Diabetes and the Glucose-6-Phosphatase Gene Family
My laboratory is interested in the glucose-6-phosphatase gene family. There are 3 members of this family designated G6PC, G6PC2 and G6PC3. These genes play a key role determining fasting blood glucose levels, a parameter that is correlated with the risk of cardiovascular-associated mortality. These genes also play important roles in the pathophysiology of type 1 and type 2 diabetes. Our current studies on these 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 G6Pase 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 then how SNPs in the gene lead to altered 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.
In previous years specific rotation projects have been designed to enable students to learn PCR, DNA cloning and tissue culture, techniques that are used in multiple laboratories at Vanderbilt. However, students that are already familiar with these techniques have the opportunity to learn about the use of gel retardation assays, transgenic mice and adenoviral technology to address questions relating to the regulation of gene transcription and the molecular biology of diabetes.