Effects of incretin hormones on β‐cell multiple delayed rectifier K+ channels

Abstract

Incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), potentiate glucose-stimulated insulin secretion in pancreatic β-cells. Voltage gated K+ (Kv) channels are considered to be involved in the insulinotropic actions of GIP and GLP-1. However, the distinct roles of incretins on Kv channels have not been fully understood. Here, we have identified subtypes of Kv channels involved in the generation of delayed rectifying currents (IDR) and characterized the effects of incretins on each subtype. In GIP receptor expressing HEK293 cells, GIP treatment resulted in 42 %, 52 % and 22 % reductions in Kv2.1, Kv1.5 and Kv3.2 macroscopic currents respectively. On the other hand, GLP-1 treatment resulted in 50 % and 59 % decreases in Kv2.1 and Kv1.5, but not in Kv 3.2 currents in GLP-1 receptor expressing HEK293 cells. Overexpression of Kv2.1, Kv1.5 and Kv3.2 improved the insulinotropic effects of incretins. Additionally, we have shown expression of Kv2.1, Kv1.5 and Kv3.2 in human islets, and that GIP and GLP-1 treatment resulted in 40.4 % and 40.5 % decreases in islet IDR, respectively. Taken together, these results indicate that GIP and GLP-1 use different subtypes of Kv channels to exert their insulinotropic effects on pancreatic β-cells. To our knowledge, this is the first demonstration of the molecular components of IDR within the enteroinsular axis where incretins are working.