| Author |
Batchuluun, Battsetseg Hardy, Alexandre B. Zhu, Dan Gaisano, Herbert Pourasgari, Farzaneh Prentice, Kacey J. Wheeler, Michael B. Liu, Ying Ho, Louisa Bhattacharjee, Alpana Dai, Feihan F. Taylor, Kathryn M. Zhang, Ming |
| Description |
Author Affiliation: Liu Y ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.); Batchuluun B ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.); Ho L ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.); Zhu D ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.); Prentice KJ ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.); Bhattacharjee A ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.); Zhang M ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.); Pourasgari F ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.); Hardy AB ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.); Taylor KM ( the Breast Cancer Molecular Pharmacology Unit, School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VIIth Avenue, Cardiff CF10 3NB United Kingdom.); Gaisano H ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and.); Dai FF ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and f.dai@utoronto.ca.); Wheeler MB ( From the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and Michael.wheeler@utoronto.ca.) |
| Abstract |
Zinc plays an essential role in the regulation of pancreatic β cell function, affecting important processes including insulin biosynthesis, glucose-stimulated insulin secretion, and cell viability. Mutations in the zinc efflux transport protein ZnT8 have been linked with both type 1 and type 2 diabetes, further supporting an important role for zinc in glucose homeostasis. However, very little is known about how cytosolic zinc is controlled by zinc influx transporters (ZIPs). In this study, we examined the β cell and islet ZIP transcriptome and show consistent high expression of ZIP6 (Slc39a6) and ZIP7 (Slc39a7) genes across human and mouse islets and MIN6 β cells. Modulation of ZIP6 and ZIP7 expression significantly altered cytosolic zinc influx in pancreatic β cells, indicating an important role for ZIP6 and ZIP7 in regulating cellular zinc homeostasis. Functionally, this dysregulated cytosolic zinc homeostasis led to impaired insulin secretion. In parallel studies, we identified both ZIP6 and ZIP7 as potential interacting proteins with GLP-1R by a membrane yeast two-hybrid assay. Knock-down of ZIP6 but not ZIP7 in MIN6 β cells impaired the protective effects of GLP-1 on fatty acid-induced cell apoptosis, possibly via reduced activation of the p-ERK pathway. Therefore, our data suggest that ZIP6 and ZIP7 function as two important zinc influx transporters to regulate cytosolic zinc concentrations and insulin secretion in β cells. In particular, ZIP6 is also capable of directly interacting with GLP-1R to facilitate the protective effect of GLP-1 on β cell survival. |
