Role of GLP-1 analogues and DPP-IV inhibitors in the treatment of type 2 diabetes

RESUMEN

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), may be responsible for up to 70% of postprandial insulin secretion. In type 2 diabetes (2DM), the incretin effect is severely reduced. Secretion of GIP is normal, but its effect on insulin secretion is lost. GLP-1 secretion and effects are also impaired, but supraphysiological doses may restore insulin secretion to near normal levels. Replacement therapy with GLP-1 might therefore be possible. GLP-1 actions include potentiation of glucose-induced insulin secretion; up-regulation of insulin and other ß-cell genes; stimulation of ß-cell proliferation and neogenesis and inhibition of ß-cell apoptosis; and inhibition of glucagon secretion, gastric emptying, and appetite and food intake. It may also have cardioprotective and neuroprotective actions. These actions make GLP-1 attractive as a therapeutic agent for 2DM, but GLP-1 is rapidly destroyed in the body by the enzyme, dipeptidyl peptidase IV (DPP-IV). Clinical strategies therefore include 1) the development of metabolically stable activators of the GLP-1 receptor (incretin mimetics); and 2) inhibition of DPP-IV (incretin enhancers). Orally active, DPP-IV inhibitors are currently undergoing clinical trials, and recent clinical studies have provided long-term proof of concept. Metabolically stable analogues/activators include the structurally related lizard peptide, exendin-4, as well as GLP-1-derived molecules that bind to albumin and thereby assume the pharmacokinetics of albumin. These molecules are effective in experimental animal models of type 2 diabetes, and have been employed successfully in clinical studies of up to 2 years’ duration, and exendin-4 (Exenatide, Byetta(R) has recently been approved for add-on therapy of 2DM

ABSTRACT

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