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 mimetics are a new class of pharmacological agents with multiple antihyperglycemic actions that mimic the actions of incretin hormones such as glucagon-like peptide (GLP)-1. Dipeptidyl peptidase (DPP-IV) inhibitors suppress the degradation of many peptides, including GLP-1, thereby extending their bioactivity. Several incretin mimetics and DPP-IV inhibitors are undergoing late-stage clinical trials for the treatment of type 2 diabetes. These agents appear to have multiple mechanisms of action, including some or all of the following: enhancement of glucose-dependent insulin secretion; suppression of inappropriately elevated glucagon secretion; slowing of gastric emptying; and decreased food intake (i.e. appetite suppression). Based on preliminary clinical data, incretin mimetics and DPP-IV inhibitors show potential for treating type 2 diabetes.
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PMID:Incretin mimetics and DPP-IV inhibitors for the treatment of type 2 diabetes. 1589 83

The sole application of an inhibitor of the dipeptidyl peptidase DP IV (also DP 4, CD26, DPP-IV or DPP-4) to a mammal subsequently leading to improved glucose tolerance marks a major breakthrough in metabolic research bearing the potential of a new revolutionary diabetes therapy. This was demonstrated in rat applying the specific DP IV inhibitor isoleucyl thiazolidine. It was published in 1996 for the first time that a specific DP IV inhibitor in a given dose was able to completely block glucagon-like peptide-1 (GLP-1) degradation in vivo resulting in improved insulin response accompanied, by accelerated peripheral glucose disposal. Later on, these results were confirmed by several research teams applying DP IV inhibitors intravenously or orally. Today, the DP IV inhibition for the treatment of metabolic disorders is a validated principle. Now, more than 10 years after the initial animal experiments, first DP IV inhibitors as investigational drugs are tested in phase 3 clinical trials.
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PMID:Type 2 diabetes--therapy with dipeptidyl peptidase IV inhibitors. 1597 77

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). Because GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined acute (single dose) and chronic (once-a-day dosing for 21 days) effects of the DPP-4 inhibitor vildagliptin (0.03-10 mg/kg) on plasma DPP-4 activity, intact GLP-1, glucose, and insulin after an oral glucose load in insulin-resistant Zucker fatty rats and acute effects in mildly insulin-resistant high-fat-fed normal rats. A single oral dose of vildagliptin in Zucker rats produced a rapid and dose-related inhibition of DPP-4: the minimum effective dose (MED) was 0.3 mg/kg. Glucose-induced increases of intact GLP-1 were greatly but similarly enhanced by vildagliptin at doses > or =0.3 mg/kg. Postload glucose excursions decreased, and the insulinogenic index (Deltainsulin/Deltaglucose at 10 min) increased, with an MED of 0.3 mg/kg and a maximally effective dose of 3 mg/kg. The effects of vildagliptin after chronic treatment were nearly identical to those of acute administration, and vildagliptin had no effect on body weight. In fat-fed normal rats, vildagliptin (3 mg/kg) also decreased postload glucose excursions and increased the insulinogenic index, but these effects were smaller than those in Zucker rats. Thus, vildagliptin is an orally effective incretin enhancer with antihyperglycemic activity in insulin-resistant rats and exhibits no tachyphylaxis. GLP-1-mediated augmentation of glucose-induced insulin release seems to make the major contribution to the antidiabetic properties of vildagliptin.
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PMID:Acute and chronic effects of the incretin enhancer vildagliptin in insulin-resistant rats. 1602 30

Glucagon-like peptide-1 (GLP-1) is an important insulinotropic hormone with potential in the treatment of type 2 diabetes. However, the short biological half-life of the peptide after cleavage by dipeptidylpeptidase IV (DPP IV) is a major limitation. Inhibition of DPP IV activity and the development of resistant GLP-1 analogues is the subject of ongoing research. In this study, we determined cell growth, insulin content, insulin accumulation and insulin secretory function of a insulin-secreting cell line cultured for 3 days with either GLP-1, GLP-1 plus the DPP IV inhibitor diprotin A (DPA) or stable N-acetyl-GLP-1. Native GLP-1 was rapidly degraded by DPP IV during culture with accumulation of the inactive metabolite GLP-1(9-36)amide. Inclusion of DPA or use of the DPP IV-resistant analogue, N-acetyl-GLP-1, improved cellular function compared to exposure to GLP-1 alone. Most notably, basal and accumulated insulin secretion was enhanced, and glucose responsiveness was improved. However, prolonged GLP-1 treatment resulted in GLP-1 receptor desensitization regardless of DPP IV status. The results indicate that prevention of DPP IV action is necessary for beneficial effects of GLP-1 on pancreatic beta cells and that prolonged exposure to GLP-1(9-36)amide may be detrimental to insulin secretory function. These observations also support the ongoing development of DPP-IV-resistant forms of GLP-1, such as N-acetyl-GLP-1.
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PMID:Function of a long-term, GLP-1-treated, insulin-secreting cell line is improved by preventing DPP IV-mediated degradation of GLP-1. 1605 Sep 49

Dipeptidyl peptidase-IV (DPP-IV) is involved in the inactivation of glucagon-like peptide-1 (GLP-1), a potent insulinotropic peptide. Thus, DPP-IV inhibition can be an effective approach to treat type 2 diabetes mellitus by potentiating insulin secretion. This study describes the biological effects of a new DPP-IV inhibitor, KR-62436 (6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitrile) in vitro and in vivo. KR-62436 inhibited rat plasma DPP-IV, porcine kidney DPP-IV as well as human DPP-IV (Caco-2) with IC50 values of 0.78, 0.49, 0.14 microM, respectively. In addition, the compound (10 microM) almost completely inhibited DPP-IV-mediated degradation of GLP-1 in vitro. KR-62436 inhibited the enzyme in a competitive manner, and exhibited selectivity against several proteases including proline-specific proteases. In vivo efficacy of the compound was examined by using normal C57BL/6J mice and ob/ob mice, a type 2 diabetes animal model. Administration of KR-62436 to C57BL/6J mice either orally or subcutaneously resulted in the suppression of plasma DPP-IV activity, increase in intact GLP-1 and insulin levels in plasma. Furthermore, the plasma glucose concentrations during oral glucose tolerance test (OGTT) were reduced upon oral administration of KR-62436. This study demonstrates that KR-62436 could be a good lead compound for further development as a new anti-diabetic agent.
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PMID:KR-62436, 6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitrile, is a novel dipeptidyl peptidase-IV (DPP-IV) inhibitor with anti-hyperglycemic activity. 1610 24

Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the glucagon/secretin peptide family, has been recently proposed to be the ancestral GH-releasing factor. Using grass carp as a model for bony fish, we examined the mechanisms for PACAP regulation of GH synthesis and secretion at the pituitary level. Nerve fibers with PACAP immunoreactivity were identified in the grass carp pituitary overlapping with the distribution of somatotrophs. At the somatotroph level, PACAP was shown to induce cAMP synthesis and Ca(2+) entry through voltage-sensitive Ca(2+) channels (VSCC). In carp pituitary cells, PACAP but not vasoactive intestinal polypeptide increased GH release, GH content, total GH production, and steady-state GH mRNA levels. PACAP also enhanced GH mRNA stability, GH promoter activity, and nuclear expression of GH primary transcripts. Increasing cAMP levels, induction of Ca(2+) entry, and activation of VSCC were all effective in elevating GH secretion and GH mRNA levels. PACAP-induced GH secretion and GH mRNA expression, however, were abolished by inhibiting adenylate cyclase and protein kinase A, removing extracellular Ca(2+) or VSCC blockade, or inactivating calmodulin (CaM)-dependent protein kinase II (CaM kinase II). Similar sensitivity to VSCC and CaM kinase II blockade was also observed by activating cAMP production as a trigger for GH release and GH gene expression. These results suggest that PACAP stimulates GH synthesis and secretion in grass carp pituitary cells through PAC(1) receptors. These stimulatory actions probably are mediated by the adenylate cyclase/cAMP/protein kinase A pathway coupled to Ca(2+) entry via VSCC and subsequent activation of CaM/CaM kinase II cascades.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) as a growth hormone (GH)-releasing factor in grass carp. I. Functional coupling of cyclic adenosine 3',5'-monophosphate and Ca2+/calmodulin-dependent signaling pathways in PACAP-induced GH secretion and GH gene expression in grass carp pituitary cells. 1612 57

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 (GLP-1) is a gastrointestinal hormone, mainly secreted after meals, which enhances glucose-induced insulin secretion and induces satiety. It has been reported that GLP-1 levels after a mixed meal and after an oral glucose load are reduced in patients with Type 2 diabetes. The reduction of oral glucose-stimulated active GLP-1 levels in patients with Type 2 diabetes has also been observed during euglycemic iperinsulinemic clamp. The reduction of post-prandial circulating active GLP-1 in Type 2 diabetic subjects, as a consequence of chronic hyperglycemia, could contribute to the reduction of early post-prandial insulin secretion; in fact, the administration of GLP-1 receptor antagonists to healthy volunteers elicits both an impairment of meal-induced insulin secretion and an increase of post-prandial glycemia similar to that observed in Type 2 diabetes. GLP-1 is rapidly inactivated by dipeptidyl peptidase IV (DPP-IV), an enzyme produced by endothelial cells in different districts and that circulates in plasma. It is still not clear whether the reduction of mealor oral-glucose stimulated GLP-1 levels in Type 2 diabetic patients is due to impairment of secretion, increase of degradation, or both. The major limitation of using GLP-1 to treat diabetic patients is the short half-life of the native compound. There are now several compounds in various stages of pre-clinical or clinical development for the treatment of Type 2 diabetes that utilize the GLP-1 signaling pathway; these include GLP-1 receptor agonists with extended half-lives, and inhibitors of DPP-IV that increase circulating levels of endogenous, intact and bioactive GLP-1.
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PMID:Glucagon-like peptide 1 (GLP-1) and metabolic diseases. 1627 73


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