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.
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- Vanderbilt Diabetes Research and Training Center
Faculty Member
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