Investigating the Role of Estrogens on the Molecular Mechanisms Modulating Pancreatic Beta Cell Health and Cardiometabolic Disease

Abstract

Sex-dependent differences in the prevalence of diabetes and cardiovascular diseases are well established. The objective of this project is to investigate the molecular mechanisms by which estrogen modulates chronic disease progression. Our lab, and others, have previously implicated endoplasmic reticulum (ER) stress in the development and progression of diabetes and cardiometabolic disease. We hypothesize that estrogens protect pancreatic beta cell health, and slow the progression of cardiometabolic disease, by modulating the unfolded protein response (UPR) in response to ER stress. Two distinct mouse models were used in these studies. The ApoE-/-Ins2+/Akita mouse model of hyperglycemia-induced atherosclerosis, in which females are significantly protected from hyperglycemia and atherosclerosis relative to males, and the TALLYHO/JngJ mouse model, in which females are protected from chronic hyperglycemia relative to males. We found that ovariectomy of female ApoE-/-Ins2+/Akita or TALLYHO/JngJ mice promoted chronic hyperglycemia. Supplementation with exogenous 17-beta estradiol significantly lowered blood glucose levels in ovariectomized ApoE-/-Ins2+/Akita mice and reduced atherosclerotic lesion development in both male and ovariectomized female mice. Pancreatic islets from sham operated ApoE-/-Ins2+/Akita female mice showed a significant increase in the expression of protective UPR factors and a decrease in pro-apoptotic factors, compared to males or ovariectomized females. To determine if alleviating ER stress could moderate hyperglycemia, male and ovariectomized female TALLYHO/JngJ mice were treated with the chemical chaperone 4-phenylbutryic acid (4-PBA). We showed that 4-PBA treatment significantly lowered fasting blood glucose levels and improved glucose tolerance. The results of this thesis suggest that estrogens play a protective role in the maintenance of beta cell health and blood glucose regulation by activating the adaptive UPR. This mechanism may explain the protection observed in premenopausal women and may lead to the development of targeted therapies to treat diabetes and cardiometabolic diseases.