The gut-brain axis and its implications for the therapy of type 2 diabetes

The gut-brain axis and incretin hormones play an important role in glucose homeostasis and the regulation of body weight. Incretins are gut hormones that stimulate insulin secretion after glucose ingestion. The “incretin effect“ describes the enhanced insulin response from orally ingested glucose compared to the insulin response after the administration of intravenous glucose leading to identical glucose excursions. It comprises between 20%-60% of the postprandial insulin secretion but is diminished in type 2 diabetes. Glucagon-like peptide-1 (GLP-1) is an important incretin. Besides stimulating postprandial insulin secretion, GLP-1 is an important central mediator of satiety. In hypothalamic nuclei it is found as neurotransmitter and has antagonistic effects to Neuropeptide-Y (NPY). In animal studies, intracerebroventricular application of GLP-1 lead to a decrease in food intake. Direct afferent autonomic vagal transmition from the GI-tract to the brain may also stimulate satiety and may also lead to a decrease in food intake. In clinical studies with continuous GLP-1 infusions in type 2 diabetic patients, an increased score in satiety, a reduced caloric intake and a reduction in body weight was observed. Furthermore, in vitro- and animal experiments demonstrated that GLP-1 increases beta-cell mass by inhibiting apoptosis and stimulating islet cell neogenesis. GLP-1 also inhibits glucagon secretion and does hardly cause hypoglycemia. It may therefore represent an attractive therapeutic principle for the treatment of type 2 diabetes due its multiple effects described above. However, only 20% of the GLP-1 administered intravenously is estimated to reach circulation as biologically intact peptide. The short biological half-life of GLP-1 is due to its enzymatic degradation by dipeptidyl-peptiase IV (DPP-4). Therefore, long-acting injectable GLP-1 analogs termed “incretin-mimetics“ that are resistant to degradation, as well as DPP-4 inhibitors that elevate endogenous GLP-1 concentrations by interfering with the degradation of GLP-1 are beginning to be introduced into the therapy of type 2 diabetes. With Exenatide (Byetta®), the first incretin mimetic was approved by the FDA in 2005. Liraglutide and further incretin mimetics will follow. Exenatide and Liraglutide have the potential to normalize hyperglycemia in type 2 diabetic patients without the danger of hypoglycemia and are associated with a potential to decrease body weight. With Vildagliptin (Galvus®) and Sitagliptin (Januvia®) phase III clinical studies have shown a significant reduction in glycated hemoglobin without weight gain and hypoglycemia in combination with Metformin or in monotherapy. In summary, the therapeutic principle of GLP-1 using incretin mimetics or DPP-4 inhibitors is a novel and attractive treatment option with multiple favourable actions for type 2 diabetes. Severe side-effects were not observed for incretin mimetics and DPP-4 inhibitors so far. Additionally these agents have shown positive effects on islet cell regeneration and neogenesis in animal models that may retard the progression of type 2 diabetes.

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