Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells
Diabetes mellitus is clinically defined by chronic hyperglycemia. Sex differences in the presentation and outcome of diabetes exist with premenopausal women having a reduced risk of developing diabetes, relative to men, or women after menopause. Accumulating evidence shows a protective role of estro...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/3/1816 |
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| author | Monica De Paoli Deep Shah Alexander Zakharia Zil Patel Zinal Patel Pakhi Pakhi Geoff H. Werstuck |
| author_facet | Monica De Paoli Deep Shah Alexander Zakharia Zil Patel Zinal Patel Pakhi Pakhi Geoff H. Werstuck |
| author_sort | Monica De Paoli |
| collection | DOAJ |
| description | Diabetes mellitus is clinically defined by chronic hyperglycemia. Sex differences in the presentation and outcome of diabetes exist with premenopausal women having a reduced risk of developing diabetes, relative to men, or women after menopause. Accumulating evidence shows a protective role of estrogens, specifically 17-beta estradiol, in the maintenance of pancreatic beta cell health; however, the mechanisms underlying this protection are still unknown. To elucidate these potential mechanisms, we used a pancreatic beta cell line (BTC6) and a mouse model of hyperglycemia-induced atherosclerosis, the ApoE<sup>−/−</sup>:Ins2<sup>+/Akita</sup> mouse, exhibiting sexual dimorphism in glucose regulation. In this study we hypothesize that 17-beta estradiol protects pancreatic beta cells by modulating the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. We observed that ovariectomized female and male ApoE<sup>−/−</sup>:Ins2<sup>+/Akita</sup> mice show significantly increased expression of apoptotic UPR markers. Sham operated female and ovariectomized female ApoE<sup>−/−</sup>:Ins2<sup>+/Akita</sup> mice supplemented with exogenous 17-beta estradiol increased the expression of adaptive UPR markers compared to non-supplemented ovariectomized female ApoE<sup>−/−</sup>:Ins2<sup>+/Akita</sup> mice. These findings were consistent to what was observed in cultured BTC6 cells, suggesting that 17-beta estradiol may protect pancreatic beta cells by repressing the apoptotic UPR and enhancing the adaptive UPR activation in response to pancreatic ER stress. |
| first_indexed | 2024-03-08T03:54:42Z |
| format | Article |
| id | doaj.art-6d755400a0274267b0afe9757ee38821 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T03:54:42Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6d755400a0274267b0afe9757ee388212024-02-09T15:14:44ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-02-01253181610.3390/ijms25031816Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta CellsMonica De Paoli0Deep Shah1Alexander Zakharia2Zil Patel3Zinal Patel4Pakhi Pakhi5Geoff H. Werstuck6Department of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street W, Hamilton, ON L8S 4L8, CanadaDepartment of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street W, Hamilton, ON L8S 4L8, CanadaDepartment of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street W, Hamilton, ON L8S 4L8, CanadaDepartment of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street W, Hamilton, ON L8S 4L8, CanadaDepartment of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street W, Hamilton, ON L8S 4L8, CanadaDepartment of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street W, Hamilton, ON L8S 4L8, CanadaDepartment of Medicine, Faculty of Health Sciences, McMaster University, 1280 Main Street W, Hamilton, ON L8S 4L8, CanadaDiabetes mellitus is clinically defined by chronic hyperglycemia. Sex differences in the presentation and outcome of diabetes exist with premenopausal women having a reduced risk of developing diabetes, relative to men, or women after menopause. Accumulating evidence shows a protective role of estrogens, specifically 17-beta estradiol, in the maintenance of pancreatic beta cell health; however, the mechanisms underlying this protection are still unknown. To elucidate these potential mechanisms, we used a pancreatic beta cell line (BTC6) and a mouse model of hyperglycemia-induced atherosclerosis, the ApoE<sup>−/−</sup>:Ins2<sup>+/Akita</sup> mouse, exhibiting sexual dimorphism in glucose regulation. In this study we hypothesize that 17-beta estradiol protects pancreatic beta cells by modulating the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. We observed that ovariectomized female and male ApoE<sup>−/−</sup>:Ins2<sup>+/Akita</sup> mice show significantly increased expression of apoptotic UPR markers. Sham operated female and ovariectomized female ApoE<sup>−/−</sup>:Ins2<sup>+/Akita</sup> mice supplemented with exogenous 17-beta estradiol increased the expression of adaptive UPR markers compared to non-supplemented ovariectomized female ApoE<sup>−/−</sup>:Ins2<sup>+/Akita</sup> mice. These findings were consistent to what was observed in cultured BTC6 cells, suggesting that 17-beta estradiol may protect pancreatic beta cells by repressing the apoptotic UPR and enhancing the adaptive UPR activation in response to pancreatic ER stress.https://www.mdpi.com/1422-0067/25/3/1816diabetes17-beta estradiolendoplasmic reticulum stressunfolded protein responsepancreatic beta cells |
| spellingShingle | Monica De Paoli Deep Shah Alexander Zakharia Zil Patel Zinal Patel Pakhi Pakhi Geoff H. Werstuck Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells International Journal of Molecular Sciences diabetes 17-beta estradiol endoplasmic reticulum stress unfolded protein response pancreatic beta cells |
| title | Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells |
| title_full | Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells |
| title_fullStr | Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells |
| title_full_unstemmed | Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells |
| title_short | Investigating the Role of 17-Beta Estradiol in the Regulation of the Unfolded Protein Response (UPR) in Pancreatic Beta Cells |
| title_sort | investigating the role of 17 beta estradiol in the regulation of the unfolded protein response upr in pancreatic beta cells |
| topic | diabetes 17-beta estradiol endoplasmic reticulum stress unfolded protein response pancreatic beta cells |
| url | https://www.mdpi.com/1422-0067/25/3/1816 |
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