Characterization of islet genes implicated in human disease
Pound, Lynley Dayle
Recent genome wide association (GWA) studies have linked single nucleotide polymorphisms (SNPs) in the G6PC2 gene with elevated fasting plasma glucose (FPG) and in the SLC30A8 gene with altered susceptibility to type 2 diabetes. To demonstrate that changes in G6PC2 and SLC30A8 expression affect FPG and T2D risk, respectively, I characterized the effect of global deletion of G6pc2 and Slc30a8 in mice.G6PC2 is expressed in insulin producing ß-cells and encodes a glucose-6-phosphatase catalytic subunit. My studies demonstrated that G6pc2 is an inhibitory component of the ß-cell glucose sensor, acting in a futile cycle to oppose glucokinase and modulate the S0.5 of glucose-stimulated insulin secretion (GSIS). I also found that sequestration of calcium into the ER, an important event in GSIS, is impaired in the absence of G6pc2, indicating that G6pc2 plays dual roles in the regulation of GSIS. These observations are consistent with human GWA study data which revealed that SNPs within the G6PC2 gene are not only associated with variations in fasting glycemia but also a reduction in insulin secretion during glucose tolerance tests.The SLC30A8 gene is expressed in islets and encodes the zinc transporter ZnT-8. On a C57BL/6J x 129SvEV genetic background, I demonstrated that Slc30a8 KO mice have reduced fasting plasma insulin levels and islets isolated from these mice have impaired GSIS. Slc30a8 KO mice displayed no differences in fasting blood glucose levels or in glucose tolerance. On the pure C57BL/6J genetic background, however, female, but not male, Slc30a8 KO mice displayed reduced fasting plasma insulin levels with no change in fasting blood glucose or GSIS from isolated islets. These observations demonstrates that both 129SvEv-specific modifier genes and gender can modulate the impact of Slc30a8 deletion,. My data therefore suggest that, despite the marked reduction of zinc in Slc30a8 KO mouse islets, the absence of ZnT-8 does not have a substantial impact on normal mouse physiology. In contrast to my studies on G6pc2, my data on Slc30a8 do not provide strong support for the GWA study results suggesting a connection between this gene and T2D risk.