Zinc levels in pancreatic islets are amongst the highest in the body and reduction in its levels in the pancreas has been associated with diabetes. The link between zinc, diabetes and islet dysfunction has recently been reiterated by genome-wide association studies that identified an islet cell membrane zinc transporter, SLC30A8 (ZnT8), as one of the risk loci for type 2 diabetes. Here we begin to elucidate the molecular mechanisms linking ZnT8 and type 2 diabetes by characterizing global and beta cell specific ZnT8 knockout mice. Our results associate absence of ZnT8 with a reduction in zinc sequestration into insulin vesicles, abnormal insulin granule morphology, down regulation of insulin processing enzymes, abnormal insulin secretion, elevated plasma proinsulin levels and diet-induced obesity and insulin resistance. Furthermore, we observed differential zinc uptake properties by two human ZnT8 variants. We report here that the W325 variant of ZnT8 is more efficient in mediating zinc transport than the at risk variant, R325. Cumulatively, these results suggest that ZnT8 is crucially important for zinc transport and zinc-insulin crystallization in insulin granules of the pancreatic beta cell.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/26261 |
| Date | 17 February 2011 |
| Creators | Wijesekara, Nadeeja |
| Contributors | Wheeler, Michael |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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