV) and the utility of DPP-IV inhibitors are also under investigation. There is a recent upsurge in the development of GLP-1 mimetics and DPP-IV inhibitors as potential therapy for type 2 diabetes. However, both the strategies are having their own advantages and limitations. The present review summarizes the concepts of GLP-1 based therapy for type 2 diabetes and the current preclinical and clinical development in GLP-1 mimetics and DPP-IV inhibitors. Further, the potential advantages and the limitations of both the strategies are discussed.
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PMID:GLP-1 based therapy for type 2 diabetes. 1648 79

The emergence of the glucoregulatory hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide has expanded our understanding of glucose homeostasis. In particular, the glucoregulatory actions of the incretin hormone GLP-1 include enhancement of glucosedependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. Two approaches have been developed to overcome rapid degradation of GLP-1. One is the use of agents that mimic the enhancement of glucose-dependent insulin secretion, and potentially other antihyperglycemic actions of incretins, and the other is the use of dipeptidyl peptidase-IV inhibitors, which reduce the inactivation of GLP-1, increasing the concentration of endogenous GLP-1. The development of incretin mimetics and dipeptidyl peptidase-IV inhibitors opens the door to a new generation of antihyperglycemic agents to treat several otherwise unaddressed pathophysiologic defects of type 2 diabetes mellitus. We review the physiology of glucose homeostasis, emphasizing the role of GLP-1, the pathophysiology of type 2 diabetes mellitus, the clinical shortcomings of current therapies, and the potential of new therapies -- including the newly approved incretin mimetic exenatide -- that elicit actions similar to those of GLP-1.
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PMID:Incretin mimetics and dipeptidyl peptidase-IV inhibitors: potential new therapies for type 2 diabetes mellitus. 1650 16


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