Androgen excess produces systemic oxidative stress and predisposes to beta-cell failure in female mice - PubMed (original) (raw)

Androgen excess produces systemic oxidative stress and predisposes to beta-cell failure in female mice

Suhuan Liu et al. PLoS One. 2010.

Abstract

In women, excess production of the male hormone, testosterone (T), is accompanied by insulin resistance. However, hyperandrogenemia is also associated with beta-cell dysfunction and type 2 diabetes raising the possibility that androgen receptor (AR) activation predisposes to beta-cell failure. Here, we tested the hypothesis that excess AR activation produces systemic oxidative stress thereby contributing to beta-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 beta-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 beta-cell failure and insulin-deficient diabetes. Conversely, T-induced predisposition to beta-cell failure is abolished in Tfm mice. We do not observe any proapoptotic effect of DHT alone or in the presence of H(2)O(2) 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 beta-cell stress, this may predispose to beta-cell failure.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Excess AR activation exacerbates STZ-induced diabetes in mice.

(A) Cumulative incidence of diabetes (random-fed blood glucose >250 mg/dl) in CF and Tfm treated with V or T (n = 10−15) after STZ challenges (150 mg/kg). (B) Random-fed blood glucose in V or T treated mice was measured after STZ injection (day 8). (C) The ratio of random-fed insulin (pg/ml)/glucose (mg/dl) in vehicle or T treated mice at day 8 was used as an index of insulin deficiency. (D) Cumulative incidence of diabetes in CF and CF treated with DHT mice (n = 10−15) after STZ challenges (150 mg/kg). (E) Random-fed blood glucose was measured after STZ injection (day 8) in V- or DHT-treated mice. (F) The ratio of random-fed insulin (pg/ml)/glucose (mg/dl) at day 8 in V- or DHT-treated mice. Values represent the mean ± SE. * P<0.05. V = vehicle.

Figure 2. Excess AR activation exacerbated STZ-induced β-cell loss in mice.

(A) β-cell number per section from CF and Tfm treated with V or T. (B) Pancreatic insulin concentration in mice from (A). (C) β-cell number in CF treated with V or DHT-treated mice. (D) Pancreas insulin content in mice from (C). Values represent the mean ± SE. * P<0.05, #P = 0.08. V = vehicle.

Figure 3. Excess AR activation in islets does not provoke inflammation or apoptosis.

(A) AR expression in pancreatic islets was measured by western blotting. (B) Relative gene expression of proinflammatory cytokines (PIC) in the islets. (C) Caspase 3/7 activity was measured in female mouse islets by luminescence following DHT dose-response treatment at the indicated concentrations. (D) Caspase 3/7 activity was measured in female mouse islets by luminescence following exposure to H2O2 (100 µM) and DHT dose-response treatment at the indicated concentrations. (E) Caspase 3/7 activity was measured in human islets as indicated in (C). (F) Caspase 3/7 activity was measured in human islets as indicated in (D). Values represent the mean ±SE. * P<0.05, **P<0.01, ***P<0.001 each condition vs. vehicle only treatment.

Figure 4. Excess AR activation provokes systemic oxidative stress.

(A) Plasma TBARS concentrations were measured in CF and Tfm mice treated with V or T. (B) TBARS level in CF treated with V or DHT mice. Values represent the mean ± SE. * P<0.05.

Figure 5. Testosterone does not affect the expression of NOX subunits in WAT.

Gene expression of gp91phox and NOX4 in perigonadal fat pads from CF treated with V or T. Values represent the mean ± SE. * P<0.05.

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Androgen excess produces systemic oxidative stress and predisposes to beta-cell failure in female mice - PubMed (original) (raw)