Investigating the protective effects of estrogen on β-cell health and the progression of hyperglycemia-induced atherosclerosis

Sex differences in the prevalence and development of diabetes and associated cardiometabolic complications are well established. The objective of this study was to analyze the effects of estrogen on the maintenance of β-cell health/function and atherosclerosis progression, using a mouse model of hyperglycemia-induced atherosclerosis, the ApoE^-/-:Ins2^+/Akita mouse. ApoE^-/-:Ins2^+/Akita mice exhibit sexual dimorphism in the control of blood glucose levels. Male ApoE^-/-:Ins2^+/Akita mice are chronically hyperglycemic due to a significant reduction in pancreatic β-cell mass. Female mice are only transiently hyperglycemic, maintain β-cell mass, and blood glucose levels normalize at 35 ± 1 days of age. To determine the effects of estrogen on pancreatic β-cell health and function, ovariectomies and estrogen supplementation experiments were performed, and pancreatic health and atherosclerosis were assessed at various time points. Ovariectomized ApoE^-/-:Ins2^+/Akita mice developed chronic hyperglycemia with significantly reduced β-cell mass. To determine whether the observed effects on ovariectomized ApoE^-/-:Ins2^+/Akita mice were due to a lack of estrogens, slow-releasing estradiol pellets were inserted subcutaneously. Ovariectomized ApoE^-/-:Ins2^+/Akita mice treated with exogenous estradiol showed normalized blood glucose levels and maintained β-cell mass. Exogenous estradiol significantly reduced atherosclerosis in both ovariectomized female and male ApoE^-/-:Ins2^+/Akita mice relative to controls. Together, these findings suggest that estradiol confers significant protection to pancreatic β-cell health and can directly and indirectly slow the progression of atherosclerosis.NEW & NOTEWORTHY This study examines the effect(s) of estrogen on β cell and cardiometabolic health/function in a novel mouse model of hyperglycemia-induced atherosclerosis (ApoE^-/-:Ins2^+/Akita). Using a combination of estrogen deprivation (ovariectomy) and supplementation strategies, we quantify effects on glucose homeostasis and atherogenesis. Our results clearly show a protective role for estrogen on pancreatic β-cell health and function and glucose homeostasis. Furthermore, estrogen supplementation dramatically reduces atherosclerosis progression in both male and female mice.