Date/Time
Date(s) - 20/04/2022
1:30 pm - 2:30 pm

Title: INVESTIGATINGTHE ROLE OF ESTROGENS ON THE MOLECULAR MECHANISMS MODULATING PANCREATIC BETACELL HEALTH AND CARDIOMETABOLIC DISEASE 

Date:  Wednesday, April 20, 2022 

Time: 1:30-2:30 

Zoom:   contact fehert@mcmaster.ca 

Host: Geoff Werstuck

 Abstract: 

Sex-dependent differences in the prevalence of diabetes andcardiovascular diseases are well established. The objective of this project isto investigate the molecular mechanisms by which estrogen modulates chronicdisease progression. Our lab, and others, have previously implicatedendoplasmic reticulum (ER) stress in the development and progression ofdiabetes and cardiometabolic disease. We hypothesize that estrogens protectpancreatic beta cell health, and slow the progression of cardiometabolicdisease, by modulating the unfolded protein response (UPR) in response to ERstress. Two distinct mouse models were used in these studies. TheApoE-/-Ins2+/Akita mouse model of hyperglycemia-induced atherosclerosis, inwhich females are significantly protected from hyperglycemia andatherosclerosis relative to males, and the TALLYHO/JngJ mouse model, in whichfemales are protected from chronic hyperglycemia relative to males. We foundthat ovariectomy of female ApoE-/-Ins2+/Akita or TALLYHO/JngJ mice promotedchronic hyperglycemia. Supplementation with exogenous 17-beta estradiolsignificantly lowered blood glucose levels in ovariectomized ApoE-/-Ins2+/Akitamice and reduced atherosclerotic lesion development in both male andovariectomized female mice. Pancreatic islets from sham operatedApoE-/-Ins2+/Akita female mice showed a significant increase in the expressionof protective UPR factors and a decrease in pro-apoptotic factors, compared tomales or ovariectomized females.  To determine if alleviating ER stresscould moderate hyperglycemia, male and ovariectomized female TALLYHO/JngJ micewere treated with the chemical chaperone 4-phenylbutryic acid (4-PBA). Weshowed that 4-PBA treatment significantly lowered fasting blood glucose levels andimproved glucose tolerance. The results of this thesis suggest that estrogensplay a protective role in the maintenance of beta cell health and blood glucoseregulation by activating the adaptive UPR. This mechanism may explain theprotection observed in premenopausal women and may lead to the development oftargeted therapies to treat diabetes and cardiometabolic diseases.