Journal
DIABETES
Volume 68, Issue 2, Pages 291-304Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db18-0638
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Funding
- National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-095118, R56-DK-118334-01]
- American Diabetes Association Career Development Award [1-15-CD-09]
- American Heart Association [BGIA-7880040]
- Texas A&M University Health Science Center
- Texas A&M AgriLife Research
- U.S. Department of Agriculture National Institute of Food and Agriculture grant [Hatch 1010958]
- 2015 American Diabetes Association Research Excellence Thomas R. Lee Award
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Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes (T2D) compared with age-matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating 17 beta-estradiol (E-2). Fasting hyperglycemia is a hallmark of T2D derived largely from dysregulation of hepatic glucose production (HGP), in which Foxo1 plays a central role in the regulation of gluconeogenesis. Here, we investigated the action of E-2 on glucose homeostasis in male and ovariectomized (OVX) female control and liver-specific Foxo1 knockout (L-F1KO) mice and sought to understand the mechanism by which E-2 regulates gluconeogenesis via an interaction with hepatic Foxo1. In both male and OVX female control mice, subcutaneous E-2 implant improved insulin sensitivity and suppressed gluconeogenesis; however, these effects of E-2 were abolished in L-F1KO mice of both sexes. In our use of mouse primary hepatocytes, E-2 suppressed HGP and gluconeogenesis in hepatocytes from control mice but failed in hepatocytes from L-F1KO mice, suggesting that Foxo1 is required for E-2 action on the suppression of gluconeogenesis. We further demonstrated that E-2 suppresses hepatic gluconeogenesis through activation of estrogen receptor (ER)alpha-phosphoinositide 3-kinase-Akt-Foxo1 signaling, which can be independent of insulin receptor substrates 1 and 2 (Irs1 and Irs2), revealing an important mechanism for E-2 in the regulation of glucose homeostasis. These results may help explain why premenopausal women have lower incidence of T2D than age-matched men and suggest that targeting ER alpha can be a potential approach to modulate glucose metabolism and prevent diabetes.
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