Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 314, Issue 3, Pages E274-E286Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00211.2017
Keywords
androgen receptor; testosterone; pancreatic beta-cells; glucose intolerance; glucose metabolism; ubiquitin-proteasome
Categories
Funding
- Japan Society for the Promotion of Science [23780141, 25450176, 16K07743]
- Mishima Kaiun Memorial Foundation, Japan
- Grants-in-Aid for Scientific Research [25450176, 23780141, 16K07743] Funding Source: KAKEN
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A deficient pancreatic beta-cell mass increases the risk of type 2 diabetes mellitus. Here, we investigated the effects of testosterone on the development of pancreatic beta-cell mass in male rats. The beta-cell mass of male rats castrated at 6 wk of age was reduced to similar to 30% of that of control rats at 16 wk of age, and castration caused glucose intolerance. Loss of beta-cell mass occurred because of decreases in islet density per pancreas and beta-cell cluster size. Castration was negatively associated with the number of Ki-67-positive beta-cells and positively associated with the number of TUNEL-positive beta-cells. These beta-cell changes could be prevented by testosterone treatment. In contrast, castration did not affect beta-cell mass in male mice. Androgen receptor (AR) localized differently in mouse and rat beta-cells. Testosterone enhanced the viability of INS-1 and INS-1 #6, which expresses high levels of AR, in rat beta-cell lines. siRNA-mediated AR knockdown or AR antagonism with hydroxyflutamide attenuated this enhancement. Moreover, testosterone did not stimulate INS-1 beta-cell viability under high D-glucose conditions. In INS-1 beta-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 beta-cell mass, at least in part, by AR activation in the beta-cells of male rats and that the beta-cell AR is degraded under hyperglycemic conditions.
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