U.S. flagAn official website of the United States government
                    Here's how you know **Official websites use .gov**
                            
                            A **.gov** website belongs to an official government organization in the United States.
 **Secure .gov websites use HTTPS**
                            
                            A **lock** (                            
                              A locked padlock                                                      
                            
                            ) or **https://** means you’ve safely connected to the .gov website. Share sensitive information only on official, secure websites.


Menu Agricultural Research Service
						
                    U.S. DEPARTMENT OF AGRICULTURE
 Davis, California
 close




            Search small
                    Search
            
            ARS Home
                                About ARS
                                Contact Us




ARS Home Pacific West Area Davis, California Research Publications at this Location





- ARS National Programs
- Search for a scientific manuscript
- Search for a research project
- ARS Software
- Programs and Projects
- Collaborations
- Subjects of Investigation
- Publications

Title:   Author  item
                                            Huang, Lipingitem
                                            Kirschke, Catherine
  Submitted to: Austin Journal of Endocrinology and Diabetes
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 2/23/2016
                                    Publication  Date: 3/16/2016
                                    Citation: Huang, L., Kirschke, C.P. 2016. Down-regulation of zinc transporter 8 (SLC30A8) in pancreatic beta-cells promotes cell survival. Austin Journal of Endocrinology and Diabetes. 3:1037.Interpretive Summary: The pancreatic islet contains high levels of zinc in granular vesicles of beta-cells where insulin is matured, crystallized, and stored before secretion. Zinc is an essential co-factor for insulin crystallization forming dense core in secretory granules. In insulin-containing secretory granules, zinc is mainly brought in by ZNT8 (SLC30A8), a zinc transporter predominantly expressed in pancreatic beta-cells in the body. A recent study in humans has revealed that haploinsufficiency of ZNT8 (only one functional ZNT8 allele instead of two) may reduce the risk of T2D. The mechanism by which ZNT8 haploinsufficiency protects individuals from T2D is not understood. The aim of this study was to investigate expression levels of ZNT8 in human normal and T2D pancreases and in pancreases isolated from mice with diet-induced insulin resistance using immunohistochemistry and to understand the molecular mechanism underlying the protection of T2D from allelic deficiency of ZNT8. Our results showed that ZNT8 expression was up-regulated in islets of both diabetic and insulin resistant conditions. shRNA knockdown Znt8 expression to ~50% of the normal level (a condition mimicked the allelic deficiency observed in humans) in MIN6 beta-cells stimulated activations of Akt, Bad, p70S6K and p38, the key kinases involved in cell proliferation and survival. Consistent with the activation of these key kinases, we observed that Znt8KD MIN6 beta-cells had reduced cell doubling time and were resistant to inflammation-induced cell death.  Our results suggest that ZNT8 over-expression due to beta-cell compensation during insulin resistance could be harmful whereas under-expression could be beneficial for beta-cell survival, pointing to a potential target for T2D prevention and/or treatment.
                                Technical Abstract: The pancreatic islet contains high levels of zinc in granular vesicles of beta-cells where insulin is matured, crystallized, and stored before secretion. Zinc is an essential co-factor for insulin crystallization forming dense core in secretory granules. In insulin-containing secretory granules, zinc is mainly brought in by ZNT8 (SLC30A8), a zinc transporter predominantly expressed in pancreatic beta-cells in the body. A recent study in humans has revealed that haploinsufficiency of ZNT8 may reduce the risk of T2D. The mechanism by which ZNT8 haploinsufficiency protects individuals from T2D is not understood. The aim of this study was to investigate expression levels of ZNT8 in human normal and T2D pancreases and in pancreases isolated from mice with diet-induced insulin resistance using immunohistochemistry and to understand the molecular mechanism underlying the protection of T2D from allelic deficiency of ZNT8. Our results showed that ZNT8 expression was up-regulated in islets of both diabetic and insulin resistant conditions. shRNA knockdown Znt8 expression to ~50% of the normal level (a condition mimicked the allelic deficiency observed in humans) in MIN6 beta-cells stimulated activations of Akt, Bad, p70S6K and p38, the key kinases involved in cell proliferation and survival. Consistent with the activation of these key kinases, we observed that Znt8KD MIN6 beta-cells had reduced cell doubling time and were resistant to inflammation-induced cell death.  Our results suggest that ZNT8 over-expression due to beta-cell compensation during insulin resistance could be harmful whereas under-expression could be beneficial for beta-cell survival, pointing to a potential target for T2D prevention and/or treatment.


Return to top


Connect with ARS Sign up


ARS Home
                            USDA.gov
                            Plain Writing
                            Policies & Links
                            Civil Rights Statements
                            FOIA
                            Accessibility Statement
                            Privacy Policy
                            Non-Discrimination Statement
                            Quality of Information
                            USA.gov
                            WhiteHouse.gov