Impairment of insulin-stimulated Akt/GLUT4 signaling is associated with cardiac contractile dysfunction and aggravates I/R injury in STZ-diabetic rats.
In this study, we established systemic in-vivo evidence from molecular to organism level to explain how diabetes can aggravate myocardial ischemia-reperfusion (I/R) injury and revealed the role of insulin signaling (with specific focus on Akt/GLUT4 signaling molecules). The myocardial I/R injury was induced by the left main coronary artery occlusion for 1 hr and then 3 hr reperfusion in control, streptozotocin (STZ)-induced insulinopenic diabetes, and insulin-treated diabetic rats. The diabetic rats showed a significant decrease in heart rate, and a prolonged isovolumic relaxation (tau) which lead to decrease in cardiac output (CO) without changing total peripheral resistance (TPR). The phosphorylated Akt and glucose transporter 4 (GLUT 4) protein levels were dramatically reduced in both I/R and non-I/R diabetic rat hearts. Insulin treatment in diabetes showed improvement of contractile function as well as partially increased Akt phosphorylation and GLUT 4 protein levels. In the animals subjected to I/R, the mortality rates were 25%, 65%, and 33% in the control, diabetic, and insulin-treated diabetic group respectively. The I/R-induced arrhythmias and myocardial infarction did not differ significantly between the control and the diabetic groups. Consistent with its anti-hyperglycemic effects, insulin significantly reduced I/R-induced arrhythmias but had no effect on I/R-induced infarctions. Diabetic rat with I/R exhibited the worse hemodynamic outcome, which included systolic and diastolic dysfunctions. Insulin treatment only partially improved diastolic functions and elevated P-Akt and GLUT 4 protein levels. Our results indicate that cardiac contractile dysfunction caused by a defect in insulin-stimulated Akt/GLUT4 may be a major reason for the high mortality rate in I/R injured diabetic rats.
Huang
Jiung-Pang
JP
Department of Life Science, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan, Republic of China. dddivekimo@yahoo.com.tw
Huang
Shiang-Suo
SS
Deng
Jen-Ying
JY
Hung
Li-Man
LM
D000818:Animals; D002303:Cardiac Output, Low / Q000209:etiology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D051275:Glucose Transporter Type 4 / Q000502:physiology*; D006339:Heart Rate; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000503:physiopathology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013311:Streptozocin
D051275:Glucose Transporter Type 4; D007328:Insulin; C495694:Slc2a4 protein, rat; D013311:Streptozocin; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt
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