Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes
| Autor: | David J. Hodson, Adrien J.R. Molinas, Weiwei Xu, Jamie Morford, Ernesto Bernal-Mizrachi, Venkata N. Sure, Andrea Zsombok, Prasad V. G. Katakam, Guadalupe Navarro, Sangho Yu, Manuel Blandino-Rosano, Heike Münzberg, Camille Allard, Sierra M. Butcher, Franck Mauvais-Jarvis, David A. Jacobson, Rui Zhang, Nicholas H. F. Fine, Suhuan Liu |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
endocrine system medicine.medical_specialty medicine.medical_treatment Hypothalamus Androgen Excess Streptozocin Mice 03 medical and health sciences Insulin resistance Hyperinsulinism Insulin-Secreting Cells Internal medicine medicine Hyperinsulinemia Animals Humans Mice Knockout Neurons Chemistry Pancreatic islets Insulin Dihydrotestosterone General Medicine medicine.disease Streptozotocin Mitochondria Mice Inbred C57BL Androgen receptor Glucose 030104 developmental biology Endocrinology medicine.anatomical_structure Diabetes Mellitus Type 2 Diet Western Receptors Androgen Androgens Female Insulin Resistance Research Article medicine.drug |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.98607 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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