Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

There is a progressive deterioration in beta-cell function and mass in type 2 diabetics. It was found that islet function was about 50% of normal at the time of diagnosis, and a reduction in beta-cell mass of about 60% was shown at necropsy. The reduction of beta-cell mass is attributable to accelerated apoptosis. The major factors for progressive loss of beta-cell function and mass are glucotoxicity, lipotoxicity, proinflammatory cytokines, leptin, and islet cell amyloid. Impaired beta-cell function and possibly beta-cell mass appear to be reversible, particularly at early stages of the disease where the limiting threshold for reversibility of decreased beta-cell mass has probably not been passed. Among the interventions to preserve or "rejuvenate" beta-cells, short-term intensive insulin therapy of newly diagnosed type 2 diabetes will improve beta-cell function, usually leading to a temporary remission time. Another intervention is the induction of beta-cell "rest" by selective activation of ATP-sensitive K+ (K(ATP)) channels, using drugs such as diazoxide. A third type of intervention is the use of antiapoptotic drugs, such as the thiazolidinediones (TZDs), and incretin mimetics and enhancers, which have demonstrated significant clinical evidence of effects on human beta-cell function. The TZDs improve insulin secretory capacity, decrease beta-cell apoptosis, and reduce islet cell amyloid with maintenance of neogenesis. The TZDs have indirect effects on beta-cells by being insulin sensitizers. The direct effects are via peroxisome proliferator-activated receptor gamma activation in pancreatic islets, with TZDs consistently improving basal beta-cell function. These beneficial effects are sustained in some individuals with time. There are several trials on prevention of diabetes with TZDs. Incretin hormones, which are released from the gastrointestinal tract in response to nutrient ingestion to enhance glucose-dependent insulin secretion from the pancreas, aid the overall maintenance of glucose homeostasis through slowing of gastric emptying, inhibition of glucagon secretion, and control of body weight. From the two major incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), only the first one or its mimetics or enhancers can be used for treatment because the diabetic beta-cell is resistant to GIP action. Because of the rapid inactivation of GLP-1 by dipeptidyl peptidase (DPP)-IV, several incretin analogs were developed: GLP-1 receptor agonists (incretin mimetics) exenatide (synthetic exendin-4) and liraglutide, by conjugation of GLP-1 to circulating albumin. The acute effect of GLP-1 and GLP-1 receptor agonists on beta-cells is stimulation of glucose-dependent insulin release, followed by enhancement of insulin biosynthesis and stimulation of insulin gene transcription. The chronic action is stimulating beta-cell proliferation, induction of islet neogenesis, and inhibition of beta-cell apoptosis, thus promoting expansion of beta-cell mass, as observed in rodent diabetes and in cultured beta-cells. Exenatide and liraglutide enhanced postprandial beta-cell function. The inhibition of the activity of the DPP-IV enzyme enhances endogenous GLP-1 action in vivo, mediated not only by GLP-1 but also by other mediators. In preclinical studies, oral active DPP-IV inhibitors (sitagliptin and vildagliptin) also promoted beta-cell proliferation, neogenesis, and inhibition of apoptosis in rodents. Meal tolerance tests showed improvement in postprandial beta-cell function. Obviously, it is difficult to estimate the protective effects of incretin mimetics and enhancers on beta-cells in humans, and there is no clinical evidence that these drugs really have protective effects on beta-cells.
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PMID:beta-cell failure in diabetes and preservation by clinical treatment. 1735 95

Orally ingested glucose leads to a greater insulin response compared to intravenously administered glucose leading to identical postprandial plasma glucose excursions, a phenomenon referred to as the "incretin effect". The incretin effect comprises up to 60% of the postprandial insulin secretion and is diminished in type 2 diabetes. One of the very important gastrointestinal hormones promoting this effect is glucagon-like peptide 1 (GLP-1). It only stimulates insulin secretion and normalizes blood glucose in humans under hyperglycemic conditions, therefore it does not cause hypoglycemia. Other important physiological actions of GLP-1 are the inhibition of glucagon secretion and gastric emptying. It further acts as a neurotransmitter in the hypothalamus stimulating satiety. In vitro and animal data demonstrated that GLP-1 increases beta-cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. In humans, the improvement of beta-cell function can be indirectly observed from the increased insulin secretory capacity after GLP-1 infusions. GLP-1 represents an attractive therapeutic principle for type 2 diabetes. However, native GLP-1 is degraded rapidly upon exogenous administration and is therefore not feasible for routine therapy. The first long-acting GLP-1 analog ("incretin mimetic") Exenatide (Byetta) has just been approved for type 2 diabetes therapy. Other compounds are being investigated in clinical trials (e.g. liraglutide, CJC1131). Dipeptidyl-peptidase IV inhibitors (DPP-IV inhibitors; e.g. Vildagliptin, Sitagliptin) that inhibit the enzyme responsible for incretin degradation are also under study.
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PMID:New therapeutic strategies for the treatment of type 2 diabetes mellitus based on incretins. 1749 80

The American Diabetes Association currently recommends an A1C goal of less than 7 percent. However, many patients are unable to achieve this goal by using oral drug combinations or diet and exercise, leaving insulin as the only treatment option. In most cases, insulin is initiated later in therapy because of its inconvenience and adverse effects (e.g., weight gain, hypoglycemia, possible role in atherogenesis). Although insulin effectively helps patients attain glucose goals, the search for new agents continues. Two injectable agents, pramlintide and exenatide, were approved in 2005 for the treatment of diabetes. Pramlintide, indicated for use in patients with type 1 and 2 diabetes, is a synthetic analogue of human amylin that acts in conjunction with insulin to delay gastric emptying and inhibit the release of glucagon. Exenatide, a glucagon-like peptide-1 mimetic, has multiple mechanisms for lowering glucose levels, including the enhancement of insulin secretion, and is indicated for use in patients with type 2 diabetes. Clinical trials have shown that both agents reduce, by a statistically significant degree, A1C levels (0.3 to 0.7 percent more than placebo), fasting plasma glucose levels, and body weight (3 to 5 lb [1.4 to 2.3 kg]). No studies have examined their effects on diabetic complications, cardiovascular disease, or overall mortality. Pramlintide and exenatide may help make glycemic goals more attainable.
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PMID:Therapies for diabetes: pramlintide and exenatide. 1761 27

The epidemic characteristics of type 2 diabetes mellitus (DM) pose a formidable challenge in terms of healthcare, given the tremendous impact it has on the healthcare resources needed not only to treat it, but also to prevent and treat the associated cardiovascular complications. This makes up the number 1 cause of DM-associated morbidity-mortality in addition to its social and personal impact. We currently have a growing number of available treatment tools that make it possible to achieve the target glycemic control in most of our patients, albeit unfortunately, only temporarily in a good many of them, because of the progressive nature of the disease. Furthermore, current therapy often entails undesirable effects, such as weight gain or the emergence of hypoglycemias that limit their optimization. Recently, a new class of drugs has been incorporated into the treatment of DM - incretin mimetics. These new drugs act in very much the same way as the intestinal hormones that are naturally secreted following the intake of nutrients, called incretins (e.g., glucagon like peptide-1 [GLP-1]), with the added advantage that these molecules are resistant to enzymatic degradation by the DPP-IV enzyme. This provides them with a half-life that makes ambulatory treatment possible, unlike natural incretins whose half-life is too short to make them viable as treatment. The incretin mimetics bind to GLP-1 receptors, increasing glucose-dependent secretion of insulin and decreasing glucose-dependent posprandial secretion of glucagon, slowing gastric emptying, and reducing food intake. All these mechanisms have a significant impact on glucose homeostasis and a beneficial effect on body weight. Moreover, studies in experimental models suggest that these new molecules might have a promising effect on pancreatic beta cell function and mass. Exenatide is the first incretin mimetic available to date. Efficacy and safety data of this drug show it as a therapeutic option for the treatment of type 2 DM.
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PMID:[Incretins as new therapeutic targets of type 2 diabetes]. 1766 2

Exenatide is an incretin mimetic indicated for the treatment of type 2 diabetes mellitus in combination with a sulfonylurea, a thiazolidinedione, metformin, or metformin plus a sulfonylurea or thiazolidinedione. Exenatide lowers postprandial blood glucose levels by stimulating glucose-dependent insulin secretion, inhibiting glucagon secretion, slowing gastric emptying, and increasing satiety. Therapy with exenatide often results in weight loss, which further assists in decreasing insulin resistance. This feature makes the drug an attractive therapeutic option for obese patients. We report the successful off-label use of exenatide in an obese, 40-year-old man with type 1 diabetes and human immunodeficiency virus (HIV) infection who had gastrointestinal intolerance to pramlintide. The patient had experienced a dramatic weight gain secondary to his antiretroviral drugs. This weight gain led to insulin resistance and the development of type 2 diabetes; thus he had characteristics of both types 1 and 2 diabetes, or double diabetes. Before the start of exenatide therapy, he weighed 123 kg, had a body mass index of 42.3 kg/m(2), and had a suboptimal hemoglobin A(1c) value of 8.7%. After 11 months of therapy, the patient lost 24 kg (19.5% of his body weight) and achieved a hemoglobin A(1c) value of 7.3%. His basal insulin requirement was reduced by 25%, and his use of short-acting insulin before breakfast and before dinner was discontinued. In addition, the patient's quality of life substantially improved, as he was able to return to work and exercise after being nearly incapacitated by his weight. To our knowledge, this is the first published case report of the use of exenatide in a patient with type 1 diabetes mellitus or human immunodeficiency virus infection. Given this experience, exenatide may prove to be a useful alternative in selected patients with type 1 diabetes.
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PMID:Off-label use of exenatide for the management of insulin-resistant type 1 diabetes mellitus in an obese patient with human immunodeficiency virus infection. 1789

Exenatide is the first in a new class of compounds, which possess similar activity to the naturally-occurring hormone glucagon-like peptide-1 (GLP-1). It mirrors many of the effects of GLP-1, improving glycaemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduced appetite. Phase III clinical trials showed exenatide therapy for 30 weeks significantly reduced glycated haemoglobin, and fasting and postprandial plasma glucose compared with baseline when added to metformin and sulfonylureas or a combination of the two, with an average weight loss of approximately 2 kg. Exenatide can also be used in combination with thiazolidinediones and may be an alternative to insulin in patients requiring additional therapy. In patients with established Type 2 diabetes, control of both glycaemia and body weight are important to minimise the risk of future diabetes complications. Open-label extensions from these pivotal trials demonstrate that patients treated with exenatide for < or = 3 years sustained the reductions in glycaemic control achieved at 30 weeks and had a progressive reduction in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Hypoglycaemia has been encountered in clinical trials of exenatide, especially on initiation of therapy with sulfonylureas (not with metformin). Exenatide may enable patients with Type 2 diabetes to improve glycaemic control and reduce or eliminate the risk of hypoglycaemia and weight gain.
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PMID:Exenatide. 1793 Oct 93

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are physiological gut peptides with insulin-releasing and extrapancreatic glucoregulatory actions. Incretin analogues/mimetics activate GLP-1 or GIP receptors whilst avoiding physiological inactivation by dipeptidyl peptidase 4 (DPP-4), and they represent one of the newest classes of antidiabetic drug. The first clinically approved GLP-1 mimetic for the treatment of type-2 diabetes is exenatide (Byetta/exendin) which is administered subcutaneously twice daily. Clinical trials of liraglutide, a GLP-1 analogue suitable for once-daily administration, are ongoing. A number of other incretin molecules are at earlier stages of development. This review discusses the various attributes of GLP-1 and GIP for diabetes treatment and summarises current clinical data. Additionally, it explores the therapeutic possibilities offered by preclinical agents, such as non-peptide GLP-1 mimetics, GLP-1/glucagon hybrid peptides, and specific GIP receptor antagonists.
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PMID:Incretin hormone mimetics and analogues in diabetes therapeutics. 1805 32

Exenatide is a 39-amino acid peptide incretin mimetic approved for adjunctive treatment of type 2 diabetes. It shares several glucoregulatory activities with the mammalian hormone, glucagon-like peptide-1 (GLP-1). In clinical use, subcutaneous exenatide injections demonstrate glucoregulatory and weight loss effects with sustained plasma concentrations in the 50-100 pM range. We investigated the pharmacokinetics of exenatide in normoglycemic rats and biological activity in diabetic db/db mice after delivery to various epithelial surfaces of the intestinal and respiratory tracts. In rats, elimination kinetics were similar for all routes of administration (median k(e) 0.017 min(-1)). Bioavailability (versus intravenous administration) and C(max) per unit dose differed markedly. For gastrointestinal administration, sublingual administration invoked the highest bioavailability (0.37%); in db/db mice, potentially therapeutic concentrations were obtainable. In contrast, intraduodenal bioavailability was low (0.0053%). In regard to respiratory surfaces, bioavailability of intratracheal exenatide was up to 13.6%, and for nasal administration, 1.68%. Both routes of administration produced therapeutic plasma concentrations and glucose-lowering in db/db mice. At high doses, aerosolized exenatide also achieved effective concentrations and glucose-lowering. In summary, the intestinal tract seems to have limited potential as a route of exenatide administration, with sublingual being most promising. In contrast, the respiratory tract appears to be more viable, comparing favorably with the clinically approved subcutaneous route. Despite little optimization of the delivery formulation, exenatide bioavailability compared favorable to that of several commercially available bioactive peptides.
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PMID:Pharmacokinetics and pharmacodynamics of exenatide following alternate routes of administration. 1829 6

Among the challenges in improving outcomes in patients with diabetes is effectively implementing existing pharmacotherapies. However, current therapies for diabetes are often limited by adverse effects such as edema, hypoglycemia, and weight gain. Understanding the role of the incretin effect on the pathophysiology of diabetes has led to the development of new therapeutic agents. Exenatide is the first in a new class of agents termed "incretin mimetics," which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1. In clinical trials, patients with type 2 diabetes treated with exenatide demonstrate sustained improvements in glycemic control, with reductions in fasting and postprandial glucose levels and improvements in glycosylated hemoglobin levels. Improvements in glycemic control with exenatide are coupled with reductions in body weight. Lipid parameters, blood pressure, and C-reactive protein have been shown to improve favorably in patients treated with exenatide. The sustained glycemic improvements and progressive reduction in body weight with exenatide treatment support a shift toward a more favorable cardiovascular risk profile and may have a positive impact on decreasing the risk of associated long-term complications.
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PMID:Exenatide as a treatment for diabetes and obesity: implications for cardiovascular risk reduction. 1836 86

The obesity epidemic in the developed and developing world is being followed by an epidemic of type 2 diabetes. In type 2 diabetes, subjects cannot manage glucose properly because they do not produce enough insulin, and the peripheral tissues have become resistant to insulin. Glucagon-like peptide 1 (GLP-1) is an intestinal peptide hormone that is secreted in response to food to regulate the postprandial blood glucose concentration. One of the actions of GLP-1 is to stimulate insulin secretion. In subjects with type 2 diabetes, intravenous or subcutaneous GLP-1 stimulated insulin production and decreased blood glucose levels. However, as GLP-1 is rapidly metabolised, it is not suitable for use in most subjects with type 2 diabetes. Exendin-4 is a 39-amino acid peptide that acts as an agonist at the GLP-1 receptor. After subcutaneous administration, synthetic exendin-4 (exenatide) decreased postprandial concentrations of glucose and insulin, and fasting glucose levels in subjects with type 2 diabetes, and the effects lasted several hours. Subsequently, exenatide was been trialled in subjects taking metformin only, a sulfonylurea only, or metformin and a sulfonylurea, and shown to improve glycemic control with few adverse events, initially over 30 weeks, and then extended to 82 weeks. Exenatide may also be as effective as insulin glargine in subjects with type 2 diabetes not adequately controlled with the oral agents. In conclusion, exenatide represents a new and beneficial addition to the medicines used to treat type 2 diabetes.
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PMID:Is exenatide improving the treatment of type 2 diabetes? Analysis of the individual clinical trials with exenatide. 1847 91


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