Testosterone Protects Against Glucotoxicity-Induced Apoptosis of Pancreatic β-Cells (INS-1) and Male Mouse Pancreatic Islets

Abstract

Male hypogonadism associates with type 2 diabetes, and T can protect pancreatic β-cells from glucotoxicity. However, the protective mechanism is still unclear. This study thus aims to examine the antiapoptotic mechanism of T in pancreatic β cells cultured in high-glucose medium. T (0.0005-2 μg/mL) was added to INS-1 cells cultured in basal glucose or high-glucose media. Then cellular apoptosis, oxidative stress, and cell viability were measured. Endoplasmic reticulum (ER) stress markers and sensors and the antiapoptotic protein (B-cell lymphoma 2) were investigated by real-time PCR and Western blot analysis. ER stress markers were also measured in male mouse pancreatic islet cultured in similar conditions. T (0.05 and 0.5 μg/mL) did not have any effect on apoptosis and viability of INS-1 cells cultured in basal glucose medium, but it could reduce apoptosis and increase viability of INS-1 cells cultured in high-glucose medium. The protective effect of T is diminished by androgen receptor inhibitor. T (0.05 μg/mL) could significantly reduce nitrotyrosine levels, mRNA, and protein levels of the ER stress markers and sensor those that were induced when INS-1 cells were cultured in high-glucose medium. It could also significantly increase the survival proteins, sarco/endoplasmic reticulum Ca(2+) ATPase-2, and B-cell lymphoma 2 in INS-1 cells cultured in the same conditions. Similarly, it could reduce ER stress markers and increase sarco/endoplasmic reticulum Ca(2+) ATPase protein levels in male mouse pancreatic islets cultured in high-glucose medium. T can protect against male pancreatic β-cell apoptosis from glucotoxicity via the reduction of both oxidative stress and ER stress.

Testosterone reduces AGTR1 expression to prevent β-cell and islet apoptosis from glucotoxicity

“…The results from our previous study indicated that testosterone conferred protection against high-glucoseinduced pancreatic b-cell apoptosis via decreased endoplasmic reticulum (ER) stress (Hanchang et al 2013). The results of this study indicated that testosterone protected against highglucose-induced pancreatic b-cell apoptosis via suppression of AGTR1 and its signaling pathway.…”

Sexual dimorphism of liver endoplasmic reticulum stress susceptibility in prepubertal rats and the effect of sex steroid supplementation

“…It has already been shown that INS‐1 cells cultured in high glucose medium present decreased viability and increased ER stress marker expression. Testosterone treatment reversed these effects, which were reduced by androgen receptor (AR) inhibitors, demonstrating a specific effect of testosterone on ER stress (Hanchang, Semprasert, Limjindaporn, Yenchitsomanus, & Kooptiwut, ). The only study to date that has evaluated the role of testosterone in hepatic ER stress also shows a protective effect of this hormone: testosterone reposition in orchiectomized rats reversed steatosis and decreased the phosphorylation of PERK, IRE1α and JNK (Jia et al., ).…”

Testosterone induces apoptosis in vascular smooth muscle cells via extrinsic apoptotic pathway with mitochondria-generated reactive oxygen species involvement

“…For example, testosterone reduces hyperglycemia-induced oxidative stress in pancreatic ␤-cells (25), decreases cardiac prooxidant state via androgen receptor-dependent mechanisms (18), and increases SOD activity in brain tissues (35). Of importance, testosterone-induced reduction of oxidative stress and endoplasmic reticulum stress in pancreatic ␤-cells occur only in high-glucose conditions; testosterone has no effects in low-normal glucose levels (25).…”