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

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 ⅐ min ؊1 ⅐ 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.

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

“…Besides, rosiglitazone has been found to prevent the loss of ATP in in vitro hearts (Sidell et al, 2002). Our findings open up a line of research directed toward the elucidation of other roles of thiazolidindiones and 15d-PGJ 2 by affecting the ATP levels in brain cells, which may have important implications after stress at the level of glutamate uptake and release.…”

Rosiglitazone Restores G-Protein Coupling, Recruitment, and Function of Renal Dopamine D 1A Receptor in Obese Zucker Rats

“…11,29,30 However, the present study as well as some recent reports show that even lower doses (3 to 5 mg/kg per day) of rosiglitazone for 7 to 14 days improve insulin sensitivity to the same extent. [31][32][33] In obese rats, fasting blood glucose levels were completely normalized to levels seen in lean rats, and plasma insulin values were reduced to similar extent with both treatment regimens of rosiglitazone.…”

Myocardial Insulin Resistance: An Overview of Its Causes, Effects, and Potential Therapy

“…Hearts from prediabetic obese Zucker rats have reduced GLUT4 expression, reduced glucose uptake and larger reductions in tissue ATP levels during low-flow ischaemia. These changes are associated with poorer post-ischaemic functional recoveries when compared to their lean control littermates [231]. Treating these rats with rosiglitazone (the insulin sensitizer) normalized myocardial total GLUT4 protein expression, myocardial ischaemic substrate metabolism and improved reperfusion functional recovery.…”