Effects Of Chronic Androgens Exposure On GSIS Function Of Rat Pancreatic β-cells

Polycystic ovary syndrome(PCOS) is a heterogeneous reproductive and metabolic disorder characterized by anovulation, hyperandrogenism and polycystic ovaries. Although up to 70% PCOS patients have insulin resistance, only about 10% develope type 2 diabetes. Whereas the mechanisms involved in remains unclear, it has been suggested that pancreatic β-cell dysfunction may play an important role. In addition, it has also been suggested that pancreatic β-cell dysfunction is closely related to the hyperandrogenism in PCOS. So far, the alteration of pancreatic β-cell function remains unclear. Based on previous studies, our study constructed PCOS rat model via chronic DHT exposure in baby female rats, which has been proved to have both metabolic and reproduction disturbances. Using this PCOS rat model, for the first time, our data show that GSIS function of PCOS rat islets is significantly impaired compared to controls, evidenced by decreased first-phase and second-phase insulin secretion under high glucose conditions; notably impaired mitochondrial function, evidenced by decreased ATP content, oxygen consumption rate under high glucose conditions; impaired mitochondrial biogenesis, evidenced by diminished mitochondrial number and decreased expression of genes involved in mitochondrial biogenesis. These data indicate that chronic androgen exposure may play an important role in pancreatic β-cell dysfunction.Hyperandrogenism, the most evident feature of PCOS, is closely related to higher insulin level in PCOS, meanwhile, a sum of studies have proved the tight relationship between hyperandrogenism and insulin resistance. More interesting, some studies have proved the tight correlation between hyperandrogenism and pancreatic β-cell dysfunction, suggesting that androgens may have direct effect on pancreatic β-cell function bypass insulin resistance, whereas, up to now, there is still no direct evidence to support that hypothesis. In our further study, we choose primary islets from normal female rats to continue our study in vitro. We found that androgens exposure could not impair the biogenesis of insulin, whereas could exert negative effect on β-cell GSIS function in a dose-dependent manner, evidenced by decreased insulin secretion under high glucose conditions. Whereas after the downregulation of androgen receptor by RNAi or androgen antagonism flutamide pretreatment, the negative effect of androgens on β-cell GSIS function was significantly reversed. Meanwhile, androgen exposure on β-cells resulted in significant mitochondrial dysfunction similar to that observed in PCOS islets, evidenced by decreased ATP content, oxygen consumption rate, impaired mitochondrial biogenesis, and decreased expression of genes involved in mitochondrial biogenesis, which indicating that increased androgen in PCOS may be the major pathogenetic factor involved in GSIS dysfunction of POCS islets.In summary, we conclude that mitochondrial dysfunction caused by androgens may partly contribute to defective GSIS function observed in PCOS rat islets.