TY - JOUR AU - Kuo, Taiyi AU - Damle, Manashree AU - González, Bryan J. AU - Egli, Dieter AU - Lazar, Mitchell A. AU - Accili, Domenico T1 - Induction of α cell–restricted Gc in dedifferentiating β cells contributes to stress-induced β cell dysfunction PY - 2019/07/11/ AB - Diabetic β cell failure is associated with β 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 β 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 β cells. Notable among them was the α cell signature gene Gc, encoding a vitamin D–binding protein. Although diabetes was associated with Gc induction, Gc-deficient islets did not induce β 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 β cell dysfunction and indicate that multiparity-induced diabetes is associated with altered β cell fate. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.128351 VL - 4 IS - 13 UR - https://doi.org/10.1172/jci.insight.128351 PB - The American Society for Clinical Investigation ER -