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  CLINICAL ADVANCES IN DIABETES MELLITUS


Minerva Endocrinologica 2006 June;31(2):133-47

language: English

Therapies for the treatment of type 2 diabetes mellitus based on incretin action

Gallwitz B.

Department of Medicine IV Eberhard-Karls-University, Tübingen, Germany


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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 feasable for routine therapy. Long-acting GLP-1 analogs (e.g. Lira- glutide®) 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 Saxaglip-tin®) that inhibit the enzyme DPP-4 responsible for incretin degradation are also under study.

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