Acute cytokine-mediated downregulation of the zinc transporter ZnT8 alters pancreatic β-cell function

Malek El Muayed; Liana K Billings; Meera R Raja; Xiaomin Zhang; Paul J Park; Marsha V Newman; Dixon B Kaufman; Thomas V O'Halloran; William L Lowe

doi:10.1677/JOE-09-0420

Made available online as an Accepted Preprint 27 May 2010
Accepted Preprint first posted online on 27 May 2010

Acute cytokine-mediated downregulation of the zinc transporter ZnT8 alters pancreatic β-cell function

Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Tarry 15-755, Chicago, Illinois 60611, USA
¹Massachusetts General Hospital, Harvard University, 55 Fruit Street, Boston, Massachusetts 02114, USA
²The Chemistry of Life Processes Institute and Department of Chemistry, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208-3113, USA
³Division of Transplant Surgery, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, Illinois 60611, USA
⁴Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, USA

(Correspondence should be addressed to M El Muayed; Email: m-muayed{at}northwestern.edu)

Abstract

Genetic studies suggest that Zn transporters such as ZnT8 play a role in insulin secretion by pancreatic β-cells; however, little is known about the dynamic roles of Zn trafficking pathways on β-cell physiology. To test the acute effects of the inflammatory cytokines interleukin 1β (IL1β) and tumor necrosis factor α (TNFα) on Zn homeostasis, the mRNA expression profile of Zn transporters of the ZnT and ZIP families was examined. Exposure of MIN6 cells or primary murine islets to IL1β or TNFα altered the mRNA expression profile of Zn transporters; most notable was decreased ZnT8 mRNA levels. siRNA-mediated gene knockdown was used to examine the effects of decreased ZnT8 expression in primary dispersed murine islet cells from C57/BL6 mice and MIN6 cells. ZnT8 knockdown in these murine islets led to reduced glucose stimulated insulin secretion without altering the total cellular insulin content or cell viability at normal or supraphysiological Zn concentrations. The labile Zn content determined by flow cytometry after loading with the Zn-specific sensor FluoZin-3 AM was decreased in MIN6 cells following ZnT8 knockdown or IL1β treatment. These results suggest that an acute decrease in ZnT8 levels impairs β-cell function and Zn homeostasis, and may contribute to inflammatory cytokine-induced alterations in β-cell function.