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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The incretin mimetic exenatide improved glycemic control and reduced body weight in patients with type 2 diabetes inadequately controlled with metformin+/-a sulfonylurea. We assessed postprandial beta-cell function by mathematical modeling, independent of confounding effects from differing ambient glucose levels among treatments. Subjects were 63% males, 55+/-10 years, BMI 33+/-6 kg/m2, HbA1C 8.1+/-1.1% (+/- SD) randomized to 5 microg exenatide or placebo twice daily for 4 weeks. Subsequently, one arm remained at 5 microg twice daily, one arm escalated to 10 microg twice daily, and one treatment arm remained on placebo for 26 weeks. Subjects continued metformin+/-a sulfonylurea. A subset with meal tests at baseline and week 30 were analyzed (n=73). Outcome measures were the model-based beta-cell function parameters dose-response relating insulin secretion to glucose concentration, rate sensitivity, and potentiation. Exenatide reduced postprandial glucose excursions. Modeling predicted an upward shift of the beta-cell dose-response. Model-predicted insulin secretion rate at a reference glucose concentration increased 72% (10 microg), increased 40% (5 microg), or decreased 21% (placebo) at week 30 [ p=0.015 (10 microg); p=0.045 (5 microg); vs. placebo]. At week 30, the 2-hour post-meal to basal potentiation factor ratio was increased to 1.53+/-0.10 (10 microg; p=0.0142 vs. placebo) or 1.40+/-0.08 (5 microg; p=0.0402 vs. placebo) compared with 1.15+/-0.06 (placebo). Exenatide caused an upward shift of the beta-cell dose-response and enhanced potentiation of insulin secretion. This model suggests exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin+/-a sulfonylurea.
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PMID:Mathematical modeling shows exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin or metformin and a sulfonylurea. 1716 61

Exenatide is the first synthetic agonist of the GLP-1 (glucagon-like peptide 1) receptor approved for clinical use in patients with type 2 diabetes. The multiplicity of its effects over glucose metabolism, appetite, body weight and its potential capacity to preserve the ?cell mass, makes it an attractive therapeutic alternative. This article attempts to review the current literature on pharmacokinetics, pharmacodynamics, efficacy, and safety of exenatide in humans, derived from the early phase I and II studies, and from the clinical controlled trials that led to its approval for clinical use as a combination therapy with sulphonylureas and metformin.
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PMID:[Exenatide: use in humans]. 1720 Nov 11

Exenatide is the first drug in the incretin mimetic class and is indicated for treatment of type 2 diabetes mellitus. Although structurally similar to the native glucagon-like peptide, this synthetic form has a much longer duration of action. Randomized trials have shown exenatide to be efficacious in improving glycemic control when combined with either metformin or a sulfonylurea. The dose is initially 5 mcg subcutaneously twice daily and may be titrated to 10 mcg subcutaneously twice daily to achieve better diabetes management. Nausea, vomiting, and diarrhea were the most common adverse events reported with exenatide therapy. Exenatide is not associated with hypoglycemia, which may provide advantages over adding insulin to a sulfonylurea or metformin.
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PMID:Exenatide (Byetta) as a novel treatment option for type 2 diabetes mellitus. 1725 50

With the rising prevalence of diabetes, new therapies that provide glucose control are needed. Although many medications are available, tight glucose control is still a challenge. In this article, the physiology of glucose homeostasis is explored with respect to type 2 diabetes. The incretin effect is explained in detail, and the incretin hormones, glucose-dependent insulinotrophic polypeptide and glucagon-like peptide 1, are investigated as well as their contribution to type 2 diabetes therapy. Studies involving dipeptidyl-peptidase 4 (DPP-4) inhibitors are summarized as to their effects on glucose homeostasis. Specifically, vildagliptin (Galvus; Novartis International AG, Basel, Switzerland) and sitagliptin (Januvia; Merck & Co, Inc, Whitehouse Station, NJ) are described. The use and efficacy of the currently available incretin mimetic, exenatide (Byetta; Amylin Pharmaceuticals, Inc and Eli Lilly and Company, San Diego, Calif, and Indianapolis, Ind), are briefly discussed. Throughout this article, the rationale for the use of DPP-4 inhibitors is presented.
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PMID:The physiology of incretin hormones and the basis for DPP-4 inhibitors. 1727 93

The dysdifferentiation of beta cells in type 2 diabetes appears to be caused and maintained by a vicious cycle of glucolipotoxicity: chronic elevations of glucose and free fatty acids induce beta cell dysdifferentiation as well as apoptosis; the resulting failure of glucose-stimulated insulin secretion tends to maintain the elevations of glucose and free fatty acids. Since extended fasts restore normoglycemia in diabetics, the resulting relief from glucotoxicity has been associated with a marked improvement in beta cell function that can be conserved after the fast if the factors precipitating diabetes--obesity, fatty and high-glycemic-index diets, sedentary lifestyle--have been adequately addressed. The new drug exenatide, an analog of the incretin hormone glucagon-like peptide-1, may be a worthwhile adjuvant to such fasting therapy, since it tends to counteract the glucolipotoxicity-induced down-regulation of the crucially important beta cell transcription factor IDX-1. Exenatide also exerts trophic effects on beta cell mass that in the longer term might help to restore diminished beta cell mass. Supraphysiological concentrations of biotin, possibly because they activate the soluble guanylate cyclase, also promote induction of IDX-1 and counteract the adverse impact of glucolipotoxicity in this regard; thus, high-dose biotin, which is well tolerated, may represent an additional adjuvant for therapeutic fasting intended to normalize beta cell function in type 2 diabetics.
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PMID:Exenatide and biotin in conjunction with a protein-sparing fast for normalization of beta cell function in type 2 diabetics. 1729 59

Exenatide, the active ingredient of BYETTA (exenatide injection), is an incretin mimetic that has been developed for the treatment of patients with type 2 diabetes. Exenatide binds to and activates the known GLP-1 receptor with a potency comparable to that of the mammalian incretin GLP-1(7-36), thereby acting as a glucoregulatory agent. AC3174 is an analog of exenatide with leucine substituted for methionine at position 14, [Leu(14)]exendin-4. The purpose of these studies was to evaluate the glucoregulatory activity and pharmacokinetics of AC3174. In RINm5f cell membranes, the potency of AC3174 for the displacement of [(125)I]GLP-1 and activation of adenylate cyclase was similar to that of exenatide and GLP-1. In vivo, AC3174, administered as a single IP injection, significantly decreased plasma glucose concentration and glucose excursion following the administration of an oral glucose challenge in both non-diabetic (C57BL/6) and diabetic db/db mice (P<0.05 vs. vehicle-treated). The magnitude of glucose lowering of AC3174 was comparable to exenatide. The ED(50) values of AC3174 for glucose lowering (60 minute post-dose) were 1.2 microg/kg in db/db mice and 1.3 microg/kg in C57BL/6 mice. AC3174 has insulinotropic activity in vivo. Administration of AC3174 resulted in a 4-fold increase in insulin concentrations in normal mice following an IP glucose challenge. AC3174 was also shown to inhibit food intake and decrease gastric emptying in rodent models. AC3174 was stable in human plasma (>90% of parent peptide was present after 5 h of incubation). In rats, the in vivo half-life of AC3174 was 42-43 min following SC administration. In summary, AC3174 is an analog of exenatide that binds to the GLP-1 receptor in vitro and shares many of the biological and glucoregulatory activities of exenatide and GLP-1 in vivo.
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PMID:Biological activity of AC3174, a peptide analog of exendin-4. 1729 77

Interventional studies have demonstrated the impact of hyperglycemia on the development of vascular complications associated with type 2 diabetes, which underscores the importance of safely lowering glucose to as near-normal as possible. Among the current challenges to reducing the risk of vascular disease associated with diabetes is the management of body weight in a predominantly overweight patient population, and in which weight gain is likely with many current therapies. 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 (GLP-1). Currently approved in the US as an injectable adjunct to metformin and/or sulfonylurea therapy, exenatide improves glycemic control through multiple mechanisms of action including: glucose-dependent enhancement of insulin secretion that potentially reduces the risk of hypoglycemia compared with insulin secretagogues; restoration of first-phase insulin secretion typically deficient in patients with type 2 diabetes; suppression of inappropriately elevated glucagon secretion to reduce postprandial hepatic output; and slowing the rate of gastric emptying to regulate glucose appearance into the circulation. Clinical trials in patients with type 2 diabetes treated with subcutaneous exenatide twice daily demonstrated sustained improvements in glycemic control, evidenced by reductions in postprandial and fasting glycemia and glycosylated hemoglobin (HbA(1c)) levels. Notably, improvements in glycemic control with exenatide were coupled with progressive reductions in body weight, which represents a distinct therapeutic benefit for patients with type 2 diabetes. Acute effects of exenatide on beta-cell responsiveness along with significant reductions in body weight in patients with type 2 diabetes may have a positive impact on disease progression and potentially decrease the risk of associated long-term complications.
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PMID:Metabolic effects of the incretin mimetic exenatide in the treatment of type 2 diabetes. 1731 71

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

Exenatide (Byetta) is a novel, synthetic, incretin mimetic, glucoregulatory peptide approved in the US and Europe for the treatment of patients with type 2 diabetes mellitus who have inadequate glycaemic control despite receiving treatment with maximum tolerated doses of metformin and/or a sulfonylurea. In randomised, controlled, phase III trials and post hoc completer analyses in this patient population, the addition of subcutaneous exenatide twice daily significantly improved glycaemic control and was associated with progressive and significant bodyweight reduction from baseline for up to 2 years. The overall intensity of glycaemic control with exenatide was similar to that achieved with once-daily insulin glargine or twice-daily biphasic insulin aspart. Exenatide was generally well tolerated. Most adverse events were mild to moderate in severity and gastrointestinal in nature. The overall rate of hypoglycaemia was similar to rates observed with placebo (when administered with metformin) and insulin comparators (when administered with metformin and a sulfonylurea). The addition of exenatide to therapy with metformin and a sulfonylurea provided significant improvements in treatment satisfaction and patients' health-related quality of life (HR-QOL). The drug was also cost effective compared with pioglitazone, glibenclamide (glyburide), insulin glargine (all in combination with metformin and/or a sulfonylurea) and metformin alone. Overall, adjunctive therapy with exenatide is a valuable therapeutic option in patients with type 2 diabetes requiring moderate improvements in glycaemic control despite treatment with metformin and/or a sulfonylurea.
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PMID:Exenatide: a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea). 1742 9

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


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