Impairment of cardiac insulin signaling and myocardial contractile performance in high-cholesterol/fructose-fed rats

Abstract

Deng J-Y, Huang J-P, Lu L-S, Hung L-M. Impairment of cardiac insulin signaling and myocardial contractile performance in high cholesterol-fructose-fed rats. Am J Physiol Heart Circ Physiol 293: H978-H987, 2007. First published March 30, 2007; doi:10.1152/ajpheart.01002.2006.-Although insulin resistance is recognized as a potent and prevalent risk factor for coronary heart disease, less is known as to whether insulin resistance causes an altered cardiac phenotype independent of coronary atherosclerosis. In this study, we investigated the relationship between insulin resistance and cardiac contractile dysfunctions by generating a new insulin resistance animal model with rats on high cholesterol-fructose diet. Male Sprague-Dawley rats were given high cholesterol-fructose (HCF) diet for 15 wk; the rats developed insulin resistance syndrome characterized by elevated blood pressure, hyperlipidemia, hyperinsulinemia, impaired glucose tolerance, and insulin resistance. The results show that HCF induced insulin resistance not only in metabolicresponse tissues (i.e., liver and muscle) but also in the heart as well. Insulin-stimulated cardiac glucose uptake was significantly reduced after 15 wk of HCF feeding, and cardiac insulin resistance was associated with blunted Akt-mediated insulin signaling along with glucose transporter GLUT4 translocation. Basal fatty acid transporter FATP1 levels were increased in HCF rat hearts. The cardiac performance of the HCF rats exhibited a marked reduction in cardiac output, ejection fraction, stroke volume, and end-diastolic volume. It also showed decreases in left ventricular end-systolic elasticity, whereas the effective arterial elasticity was increased. In addition, the relaxation time constant of left ventricular pressure was prolonged in the HCF group. Overall, these results indicate that insulin resistance reduction of cardiac glucose uptake is associated with defects in insulin signaling. The cardiac metabolic alterations that impair contractile functions may lead to the development of cardiomyopathy.Akt; glucose transporter; cardiac dysfunction; high cholesterol-fructose diet; insulin resistance HEART DISEASE IS A LEADING CAUSE of death in diabetic patients (43), with coronary artery disease (CAD) and atherosclerosis being the primary reasons for increased incidence of cardiovascular dysfunction (43, 38). However, a predisposition to heart failure might also reflect the effects of underlying abnormalities in cardiac diastolic function that can be detected in asymptomatic patients with diabetes (13, 4). Several etiological factors have been put forward to explain why hyperglycemia and/or diabetes tends to lead to diabetic cardiomyopathy. The accumulation of connective tissues, insoluble collagens (1), and abnormalities of various proteins that regulate ion flux (specifically, intracellular calcium) (18), has been proposed as an explanation for left ventricular wall stiffness and contractile dysfunctions. Recently, was speculated that diabetic cardiomyopathy could also occur as ...

Activation of Estrogen Receptor Is Crucial for Resveratrol-Stimulating Muscular Glucose Uptake via Both Insulin-Dependent and -Independent Pathways

“…To mimic Western eating habits characterized by consuming a high-cholesterol diet combined with sugarsweetened beverages, we fed rats with a high-cholesterol diet combination with 10% fructose in drinking water (HCF diet) for 15 weeks and found that these rats could develop a phenotype of insulin resistance syndrome characterized by an increase in blood pressure, hyperlipidemia, hyperinsulinemia, and impaired glucose tolerance with relative normal body weight gain, as previously described (15). Since the beneficial effects of RSV on obesity and insulin resistance were functionally intertwined in an obesity-induced insulin-resistant animal model (12,13), HCF diet-fed rats instead of obese rats were chosen in the present study to test whether ER signaling is directly involved in the effects of RSV on diet-induced whole-body and muscular insulin resistance without the potential disturbance of RSV-mediated anti-obese effect to data interpretation.…”

Insulin Resistance and Cardiomyopathy

“…The basal FATP1 (fatty acid transporter 1) levels were increased in HCF rat hearts. The cardiac performance of the HCF rats showed a marked reduction (25). Our results indicate that high-cholesterol food and sugar-sweetened beverages that lead to maladaptive metabolic processes may interfere with the action of insulin and increase susceptibility for the development of cardiomyopathy (25).…”

“…Our laboratory study reveals that a high cholesterol-fructose (HCF) diet also induces insulin resistance not only in metabolicresponsive tissues (i.e. liver and muscle) but also in the heart as well (25). Insulin-stimulated cardiac glucose uptake was significantly reduced after 15 weeks of HCF feeding, and cardiac insulin resistance was associated with blunted Akt-mediated insulin signaling along with GLUT4 translocation.…”

“…The HCF diet-induced insulin resistance not only occurred in metabolic-response tissues but also in the heart as well. These results indicate cardiac insulin resistanceassociated metabolic alterations may consequently lead to the development of cardiomyopathy and contractile dysfunction (25). Diabetes causes metabolic dysregulation and contains numerous risk factors which are associated with cardiomyopathy and heart failure.…”

Roles of Obese-Insulin Resistance and Anti-Diabetic Drugs on the Heart with Ischemia-Reperfusion Injury

“…In the heart, metabolic flexibility is its ability to alter fuel oxidation to fuel availability [47]. Under insulin resistant conditions, an impairment of insulin signaling occurs, followed by reduced glucose uptake and reduced ability of the heart to use glucose as a substrate for ATP production [48]. Thus, a large amount of FFA is delivered to the heart, and it has been implicated in the accumulation of intracellular lipids.…”