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)

Exenatide is a glucagon-like peptide-1 agonist. It is being investigated as an add-on therapy for patients with type 2 diabetes mellitus who are taking oral antidiabetic drugs. Evidence indicates that exenatide reduces glycosylated hemoglobin and plasma glucose levels when compared with placebo. Limitations of the therapy include the need for twice daily injections and potentially dose-limiting nausea and vomiting. Long-term studies are required to determine the effects of exenatide on disease-related morbidity and mortality.
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PMID:Exenatide for the treatment of type 2 diabetes mellitus. 1638 94

Type 2 diabetes is characterized by hyperglycemia resulting from insulin resistance in the setting of inadequate beta-cell compensation. Currently available therapeutic agents lower blood glucose through multiple mechanisms but do not directly reverse the decline in beta-cell mass. Glucagon-like peptide-1 (GLP-1) receptor agonists, exemplified by Exenatide (exendin-4), not only acutely lower blood glucose but also engage signaling pathways in the islet beta-cell that lead to stimulation of beta-cell replication and inhibition of beta-cell apoptosis. Similarly, glucose-dependent insulinotropic polypeptide (GIP) receptor activation stimulates insulin secretion, enhances beta-cell proliferation, and reduces apoptosis. Moreover, potentiation of the endogenous postprandial levels of GLP-1 and GIP via inhibition of dipeptidyl peptidase-IV (DPP-IV) also expands beta-cell mass via related mechanisms. The thiazolidinediones (TZDs) enhance insulin sensitivity, reduce blood glucose levels, and also preserve beta-cell mass, although it remains unclear whether TZDs affect beta-cell mass via direct mechanisms. Complementary approaches to regeneration of beta-cell mass involve combinations of factors, exemplified by epidermal growth factor and gastrin, which promote islet neogenesis and ameliorate diabetes in rodent studies. Considerable preclinical data support the concept that one or more of these therapeutic approaches, alone or in combination, may potentially reverse the decline in beta-cell mass that is characteristic of the natural history of type 2 diabetes.
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PMID:Therapeutic approaches to preserve islet mass in type 2 diabetes. 1640 49

Type 2 diabetes is recognised as a major cardiovascular risk factor, and future therapies must therefore address more than just blood glucose levels. Novel approaches to the treatment of type 2 diabetes are now at various stages of development or regulatory approval. Exenatide and pramlintide, analogues of gut-derived hormones glucagon-like peptide-1 (GLP-1) and amylin, respectively, have demonstrated improvements in glycaemic control and bodyweight in clinical studies and have been recently approved for treatment of type 2 diabetes. Initial studies have indicated that agents that activate both peroxisome proliferator-activated receptor (PPAR)alpha and gamma improve glycaemic control and have beneficial effects on lipid profiles. Two dual PPARalpha/gamma agonists, muraglitazar and tesaglitazar, are under regulatory review and in phase III trials, respectively. Modulation of the endogenous endocannabinoid system by rimonabant, which is under regulatory review, has been shown to improve body weight, atherogenic lipid profiles and glycaemic control. In addition, enhanced understanding of the pathophysiology underlying the microvascular complications of type 2 diabetes has led to the development of targeted therapies for conditions such as diabetic retinopathy, including the protein kinase C (PKC)-antagonist ruboxistaurin, now in phase III trials. Such therapies should enable physicians to achieve more for their patients with type 2 diabetes.
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PMID:Diabetes: assessing the pipeline. 1650 99

Cells in the gastrointestinal tract secrete several hormones that stimulate insulin secretion, one of which is glucagon-like peptide (GLP-1). Several new drugs act through the GLP-1 signaling system to stimulate insulin release and regulate blood glucose levels in patients with diabetes. One such compound, exenatide (Byetta), has recently become available, and others are in clinical development.
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PMID:New therapies for type 2 diabetes based on glucagon-like peptide 1. 1661 Mar 99

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.
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PMID:Newer therapeutic options for children with diabetes mellitus: theoretical and practical considerations. 1662 19

Orally ingested glucose leads to a much higher insulin response than intravenous glucose leading to identical postprandial plasma glucose excursions. This phenomenon, termed ''incretin effect'' comprises up to 60% of the postprandial insulin secretion and is diminished in type 2 diabetes. The gastrointestinal hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) promote the incretin effect. Type 2 diabetes is characterized by an incretin defect: while GIP does not stimulate insulin secretion, GLP-1 action is still preserved under supraphysiological concentrations. GLP-1 stimulates insulin secretion only under hyperglycaemic conditions, therefore it does not cause hypoglycaemia. Furthermore, GLP-1 inhibits glucagon secretion and delays gastric emptying. In vitro and animal data demonstrated that GLP-1 increases beta cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. The improvement of beta cell function can be indirectly observed from the increased insulin secretory capacity of humans receiving GLP-1. In contrast to GIP, GLP-1 may represent an attractive therapeutic method for type 2 diabetes due to its multiple effects also including the simulation of satiety in the central nervous system by acting as transmitter or by crossing the blood brain barrier. Native GLP-1 is degraded rapidly upon intravenous or subcutaneous administration and is therefore not feasible for routine therapy. Long-acting GLP-1 analogs (e.g. Liraglutide) and exendin-4 (Exenatide, Byetta) that are resistant to degradation, called ''incretin mimetics'' are approved (Exenatide, Byetta) or in clinical trials. DPP-4-inhibitors (e.g. Vildagliptin), Sitagliptin and Saxagliptin) that inhibit the enzyme DPP-4 responsible for incretin degradation are also under study.
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PMID:Therapies for the treatment of type 2 diabetes mellitus based on incretin action. 1668 37

Glucagon and the glucagon-like peptides are derived from a common proglucagon precursor, and regulate energy homeostasis through interaction with a family of distinct G protein coupled receptors. Three proglucagon-derived peptides, glucagon, GLP-1, and GLP-2, play important roles in energy intake, absorption, and disposal, as elucidated through studies utilizing peptide antagonists and receptor knockout mice. The essential role of glucagon in the control of hepatic glucose production, taken together with data from studies employing glucagon antagonists, glucagon receptor antisense oligonucleotides, and glucagon receptor knockout mice, suggest that reducing glucagon action may be a useful strategy for the treatment of type 2 diabetes. GLP-1 secreted from gut endocrine cells controls glucose homeostasis through glucose-dependent enhancement of beta-cell function and reduction of glucagon secretion and gastric emptying. GLP-1 administration is also associated with reduction of food intake, prevention of weight gain, and expansion of beta-cell mass through stimulation of beta-cell proliferation, and prevention of apoptosis. GLP-1R agonists, as well as enzyme inhibitors that prevent GLP-1 degradation, are in late stage clinical trials for the treatment of type 2 diabetes. Exenatide (Exendin-4) has been approved for the treatment of type 2 diabetes in the United States in April 2005. GLP-2 promotes energy absorption, inhibits gastric acid secretion and gut motility, and preserves mucosal epithelial integrity through enhancement of crypt cell proliferation and reduction of epithelial apoptosis. A GLP-2R agonist is being evaluated in clinical trials for the treatment of inflammatory bowel disease and short bowel syndrome. Taken together, the separate receptors for glucagon, GLP-1, and GLP-2 represent important targets for developing novel therapeutic agents for the treatment of disorders of energy homeostasis.
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PMID:Glucagon and glucagon-like peptide receptors as drug targets. 1671 85

Exenatide is a glucagon-like peptide 1 receptor agonist, which has recently received FDA approval in the US for the treatment of Type 2 diabetes. Exenatide is an incretin mimetic that improves glycaemic control in patients with diabetes through acute mechanisms, such as glucose-dependent stimulation of insulin secretion, suppression of inappropriate glucagon secretion and slowing of gastric emptying, as well as chronic mechanisms that include enhancement of beta-cell mass in rodent studies and weight loss and inhibition of food intake in humans. This article reviews the mechanisms of exenatide action, as well as its efficacy in the treatment of Type 2 diabetes.
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PMID:Exenatide: a GLP-1 receptor agonist as novel therapy for Type 2 diabetes mellitus. 1672 15

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.
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PMID:Investigation of exenatide elimination and its in vivo and in vitro degradation. 1672 26

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


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