Project: Research project

Project Details


The major insulin-responsive tissue primarily responsible for the
maintenance of normal glucose homeostasis is skeletal muscle. This
tissue expresses a specific glucose transporter isoform termed GLUT4
which is substantially decreased in insulin-deficient diabetes. Further,
several studies have documented that marked insulin resistance is
associated with several forms of diabetes and may be the initiating event
in the development of NIDDM. In addition, diabetic patients have an
increased risk of coronary morbidity associated with acute myocardial
infarction. Patient studies have suggested that the decrease in glucose
uptake in the diabetic heart may be a key feature for lack of tissue
viability during ischemic episodes. Since cardiac muscle GLUT4 mRNA and
protein levels are also decreased in diabetes, the inability to increase
glucose uptake during ischemia may be directly related to the decreased
expression of GLUT4 mRNA.

Based upon the central role of muscle GLUT4 expression in the
pathophysiology associated with diabetes, we have proposed a series of
studies to address the muscle-specific and hormonal/metabolic-dependent
regulation of this gene. The basic molecular events involved in glucose
transporter gene regulation are clearly central issues which are
important for both our understanding of muscle-specific gene regulation
as well as in the control of glucose homeostasis, metabolism and energy
production. To accomplish these goals we plan to examine the
hormonal/metabolic regulation of muscle GLUT4 transcription and to
identify the cis-DNA elements responsible for the control of GLUT4
expression. In addition, we propose to identify and characterize
muscle-specific DNA binding factors which mediate the normal
physiological regulation of this gene.

In these studies we will use nuclear run-on analysis to determine the
transcription rate of the endogenous GLUT4 gene. Transient transfection
assays of reporter constructs using direct injection of DNA into
hindquarter muscle will be used to identify cis-DNA elements responsible
for the tissue-specific and hormonal/metabolic dependent regulation of
GLUT4 expression. In a complimentary approach, several reporter
constructs will be integrated into transgenic mice and assayed for the
normal program of GLUT4 expression. In this manner, we hope to develop
an understanding of the complex regulation of muscle GLUT4 expression and
a molecular basis for peripheral tissue resistance to insulin action in
Effective start/end date9/30/929/29/95


  • Genetics


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