Functional analysis of ZnT8 in islet cells and its application to diabetes - Diabetes mellitus has been rapidly increasing and is approaching pandemic levels worldwide. Pancreatic b-cell function and mass are found to be reduced in the clinical onset of type 1 and 2 diabetes causing deterioration of glycemic control. In type 1 diabetes (T1D), the loss of b-cell function is more severe and mainly due to a T-cell mediated autoimmune destruction of b-cells in genetically predisposed individuals. In type 2 diabetes (T2D), the pathogenesis is complex, and in many cases, the reduction of b-cell function and mass is associated with different degrees of insulin resistance and b-cell stress. As such, there has been great interest in devising new therapeutic strategies to maintain or restore b-cell function, and to prevent b-cell loss for treating both forms of diabetes. Based on extensive human genetic and physiological data, ZnT8 protein (encoded by the SLC30A8 gene) has emerged as a therapeutic target for b-cell protection and diabetes prevention/treatment. ZnT8 mutants including loss of function mutant p.Arg138* and point mutant p.Trp325 have been found to be protective against diabetes, yet the underlying precise molecular mechanisms remain uncertain. To gain mechanistic insights and to understand the physiological roles of ZnT8 in islet biology and in diabetes, this project takes an integrated approach by combining diverse approaches including islet biology, protein biochemistry, differential metabolomics, chemical biology and high throughput screening. ZnT8 has been known as a zinc transporter responsible for importing Zn2+ into the dense core granules of islet endocrine cells. Our recent studies suggest that, besides Zn2+, ZnT8 may also transport small organic molecules into the dense core granules. The central aim of this proposal is to characterize this novel transporter activity of ZnT8 in islet b-cell; to identify endogenous substrates/metabolites of ZnT8; and to exploit this small organic molecule (SOM) transport activity to develop ZnT8 inhibitors for b-cell protection. If successful, we anticipate that concepts and approaches developed in this proposal will have important and far-reaching implications for studying islet cell biology, and uncovering new mechanisms for b-cell protection and functional enhancement.
