Regulation of the circadian clock gene expression in human adipose tissue by glucose-dependent insulinotropic polypeptide (GIP)

Abstract

Aims: Recently was shown that Insulin has a direct impact on the circadian clock gene regulation. GIP is an incretin hormone released after food intake. Therefore GIP and Insulin are synergistically increased in the postprandial state. We hypothesised that GIP modulates the circadian gene expression in human adipose tissue. Methods: Moderately obese male subjects (n = 14) underwent one to three of the following procedures: 1) isotonic saline- or GIP-infusion (11); 2) hyperinsulinemic-euglycemic clamp (EC, n = 11) (+/-GIP); 3) hyperinsulinemic-hyperglycemic clamp (HC, n = 8) (+/-GIP). Subjects with Type 2 diabetes (n = 11) underwent HC (+/-GIP) under the same conditions. All clamps were performed for 4h. Subcutaneous adipose tissue biopsies were obtained before and after infusion. The expression of Clock genes PER2, PER3, RORα, REV-ERBα, TEF was measured by RT-PCR. Results: In healthy subjects, PER2 and TEF gene expression were increased by insulin and glucose after HC. We observed a trend up regulation of PER2, PER3 genes and a significant down regulation of REV-ERBα gene by insulin after EC+NaCl. Furthermore, we found a trend reduction of insulin-glucose impact on PER2, TEF and REV-ERBα genes by GIP in HC. GIP infusion alone alters the expression of the core clock genes PER3 and RORα. Otherwise in type 2 diabetes subjects we couldn't find any differences in the gene expression of PER2, TEF, REV-ERBα by the HC+GIP infusion. Conclusion: Our results demonstrate that GIP alters the clock-gene expression in human adipose tissue. Although GIP stimulates the insulin secretion in a glucose-dependent manner we could find that GIP suppresses and alters the insulin regulated circadian rhythms. In type 2 diabetes patients the inhibitory effect of GIP under the same conditions is missing.