Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 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

Exenatide (Ex-4) is a novel anti-diabetic drug that stimulates insulin secretion and enhances beta-cell mass, but the mechanisms involved are not fully understood. We found that Ex-4 protects INS-1 beta-cells against oxidative stress-induced apoptosis (TUNEL) and also reduces expression (mRNA and protein) of thioredoxin-interacting protein (TXNIP), a pro-apoptotic factor involved in beta-cell glucose toxicity and oxidative stress. This reduction was observed in INS-1 cells, mouse, and human islets as well as in wild-type mice receiving Ex-4 and was accompanied by decreased expression of the apoptotic factors caspase-3 and Bax. To determine whether Ex-4-mediated TXNIP reduction is critical for this inhibition of apoptosis, we stably overexpressed TXNIP in INS-1 cells, which completely blunted the anti-apoptotic Ex-4 effects. Thus, Ex-4 inhibits apoptosis by reducing TXNIP expression and early initiation of Ex-4 treatment may help preserve endogenous beta-cell mass, protect against oxidative stress, and delay type 2 diabetes progression.
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PMID:Exenatide inhibits beta-cell apoptosis by decreasing thioredoxin-interacting protein. 1678 54

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

The first antidiabetic treatment (exenatide; Byetta) based on the incretin hormone glucagon-like peptide-1 (GLP-1) was approved in 2005 as an adjunctive therapy in diabetic patients in whom sulfonylurea, metformin or both had failed. Many GLP-1 mimetics or dipeptidyl peptidase IV inhibitors are currently in clinical development for the treatment of type 2 diabetes and show promising results in the improvement of glucose homeostasis. Furthermore, the ability of GLP-1 to enhance pancreatic beta-cell mass could delay progression of the disease. However, only several years of treatment in humans will confirm the long-term efficacy of GLP-1 mimetics and enhancers on glycemic control. To take advantage of the multifaceted actions of GLP-1, a better understanding of the physiological roles of GLP-1 is required.
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PMID:GLP-1 and type 2 diabetes: physiology and new clinical advances. 1698 6

Exenatide, a treatment for type 2 diabetes, slows gastric emptying as part of its pharmacologic action and may alter the absorption of concomitant oral drugs. This open-label, 2-period, fixed-sequence study evaluated the influence of exenatide coadministration on the pharmacokinetics and pharmacodynamics of warfarin, a narrow therapeutic index drug, in healthy men (N = 16). A single, 25-mg oral dose of warfarin, with a standardized breakfast, was administered alone in period 1 and concomitantly with 10 microg exenatide subcutaneous twice daily in period 2. Exenatide did not produce significant changes in R- or S-warfarin pharmacokinetics. Although there were minor reductions in warfarin anticoagulant effect, the ratios of geometric means for the area under the international normalized ratio (INR)-time curve from dosing until the time of the last measurable INR value or maximum-observed INR response being 0.94 (0.93-0.96) and 0.88 (0.84-0.92), respectively, the magnitude and direction of these changes do not suggest a safety concern from this interaction.
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PMID:Effect of exenatide on the pharmacokinetics and pharmacodynamics of warfarin in healthy Asian men. 1698 7

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

The therapeutic options for treating type 2 diabetes have been widened by the introduction of exenatide as the first incretin mimetic. Incretins are gut hormones that contribute to the stimulation of insulin secretion after a carbohydrate rich meal. The incretin hormone glucagon-like peptide-1 (GLP-1) not only stimulates insulin secretion under hyperglycaemic conditions, but also suppresses glucagon secretion, slows gastric emptying, induces satiety and improves beta cell function in type 2 diabetes. These beneficial effects have awakened the interest to use GLP-1 for the treatment of type 2 diabetes. Because of its short biological half-life, GLP-1 itself is not practical for type 2 diabetes therapy. Exenatide is a peptide found in the lizard Heloderma suspectum and has a high similarity to GLP-1. Exenatide belongs to the novel class of incretin mimetics because of its incretin-like action. It has a much longer biological half life than GLP-1 and is a GLP-1 receptor agonist that can be used for therapeutic purposes by twice daily injection. Clinical studies and clinical experience with exenatide have shown a significant reduction in HbA1c, fasting- and postprandial glucose and a marked reduction in body weight in type 2 diabetic patients. Animal studies reveal an improvement of beta cell function and an increase in beta cell mass after exenatide treatment. This review gives an overview on exenatide, its pharmacological profile and its role and potential in the therapeutic setting of type 2 diabetes. Furthermore, future developments concerning exenatide application are highlighted.
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PMID:Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data. 1710 59

Endocrinology has recently witnessed several important developments: The Epidemiology of Diabetes Interventions and Complications study, a follow-up to the landmark Diabetes Control and Complications trial, found that strict glucose control early in the course of type 1 diabetes reduces the risk of microvascular and cardiovascular complications and provides prolonged benefits even if intensive control is not so tightly maintained. Inhaled insulin preparations are now available for mealtime coverage. We now have two new injectable medications for diabetes; pramlintide (Symlin) and exenatide (Byetta) are good adjuncts for patients with both type 1 and type 2 diabetes who have trouble reaching their hemoglobin A1c target, and they can help control and even reduce weight. Thyroxine (T4), instead of being merely a "prohormone," has been found to have direct actions on cells, leading to rapid clinical effects and possibly oncogenesis and angiogenesis. The therapeutic range for thyrotropin (TSH) may be much narrower than traditionally believed: some have proposed that the normal range should be redefined as 0.4 to 2.5 mIU/L. New evidence shows that vitamin D is important for more than calcium control and may help prevent type 1 diabetes.
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PMID:Endocrinology update 2006. 1712 44


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