Exploring the Role of ZnT8 in Islet Beta Cell Function and Type 2 Diabetes

Abstract

Type 2 diabetes (T2D) is characterized by hyperglycemia, which arises due to insulin resistance and beta cell failure and/or decreased beta cell mass. Genome-wide association studies have shown that single nucleotide polymorphisms in the SLC30A8 locus confer altered risk of T2D. Additional human genetic data show that SLC30A8 haploinsufficiency is protective against T2D development. Zinc transporter 8 (ZnT8), encoded by SLC30A8, is predominantly expressed in islet beta cells and localizes to insulin secretory vesicles. Studies of Slc30a8 KO mouse models observed a consistent decrease in islet zinc content, but no clear role for ZnT8 in glucose-stimulated insulin secretion (GSIS). We hypothesized that (i) ZnT8 is critical for the regulation of GSIS in mice, but this only becomes apparent in the absence of another zinc transporter, ZnT7; and (ii) Slc30a8 haploinsufficiency has beneficial effects on glucose metabolism in mice as in humans. To address these hypotheses, we generated several mouse models. A double KO (DKO) mouse lacking both ZnT7 and ZnT8 was generated, and the data demonstrated that deletion of ZnT7 alone had complex effects on glucose and insulin levels in vivo but no effect on GSIS in isolated islets. In contrast, GSIS was abolished in DKO islets. We also examined the protective effect of Slc30a8 haploinsufficiency in the context of diet-induced obesity (DIO). The results demonstrated a protection against DIO and improved glucose tolerance in ZnT8 heterozygous and KO mice compared to WT mice. Additionally, we examined the expression of Slc30a8 in Guinea pig pancreatic tissue and discovered that Slc30a8 is a pseudogene in Guinea pigs. Together, these data demonstrate that ZnT8 is not essential for beta cell function. Overall, the results of these studies suggest that altered ZnT8 function may affect T2D susceptibility through actions in other tissues where it is expressed at low levels rather than through effects on pancreatic islet function.