Beta cell specific ZnT8 gene deficiency and resulting loss in zinc content significantly improve insulin secretion.

Autor: Piro A; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada., Luo Y; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada., Zhang Z; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Department of Endocrinology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China., Ye W; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada., Kang F; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada., Xie L; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada., Wang Y; Advanced Diagnostics, Toronto General Hospital Research Institute, Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada., Dai FF; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada., Gaisano HY; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada., Rocheleau JV; Advanced Diagnostics, Toronto General Hospital Research Institute, Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada., Prentice KJ; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada., Wheeler MB; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: michael.wheeler@utoronto.ca.
Jazyk: angličtina
Zdroj: Molecular and cellular endocrinology [Mol Cell Endocrinol] 2024 Dec 01; Vol. 594, pp. 112376. Date of Electronic Publication: 2024 Sep 23.
DOI: 10.1016/j.mce.2024.112376
Abstrakt: Zinc transporter 8 (ZnT8) is highly expressed in pancreatic beta cells, localizes to insulin secretory granules (ISG), and regulates zinc content. ZnT8 gene polymorphisms have revealed a relationship between ZnT8 activity and type 2 diabetes (T2D) risk, however, the role of beta-cell ZnT8 is not well understood. A beta cell specific ZnT8 knockout (ZnT8 BKO) mouse model was investigated. ZnT8 BKO islets showed significantly reduced ZnT8 gene expression and reduced zinc content. Compared to controls, ZnT8 BKO mice displayed significantly elevated plasma insulin levels and improved glucose tolerance following acute insulin resistance induced via S961. Glucose stimulated insulin secretion from isolated ZnT8 BKO pancreatic islets revealed enhanced insulin secretion capacity. The difference in insulin secretion between ZnT8 BKO and control islets was negated upon zinc supplementation, and the inhibitory effect of zinc on insulin secretion was confirmed in human islets. These results indicate that the loss of ZnT8 activity and accompanying reduced cellular zinc are associated with increased insulin secretion capacity. The reduction in secreted insulin content upon zinc supplementation in ZnT8 BKO islets suggests that ISG-released zinc normally tempers insulin secretion.
Competing Interests: Declaration of competing interest This study was funded by a Canadian Institutes of Health Research operating grant (PJT-180576) to MBW. AP was supported by the Banting and Best Diabetes Centre – University Health Network Graduate Award and Ontario Graduate Scholarship. These sources provided significant support for the project, however there are no conflicts of interest to declare.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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