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. Author manuscript; available in PMC: 2015 Aug 1.
Published in final edited form as: Trends Endocrinol Metab. 2014 Apr 18;25(8):415–424. doi: 10.1016/j.tem.2014.03.008

Figure 1. Hypothetical unified model to reconcile rare and common SLC30A8 genetic data.

Figure 1

The best characterized pathway for GSIS is shown, though other pathways clearly contribute [100]. We speculate that the minor rs13266634 allele encoding the 325 Trp ZnT8 variant and rare mutations leading to haploinsufficiency are protective against T2D due by prolonging the transient increase in cytoplasmic zinc levels that occur during GSIS thereby reducing the deleterious effects of ROS. In Panel A we speculate that the minor rs13266634 allele encoding the 325 Trp ZnT8 variant enhances cytoplasmic zinc levels mainly through increased re-uptake of co-secreted Zn2+ at the plasma membrane. In Panel B we speculate that rare mutations leading to haploinsufficiency enhance cytoplasmic Zn2+ levels mainly through a reduced rate of uptake into ISGs and that SLC39 family members can compensate for the slight decrease in ZnT8 mediated uptake at the plasma membrane.