TY - JOUR
T1 - G6PC2 controls glucagon secretion by defining the set point for glucose in pancreatic α cells
AU - Bahl, Varun
AU - Rifkind, Reut
AU - Waite, Eric
AU - Hamdan, Zenab
AU - May, Catherine Lee
AU - Manduchi, Elisabetta
AU - Voight, Benjamin F.
AU - Lee, Michelle Y.Y.
AU - Tigue, Mark
AU - Manuto, Nicholas
AU - Glaser, Benjamin
AU - Avrahami, Dana
AU - Kaestner, Klaus H.
N1 - Publisher Copyright:
Copyright © 2025 The Authors.
PY - 2025/1/1
Y1 - 2025/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85214338141&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.adi6148
DO - 10.1126/scitranslmed.adi6148
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C2 - 39742505
AN - SCOPUS:85214338141
SN - 1946-6234
VL - 17
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 779
M1 - eadi6148
ER -