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

Impaired glucose suppression of glucagon secretion (GSGS) is a hallmark of type 2 diabetes. A critical role for -cell intrinsic mechanisms in regulating glucagon secretion was previously established through genetic manipulation of the glycolytic enzyme glucokinase (GCK) in mice. Genetic variation at the G6PC2 locus, 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 the G6PC2 promoter are located in open chromatin not just in {beta}- but also in -cells, and document allele-specific G6PC2 expression of linked variants in human - cells. Using -cell specific gene ablation of G6pc2 in 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 -cells. Collectively, our data demonstrate that G6PC2 impacts glycemic control via its action in -cells and suggest that G6PC2 inhibitors could help control blood glucose through a novel, bi-hormonal mechanism.