The pathogenesis of cardiac dysfunction in diabetes is partially understood. Our goal is to determine the mechanisms by which reduced insulin signaling in cardiomyocytes and vascular endothelium contributes to the pathogenesis of diabetic cardiomyopathy. Our overall hypotheses are: (1) In diabetes, deficient or reduced insulin signaling in cardiomyocytes leads to an initial defect in glucose/pyruvate oxidation, and a secondary increase in fatty acid oxidation that leads to increased production of reactive oxygen species (ROS) that ultimately causes progressive mitochondrial injury. Increased fatty acid delivery to insulin resistant cardiomyocytes during diabetes will accelerate mitochondrial dysfunction. (2) In the heart the (acute and chronic) regulation of cardiac muscle substrate metabolism by insulin involves paracrine interactions between cardiomyocytes and other cells in the heart such as endothelial cells. Thus, impaired insulin signaling in these cells and in cardiomyocytes both contribute to altered cardiac metabolism and function. The consequences of these defects will be exaggerated when cardiac energy requirements are increased such as during left ventricular hypertrophy.
Aim 1 : will determine the mechanisms by which chronic deficiency of insulin signaling in cardiomyocytes impairs mitochondrial oxidative capacity and predisposes the heart to lipotoxic injury. Studies will be performed in mice with constitutive and inducible deletion of insulin signaling in cardiomyocytes. We will determine the mechanisms for changes in PDH activity, the mechanisms that lead to increased fatty acid utilization in these models and the role of increased ROS generation in precipitating mitochondrial dysfunction and lipotoxic cardiomyopathy.
Aim 2 : will determine the mechanisms by which non-myocyte cells in the heart modulate cardiomyocyte metabolism. We will determine if loss of insulin signaling in these compartments will accelerate or exacerbate the metabolic and functional impairment in hearts that lack insulin signaling in cardiomyocytes by studying hearts deprived of insulin signaling in endothelial cells and cardiomyocytes under basal conditions and following pressure overload hypertrophy. The role of nitric oxide in the paracrine regulation of myocardial metabolism by insulin will be determined. These studies will shed important insight into the regulation of cardiac function and metabolism by insulin and the role of impaired insulin signaling in the pathogenesis of diabetic cardiomyopathy. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL070070-02S1
Application #
7078065
Study Section
Metabolism Study Section (MET)
Program Officer
Varghese, Jamie
Project Start
2004-02-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
2
Fiscal Year
2005
Total Cost
$26,161
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Bugger, Heiko; Riehle, Christian; Jaishy, Bharat et al. (2012) Genetic loss of insulin receptors worsens cardiac efficiency in diabetes. J Mol Cell Cardiol 52:1019-26
Young, Christian D; Lewis, Andrew S; Rudolph, Michael C et al. (2011) Modulation of glucose transporter 1 (GLUT1) expression levels alters mouse mammary tumor cell growth in vitro and in vivo. PLoS One 6:e23205
Symons, J David; Hu, Ping; Yang, Ying et al. (2011) Knockout of insulin receptors in cardiomyocytes attenuates coronary arterial dysfunction induced by pressure overload. Am J Physiol Heart Circ Physiol 300:H374-81

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