The islet estrogen receptor-α is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes.
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.
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Gamze
G
Kilic
Department of Medicine, Division of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, United States of America.
Ana I
AI
Alvarez-Mercado
Montreal Diabetes Research Center, CRCHUM and Department of Medicine, University of Montréal, Montréal, QC, Canada.
Bader
B
Zarrouki
Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Darren
D
Opland
Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, United States of America.
Chong Wee
CW
Liew
Department of Medicine, Division of Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Laura C
LC
Alonso
Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
Martin G
MG
Myers
Pole of Endocrinology, Diabetes and Nutrition, Institute of Clinical and Experimental Research, Catholic University of Louvain, Brussels, Belgium.
Jean-Christophe
JC
Jonas
Montreal Diabetes Research Center, CRCHUM and Department of Medicine, University of Montréal, Montréal, QC, Canada.
Vincent
V
Poitout
Section of Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center and Harvard Medical School, Boston, Massachusetts, United States of America.
Rohit N
RN
Kulkarni
Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America ; Department of Medicine, Division of Endocrinology and Metabolism, Tulane University Health Sciences Center, School of Medicine, New Orleans, LA, United States of America.
Franck
F
Mauvais-Jarvis
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000517:prevention & control*; D047628:Estrogen Receptor alpha / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006943:Hyperglycemia / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D007328:Insulin / Q000172:deficiency*; D019426:Integrases / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D047628:Estrogen Receptor alpha; D004967:Estrogens; D007328:Insulin; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C045073:Cre recombinase; D019426:Integrases