Gs/Gq signaling switch in ? cells defines incretin effectiveness in diabetes.

ABSTRACT: By restoring glucose-regulated insulin secretion, glucagon-like peptide-1-based (GLP-1-based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic ? cells. However, the reason why only GLP-1-based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved. ATP-sensitive K+ (KATP) channels play a crucial role in coupling the systemic metabolic status to ? cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of ? cells due to genetic (? cell-specific Kcnj11-/- mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the KATP channel led to a switch from Gs to Gq in a major amplifying pathway of insulin secretion. The switch determined the relative insulinotropic effectiveness of GLP-1 and GIP, as GLP-1 can activate both Gq and Gs, while GIP only activates Gs. The findings were corroborated in other models of persistent depolarization: a spontaneous diabetic KK-Ay mouse and nondiabetic human and mouse ? cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in ? cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes.

SUBMITTER: Oduori OS 

PROVIDER: S-EPMC7685756 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature