Androgen signaling expands β-cell mass in male rats and β-cell androgen receptor is degraded under high-glucose conditions

• Published in: American journal of physiology: endocrinology and metabolism Vol. 314; no. 3; pp. E274 - E286
• Main Authors: Harada, Naoki, Yoda, Yasuhiro, Yotsumoto, Yusuke, Masuda, Tatsuya, Takahashi, Yuji, Katsuki, Takahiro, Kai, Kenji, Shiraki, Nobuaki, Inui, Hiroshi, Yamaji, Ryoichi
• Format: Journal Article
• Language: English
• Published: United States 01.03.2018
• Subjects: Androgens - pharmacology; Animals; Cell Count; Cell Proliferation - drug effects; Cells, Cultured; Dose-Response Relationship, Drug; Glucose - pharmacology; Humans; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - physiology; Male; Mice; Mice, Inbred C57BL; Proteolysis - drug effects; Rats; Rats, Wistar; Receptors, Androgen - metabolism; Signal Transduction - drug effects; glucose intolerance; pancreatic β-cells; ubiquitin-proteasome; androgen receptor; testosterone; glucose metabolism
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00211.2017

A deficient pancreatic β-cell mass increases the risk of type 2 diabetes mellitus. Here, we investigated the effects of testosterone on the development of pancreatic β-cell mass in male rats. The β-cell mass of male rats castrated at 6 wk of age was reduced to ~30% of that of control rats at 16 wk of age, and castration caused glucose intolerance. Loss of β-cell mass occurred because of decreases in islet density per pancreas and β-cell cluster size. Castration was negatively associated with the number of Ki-67-positive β-cells and positively associated with the number of TUNEL-positive β-cells. These β-cell changes could be prevented by testosterone treatment. In contrast, castration did not affect β-cell mass in male mice. Androgen receptor (AR) localized differently in mouse and rat β-cells. Testosterone enhanced the viability of INS-1 and INS-1 #6, which expresses high levels of AR, in rat β-cell lines. siRNA-mediated AR knockdown or AR antagonism with hydroxyflutamide attenuated this enhancement. Moreover, testosterone did not stimulate INS-1 β-cell viability under high d-glucose conditions. In INS-1 β-cells, d-glucose dose dependently (5.5-22.2 mM) downregulated AR protein levels both in the presence and absence of testosterone. The intracellular calcium chelator (BAPTA-AM) could prevent this decrease in AR expression. AR levels were also reduced by a calcium ionophore (A23187), but not by insulin, in the absence of the proteasome inhibitor MG132. Our results indicate that testosterone regulates β-cell mass, at least in part, by AR activation in the β-cells of male rats and that the β-cell AR is degraded under hyperglycemic conditions.