Induction of α cell-restricted Gc in dedifferentiating β cells contributes to stress-induced β cell dysfunction

Diabetic beta cell failure is associated with beta 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 beta 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 beta cells. Notable among them was the u. cell signature gene Gc, encoding a vitamin D-binding protein. Although diabetes was associated with Gc induction, Gc-deficient islets did not induce beta 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 clamp studies. The data are consistent with a functional role of Gc activation in beta cell dysfunction and indicate that multiparity-induced diabetes is associated with altered beta cell fate.