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Androgen excess predisposes women to type 2 diabetes (T2D), but the mechanism of this is poorly understood. We report that female mice fed a Western diet and exposed to chronic androgen excess using dihydrotestosterone (DHT) exhibit hyperinsulinemia and insulin resistance associated with secondary pancreatic beta cell failure, leading to hyperglycemia. These abnormalities are not observed in mice lacking the androgen receptor (AR) in beta cells and partially in neurons of the mediobasal hypothalamus (MBH) as well as in mice lacking AR selectively in neurons. Accordingly, i.c.v. infusion of DHT produces hyperinsulinemia and insulin resistance in female WT mice. We observe that acute DHT produces insulin hypersecretion in response to glucose in cultured female mouse and human pancreatic islets in an AR-dependent manner via a cAMP- and mTOR-dependent pathway. Acute DHT exposure increases mitochondrial respiration and oxygen consumption in female cultured islets. As a result, chronic DHT exposure in vivo promotes islet oxidative damage and susceptibility to additional stress induced by streptozotocin via AR in beta cells. This study suggests that excess androgen predisposes female mice to T2D following AR activation in neurons, producing peripheral insulin resistance, and in pancreatic beta cells, promoting insulin hypersecretion, oxidative injury, and secondary beta cell failure.

Original publication

DOI

10.1172/jci.insight.98607

Type

Journal article

Journal

JCI Insight

Publication Date

2018

Volume

3

Keywords

Androgens/*metabolism Animals Diabetes Mellitus, Type 2/*metabolism Diet, Western Dihydrotestosterone/metabolism Female Glucose/metabolism Humans Hyperinsulinism Hypothalamus Insulin Resistance Insulin-Secreting Cells/drug effects/*metabolism Mice Mice, Inbred C57BL Mice, Knockout Mitochondria/drug effects/metabolism Neurons/*metabolism Receptors, Androgen/drug effects/genetics/metabolism Streptozocin/pharmacology *Beta cells *Diabetes *Endocrinology *Metabolism *Sex hormones