G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic α cells.

Abstract

Elevated glucagon concentrations have been reported in patients with type 2 diabetes (T2D). 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 the glucose-6-phosphatase catalytic subunit 2 (<i>G6PC2</i>) locus, encoding an enzyme that opposes GCK, has been reproducibly associated with fasting blood glucose and hemoglobin A1c. Here, we found that trait-associated variants in the <i>G6PC2</i> promoter are located in open chromatin not just in β but also in α cells and documented allele-specific <i>G6PC2</i> expression of linked variants in human α cells. Using α cell-specific gene ablation of <i>G6pc2</i> in mice, we showed that this gene plays a critical role in controlling glucose suppression of amino acid-stimulated glucagon secretion independent of alterations in insulin output, islet hormone content, or islet morphology, findings that we confirmed in primary human α cells. Collectively, our data demonstrate that <i>G6PC2</i> affects glycemic control via its action in α cells and possibly suggest that G6PC2 inhibitors might help control blood glucose through a bihormonal mechanism.