Abstract
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.
Highlights
Diabetes mellitus is the world's fastest-growing disease with high morbidity and mortality rates predominantly as results of cardiovascular diseases [1,2]
The Influences of Hyperglycemia on Cardiovascular System Male SD rats were intravenously injected with streptozotocin (STZ) to induce insulinopenic diabetes which was characterized by elevations in plasma glucose level above 300 mg/dl and by exhibiting symptoms of polyphagia, polyuria, and polydipsia
Animals treated with STZ resulted in consistent hyperglycemia and hypoinsulinemia that persisted over the 3 week period
Summary
Diabetes mellitus is the world's fastest-growing disease with high morbidity and mortality rates predominantly as results of cardiovascular diseases [1,2]. Acute ischemic syndromes, peripheral arterial disease, and advanced cardiovascular disease (CVD) complications occur more commonly in patients with diabetes than in those without. The cost of publication in Journal of Biomedical Science is bourne by the National Science Council,Taiwan. Journal of Biomedical Science 2009, 16:77 http://www.jbiomedsci.com/content/16/1/77. It has been speculated that myocardial insulin resistance develops in animal models of both type 1 and type 2 diabetes [4]. Various studies to date indicate multiple sites of impaired insulin signaling in various animal models; all the findings clearly support the existence of myocardial insulin resistance [4]. Insulin-stimulated glucose uptake, protein synthesis and glycogen synthesis have been shown to be reduced in the heart and cardiomyocytes of diabetic rats [5,6]
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