G6PC2 controls glucagon secretion by defining the setpoint for glucose in pancreatic α-cells

Abstract

AbstractImpaired glucose suppression of glucagon secretion (GSGS) is a hallmark of type 2 diabetes. A critical role for α-cell intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at theG6PC2locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c levels. Here, we find that trait-associated variants in theG6PC2promoter are located in open chromatin not just in β− but also in α-cells, and document allele-specificG6PC2expression of linked variants in human α– cells. Using α-cell specific gene ablation ofG6pc2in mice, we show that this gene plays a critical role in controlling glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology; findings we confirmed in primary human α-cells. Collectively, our data demonstrate thatG6PC2impacts glycemic control via its action in α-cells and suggest thatG6PC2inhibitors could help control blood glucose through a novel, bi-hormonal mechanism.