Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes.
JCI Insight. 2018-06-21; 3(12):
DOI: 10.1172/jci.insight.98607
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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 β
cell failure, leading to hyperglycemia. These abnormalities are not observed in
mice lacking the androgen receptor (AR) in β 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 β cells. This study suggests that excess androgen
predisposes female mice to T2D following AR activation in neurons, producing
peripheral insulin resistance, and in pancreatic β cells, promoting insulin
hypersecretion, oxidative injury, and secondary β cell failure.