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

Abstract

Hypogonadism in men is associated with an increased incidence of type 2 diabetes. Supplementation with testosterone has been shown to protect pancreatic b-cell against apoptosis due to toxic substances including streptozotocin and high glucose. One of the pathological mechanisms of glucose-induced pancreatic b-cell apoptosis is the induction of the local rennin-angiotensin-aldosterone system (RAAS). The role of testosterone in regulation of the pancreatic RAAS is still unknown. This study aims to investigate the protective action of testosterone against glucotoxicity-induced pancreatic b-cell apoptosis via alteration of the pancreatic RAAS pathway. Rat insulinoma cell line (INS-1) cells or isolated male mouse islets were cultured in basal and high-glucose media in the presence or absence of testosterone, losartan, and angiotensin II (Ang II), then cell apoptosis, cleaved caspase 3 expression, oxidative stress, and expression of angiotensin II type 1 receptor (AGTR1) and p47 phox mRNA and protein were measured. Testosterone and losartan showed similar effects in reducing pancreatic b-cell apoptosis. Testosterone significantly reduced expression of AGTR1 protein in INS-1 cells cultured in high-glucose medium or high-glucose medium with Ang II. Testosterone decreased the expression of AGTR1 and p47 phox mRNA and protein in comparison with levels in cells cultured in high-glucose medium alone. Furthermore, testosterone attenuated superoxide production when co-cultured with high-glucose medium. In contrast, when cultured in basal glucose, supplementation of testosterone did not have any effect on cell apoptosis, oxidative stress, and expression of AGT1R and p47 phox .In addition, high-glucose medium did not increase cleaved caspase 3 in AGTR1 knockdown experiments. Thus, our results indicated that testosterone prevents pancreatic b-cell apoptosis due to glucotoxicity through reduction of the expression of ATGR1 and its signaling pathway.

Inter-organ communication and regulation of beta cell function

“…The main gonadal sex steroids testosterone (58, 59)and oestrogen (60) have been reported to protect pancreatic beta cells from damaging insults such as glucotoxicity or streptozotocin-induced oxidative stress. In humans, oestrogen replacement in menopausal women reduces the incidence of diabetes mellitus.…”

Post-Transcriptional Control of Angiotensin II Type 1 Receptor Regulates Osteosarcoma Cell Death

“…Cellular apoptosis is regulated by certain proteins, which are apoptosis activating proteins, e.g. Bid, Bak, Bad, and angiotensin II type 1 receptor (AGTR1) [14, 15]. …”

Androgen derivatives affect immunopresence but not activity of antioxidant enzymes in pancreatic islets during diabetogen-induced apoptosis

“…Our group has been shown that testosterone is a potent cytoprotector of beta-cells in the male but not in the female (Palomar-Morales et al, 2010), and we assume that the ameliorative effect of androgens is mediated by a change in the scavenging enzymes activity; however, since beta-cells are very susceptible to oxidative changes due a low antioxidant capacity and reduced expression of these enzymes (Hotta et al, 1998;Kajimoto and Kaneto, 2004), the experimental approach was to obtain isolated islets, and measure the enzymatic activity in vitro conditions. A time of 6 hours was chosen since in previous reports (Morimoto et al, 2005;Palomar-Morales et al, 2010;Kooptiwut et al, 2015), at this time the highest effect of both STZ and androgens was found. However, it is possible that, in order to show appreciable effects in enzymatic activity of antioxidant enzymes, the time frame should be longer.…”

“…Recently, it has been shown that testosterone protects against glucose-induced apoptosis in isolated mouse β-cells. The effect of testosterone appears to be mediated by amelioration of oxidative stress for a decrease in the activity of NADH-oxidase (Kooptiwut et al, 2015). Testosterone protects INS-1 cells for glucose-induced apoptosis, via the reduction of both oxidative stress and ER stress (Hangchang et al, 2013).…”