Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gut peptides, exemplified by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GIP and GLP-1 also promote beta cell proliferation and inhibit apoptosis, leading to expansion of beta cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion. Furthermore, GLP-1, unlike GIP, potently stimulates insulin secretion and reduces blood glucose in human subjects with type 2 diabetes. This article summarizes current concepts of incretin action and highlights the potential therapeutic utility of GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes.
 ...
PMID:The biology of incretin hormones. 1651 3

Vildagliptin is a competitive and reversible inhibitor of dipeptidyl peptidase-4. Dipeptidyl peptidase-4 inhibitors act mainly by preventing the rapid degradation of glucagon-like peptide-1. In clinical trials, vildagliptin improves glycaemic control both as monotherapy and in combination with metformin for periods of < or = 52 weeks in subjects with Type 2 diabetes. This is evident by reduced fasting and prandial glucose levels, and reduced glycosylated haemoglobin levels. Vildagliptin acts by increasing active glucagon-like peptide-1, improving beta-cell function and inhibiting glucagon secretion. Furthermore, vildagliptin has proven to be safe and tolerable, with a low occurrence of hypoglycaemia. Further studies are now required to evaluate its long-term durability, effects, safety and tolerability in comparison with other antidiabetic agents and in different patient subgroups.
 ...
PMID:Vildagliptin: an inhibitor of dipeptidyl peptidase-4 with antidiabetic properties. 1654 92

Incretin levels approach normal physiological values following treatment with dipeptidyl peptidase (DPP)-IV inhibitors. This is in contrast to incretin levels resulting from the exogenous administration of glucagon-like peptide (GLP)-1 and its analogs, which can reach super-physiological values. This review describes the role of DPP-IV inhibitors as incretin enhancers in the regulation of glucose homeostasis in type 2 diabetic patients. The roles of incretins and the effect of DPP-IV on their actions are described, as are new therapeutic interventions based on the restoration of impaired incretin secretion in type 2 diabetic patients and obese individuals. In addition, the relevance of DPP-IV inhibition for weight control, its potential influence on beta-cell mass, and possible new indications are discussed, as are the implications of the currently available clinical data.
 ...
PMID:Dipeptidyl peptidase-IV inhibitors can restore glucose homeostasis in type 2 diabetics via incretin enhancement. 1662 20

Recent studies in adult patients with type 1 diabetes mellitus (T1DM) and T2DM have examined the potential utility, benefits, and side effects of agents that augment insulin secretion after oral ingestion of nutrients in comparison with intravenous nutrient delivery, the so-called incretins. Two families of incretin-like substances are now approved for use in adults. Glucagon-like peptide-1 (GLP-1) or agents that bind to its receptor (exenatide, Byetta) or agents that inhibit its destruction [dipeptidyl peptidase-IV (DPP-IV) inhibitors, Vildagliptin] improve insulin secretion, delay gastric emptying, and suppress glucagon secretion while decreasing food intake without increasing hypoglycemia. Pramlintide, a synthetic amylin analog, also decreases glucagon secretion and delays gastric emptying, improves hemoglobin A1c (HbA1C), and facilitates weight reduction without causing hypoglycemia. We review the historical discovery of these agents, their physiology [corrected] and their current applications. Remarkably, only one or two studies have been reported in children. Pediatricians caring for children with T1DM and T2DM should become familiar with these agents and investigate their applicability, as they seem likely to enhance our therapeutic armamentarium to treat children with diabetes mellitus.
 ...
PMID:Newer therapeutic options for children with diabetes mellitus: theoretical and practical considerations. 1662 19

Exenatide is a 39 amino acid incretin mimetic for the treatment of type 2 diabetes, with glucoregulatory activity similar to glucagon-like peptide-1 (GLP-1). Exenatide is a poor substrate for the major route of GLP-1 degradation by dipeptidyl peptidase-IV, and displays enhanced pharmacokinetics and in vivo potency in rats relative to GLP-1. The kidney appears to be the major route of exenatide elimination in the rat. We further investigated the putative sites of exenatide degradation and excretion, and identified primary degradants. Plasma exenatide concentrations were elevated and sustained in renal-ligated rats, when compared to sham-operated controls. By contrast, exenatide elimination and degradation was not affected in rat models of hepatic dysfunction. In vitro, four primary cleavage sites after amino acids (AA)-15, -21, -22 and -34 were identified when exenatide was degraded by mouse kidney membranes. The primary cleavage sites of exenatide degradation by rat kidney membranes were after AA-14, -15, -21, and -22. In rabbit, monkey, and human, the primary cleavage sites were after AA-21 and -22. Exenatide was almost completely degraded into peptide fragments <3 AA by the kidney membranes of the species tested. The rates of exenatide degradation by rabbit, monkey and human kidney membranes in vitro were at least 15-fold slower than mouse and rat membranes. Exenatide (1-14), (1-15), (1-22), and (23-39) were not active as either agonists or antagonists to exenatide in vitro. Exenatide (15-39) and (16-39) had moderate-to-weak antagonist activity compared with the known antagonist, exenatide (9-39). In conclusion, the kidney appears to be the primary route of elimination and degradation of exenatide.
 ...
PMID:Investigation of exenatide elimination and its in vivo and in vitro degradation. 1672 26

Dipeptidyl peptidase IV (DPP-IV) belongs to a family of serine peptidases, and due to its indirect regulatory role in plasma glucose modulation, DPP-IV has become an attractive pharmaceutical target for diabetes therapy. DPP-IV inactivates the glucagon-like peptide (GLP-1) and several other naturally produced bioactive peptides that contain preferentially a proline or alanine residue in the second amino acid sequence position by cleaving the N-terminal dipeptide. To elucidate the details of the active site for structure-based drug design, we crystallized a natural source preparation of DPP-IV isolated from rat kidney and determined its three-dimensional structure using X-ray diffraction techniques. With a high degree of similarity to structures of human DPP-IV, the active site architecture provides important details for the design of inhibitory compounds, and structures of inhibitor-protein complexes offer detailed insight into three-dimensional structure-activity relationships that include a conformational change of Tyr548. Such accommodation is exemplified by the response to chemical substitution on 2-cyanopyrrolidine inhibitors at the 5 position, which conveys inhibitory selectivity for DPP-IV over closely related homologues. A similar conformational change is also observed in the complex with an unrelated synthetic inhibitor containing a xanthine core that is also selective for DPP-IV. These results suggest the conformational flexibility of Tyr548 is unique among protein family members and may be utilized in drug design to achieve peptidase selectivity.
 ...
PMID:Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors. 1676 43

Type 2 diabetes is thought to develop as a result of progressive beta-cell dysfunction in the setting of insulin resistance, leading to increased risks of microvascular and macrovascular complications. Type 2 diabetes is currently treated with diet and exercise, followed by oral drug therapy, and finally exogenous insulin. While this approach is known to improve glycemic control, none of the currently available therapies significantly improve beta-cell function. In addition, this approach does not address defects in hormonal secretion thought to play key roles in the pathophysiology of type 2 diabetes. Type 2 diabetes is characterized by excess glucagon secretion and insufficient secretion of the hormone amylin from the pancreatic beta-cell. In addition, individuals with type 2 diabetes demonstrate insufficient secretion of the incretin hormone glucagon-like peptide-1 (GLP-1). Novel therapies that leverage the so-called "incretin effect" of GLP-1 (including the incretin mimetics and dipeptidyl peptidase-IV (DPP-IV) inhibitors) are being actively developed for the management of type 2 diabetes. Incretin mimetics are either derivatives of GLP-1, modified to resist proteolysis, or are novel peptides that share glucoregulatory functions with GLP-1 and are naturally resistant to proteolysis. DPP-IV inhibitors enhance the concentration of endogenous GLP-1 by limiting proteolysis of native GLP-1. With the approval of exenatide- the first "incretin mimetic"-treatment of type 2 diabetes will no doubt be changed. An understanding of the effects of these compounds will be needed to enhance the clinical approach to diabetes treatment.
 ...
PMID:Incretin mimetics and dipeptidyl peptidase-IV inhibitors: a review of emerging therapies for type 2 diabetes. 1680 Jul 60

Sitagliptin (MK-0431) is an oral, potent, and selective dipeptidyl peptidase-IV (DPP-4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle-aged (45-63 years), nondiabetic, obese (body mass index: 30-40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady-state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to approximately 90% inhibition of plasma DPP-4 activity, increased active glucagon-like peptide-1 (GLP-1) levels by 2.7-fold (P < .001), and decreased post-oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP-4 activity, increased active GLP-1, and reduced glycemic excursion.
 ...
PMID:Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. 1685 72

The actions of the structurally related proglucagon-derived peptides (PGDPs)-glucagon, glucagon-like peptide (GLP)-1 and GLP-2-are focused on complementary aspects of energy homeostasis. Glucagon opposes insulin action, regulates hepatic glucose production, and is a primary hormonal defense against hypoglycemia. Conversely, attenuation of glucagon action markedly improves experimental diabetes, hence glucagon antagonists may prove useful for the treatment of type 2 diabetes. GLP-1 controls blood glucose through regulation of glucose-dependent insulin secretion, inhibition of glucagon secretion and gastric emptying, and reduction of food intake. GLP-1-receptor activation also augments insulin biosynthesis, restores beta-cell sensitivity to glucose, increases beta-cell proliferation, and reduces apoptosis, leading to expansion of the beta-cell mass. Administration of GLP-1 is highly effective in reducing blood glucose in subjects with type 2 diabetes but native GLP-1 is rapidly degraded by dipeptidyl peptidase IV. A GLP-1-receptor agonist, exendin 4, has recently been approved for the treatment of type 2 diabetes in the US. Dipeptidyl-peptidase-IV inhibitors, currently in phase III clinical trials, stabilize the postprandial levels of GLP-1 and gastric inhibitory polypeptide and lower blood glucose in diabetic patients via inhibition of glucagon secretion and enhancement of glucose-stimulated insulin secretion. GLP-2 acts proximally to control energy intake by enhancing nutrient absorption and attenuating mucosal injury and is currently in phase III clinical trials for the treatment of short bowel syndrome. Thus the modulation of proglucagon-derived peptides has therapeutic potential for the treatment of diabetes and intestinal disease.
 ...
PMID:Biologic actions and therapeutic potential of the proglucagon-derived peptides. 1692 63

The enzyme dipeptidyl peptidase-IV (DPP-IV) inactivates a variety of bioactive peptides, including glucagon-like peptide-1 (GLP-1) and growth hormone releasing hormone (GHRH). Inhibiting DPP-IV in order to increase circulating GLP-1 is of interest as a treatment for Type II diabetes. Inactivation of DPP-IV may also increase circulating GHRH, potentially enhancing growth in domestic animals. To test the hypothesis that inhibition of DPP-IV activity will influence the growth hormone/ IGF-1 axis, growing pigs (Sus scrofa domesticus, 78 kg) were treated with a DPP-IV inhibitor (Compound 1, the 2,5-difluor-ophenyl analog of the triazolopiperazine MK0431, sitagliptin), and plasma concentrations of IGF-1 were monitored. Pigs were administered either sterile saline (0.11 ml/kg followed by a continuous infusion at 2 ml/hr for 72 hrs, controls, n = 2), Compound 1 (2.78 mg/kg followed by a continuous infusion at 0.327 mg/kg x hr for 72 hrs, n = 4) or GHRH (0.11 ml/kg sterile saline, followed by a continuous infusion of GHRH at 2.5 microg/ kg x hr for 48 hrs, n = 4). Plasma concentrations of Compound 1 were maintained at 1 microM, which resulted in a 90% inhibition of circulating DPP-IV activity. Relative to the predose 24-hr period, area under the IGF-1 concentration curve (AUC) tended to be lower (P = 0.062) with Compound 1 (.79 +/- 130 ng/ml x hr) than controls (543 +/- 330 ng/ml x hr). GHRH treatment increased the IGF-1 AUC (1210 +/- 160 ng/ml x hr, P = 0.049 vs. controls and P = 0.001 vs. Compound 1). We conclude that inhibition of DPP-IV does not alter the circulating levels of IGF-1 in the growing pig.
 ...
PMID:Inhibition of dipeptidyl-peptidase IV does not increase circulating IGF-1 concentrations in growing pigs. 1694 6


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>