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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(1):1-8. 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 ß-cells where insulin is matured, crystallized, and stored before secretion. Zinc is an essential co-factor for insulin crystallization forming dense cores in secretory granules. In insulin-containing secretory granules, zinc is mainly brought in by ZNT8 (SLC30A8), a zinc transporter predominantly expressed in pancreatic ß-cells in the body. A recent study in humans has revealed that haploinsufficiency of ZNT8 may reduce the risk of Type 2 Diabetes (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 from mice with diet-induced insulin resistance using immunohistochemistry and to understand the molecular mechanism underlying the protection from T2D by allelic deficiency of ZNT8. Our results showed that ZNT8 expression was upregulated in islets of both diabetic and insulin resistant conditions. shRNA knockdown of Znt8 expression to ~50% of the normal level (a condition which mimicked the allelic deficiency in humans) in MIN6 ß-cells stimulated activations of Akt, p70S6K and p38, key kinases involved in cell proliferation and survival. Consistent with these observations, we showed that Znt8KD MIN6 ß-cells had increased cell proliferation and were resistant to inflammation-induced cell death. Our results suggest that ZNT8 upregulation due to ß-cell compensation during insulin resistance could be harmful for ß-cell survival whereas down regulation could be beneficial, pointing to a potential target for T2D prevention and/or treatment. |
