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) 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

Glucagon-like peptide 1 (GLP-1) was discovered as an insulinotropic gut hormone, suggesting a physiological role as an incretin hormone, i.e., being responsible, in part, for the higher insulin secretory response after oral as compared to intravenous glucose administration. This difference, the incretin effect, is partially lost in patients with Type 2 diabetes. The actions of GLP-1 include (a) a stimulation of insulin secretion in a glucose-dependent manner, (b) a suppression of glucagon, (c) a reduction in appetite and food intake, (d) a deceleration of gastric emptying, (e) a stimulation of beta-cell neogenesis, growth and differentiation in animal and tissue culture experiments, and (f) an in vitro inhibition of beta-cell apoptosis induced by different toxins. Intravenous GLP-1 can normalize and subcutaneous GLP-1 can significantly lower plasma glucose in the majority of patients with Type 2 diabetes. GLP-1 itself, however, is inactivated rapidly in vivo and thus does not appear to be useful as a therapeutic agent in the long-term treatment of Type 2 diabetes. Other agents acting on GLP-1 receptors have been found (like exendin-4) or developed as GLP-1 derivatives (like liraglutide or GLP-1/CJC-1131). Clinical trials with exenatide (two injections per day) and liraglutide (one injection per day) have shown reductions in glucose concentrations and HbA1c by more than 1%, associated with moderate weight loss (2-3 kg), but also some nausea and, rarely, vomiting. It is hoped that this new class of drugs interacting with the GLP-1 or other incretin receptors, the so-called "incretin mimetics", will broaden our armamentarium of antidiabetic medications in the nearest future.
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PMID:Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. 1578 Apr 33

We recently reported that intraduodenal infusion of lauric acid (C12) (0.375 kcal/min, 106 mM) stimulates isolated pyloric pressure waves (IPPWs), inhibits antral and duodenal pressure waves (PWs), stimulates release of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), and suppresses energy intake and that these effects are much greater than those seen in response to isocaloric decanoic acid (C10) infusion. Administration of C12 was, however, associated with nausea, confounding interpretation of the results. The aim of this study was to evaluate the effects of different intraduodenal doses of C12 on antropyloroduodenal (APD) motility, plasma CCK and GLP-1 concentrations, appetite, and energy intake. Thirteen healthy males were studied on 4 days in double-blind, randomized fashion. APD pressures, plasma CCK and GLP-1 concentrations, and appetite perceptions were measured during 90-min ID infusion of C12 at 0.1 (14 mM), 0.2 (28 mM), or 0.4 (56 mM) kcal/min or saline (control; rate 4 ml/min). Energy intake was determined at a buffet meal immediately following infusion. C12 dose-dependently stimulated IPPWs, decreased antral and duodenal motility, and stimulated secretion of CCK and GLP-1 (r > 0.4, P < 0.05 for all). C12 (0.4 kcal/min) suppressed energy intake compared with control, C12 (0.1 kcal/min), and C12 (0.2 kcal/min) (P < 0.05). These effects were observed in the absence of nausea. In conclusion, intraduodenal C12 dose-dependently modulated APD motility and gastrointestinal hormone release in healthy male subjects, whereas effects on energy intake were only apparent with the highest dose infused (0.4 kcal/min), possibly because only at this dose was modulation of APD motility and gastrointestinal hormone secretion sufficient for a suppressant effect on energy intake.
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PMID:Dose-related effects of lauric acid on antropyloroduodenal motility, gastrointestinal hormone release, appetite, and energy intake in healthy men. 1596 31

Exenatide is the first in a new class of compounds that exhibit activity similar to the naturally occurring hormone glucagon-like peptide-1 (GLP-1). Released from cells in the gut in response to food, GLP-1 binds to pancreatic beta-cell receptors to stimulate the release of insulin. Exenatide mirrors many of the effects of GLP-1, improving glycemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, reduced appetite and enhanced beta-cell function. As stimulation of insulin secretion occurs only in the presence of elevated blood glucose concentrations, the risk of hypoglycemia should be greatly reduced with exenatide. In addition to positive therapeutic effects on fasting and postprandial glucose levels, exenatide treatment is associated with significant, dose-dependent reductions in glycated hemoglobin (HbA1c) from baseline and progressive reductions in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but it can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Exenatide may enable patients with type 2 diabetes to achieve glycemic control while reducing or eliminating the risk of hypoglycemia and weight gain. These would represent significant therapeutic gains.
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PMID:Exenatide. 1634 Dec 88

Recognizing that type 1 diabetes was characterized not only by insulin deficiency, but also by amylin deficiency, Cooper (Cooper, 1991) predicted that certain features of the disease could be related thereto, and he proposed amylin/insulin co-replacement therapy. Although the early physiological rationale was flawed, the idea that glucose control could be improved over that attainable with insulin alone without invoking the ravages of worsening insulin-induced hypoglycemia was vindicated. The proposal spawned a first-in-class drug development program that ultimately led to marketing approval by the U.S. Food and Drug Administration of the amylinomimetic pramlintide acetate in March 2005. The prescribers' package insert (Amylin Pharmaceuticals Inc., 2005), which includes a synopsis of safety and efficacy of pramlintide, is included as Appendix 1. Pramlintide exhibited a terminal t1/2, in humans of 25-49 min and, like amylin, was cleared mainly by the kidney. The dose-limiting side effect was nausea and, at some doses, vomiting. These side effects usually subsided within the first days to weeks of administration. The principal risk of pramlintide co-therapy was an increased probability of insulin-induced hypoglycemia, especially at the initiation of therapy. This risk could be mitigated by pre-emptive reduction in insulin dose. Pramlintide dosed at 30-60 microg three to four times daily in patients with type 1 diabetes, and at doses of 120 microg twice daily in patients with type 2 diabetes, invoked a glycemic improvement, typically a decrease in HbA1c of 0.4-0.5% relative to placebo, that was sustained for at least 1 year. This change relative to control subjects treated with insulin alone typically was associated with a reduction in body weight and insulin use, and was not associated with an increase in rate of severe hypoglycemia other than at the initiation of therapy. Effects observed in animals, such as slowing of gastric emptying, inhibition of nutrient-stimulated glucagon secretion, and inhibition of food intake, generally have been replicated in humans. A notable exception appears to be induction of muscle glycogenolysis and increase in plasma lactate.
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PMID:Clinical studies. 1649 55

Liraglutide is a once-daily glucagon-like peptide-1 analogue being developed for the treatment of type 2 diabetes. The aim of this study was to investigate the effect of age and gender on the pharmacokinetics of liraglutide. Eight male and 8 female subjects were recruited from an 18- to 45-year-old group and an over-65-year-old group, respectively. All subjects received a single subcutaneous dose of 1.0 mg liraglutide. The area under the liraglutide plasma concentration curve from time 0 to last quantifiable concentration adjusted for body weight (significant covariate; P = .001) was found to be equivalent in young and elderly subjects (primary end point), with an estimated ratio of 0.94 (90% confidence interval, 0.84-1.06; P = .39). No significant impact of gender was observed (P = .38; estimated ratio, 1.08; 90% confidence interval, 0.93-1.26). Adverse events were of mild or moderate severity. The most frequently reported events were headache, vomiting, and nausea. When adjusted for body weight, no effect of gender or age was found on the pharmacokinetics of liraglutide.
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PMID:An open-label, parallel group study investigating the effects of age and gender on the pharmacokinetics of the once-daily glucagon-like peptide-1 analogue liraglutide. 1670 10

Pramlintide is the first new antihyperglycemic agent approved for both type 2 and type 1 diabetes since insulin was developed in the 1920s. It is a synthetic analogue of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells. Pramlintide helps regulate the rate of glucose appearance and improves glucose control postprandially. This action is accomplished through suppressing inappropriate postprandial glucagon secretion and regulating gastric emptying, and is associated with a feeling of satiety. It is given at mealtimes and is indicated for use in type 2 and type 1 diabetes as an adjunct treatment in patients who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy. Pramlintide therapy should only be considered for patients who are receiving ongoing care under the guidance of a health care professional skilled in the use of insulin and supported by services of diabetes educators. Pramlintide is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia, particularly in type 1 diabetes. Appropriate patient selection, careful patient instruction, and insulin dose adjustments help reduce this risk. In type 2 diabetes, pramlintide is initiated at 60 microg and may be increased to 120 microg two to three times daily with meals. In type 1 diabetes, pramlintide is initiated at 15 microg and may be increased to 30 or 60 microg with meals. Mealtime insulin should be reduced by 50% at pramlintide initiation and adjusted as the pramlintide dose is increased. It should be given subcutaneously with an insulin syringe and should not be mixed with insulin. The most commonly reported side effect is mild to moderate nausea with initiation, which is usually transient and short term in nature. Frequent self-monitoring of blood glucose is important during initiation to assist in insulin adjustments. Insulin type, dose, and timing as well as basal/bolus balance may require adjustment during pramlintide initiation. Despite requiring additional injections, patients report satisfaction with pramlintide therapy.
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PMID:Use of pramlintide: the patient's perspective. 1675 52

Maintaining glycemic control is the primary goal for preventing macrovascular and microvascular complications associated with type 2 diabetes. Currently available antidiabetic drugs work in different ways to lower blood glucose levels; unfortunately, each of them has its tolerability and safety concerns. Exenatide is the first drug in a new class known as the incretin mimetic agents. It improves glucose control by mimicking the effects of glucagon-like peptide-1, a natural mammalian incretin hormone secreted during food intake. Exenatide was approved by the U.S. Food and Drug Administration for the treatment of type 2 diabetes in conjunction with metformin and/or sulfonylurea. The recommended dosage is 5 mug to 10 mug twice daily subcutaneously before breakfast and dinner. In randomized, placebo-controlled, 30-week clinical studies, exenatide improved glycemic control and promoted weight loss of up to 2.8 kg. The most common adverse effects were nausea (44%), vomiting (13%), diarrhea (13%), and hypoglycemia (5-36%). Hypoglycemia occurred in a dose-dependent fashion. Patients should be closely monitored for hypoglycemia, especially when exenatide is added to sulfonylurea therapy. Overall, exenatide provides a treatment option for patients with type 2 diabetes who fail to obtain glycemic control while on a maximum dose of metformin and/or sulfonylurea therapy. It is also an alternative therapy for those patients who cannot tolerate other antidiabetic drugs.
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PMID:Exenatide: a novel incretin mimetic agent for treating type 2 diabetes mellitus. 1678 34

Incretin mimetics are a new class of pharmacological agents with multiple antihyperglycemic actions that mimic several of the actions of incretin hormones originating in the gut, such as glucagon-like peptide (GLP)-1. Dipeptidyl peptidase-IV (DPP-IV) inhibitors suppress the degradation of many peptides, including GLP-1, thereby extending their bioactivity. These agents seem to have multiple mechanisms of action for the treatment of type 2 diabetes mellitus (T2DM), including some or all the following: enhancement of glucose-dependent insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and decreased food intake. Exenatide (BYETTA) is the first incretin mimetic approved for clinical use by the US Food and Drug Administration. In phase 3 clinical trials, exenatide reduced HbA(1c) by approximately 1% and body weight by approximately 2 kg in T2DM patients failing to achieve glycemic control with metformin and/or a sulfonylurea, with mild-to-moderate nausea the most common side effect. Several GLP-1 analogues and DPP-IV inhibitors are in late-stage clinical testing and may soon become available for treating T2DM patients. The use of these agents may provide an opportunity to bring about new improvements in diabetes care.
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PMID:Incretin mimetics and DPP-IV inhibitors: new paradigms for the treatment of type 2 diabetes. 1709 Jul 94

Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) (1-2%), associated with weight loss (2-5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA1c by 0.5-1.0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand beta-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.
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PMID:The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. 1725 57


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