Androgen Excess Produces Systemic Oxidative Stress and Predisposes to β-Cell Failure in Female Mice

Abstract

In women, excess production of the male hormone, testosterone (T), is accompanied by insulin resistance. However, hyperandrogenemia is also associated with β-cell dysfunction and type 2 diabetes raising the possibility that androgen receptor (AR) activation predisposes to β-cell failure. Here, we tested the hypothesis that excess AR activation produces systemic oxidative stress thereby contributing to β-cell failure. We used normal female mice (CF) and mice with androgen resistance by testicular feminization (Tfm). These mice were exposed to androgen excess and a β-cell stress induced by streptozotocin (STZ). We find that following exposure to T, or the selective AR-agonist dehydrotestosterone (DHT), CF mice challenged with STZ, which are normally protected, are prone to β-cell failure and insulin-deficient diabetes. Conversely, T-induced predisposition to β-cell failure is abolished in Tfm mice. We do not observe any proapoptotic effect of DHT alone or in the presence of H2O2 in cultured mouse and human islets. However, we observe that exposure of CF mice to T or DHT provokes systemic oxidative stress, which is eliminated in Tfm mice. This work has significance for hyperandrogenic women; excess activation of AR by testosterone may provoke systemic oxidative stress. In the presence of a prior β-cell stress, this may predispose to β-cell failure.

Insulin Directly Regulates Steroidogenesis via Induction of the Orphan Nuclear Receptor DAX-1 in Testicular Leydig Cells

“…In contrast, testosterone treatment improves insulin sensitivity by changing the body composition of subjects with hypogonadism due to T2D (6,7). However, excess androgen can increase oxidative stress and induce beta cell failure in rodent models (8). Furthermore, elevated leptin levels, presumably due to leptin resistance, inhibit basal and human chorionic gonadotropininduced testosterone secretion in rat testes and human obese males (9,10).…”

Is Xanthine oxidase activity in polycystic ovary syndrome associated with inflammatory and cardiovascular risk factors?

“…Increased ROS production and oxidative stress creates an inflammatory environment that impairs glucose uptake in muscle and adipose tissue, decreases the insulin secretion from pancreatic B cells, and contributes to hyperandrogenism (Costello et al, 2007). Several clinical features of PCOS, such as IR, obesity, and abdominal adiposity, may contribute to the development of oxidative stress, which may then worsen these metabolic conditions (Liu et al, 2010;Vincent and Taylor, 2005).…”

Pancreatic β-cell dysfunction in polycystic ovary syndrome: role of hyperglycemia-induced nuclear factor-κB activation and systemic inflammation

“…In humans, however, induction of hyperandrogenism in healthy individuals has no effect on ␤-cell function or viability (11). The ability of hyperandrogenism to contribute to pancreatic dysfunction in PCOS is most likely through the induction of oxidative stress and inflammation from MNC that may ultimately promote ␤-cell failure in susceptible individuals (33). Circulating androgens are positively associated with glucose-stimulated NF-B activation and TNF-␣ secretion from MNC along with plasma TBARS and hs-CRP, and negatively associated with glucose-stimulated IB protein content.…”