Thiazolidinedione Treatment Normalizes Insulin Resistance and Ischemic Injury in the Zucker Fatty Rat Heart

Thiazolidinedione Treatment Normalizes Insulin Resistance and Ischemic Injury in the Zucker Fatty Rat Heart Robert J. Sidell 1 , Mark A. Cole 1 , Nicholas J. Draper 1 , Martine Desrois 1 , Robin E. Buckingham 2 and Kieran Clarke 1 1 Department of Biochemistry, University of Oxford, Oxford, U.K. 2 GlaxoSmithKline, Harlow, Essex, U.K. Abstract Obesity is associated with risk factors for cardiovascular disease, including insulin resistance, and can lead to cardiac hypertrophy and congestive heart failure. Here, we used the insulin-sensitizing agent rosiglitazone to investigate the cellular mechanisms linking insulin resistance in the obese Zucker rat heart with increased susceptibility to ischemic injury. Rats were treated for 7 or 14 days with 3 mg/kg per os rosiglitazone. Hearts were isolated and perfused before and during insulin stimulation or during 32 min low-flow ischemia at 0.3 ml · min −1 · grams wet wt −1 and reperfusion. d [2- 3 H]glucose was used as a tracer of glucose uptake, and phosphorus-31 nuclear magnetic resonance spectroscopy was used to follow energetics during ischemia. At 12 months of age, obese rat hearts were insulin resistant with decreased GLUT4 protein expression. During ischemia, glucose uptake was lower and depletion of ATP was greater in obese rat hearts, thereby significantly impairing recovery of contractile function during reperfusion. Rosiglitazone treatment normalized the insulin resistance and restored GLUT4 protein levels in obese rat hearts. Glucose uptake during ischemia was also normalized by rosiglitazone treatment, thereby preventing the greater loss of ATP and restoring recovery of contractile function to that of lean rat hearts. We conclude that rosiglitazone treatment, by normalizing glucose uptake, protected obese rat hearts from ischemic injury. Footnotes Address correspondence and reprint requests to Dr. Kieran Clarke, Department of Biochemistry, University of Oxford, South Parks Rd., Oxford OX1 3QU, U.K. E-mail: kieran{at}bioch.ox.ac.uk . Received for publication 5 November 2001 and accepted in revised form 9 January 2002. DP, developed pressure; DTT, dithiothreitol; FFA, free fatty acid; gww, grams wet weight; IRS-1, insulin receptor substrate-1; PCr, phosphocreatine; 31 P NMR, phosphorus-31 nuclear magnetic resonance; PPARγ, peroxisome proliferator-activated receptor-γ; RPP, rate-pressure product; TBST, Tris-buffered saline with Tween; TG, triglyceride; TZD, thiazolidinedione. DIABETES