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), an intestinal hormone secreted by L cells in response to luminal nutrients(carbohydrate and fat), enhances glucose-induced insulin secretion. Impairment of glucose-induced insulin secretion in patients with type 2 diabetes can be restored to near-normal by GLP-1 administration. In addition, GLP-1 possesses multiple biological effects which are favorable for the treatment of type 2 diabetes: inhibition of glucagon secretion, slowing of gastric emptying, reduction of appetite and food intake, upregulation of genes essential for insulin secretion(glucokinase, GLUT-2 etc), and beta cell proliferation and differentiation. Some long-acting GLP-1 derivatives which are resistant to the degradation by enzyme dipeptidyl peptidase-IV are currently under the clinical trial and are reportedly promising for the treatment of type 2 diabetes, because of impressive effects on glycemic control, availability by oral administration and very few adverse effects.
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PMID:[Glucagon-like peptide-1(GLP-1)]. 1520 60

Dipeptidyl peptidase-IV (DPP-IV) regulates metabolism by degrading incretins involved in nutritional regulation. Metformin and pioglitazone improve insulin sensitivity whereas glyburide promotes insulin secretion. Zucker diabetic rats were treated with these antidiabetic agents for 2 weeks and DPP-IV activity and expression were determined. Serum DPP-IV activity increased whereas tissue activity decreased as the rats aged. Treatment of rats with metformin, pioglitazone, and glyburide did not alter DPP-IV mRNA expression in liver or kidney. Metformin and pioglitazone significantly (P<0.05) reduced serum DPP-IV activity and glycosylated hemoglobin. Glyburide did not lower DPP-IV activity or glycosylated hemoglobin. Regression analysis showed serum DPP-IV activity correlated with glycosylated hemoglobin (r=0.92) and glucagon-like peptide-1 levels (r=-0.49). Metformin, pioglitazone, and glyburide had no effect on serum DPP-IV activity in vitro, indicating these are not competitive DPP-IV inhibitors. We propose the in vivo inhibitory effects observed with metformin and pioglitazone on serum DPP-IV activity results from reduced DPP-IV secretion.
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PMID:Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments. 1546 87

Glucagon-like peptide-2 and its dipeptidyl peptidase (DP-IV) resistant analogue teduglutide are trophic for the gastrointestinal epithelium. Exposure increases villus height and crypt size and results in increased overall intestinal weight. As these effects may be mediated through stimulation of the stem cell compartment, they may promote intestinal healing and act as potential anti-mucositis agents in patients undergoing cancer chemotherapy. A study was initiated to investigate the protective effects of teduglutide on the murine small intestinal epithelium following gamma-irradiation using the crypt microcolony assay as a measure of stem cell survival and functional competence. Teduglutide demonstrated intestinotrophic effects in both CD1 and BDF1 mouse strains. In BDF1 mice, subcutaneous injection of GLP-2 or teduglutide (0.2 mg/kg/day, b.i.d.) for 14 days increased intestinal weight by 28% and resulted in comparable increases in crypt size, villus height and area. Teduglutide given daily for 6 or 14 days prior to whole body, gamma-irradiation significantly increased crypt stem cell survival when compared with vehicle-treated controls. The mean levels of protection over a range of doses provided protection factors from 1.3 to 1.5. A protective effect was only observed when teduglutide was given before irradiation. These results suggest that teduglutide has the ability to modulate clonogenic stem cell survival in the small intestine and this may have a useful clinical application in the prevention of cancer therapy-induced mucositis.
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PMID:Teduglutide ([Gly2]GLP-2) protects small intestinal stem cells from radiation damage. 1554 72

DP (dipeptidyl peptidase) IV is the archetypal member of its six-member gene family. Four members of this family, DPIV, FAP (fibroblast activation protein), DP8 and DP9, have a rare substrate specificity, hydrolysis of a prolyl bond two residues from the N-terminus. The ubiquitous DPIV glycoprotein has proved interesting in the fields of immunology, endocrinology, haematology and endothelial cell and cancer biology and DPIV has become a novel target for Type II diabetes therapy. The crystal structure shows that the soluble form of DPIV comprises two domains, an alpha/beta-hydrolase domain and an eight-blade beta-propeller domain. The propeller domain contains the ADA (adenosine deaminase) binding site, a dimerization site, antibody epitopes and two openings for substrate access to the internal active site. FAP is structurally very similar to DPIV, but FAP protein expression is largely confined to diseased and damaged tissue, notably the tissue remodelling interface in chronically injured liver. DPIV has a variety of peptide substrates, the best studied being GLP-1 (glucagon-like peptide-1), NPY (neuropeptide Y) and CXCL12. The DPIV family has roles in bone marrow mobilization. The functional interactions of DPIV and FAP with extracellular matrix confer roles for these proteins in cancer biology. DP8 and DP9 are widely distributed and indirectly implicated in immune function. The DPL (DP-like) glycoproteins that lack peptidase activity, DPL1 and DPL2, are brain-expressed potassium channel modulators. Thus the six members of the DPIV gene family exhibit diverse biological roles.
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PMID:Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. 1558 1

Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently being explored as a new approach to the treatment of type 2 diabetes. This concept has emerged from the powerful and rapid action of the enzyme to inactivate glucagon-like peptide-1 (GLP-1). However, other bioactive peptides with potential influence of islet function are also substrates of DPP-4. Whether this inactivation may add to the beneficial effects of DPP-4 inhibition is not known. In this study, we explored whether DPP-4 inhibition by valine-pyrrolidide (val-pyr; 100 micromol/kg administered through gastric gavage at t = -30 min) affects the insulin and glucose responses to iv glucose (1 g/kg) together with GLP-1 (10 nmol/kg), glucose-dependent insulinotropic polypeptide (GIP; 10 nmol/kg), pituitary adenylate cyclase-activating polypeptide 38 (PACAP38; 1.3 nmol/kg), or gastrin-releasing peptide (GRP; 20 nmol/kg) given at t = 0 in anesthetized C57BL/6J mice. It was found that the acute (1-5 min) insulin response to GLP-1 was augmented by val-pyr by 80% (4.2 +/- 0.4 vs. 7.6 +/- 0.8 nmol/liter), that to GIP by 40% (2.7 +/- 0.3 vs. 3.8 +/- 0.4 nmol/liter), that to PACAP38 by 75% (4.6 +/- 0.5 vs. 8.1 +/- 0.6 nmol/liter), and that to GRP by 25% (1.8 +/- 0.2 vs. 2.3 +/- 0.3 nmol/liter; all P < 0.05 or less). This was associated with enhanced glucose elimination rate after GLP-1 [glucose elimination constant (K(G)) 2.1 +/- 0.2 vs. 3.1 +/- 0.3%/min] and PACAP38 (2.1 +/- 0.3 vs. 3.2 +/- 0.3%/min; both P < 0.01), but not after GIP or GRP. The augmented insulin response to GRP by val-pyr was prevented by the GLP-1 receptor antagonist, exendin(3) (9-39), raising the possibility that GRP effects may occur secondary to stimulation of GLP-1 secretion. We conclude that DPP-4 inhibition augments the insulin response not only to GLP-1 but also to GIP, PACAP38, and GRP.
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PMID:Inhibition of dipeptidyl peptidase-4 augments insulin secretion in response to exogenously administered glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and gastrin-releasing peptide in mice. 1560 13

Glucagon-like peptide-1 (GLP-1) is an incretin hormone with antidiabetic action through its ability to stimulate insulin secretion, increase beta cell neogenesis, inhibit beta cell apoptosis, inhibit glucagon secretion, delay gastric emptying and induce satiety. It has therefore been explored as a novel treatment of type 2 diabetes. A problem is, however, that GLP-1 is rapidly inactivated by the dipeptidyl peptidase-4 (DPP-4) enzyme, which results in a short circulating half-life of the active form of GLP-1 (< 2 min). Two strategies have been employed to overcome this obstacle as a treatment of diabetes. One is to use GLP-1 receptor agonists that have a prolonged half-life due to reduced degradation by DPP-4. These GLP-1 mimetics include exenatide and liraglutide. Another strategy is to inhibit the enzyme DPP-4, which prolongs the half-life of endogenously released active GLP-1. Both these strategies have been successful in animal studies and in clinical studies of up to one year's treatment. This review will summarize the background and the current (mid 2004) clinical experience with these two strategies.
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PMID:GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of type 2 diabetes. 1565 21

The most prevalent form of diabetes is non-insulin-dependent or Type 2 diabetes. Innovative strategies to enhance insulin secretion and thereby improve glucose tolerance in patients with this type of diabetes are currently under preclinical and clinical investigation. These therapies include the applications of incretin hormones; gut hormones released postprandially that stimulate insulin secretion in pancreatic beta-cells. Because incretin actions are rapidly terminated by N-terminal cleavage of these peptide hormones by the amino-peptidase dipeptidyl peptidase IV (DPP IV, CD26), the utility of DPP IV inhibitors for the treatment of Type 2 diabetes is also under investigation. This review compares the therapeutic potential and possible side effects of metabolically stable analogues/peptide agonists of the incretin glucagon-like peptide-1 (GLP-1) with the application of DPP IV inhibitors that reduce the rate of endogenous degradation of GLP-1 and other incretins. GLP-1 analogues have been shown to be highly efficacious in the treatment of Type 2 diabetes, with minimal side effects. Of particular importance is the fact that they do not induce hypoglycaemia. However, they are currently available only in an injectable form. In contrast, DPP IV inhibitors have the clear advantage of oral application resulting in better patient compliance. Furthermore, they also potentiate the actions of other incretins normally degraded by the action of DPP IV. However, they possess more potential side effects. Taken together, both approaches offer promising new drugs for the treatment of Type 2 diabetes.
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PMID:Therapeutic assessment of glucagon-like peptide-1 agonists compared with dipeptidyl peptidase IV inhibitors as potential antidiabetic drugs. 1570 22

Glucagon-like peptide-1 (GLP-1) is synthesized from proglucagon in enteroendocrine cells and regulates glucose homeostasis via multiple complementary actions on appetite, gastrointestinal motility and islet hormone secretion. GLP-1 is secreted from the distal gut in response to food ingestion, and levels of circulating GLP-1 may be diminished in patients with type 2 diabetes mellitus. GLP-1 administration stimulates glucose-dependent insulin secretion, inhibits glucagon secretion, and lowers blood glucose in normal and diabetic rodents and in humans. GLP-1 exerts additional glucose-lowering actions in patients with diabetes mellitus already treated with metformin or sulfonylurea therapy. GLP-1 inhibits gastric emptying in healthy individuals and those with diabetes mellitus, and excess GLP-1 administration may cause nausea or vomiting in susceptible individuals. Chronic GLP-1 treatment of normal or diabetic rodents is associated with bodyweight loss and GLP-1 agonists transiently inhibit food intake and may prevent bodyweight gain in humans. The potential for GLP-1 therapy to prevent deterioration of beta-cell function is exemplified by studies demonstrating that GLP-1 analogs stimulate proliferation and neogenesis of beta-cells, leading to expansion of beta-cell mass in diabetic rodents. The rapid N-terminal inactivation of bioactive GLP-1 by dipeptidyl peptidase-IV (DPP-IV) limits the utility of the native peptide for the treatment of patients with diabetes mellitus, and has fostered the development of more potent and stable protease-resistant GLP-1 analogs which exhibit longer durations of action. The importance of DPP-IV for glucose control is illustrated by the phenotype of rodents with genetic inactivation of DPP-IV which exhibit reduced glycemic excursion and increased levels of circulating GLP-1 in vivo. Inhibitors of DPP-IV potentiate incretin action by preventing degradation of GLP-1 and glucose-dependent insulinotropic peptide, and lower blood glucose in normal rodents and in experimental models of diabetes mellitus. Hence, orally available DPP-IV inhibitors also represent a new class of therapeutic agents that enhance incretin action for the treatment of patients with type 2 diabetes mellitus.
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PMID:Harnessing the therapeutic potential of glucagon-like peptide-1: a critical review. 1576 27

Inhibitors of the regulatory protease dipeptidyl peptidase-IV (DPP-IV) are currently under development in preclinical and clinical studies (several pharmaceutical companies, now in Phase III) as potential drugs for the treatment of type 2 diabetes. Their development is based on the observation that DPP-IV rapidly inactivates the incretin hormone glucagon-like peptide-1 (GLP-1), which is released postprandially from the gut and increases insulin secretion. DPP-IV inhibitors stabilise endogenous GLP-1 at physiological concentrations, and induce insulin secretion in a glucose-dependent manner; therefore, they do not demonstrate any hypoglycaemic effects. Furthermore, they are orally bioavailable. In addition to their ability to protect GLP-1 against degradation, DPP-IV inhibitors also stabilise other incretins, including gastric inhibitory peptide and pituitary adenylate cyclase-activating peptide. They also reduce the antagonistic and desensitising effects of the fragments formed by truncation of the incretins. In clinical studies, when used for the treatment of diabetes over a 1-year period, DPP-IV inhibitors show improved efficacy over time. This finding can be explained by a GLP-1-induced increase in the number of beta cells. Potential risks associated with DPP-IV inhibitors include the prolongation of the action of other peptide hormones, neuropeptides and chemokines cleaved by the protease, and their interaction with DPP-IV-related proteases. Based on their mode of action, DPP-IV inhibitors seem to be of particular value in early forms of type 2 diabetes, either alone or in combination with other types of oral agents.
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PMID:Dipeptidyl peptidase inhibitors as new drugs for the treatment of type 2 diabetes. 1577 Apr 66

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are gut-derived incretins secreted in response to nutrient ingestion. Both incretins potentiate glucose-dependent insulin secretion and enhance beta-cell mass through regulation of beta-cell proliferation, neogenesis and apoptosis. In contrast, GLP-1, but not GIP, inhibits gastric emptying, glucagon secretion, and food intake. Furthermore, human subjects with Type 2 diabetes exhibit relative resistance to the actions of GIP, but not GLP-1R agonists. The physiological importance of both incretins has been investigated through generation and analysis of incretin receptor knockout mice. Elimination of incretin receptor action in GIPR-/- or GLP-1R-/- mice produces only modest impairment in glucose homeostasis. Similarly, double incretin receptor knockout (DIRKO) mice exhibit normal body weight and normal levels of plasma glucagon and hypoglycemic responses to exogenous insulin. However, glucose-stimulated insulin secretion is significantly decreased following oral but not intraperitoneal glucose challenge in DIRKO mice and the glucose lowering actions of dipeptidyl peptidase-IV (DPP-IV) inhibitors are extinguished in DIRKO mice. Hence, incretin receptor signaling exerts physiologically relevant actions critical for glucose homeostasis, and represents a pharmacologically attractive target for development of agents for the treatment of Type 2 diabetes.
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PMID:GIP and GLP-1 as incretin hormones: lessons from single and double incretin receptor knockout mice. 1578 Apr 32


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