Development of Diabetic Cardiomyopathy in GLUT4 +/- Mice

Project: Research project

Project Details

Description

DESCRIPTION: (Scanned from the applicant's abstract) Mice with a single
knockout allele of GLUT4(+/-) on a low fat diet develop type II diabetes
including hyperinsulinemia, hyperglycemia, hyperleptinemia, mild hypertension,
cardiomyopathy and liver steatosis with age. These pathologies occur
independent of obesity, dyslipidemia, pancreatic failure and hepatic insulin
resistance. We propose to conduct the first in vivo longitudinal study which
examines critical molecular/metabolic/energetic alterations leading to diabetic
cardiomyopathy. This addresses the important interplay between whole body
metabolism and circulating factors that regulate cellular processes which
result in end organ pathology. The central hypothesis is global reduction of
GLUT4 expression and/or function leads to alterations in cardiac insulin
action, glucose metabolism and energetics mediated by reductions in the
activity of PPARgamma and Akt/PKB which result in altered contractile function
and diabetic cardiomyopathy. Altered substrate use with increased reliance upon
fatty acid metabolism is associated with increased oxidative stress and
mitochondrial uncoupling that result in diminished energy reserves. Insulin
sensitizer treatment with BRL49653, a thiazolidinedione (TZD) that activates
PPARg, will improve whole body glucose homeostasis and cardiac function through
alterations in AktJPKB activity, substrate usage and expression of uncoupling
protein (UCP) and glucose transporter (GLUT) genes/proteins. These studies will
provide unique insight into molecular, metabolic, and morphologic alterations
in GLUT4+/- hearts as mice progress to diabetes that should facilitate
development of therapeutics to prevent and/or minimize diabetic cardiomyopathy
in humans.

To accomplish these goals we have four specific aims. Each aim will identify
alterations in insulin action through Akt/PKB, GLUT4- and GLUTx1 translocation,
substrate partitioning/trafficking, and GLUT and UCP2/3 gene/protein expression
in hearts of GLUT4+/- and control mice. Molecular and cellular analyses will be
correlated with morphologic and hemodynamic changes in heart and alterations in
whole body glucose homeostasis and circulating serum factors (e.g. leptin,
insulin, T3/T4, glucose, free fatty acids) as mice progress from normal (N/N)
to prediabetic (N/H) to overt diabetic (H/H) phenotypes. Effects of short term
treatment with the TZD BRL49653 (PPARg agonist) on these parameters will be
defined before significant alterations in body weight or adiposity can be
measured. The latter studies will determine the mechanism of action of TZDs in
the heart and may reveal novel therapeutic targets and applications.
StatusFinished
Effective start/end date4/1/973/31/07

Funding

  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute: $375,750.00
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute: $376,032.00
  • National Heart, Lung, and Blood Institute: $376,875.00

ASJC

  • Cardiology and Cardiovascular Medicine
  • Physiology
  • Endocrinology, Diabetes and Metabolism

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