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

Varun Bahl, Reut Rifkind, Eric Waite, Zenab Hamdan, Catherine Lee May, Elisabetta Manduchi, Benjamin F. Voight, Michelle Y.Y. Lee, Mark Tigue, Nicholas Manuto, Benjamin Glaser, Dana Avrahami*, Klaus H. Kaestner*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 (G6PC2) 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 G6PC2 promoter are located in open chromatin not just in β but also in α cells and documented allele-specific G6PC2 expression of linked variants in human α cells. Using α cell-specific gene ablation of G6pc2 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 G6PC2 affects glycemic control via its action in α cells and possibly suggest that G6PC2 inhibitors might help control blood glucose through a bihormonal mechanism.

Original languageEnglish
Article numbereadi6148
JournalScience Translational Medicine
Volume17
Issue number779
DOIs
StatePublished - 1 Jan 2025

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