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)

Glucagon-like peptide-1 (GLP-1 (7-36) amide) is a gut hormone released from L-cells in the small intestine in response to the ingestion of nutrients and enhances the glucose-dependent secretion of insulin from pancreatic beta-cells. In type 2 diabetic patients, the continuous infusion of GLP-1 (7-36) amide decreases plasma glucose and hemoglobin A1c concentrations and improves beta-cell function. Hormone action is rapidly terminated by the N-terminal cleavage of GLP-1 at Ala2 by the aminopeptidase, dipeptidyl peptidase IV (DPPIV). The short in vivo half-life of GLP-1 (< 3 min) poses challenges to the development of exogenous GLP-1-based therapy. The inhibition of endogenous GLP-1 degradation by reducing DPPIV activity is an alternative strategy for improving the incretin action of GLP-1 in vivo. This review summarizes recent advances in the design of potent and selective small molecule inhibitors of DPPIV and the potential challenges to the development of DPPIV inhibitors for the treatment of impaired glucose tolerance and type 2 diabetes.
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PMID:Dipeptidyl peptidase IV inhibitors for the treatment of impaired glucose tolerance and type 2 diabetes. 1280 80

Exendin-4, a 39-amino acid (AA) peptide, is a long-acting agonist at the glucagon-like peptide-1 (GLP-1) receptor. Consequently, it may be preferable to GLP-1 as a long-term treatment for type 2 diabetes mellitus. Exendin-4 (Ex-4), unlike GLP-1, is not degraded by dipeptidyl peptidase IV (DPP IV), is less susceptible to degradation by neutral endopeptidase, and possesses a nine-AA C-terminal sequence absent from GLP-1. Here we examine the importance of these nine AAs for biological activity of Ex-4, a sequence of truncated Ex-4 analogs, and native GLP-1 and GLP-1 analogs to which all or parts of the C-terminal sequence have been added. We found that removing these AAs from Ex-4 to produce Ex (1-30) reduced the affinity for the GLP-1 receptor (GLP-1R) relative to Ex-4 (IC50: Ex-4, 3.22+/-0.9 nM; Ex (1-30), 32+/-5.8 nM) but made it comparable to that of GLP-1 (IC50: 44.9+/-3.2 nM). The addition of this nine-AA sequence to GLP-1 improved the affinity of both GLP-1 and the DPP IV resistant analog GLP-1 8-glycine for the GLP-1 receptor (IC50: GLP-1 Gly8 [GG], 220+/-23 nM; GLP-1 Gly8 Ex (31-39), 74+/-11 nM). Observations of the cAMP response in an insulinoma cell line show a similar trend for biological activity.
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PMID:The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity. 1283 4

Inhibition of dipeptidyl peptidase IV (DPP-IV), the main glucagon-like peptide 1 (GLP1)-degrading enzyme, has been proposed for the treatment of type II diabetes. We expressed and purified the ectodomain of human DPP-IV in Pichia pastoris and determined the X-ray structure at 2.1 A resolution. The enzyme consists of two domains, the catalytic domain, with an alpha/beta hydrolase fold, and a beta propeller domain with an 8-fold repeat of a four-strand beta sheet motif. The beta propeller domain contributes two important functions to the molecule that have not been reported for such structures, an extra beta sheet motif that forms part of the dimerization interface and an additional short helix with a double Glu sequence motif. The Glu motif provides recognition and a binding site for the N terminus of the substrates, as revealed by the complex structure with diprotin A, a substrate with low turnover that is trapped in the tetrahedral intermediate of the reaction in the crystal.
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PMID:Structural basis of proline-specific exopeptidase activity as observed in human dipeptidyl peptidase-IV. 1290 26

Type 2 diabetes mellitus is a metabolic disease resulting in raised blood sugar which, if not satisfactorily controlled, can cause severe and often debilitating complications. Unfortunately, for many patients, the existing therapies do not give adequate control. Glucagon-like peptide-1 (GLP-1) is an incretin hormone which has a spectrum of activities which oppose the symptoms of diabetes. Of particular significance is the fact that these actions are glucose-dependent, meaning that the risk of severe hypoglycemia is practically eliminated. The recent elucidation of the key role of dipeptidyl peptidase IV in determining the metabolic stability of GLP-1 has given the rationale for two novel therapeutic strategies, namely, GLP-1 analogs which are resistant to the enzyme and inhibitors of the enzyme which boost levels of endogenous intact GLP-1. These approaches aim to maximize the therapeutic advantages offered by GLP-1 and give the hope of providing effective glycemic control without the risk of overt hypoglycemia.
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PMID:Glucagon-like peptide-1: a basis for new approaches to the management of diabetes. 1297 81

The gut expresses peptide hormones in endocrine cells and neuropeptides in autonomic nerves. Several of these peptides have the ability to stimulate insulin secretion. Gut hormones that are released after meal ingestion and stimulate insulin secretion postprandially are called incretins. In humans, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the most important incretins. The potential use of these insulinotropic gut peptides for the treatment of diabetes has been considered. This has been most successful for GLP-1, which exerts antidiabetogenic properties in subjects with type 2 diabetes by stimulating insulin secretion, increasing beta-cell mass, inhibiting glucagon secretion, delaying gastric emptying, and inducing satiety. However, GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV), making it unattractive as a therapeutic agent because of a very short half-life. Successful strategies to overcome this difficulty are the use of DPPIV-resistant GLP-1 receptor agonists, such as NN2211 or exendin-4, and the use of inhibitors of DPPIV, such as NVPDPP728 and P32/98. These two approaches are explored in clinical investigations.
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PMID:Gut peptides and type 2 diabetes mellitus treatment. 1297 25

In Type 2 diabetes, glucose homeostasis is impaired due to either a decrease in insulin secretion or insulin action. In this symposium, molecular targets that could have an impact on either or both of these defects were discussed and data related to specific compounds were presented. Protein tyrosine phosphatase 1B inhibitors that relieve the negative control on insulin action and are active in cell assays, dipeptidyl peptidase IV inhibitors that raise postprandial glucagon-like peptide 1 levels in animals and humans, and pyruvate dehydrogenase kinase inhibitors that increase the levels of pyruvate dehydrogenase, which in turn improve insulin sensitivity, were all discussed. Roche presented for the first time their novel glucokinase activators and discussed both the in vitro and in vivo activity profiles of representative glucokinase activators as potential therapy for Type 2 diabetes. Second generation retinoid X receptor modulators that retain the desirable effects of full agonists, while devoid of their negative attributes, such as triglyceride accumulation, were discussed. Also, clinical efficacy results of synthetic exendin-4, Exenatide trade mark, a glucagon-like peptide 1 analogue, were presented. In the area of obesity, agonists of several central (melanocortin type 4, serotonin subtype 2C and cannabinoid receptor 1) receptors and one peripheral G-protein-coupled receptor, cholecystokinin receptor-A, all of which lead to reduced food intake in animals, were discussed.
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PMID:Metabolic diseases drug discovery world summit. July 28-29, 2003, San Diego, CA, USA. 1451 91

Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic beta-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing beta-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate beta-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted.
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PMID:Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. 1452 86

The enzyme and binding protein dipeptidyl peptidase IV (DPPIV/CD26) has a unique enzymatic specificity in cleaving dipeptides from neuropeptides, chemokines, and hormones. Thus, DPPIV is potentially involved in the regulation of functions of the immune, endocrine, and nervous systems. In the present study, we compared DPPIV-deficient, mutant Japanese [F344/DuCrj(DPPIV-)] and German [F344/Crl(Ger/DPPIV-)] F344 rat substrains with a wild-type-like F344 substrain [F344/Crl(Por)] from the United States in a multitiered strategy using a number of different behavioral tests. General health, neurological and motor functions, and sensory abilities of the different F344 substrains were not different. A reduced body weight and a reduced water consumption were observed in mutant animals. DPPIV-deficient rats exhibited increased pain sensitivity in a non-habituated hot plate test, indicative of a reduced stress-induced analgesia. In line with this finding, reduced stress-like responses in tasks like the open field (OF), social interaction (SI), and passive avoidance test were found. Differences in DPPIV-like activity appear to be involved in neurophysiological processes because DPPIV-deficient animals were less susceptible to the sedative effects of ethanol. The varying phenotypes of the F344 substrains are likely to be mediated by differential degradation of DPPIV substrates such as substance P, glucagon-like peptide (GLP)-1, enterostatin, and especially neuropeptide Y (NPY). Potentially, DPPIV-deficient substrains represent an important tool for biomedical research, focusing on the involvement of DPPIV and its substrates in behavioral and physiological processes.
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PMID:Extreme reduction of dipeptidyl peptidase IV activity in F344 rat substrains is associated with various behavioral differences. 1456 17

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation. However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced beta-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)-treated minipig, using the DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg). VP did not significantly affect levels of intact GLP-1 but increased levels of intact GIP (from 4543 +/- 1880 to 9208 +/- 3267 pM x min; P <.01), thus improving glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 +/- 480 to 1582 +/- 353 mM x min; P =.05). VP did not increase insulin levels during the oral glucose tolerance test (OGTT) but increased the insulinogenic index in normal animals (from 83 +/- 42 to 192 +/- 108; P <.05), but not after NIA + STZ, possibly because of less residual insulin secretory capacity in these animals. GIP seems to contribute to the antihyperglycemic effect of VP in this model; however, additional mechanisms for the effect of DPPIV inhibition cannot be excluded. The authors conclude that DPPIV inhibitors may be useful to treat type 2 diabetes, even when this is due to reduced beta-cell mass.
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PMID:Valine pyrrolidide preserves intact glucose-dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass. 1463 May 71

Although the incretin hormone glucagon-like peptide-1 (GLP-1) is a potent stimulator of insulin release, its rapid degradation in vivo by the enzyme dipeptidyl peptidase IV (DPP IV) greatly limits its potential for treatment of type 2 diabetes. Here, we report two novel Ala(8)-substituted analogues of GLP-1, (Abu(8))GLP-1 and (Val(8))GLP-1 which were completely resistant to inactivation by DPP IV or human plasma. (Abu(8))GLP-1 and (Val(8))GLP-1 exhibited moderate affinities (IC(50): 4.76 and 81.1 nM, respectively) for the human GLP-1 receptor compared with native GLP-1 (IC(50): 0.37 nM). (Abu(8))GLP-1 and (Val(8))GLP-1 dose-dependently stimulated cAMP in insulin-secreting BRIN BD11 cells with reduced potency compared with native GLP-1 (1.5- and 3.5-fold, respectively). Consistent with other mechanisms of action, the analogues showed similar, or in the case of (Val(8))GLP-1 slightly impaired insulin releasing activity in BRIN BD11 cells. Using adult obese (ob/ob) mice, (Abu(8))GLP-1 had similar glucose-lowering potency to native GLP-1 whereas the action of (Val(8))GLP-1 was enhanced by 37%. The in vivo insulin-releasing activities were similar. These data indicate that substitution of Ala(8) in GLP-1 with Abu or Val confers resistance to DPP IV inactivation and that (Val(8))GLP-1 is a particularly potent N-terminally modified GLP-1 analogue of possible use in type 2 diabetes.
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PMID:Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo. 1466 13


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