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)

A novel therapy for type 2 diabetes is based on the gut hormone, glucagon-like peptide-1 (GLP-1). GLP-1 is released from the gut during a meal intake and stimulates insulin secretion. The hormone also inhibits glucagon secretion, delays gastric emptying and induces satiety. It has been shown to reduce circulating glucose both under fasting conditions and after meal intake in subjects with type 2 diabetes. A problem in developing this novel therapy is that GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), which results in a short half-life of the hormone requiring continuous infusion. Two strategies have been developed to circumvent this drawback. One strategy is the use of DPP-4 resistant GLP-1 receptor agonists (exenatide and liraglutide) and another strategy is to inhibit DPP-4 activity (LAF237). Both these strategies have been successful in clinical studies.
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PMID:[New strategy in type 2 diabetes tested in clinical trials. Glucagon-like peptide 1 (GLP-1) affects basic caused of the disease]. 1578 5

Dipeptidyl peptidase-IV is a cell surface protease which plays an important role in glucose homeostasis through proteolytic inactivation of incretin hormones, primarily glucagon like peptide-1 (GLP-1). Substrate N-terminal amino acid (S2-S1) specificity is rather clearly defined, while no substantial information is available on the significance of amino acid interactions towards the C-terminus after the scissile bond (so called prime S1'-S4' or distant S5'-S28' sites). In the present study the increasing length of the peptide towards prime sites (S1'-S4') resulted in approximately 7-fold decrease in Km. Moreover, the Km for GLP-1 cleavage was comparable to that of an S2-S4' peptide, suggesting that few, if any, important enzyme-substrate interactions occur beyond the active site. Effect of substrate length on kcat was less obvious, but kcat/Km showed an increasing trend when His-Ala-pNA (representing the natural two N-terminal residues) was compared to GLP-1. To probe the impact of increasing substrate length on the free energy of activation (as has been suggested for elastase and chymotrypsin) we performed temperature studies. To adequately interpret thermodynamic data we sought to understand what steps limit the kcat expression. Steady-state parameters of the reactions catalyzed by serine proteases are composed of microscopic constants describing binding, acylation, and deacylation steps. Viscosity and pre-steady-state studies suggested that His-Ala-pNA cleavage is limited in the deacylation half-reaction, most likely the product release step. Thus, the free energy of activation, as calculated from the Eyring equation, is underestimated (at least for His-Ala-pNA) and the effect of substrate length on the acylation step (and transition-state stabilization) could not be unambiguously assessed.
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PMID:Probing prime substrate binding sites of human dipeptidyl peptidase-IV using competitive substrate approach. 1579 49

The formation of hepatic bile requires that water be transported across liver epithelia. Rat hepatocytes express three aquaporins (AQPs): AQP8, AQP9, and AQP0. Recognizing that cholesterol and sphingolipids are thought to promote the assembly of proteins into specialized membrane microdomains, we hypothesized that canalicular bile secretion involves the trafficking of vesicles to and from localized lipid-enriched microdomains in the canalicular plasma membrane. Hepatocyte plasma membranes were sonicated in Triton and centrifuged overnight on a sucrose gradient to yield a Triton-soluble pellet and a Triton-insoluble, sphingolipid-enriched microdomain fraction at the 5%/30% sucrose interface. The detergent-insoluble portion of the hepatocyte plasma membrane was enriched in alkaline phosphatase (a microdomain-positive marker) and devoid of amino-peptidase N (a microdomain-negative marker), enriched in caveolin, both AQP8 and AQP9, but negative for clathrin. The microdomain fractions contained chloride-bicarbonate anion exchanger isoform 2 and multidrug resistance-associated protein 2. Exposure of isolated hepatocytes to glucagon increased the expression of AQP8 but not AQP9 in the microdomain fractions. Sphingolipid analysis of the insoluble fraction showed the predominant species to be sphingomyelin. These data support the presence of sphingolipid-enriched microdomains of the hepatocyte membrane that represent potential localized target areas for the clustering of AQPs and functionally related proteins involved in canalicular bile secretion.
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PMID:Membrane microdomains in hepatocytes: potential target areas for proteins involved in canalicular bile secretion. 1583 30

Glucagon-like peptide-1 (GLP-1) is a proglucagon-derived peptide secreted from gut endocrine cells in response to nutrient ingestion. The multifaceted actions of GLP-1 include the following: (1) the stimulation of insulin secretion and of its gene expression, (2) the inhibition of glucagon secretion, (3) the inhibition of food intake, (4) the proliferation and differentiation of beta cells, and (5) the protection of beta-cells from apoptosis. The therapeutic utility of the native GLP-1 molecule is limited by its rapid enzymatic degradation by a serine protease termed dipeptidyl peptidase-IV (DPP-IV). The present article reviews the research studies aimed at elucidating the biosynthesis, metabolism, and molecular characteristics of GLP-1 since it is from these studies that the development of a GLP-1-like pharmacological agent may be derived.
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PMID:Structure and function studies of glucagon-like peptide-1 (GLP-1): the designing of a novel pharmacological agent for the treatment of diabetes. 1585 57

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 incretin effect is a phenomenon in which enteral glucose administration provokes greater insulin secretion than intravenous administration. The main incretins, glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1 are defective in Type 2 diabetes; whereas glucose-dependent insulinotropic peptide displays diminished effectiveness, GLP-1 secretion is decreased; thus, GLP-1 was a stronger candidate for a new class of anti-diabetic agents designed to potentiate the incretin effect. In the past decade, GLP-1 mimetics, peptidase inhibitors and GLP-1 have been developed. Early randomised trials show that these agents contribute to glucose homeostasis and enhance beta-cell function, without causing hypoglycaemia or weight gain. This review includes an historical perspective, physiology of incretins, and discussions of the pathophysiology in Type 2 diabetes, pharmacology of the main agents and randomised clinical trials published to date.
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PMID:The incretin effect and its potentiation by glucagon-like peptide 1-based therapies: a revolution in diabetes management. 1600 98

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

Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM.
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PMID:Diprolyl nitriles as potent dipeptidyl peptidase IV inhibitors. 1604 20

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


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