CD36 as a target to restore cardiac insulin resistance

Cardiac insulin resistance, which is associated with increased cardiac fatty acid uptake, increased sarcolemmal CD36 and reduced insulin‐stimulated glucose uptake, has attracted attention as a therapeutic target in diseases like diabetes and obesity. In this study, we aimed at restoring insulin resistance in cardiomyocytes (CM) by anti‐CD36‐antibodies (αCD36), or increasing glucose uptake by overexpression of a) constitutively active AMP‐activated protein kinase (AMPK‐CA) or b) protein kinase D (PKD‐CA). Primary rat CM were cultured for 48 h in presence or absence of insulin (HI) or palmitate (HP) and insulin sensitivity and lipid content were determined. Similar experiments were performed in presence of αCD36, control adenovirus (Av), Av AMPK‐CA or Av PKD‐CA. CM cultured in HI or HP were equally insulin resistant as CM from insulin resistant rodent models, i.e., increased lipid stores and reduced insulin sensitivity. Culturing CM with αCD36 prevented insulin resistance and normalized 1) basal palmitate uptake, 2) triglyceride stores, 3) insulin‐stimulated glucose uptake and 4) insulin‐stimulated Akt‐phosphorylation. In insulin resistant CM, Av AMPK‐CA restored protein phosphorylation and Av PKD‐CA normalized lipid stores. In conclusion, cardiac insulin resistance can be prevented by CD36 inhibition, and reversed by increased activation of AMPK or PKD. Funding DFN Grant 2006.00.044.