Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka , Japan.
Department of Life Science and Technology, School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa , Japan.
Am J Physiol Endocrinol Metab. 2018 Mar 1;314(3):E274-E286. doi: 10.1152/ajpendo.00211.2017. Epub 2017 Nov 14.
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.
胰岛β细胞数量不足会增加 2 型糖尿病的风险。在这里，我们研究了睾酮对雄性大鼠胰岛β细胞数量发育的影响。6 周龄雄性大鼠去势后，其胰岛β细胞质量减少至 16 周龄时对照组的约 30%，且去势导致葡萄糖不耐受。β细胞质量的减少是由于胰岛密度和β细胞簇大小的降低所致。去势与 Ki-67 阳性β细胞的数量呈负相关，与 TUNEL 阳性β细胞的数量呈正相关。这些β细胞变化可以通过睾酮治疗来预防。相比之下，去势对雄性小鼠的β细胞质量没有影响。雄激素受体（AR）在小鼠和大鼠β细胞中的定位不同。睾酮增强了高表达 AR 的大鼠β细胞系 INS-1 和 INS-1 #6 的活力。siRNA 介导的 AR 敲低或 AR 拮抗剂羟基氟他胺减弱了这种增强作用。此外，睾酮在高葡萄糖条件下不会刺激 INS-1 β细胞活力。在 INS-1 β细胞中，d-葡萄糖浓度依赖性（5.5-22.2 mM）下调了 AR 蛋白水平，无论是否存在睾酮。细胞内钙螯合剂（BAPTA-AM）可以防止 AR 表达的这种下降。钙离子载体（A23187）也可以降低 AR 水平，但在没有蛋白酶体抑制剂 MG132 的情况下，胰岛素不能降低 AR 水平。我们的结果表明，睾酮通过 AR 激活调节雄性大鼠β细胞的β细胞质量，并且在高血糖条件下β细胞 AR 被降解。
