Induction of ? cell-restricted Gc in dedifferentiating ? cells contributes to stress-induced ?-cell dysfunction.

ABSTRACT: Diabetic ? cell failure is associated with ? cell dedifferentiation. To identify effector genes of dedifferentiation, we integrated analyses of histone methylation as a surrogate of gene activation status and RNA expression in ? cells sorted from mice with multiparity-induced diabetes. Interestingly, only a narrow subset of genes demonstrated concordant changes to histone methylation and RNA levels in dedifferentiating ? cells. Notable among them was the ? cell signature gene Gc, encoding a vitamin D-binding protein. While diabetes was associated with Gc induction, Gc-deficient islets did not induce ? cell dedifferentiation markers and maintained normal ex vivo insulin secretion in the face of metabolic challenge. Moreover, Gc-deficient mice exhibited a more robust insulin secretory response than normal controls during hyperglycemic clamps. The data are consistent with a functional role of Gc activation in ? cell dysfunction, and indicate that multiparity-induced diabetes is associated with altered ? cell fate.

SUBMITTER: Kuo T 

PROVIDER: S-EPMC6629129 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature