Gs/Gq signaling switch in beta cells defines incretin effectiveness in diabetes

• 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 beta 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+ (K-ATP) channels play a crucial role in coupling the systemic metabolic status to beta cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of beta cells due to genetic cell-specific Kcnj11(-/-)mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the K-ATP 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 beta cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in beta cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)

Nyckelord

dependent insulinotropic polypeptide

glucagon-like peptide-1

protein-kinase-c

k-atp channels

down-regulation

receptor expression

ca2+ influx

secretion

gip

glp-1

Research & Experimental Medicine

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