Azeddine Ibrahimi
Research Assistant Professor of Physiology & Biophysics

Effect of insulin resistance and diabetes on heart function and tolerance to ischemia

Long-chain fatty acids (FA) are quantitatively the most important substrates for energy. They are also precursors of phospholipids which are essential membrane components and of prostaglandins which have a variety of regulatory effects. In addition, FA mediate or regulate a wide range of important biological processes. FA have been shown to directly modulate ion channel activation, enzyme function, synaptic transmission and gene expression. On a more general level, FA have been implicated in the physiopathology of obesity and diabetes, immune responses and atherosclerosis, cystic fibrosis and breast cancer. This emphasizes their large potential role as general metabolic regulators.
The mechanism of FA transfer across cell membranes has long been postulated to occur by passive diffusion through the lipid bilayer. However, early studies of FA permeation of adipocyte membranes yielded evidence that was not consistent with a simple diffusion process. These studies led to the identification of an adipocyte 88 kD membrane protein FA transporter. The protein (termed FAT for FA translocase) was isolated and the corresponding cDNA cloned from a rat adipose cDNA library. The clone coded for a protein with 85% homology to human platelet CD36.
FA transport into the murine heart, in vivo, is largely dependent on CD36 and its deficiency decreases FA uptake by greater than 60%. Humans with CD36 deficiency have a myocardial defect in fatty acid uptake that is of a very similar magnitude to that observed in the mouse. In addition, the recently reported link between CD36 expression levels and susceptibility to insulin resistance suggests that it may under some conditions contribute to the etiology of diabetic cardiomyopathy.
We recently, examined the role of CD36-facilitated FA uptake in cardiac function during ischemia-reperfusion using three mice models, with different levels of CD36 expression, and perfusions with and without FA. Cardiac output and end-diastolic pressure were evaluated prior to and after ischemia providing a first characterization of heart function in a model of defective fatty acid metabolism. The data indicate that CD36 expression by facilitating fatty acids uptake and utilization enhances energy stores in the myocytes and this is important for functional recovery after ischemia and reperfusion. We intend to dissect the relationship between alterations in heart function and severity of diabetes in CD36 animal models.