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

Abstract

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.

Role of androgens in energy metabolism affecting on body composition, metabolic syndrome, type 2 diabetes, cardiovascular disease, and longevity: lessons from a meta-analysis and rodent studies

“…Two separate short polyglutamine repeats, proximal to the C-terminus of the polymorphic polyglutamine tract, are also involved in AR transactivation [93]. AR-mediated androgen activities contribute to the development and functions of male reproductive tissues [94] such as the prostate, seminal vesicle, and epididymis, and also to the development of non-reproductive tissues such as the liver [95], adipocyte [96,97], muscle [98], kidney [99], heart [100], adrenal gland [101], and pancreatic β-cells [102,103]. The mechanisms underlying the links between testosterone and energy metabolism have been studied using rodent models of castration and AR knockout (AR-KO).…”

“…The amount of insulin secreted depends on β-cell mass and β-cell function (i.e., the ability of each β-cell to secrete insulin in response to glucose); reductions in either these variable can contribute to the development of T2DM [163][164][165][166]. Androgen signaling seems to serve different roles in β-cell function in a species-dependent manner [103,167]. β-Cell AR-KO male mice exhibited reduced insulin secretion, without a loss of β-cell mass, and HFD-dependent glucose intolerance [102].…”

“…In mice, the extranuclear AR stimulates glucagon-like peptide-1 signaling, leading to an enhancement of insulin secretion. In male rats, the AR is predominantly localized in the nucleus [103,168] and increases β-cell mass both by increasing β-cell growth and reducing β-cell death [103]. Ten weeks after castration, the β-cell mass was reduced to 30% of that observed in control rats and an excessive rise in glucose levels was observed 30 min after glucose injection [103].…”

“…In male rats, the AR is predominantly localized in the nucleus [103,168] and increases β-cell mass both by increasing β-cell growth and reducing β-cell death [103]. Ten weeks after castration, the β-cell mass was reduced to 30% of that observed in control rats and an excessive rise in glucose levels was observed 30 min after glucose injection [103]. This type of glucose intolerance reflects impairment of β-cell function [166], and castration has been shown to decrease insulin levels following a glucose load in male rats [162].…”

Serum Fetuin-A and Insulin Levels in Classic Congenital Adrenal Hyperplasia

“…Testosterone has also been shown to participate in the regulation of hepatic fetuin-A expression, through activation of the androgen receptor (AR) [6]. As AR expression has been described in organs such as the pancreas and liver [7], excess testosterone could result in insulin hypersecretion and increased fetuin-A levels.…”