The islet estrogen receptor-α is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes

• Published in: PloS one 2014-02, Vol.9 (2), p.e87941-e87941
• Main Authors: Kilic, Gamze, Alvarez-Mercado, Ana I, Zarrouki, Bader, Opland, Darren, Liew, Chong Wee, Alonso, Laura C, Myers, Jr, Martin G, Jonas, Jean-Christophe, Poitout, Vincent, Kulkarni, Rohit N, Mauvais-Jarvis, Franck
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Alloxan; Animal tissues; Animals; Apoptosis; Arcuate nucleus; Biology; Blotting, Western; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain research; Cell survival; Cytokines; Destruction; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - etiology; Diabetes Mellitus, Experimental - prevention & control; Endocrinology; Estrogen Receptor alpha - physiology; Estrogen receptors; Estrogens; Estrogens - pharmacology; Exposure; Female; Gene expression; Glucose; Health sciences; Hyperglycemia; Hyperglycemia - physiopathology; Hypothalamus; Hypothalamus (ventromedial); Immunoenzyme Techniques; Immunoglobulins; Insulin; Insulin - deficiency; Integrases - metabolism; Internal medicine; Islets of Langerhans; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Liquid oxygen; Male; Medicine; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclei; Oxidative Stress; P system; Pancreas; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptor mechanisms; Receptors; Receptors, G-Protein-Coupled - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Rodents; Sex hormones
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0087941

The female steroid, 17β-estradiol (E2), is important for pancreatic β-cell function and acts via at least three estrogen receptors (ER), ERα, ERβ, and the G-protein coupled ER (GPER). Using a pancreas-specific ERα knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERαKO ⁻/⁻), we previously reported that islet ERα suppresses islet glucolipotoxicity and prevents β-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERα to prevent β-cell apoptosis in vivo. However, the contribution of the islet ERα to β-cell survival in vivo, without the contribution of ERα in other tissues is still unclear. Using the PERαKO ⁻/⁻ mouse, we show that ERα mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERα elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERαKO ⁻/⁻ mice exhibited a predisposition to β-cell destruction and insulin deficient diabetes. In male PERαKO ⁻/⁻ mice, exposure to E2 partially prevented alloxan-induced β-cell destruction and diabetes. ERα mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERα mRNA by hyperglycemia was retained in insulin receptor-deficient β-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERα expression acts to naturally protect β-cells against oxidative injury.