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Induction of α cell–restricted Gc in dedifferentiating β cells contributes to stress-induced β cell dysfunction
Taiyi Kuo, … , Mitchell A. Lazar, Domenico Accili
Taiyi Kuo, … , Mitchell A. Lazar, Domenico Accili
Published May 23, 2019
Citation Information: JCI Insight. 2019;4(13):e128351. https://doi.org/10.1172/jci.insight.128351.
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Research Article Endocrinology Metabolism

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

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Abstract

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.

Authors

Taiyi Kuo, Manashree Damle, Bryan J. González, Dieter Egli, Mitchell A. Lazar, Domenico Accili

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