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Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes.

ABSTRACT: 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.

SUBMITTER: Navarro G

PROVIDER: S-EPMC6124401 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes.

Navarro Guadalupe G Allard Camille C Morford Jamie J JJ Xu Weiwei W Liu Suhuan S Molinas Adrien Jr AJ Butcher Sierra M SM Fine Nicholas Hf NH Blandino-Rosano Manuel M Sure Venkata N VN Yu Sangho S Zhang Rui R Münzberg Heike H Jacobson David A DA Katakam Prasad V PV Hodson David J DJ Bernal-Mizrachi Ernesto E Zsombok Andrea A Mauvais-Jarvis Franck F

JCI insight 20180621 12

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 ( ...[more]

PMID: 29925687

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Project description:Aims/Hypothesis: Galectin 3 appears to play a proinflammatory role in several inflammatory and autoimmune diseases. Also, there is evidence that galectin 3 plays a role in both type-1 and type-2 diabetes. During obesity, hematopoietic cell-derived galectin 3 induces insulin resistance. While the role of galectin 3 expressed in islet-invading immune cells in both type-1 and type-2 diabetes has been studied, the importance of the expression of this molecule on the target pancreatic β cells has not been defined. Methods: To clarify the role of galectin 3 expression in β cells during obesity-induced diabetogenesis, we developed transgenic mice selectively overexpressing galectin 3 in β cells and tested their susceptibility to obesity-induced type-2 diabetes. Obesity was induced with a 16-week high-fat diet regime. Pancreatic β cells were tested for susceptibility to apoptosis induced by non-esterified fatty acids and cytokines as well as parameters of oxidative stress. Results: Our results demonstrated that overexpression of galectin 3 increases β-cell apoptosis in HFD conditions and increases the percentage of proinflammatory F4/80+ macrophages in islets that express galectin 3 and TLR4. In isolated islets, we have shown that galectin 3 overexpression increases cytokine and palmitate-triggered β-cell apoptosis and also increases NO2--induced oxidative stress of β cells. Also, in pancreatic lymph nodes, macrophages were shifted toward a proinflammatory TNF-α-producing phenotype. Conclusions/Interpretation: By complementary in vivo and in vitro approaches, we have shown that galectin 3-overexpression facilitates β-cell damage, enhances cytokine and palmitate-triggered β-cell apoptosis, and increases NO2--induced oxidative stress in β cells. Further, the results suggest that increased expression of galectin 3 in the pancreatic β cells affects the metabolism of glucose and glycoregulation in mice on a high-fat diet, affecting both fasting glycemic values and glycemia after glucose loading.

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Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes.

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Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes.

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