About our Research,
Our current studies on the G6PC, G6PC2, and G6PC3 genes are focused on the following questions:
1. G6PC, also known as G6Pase, catalyzes the terminal step in glycogenolysis and gluconeogenesis. These pathways are central to hepatic glucose production (HGP). We are interested in the transcriptional regulation of this gene since increased expression of G6PC contributes to the increased HGP characteristic of both type 1 and type 2 diabetes. Our studies mainly focus on the molecular mechanisms that mediate the regulation of G6Pase gene transcription by hormones, especially insulin, cAMP and glucocorticoids, and transcription factors, such as FOXO1 and PGC-1.
2. G6PC2, also known as IGRP, encodes an islet-specific glucose-6-phosphatase catalytic subunit-related protein. G6PC2 is a major autoantigen in both mouse and human type 1 diabetes. There are three goals for the on-going experiments in this project. The first is to elucide the molecular basis for the islet-specific expression of the G6PC2 gene. The experiments involve the use of both tissue culture cells and transgenic mice. The data suggest that the regulation of G6PC2 gene expression is determined, in part, by novel factors. As such, the identification of these novel factors will potentially aid other investigators who are attempting to understand the process whereby islet stem cells differentiate towards that of a beta cell lineage. The second goal of this project is to determine the biological function of G6PC2 through the analysis of G6pc2 knockout mice. Recent genome wide association studies showed that single nucleotide polymorphisms (SNPs) in the G6PC2 gene contribute to the variation in fasting blood glucose levels in humans and hence the risk of cardiovascular-associated mortality. The third goal of our G6PC2-related studies is to determine whether and, if so then how, SNPs in the gene lead to altered G6PC2 gene expression or G6PC2 activity.
3. G6PC3, also known as UGRP, encodes a ubiquitiously expressed glucose-6-phosphatase catalytic subunit-related protein. G6PC3 catalyzes the hydrolysis of glucose-6-phosphate but the role of this protein in vivo is unknown. Addressing that question is the focus of our G6PC3-related studies.
Our current studies on Zinc Transporter 8 are focused on the following questions:
1. The prevalence type 2 diabetes (T2D) continues to increase worldwide. Multiple SNPs associated with altered risk of T2D have been identified through genome wide association studies including rs13266634 in the SLC30A8 locus, which encodes zinc transporter 8 (ZnT8). In addition, rare mutations resulting in SLC30A8 haploinsufficiency are protective against T2D. Using several mouse models, we are investigating the role that ZnT8 plays in b cell function and the potential of ZnT8 as a therapeutic target for T2D.