Onset of diabetes in Zucker diabetic fatty (ZDF) rats leads to improved recovery of function after ischemia in the isolated perfused heart

Abstract

The aim of this study was to determine whether the transition from insulin resistance to hyperglycemia in a model of type 2 diabetes leads to intrinsic changes in the myocardium that increase the sensitivity to ischemic injury. Hearts from 6-, 12-, and 24-wk-old lean (Control) and obese Zucker diabetic fatty (ZDF) rats were isolated, perfused, and subjected to 30 min of low-flow ischemia (LFI) and 60 min of reperfusion. At 6 wk, ZDF animals were insulin resistant but not hyperglycemic. By 12 wk, the ZDF group was hyperglycemic and became progressively worse by 24 wk. In spontaneously beating hearts rate-pressure product (RPP) was depressed in the ZDF groups compared with age-matched Controls, primarily due to lower heart rate. Pacing significantly increased RPP in all ZDF groups; however, this was accompanied by a significant decrease in left ventricular developed pressure. There was also greater contracture during LFI in the ZDF groups compared with the Control group; surprisingly, however, functional recovery upon reperfusion was significantly higher in the diabetic 12- and 24-wk ZDF groups compared with age-matched Control groups and the 6-wk ZDF group. This improvement in recovery in the ZDF diabetic groups was independent of substrate availability, severity of ischemia, and duration of diabetes. These data demonstrate that, although the development of type 2 diabetes leads to progressive contractile and metabolic abnormalities during normoxia and LFI, it was not associated with increased susceptibility to ischemic injury.

Ischaemic preconditioning does not protect the heart in obese and lean animal models of Type 2 diabetes

“…The present study in Type 2 diabetes demonstrates that hearts from diabetic rats are protected against ischaemic damage because infarct size was smaller in both obese and lean diabetic animals than in non-diabetic animals. However, in contrast to a recent study demonstrating increased post-ischaemic left ventricular recovery after low-flow ischaemia [14], our data show no improvement of post ischaemic left ventricular function in Type 2 diabetic animals, although infarct size, compared to non-diabetic control animals, was smaller, suggesting a contractile dysfunction in non-infarcted diabetic myocardium. This is supported by a previous study [15], which reported a dissociation between protection against isoproterenol-induced myocardial fibrosis and the haemodynamic response, which was unaffected in a model of Type 1 diabetes.…”

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

“…This agrees well with results obtained ex-vivo [5][6][7] and in-vivo [4,8,9] in rats fed a HF diet. However, this is in total opposition with the results from ZDF rats [13,14] and SMC-fed animals [2,3]. Yet, the two last situations are associated with increased blood glucose, whereas the increased chow intake was not in our study.…”

“…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].…”