Incretin Augmentation of Insulin Secretion

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The observation that food ingestion or enteral glucose administration provoked a greater stimulation of insulin release than similar amounts of glucose infused intravenously led to the recognition of gastrointestinal hormones known as incretins. Although a number of neurotransmitters and gut hormones possess incretin-like activity, several lines of evidence (immunoneutralization, administration of antagonists, and knockout studies) suggest that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) represent the dominant peptides responsible for nutrient-augmented stimulation of insulin secretion. Exenatide, the first GLP-1 agonist, has recently received FDA approval for adjuvant therapy in T2DM (see Section

Dipeptidyl peptidase-IV (DPP-IV) is a membrane-associated peptidase that is widely distributed in tissues and also exists as a soluble circulating form. Several DPP-IV inhibitors have been characterized and shown to lower blood glucose via prolongation of circulating GLP-1 and GIP action.87 Animal studies with DPP-IV inhibitors show promising results. Progressive improvement in glycemic control, enhanced insulin secretory response, increased insulin-stimulated muscle glucose uptake, and improved hepatic and peripheral insulin sensitivity have been noted. Vildagliptin (LAF-237), a DPP-IVinhibitor, is in phase III clinical trials forT2DM. It markedly reduces DPP-IVactivity within 30 min and continues to show activity for at least 10 h. In a recently reported trial that compared metformin plus LAF-237 50mgday_ 1 with metformin plus placebo, LAF-237 reduced HbA1C levels by 0.7% in 12 weeks.88 The LAF-237 group also showed significant reductions in FPG levels and improvements in mean prandial glucose. The dipeptidyl peptidase-IV (DPP-IV) inhibitor, sitagliptin was approved as monotherapy for type 2 diabetes in October 2006.

Glucose-dependent insulinotropic polypeptide (GIP), also known as gastric inhibitory polypeptide, is a 42 amino acid peptide released from intestinal cells in response to nutrient absorption. Similarly to GLP-1, GIP undergoes rapid metabolism by DPP-IV via amino-terminal inactivation. GIP promotes b-cell proliferation89 and stimulates glucose-dependent b-cell insulin secretion,90 but has no effect on glucagon secretion or gastric emptying. GIP infusion in normal human subjects did not affect glucose, insulin, or C-peptide at normoglycemia. Although there are no GIP analogs currently in phase III clinical trials, there remains interest in the possibility that GIP analogs resistant to DPP-IV may exhibit therapeutic potential.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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