Physiology and Pathophysiology of Incretins: From Bench to Bedside and Vice Versa

PL-DM

Physiology and Pathophysiology of the Incretins: From Bench to Bedside and Vice Versa

nobuYa InagaKI

Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Japan

Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the incretin hormones released from enteroendocrine K-cells and L-cells, respectively, in response to nutrient ingestion to potentiate glucoSE-stimulated insulin secretion. GIP and GLP-1 are thought to play an important role in early phase glucoSE-induced insulin secretion in normal subjects. However, GIP signaling is down-regulated inβ-cells of diabetic subjects with impaired early phase glucoSEinduced insulin secretion, which is especially common in Japan. Presently, incretin-based therapy that augments incretin action is widely used in treatment of type 2 diabetes in Japan, where its effects are pronounced.

The prevalence of obesity is increasing in Asia as it is elsewhere. In Japan, increased fat intake is supposed to underlie increasing obesity. Under condition of normal glucose tolerance, fat intake is a strong stimulant of GIP secretion and a chronic high-fat diet induces obesity through GIP hypersecretion. On the other hand, reduction of GIP secretion or signaling in mice alleviates obesity and lessens the degree of insulin resistance under high-fat diet conditions. To clarify the mechanism by which fat ingestion stimulates GIP secretion, we established GIP-GFP knock-in (GIP-GFP) mice to visualize K-cells by EGFP. By microarray analysis of K-cells isolated from these mice, we have identified fatty acid binding protein (FABP)-5, which is expressed exclusively in K-cells in small intestine. In addition, we found that GPR120 is abundantly expressed in the K-cells of upper small intestine. We also found that these molecules are involved in fat-induced GIP secretion. We have identified regulatory factor X 6 (Rfx6), a transcriptional factor, which is expressed exclusively in K-cells in small intestine, and found that Rfx6 is involved in transcription of the GIP gene and that its expression is up-regulated by chronic HFD loading. Regulation of these molecules may therefore open the way to novel therapeutic approaches to prevention of high-fat induced obesity.