title: 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 β-cell against apoptosis due to toxic substances including streptozotocin and high glucose. One of the pathological mechanisms of glucose-induced pancreatic β-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 β-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 β-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 β-cell apoptosis due to glucotoxicity through reduction of the expression of ATGR1 and its signaling pathway.
authors.affiliation: Department of PhysiologyDepartment of AnatomyDivision of Molecular MedicineDepartment of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand suwattanee.koo@mahidol.ac.th.
authors.forename: Suwattanee
authors.initials: S
authors.lastname: Kooptiwut
authors.affiliation: Department of PhysiologyDepartment of AnatomyDivision of Molecular MedicineDepartment of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Wanthanee
authors.initials: W
authors.lastname: Hanchang
authors.affiliation: Department of PhysiologyDepartment of AnatomyDivision of Molecular MedicineDepartment of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Namoiy
authors.initials: N
authors.lastname: Semprasert
authors.affiliation: Department of PhysiologyDepartment of AnatomyDivision of Molecular MedicineDepartment of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Mutita
authors.initials: M
authors.lastname: Junking
authors.affiliation: Department of PhysiologyDepartment of AnatomyDivision of Molecular MedicineDepartment of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Thawornchai
authors.initials: T
authors.lastname: Limjindaporn
authors.affiliation: Department of PhysiologyDepartment of AnatomyDivision of Molecular MedicineDepartment of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
authors.forename: Pa-thai
authors.initials: PT
authors.lastname: Yenchitsomanus
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000633:toxicity*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology*
chemical_list: C544066:Agtr1a protein, mouse; D044140:Receptor, Angiotensin, Type 1; D013739:Testosterone; D005947:Glucose
keywords: angiotensin II type 1 receptor (AGTR1); apoptosis; glucotoxicity; pancreatic β-cell; signaling pathway; testosterone