Impact of altered substrate utilization on cardiac function in isolated hearts from Zucker diabetic fatty rats

Abstract

The goal of this study was to determine whether changes in cardiac metabolism in Type 2 diabetes are associated with contractile dysfunction or impaired response to ischemia. Hearts from Zucker diabetic fatty (ZDF) and lean control rats were isolated and perfused with glucose, lactate, pyruvate, and palmitate. The rates of glucose, lactate, pyruvate, and palmitate oxidation rates and glycolysis were determined during baseline perfusion and low-flow ischemia (LFI; 0.3 ml/min for 30 min) and after LFI and reperfusion. Under all conditions, ATP synthesis from palmitate was increased and synthesis from lactate was decreased in the ZDF group, whereas the contribution from glucose was unchanged. During baseline perfusion, the rate of glycolysis was lower in the ZDF group; however, during LFI and reperfusion, there were no differences between groups. Despite these metabolic shifts, there were no differences in oxygen consumption or ATP production rates between the groups under any perfusion conditions. Cardiac function was slightly depressed before LFI in the ZDF group, but during reperfusion, function was improved relative to the control group despite the increased dependence on fatty acids for energy production. These data suggest that in this model of diabetes, the shift from carbohydrates to fatty acids for oxidative energy production did not increase myocardial oxygen consumption and was not associated with impaired response to ischemia and reperfusion. contractile dysfunction; ischemia; nuclear magnetic resonance spectroscopy; carbohydrate metabolism DIABETES IS LINKED TO OBESITY, dyslipidemia, and hypertension (16,34,40,41), all of which are independent risk factors for cardiovascular disease (33,34,43); however, there is growing evidence to support the existence of a specific diabetic cardiomyopathy that is independent of other risk factors for heart disease (8 -11, 14, 21, 39, 42-44, 47, 48, 51). One of the earliest changes that occurs after the onset of experimentally induced diabetes is in the regulation of cardiac metabolism, typically characterized by increased fatty acid oxidation and decreased carbohydrate use (9). It has been suggested (26) that this shift in metabolism may play a role in the development of diabetic cardiomyopathy, which leads to both impaired contractile function as well as increased susceptibility to ischemic injury. For example, Belke et al. (2) found that increasing GLUT4 expression in hearts from diabetic db/db mice not only reversed the metabolic defects but also normalized cardiac function. However, treatment with a peroxisome proliferatoractivated receptor-␥ agonist in the same animal model of diabetes normalized the changes in cardiac metabolism, but contractile function remained depressed (5). Thus the potential role of altered substrate utilization in the development of cardiac dysfunction in diabetes remains to be determined.The increase in cardiac fatty acid utilization that occurs with diabetes is proposed to be detrimental because fatty acids are less-efficient fuels that...

Increased Abdominal Adiposity Exacerbates Ex-Vivo Cardiac Reperfusion Injury through Augmented Mitochondrial Oxidative Stress

“…This confirms the effect of IAA in different ex-vivo models, including in Western diet-fed rats [5,7], ZDF animals [13,14,45] and mice subjected to ON [11]. This phenomenon was associated with lower coronary flow and cardiac metabolic efficiency.…”

“…Yet, our perfusion fluid contained only glucose as an energy substrate, which is usually sufficient to allow the heart to develop high mechanical activity, even in working mode [46,47]. Other researchers have supplied their isolated hearts with a mixture of glucose, lactate, pyruvate and palmitate [13,14]. Although this precaution could improve cardiac energy metabolism, it cannot mimic the in-vivo situation in which the systemic NEFA level could be modified by IAA [48].…”

“…The diabetic Zucker fatty rat, a genetic model of hyperphagy and hyperglycaemia caused by a Westerntype diet, displays decreased CSI until the age of 6 months [13,14] but then has increased CSI thereafter [15].…”

Alterations in fatty acid metabolism and sirtuin signaling characterize early type-2 diabetic hearts of fructose-fed rats

“…2004; Wang et al. 2005, 2015) and has been linked to the activation of PPAR α and its coactivator PGC1 α (Duncan et al. 2007; Finck et al.…”

Insulin Resistance and Cardiomyopathy

“…Obese Zucker rats exhibit hyperlipidemia, www.intechopen.com hypercholesterolemia, and insulin resistance. The cardiac contractile functions and carbohydrate oxidation rates are reduced and fatty acid utilization is increased in the Zucker rat heart (28,(112)(113)(114)(115). In contrast, several studies indicate that Zucker rats display insulin resistance without overt signs of diabetes (hyperglycemia and hyperlipidemia).…”