Title | The islet estrogen receptor-α is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Kilic G, Alvarez-Mercado AI, Zarrouki B, Opland D, Liew CWee, Alonso LC, Myers MG, Jonas J-C, Poitout V, Kulkarni RN, Mauvais-Jarvis F |
Journal | PLoS One |
Volume | 9 |
Issue | 2 |
Pagination | e87941 |
Date Published | 2014 |
ISSN | 1932-6203 |
Keywords | Animals, Blotting, Western, Brain, Diabetes Mellitus, Experimental, Estrogen Receptor alpha, Estrogens, Female, Hyperglycemia, Immunoenzyme Techniques, Insulin, Integrases, Islets of Langerhans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Oxidative Stress, Rats, Rats, Wistar, Real-Time Polymerase Chain Reaction, Receptors, G-Protein-Coupled, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger |
Abstract | 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. |
DOI | 10.1371/journal.pone.0087941 |
Alternate Journal | PLoS ONE |
PubMed ID | 24498408 |
PubMed Central ID | PMC3912162 |
Grant List | R01 DK095140 / DK / NIDDK NIH HHS / United States R00 DK090210 / DK / NIDDK NIH HHS / United States R01DK58096 / DK / NIDDK NIH HHS / United States R01 DK058096 / DK / NIDDK NIH HHS / United States R01DK095140 / DK / NIDDK NIH HHS / United States R01DK67536 / DK / NIDDK NIH HHS / United States MOP 77686 / / Canadian Institutes of Health Research / Canada R01DK074970 / DK / NIDDK NIH HHS / United States R01 DK067536 / DK / NIDDK NIH HHS / United States P30 DK020572 / DK / NIDDK NIH HHS / United States |