Review

New Therapeutic Strategies for the Treatment of Type 2 Diabetes Mellitus Based on Incretins

Baptist Gallwitz

Keywords: type 2 diabetes, incretin, incretin mimetics, GLP-1, DPP-IV inhibitors, vildagliptin, sitagliptin

Abstract

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 β-cell mass by stimulating islet cell neogenesis and by inhibiting apoptosis of islets. In humans, the improvement of β-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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