Acute insulin withdrawal from diabetic BB rats decreases myocardial glycolysis during low-flow ischemia

Abstract

We have previously demonstrated that withdrawal of insulin treatment from BB diabetic rats for a 24-hour period will increase the failure rate of hearts subjected to low-flow ischemia. The purpose of this study was to determine if this increased severity of ischemia was related to a decrease in glycolytic rates during ischemia. Two groups of insulin-dependent diabetic BB Wistar rats were used; in one group, insulin treatment was withheld from rats 24 hours prior to study (uncontrolled), while in the second group, the daily insulin injection was not withheld (insulin-treated). Isolated working hearts obtained from these animals were perfused with 30 mmol/L ( 2- 3H U- 14C )-glucose and 1.2 mmol/L palmitate, at an 11.5 mm Hg left atrial preload and 80 mm Hg aortic afterload. Hearts were subjected to a 15-minute aerobic perfusion followed by 60 minutes of low-flow ischemia (coronary flow, 0.5 mL/min). Under aerobic conditions, steady-state glucose oxidation rates (measured as 14CO 2 production) were decreased in the uncontrolled group compared with the insulin-treated group (85.3 ± 21.5 v 406.2 ± 120.1 nmol/min/g dry weight, respectively; P < .05). Steady-state glycolytic rates (measured as 3H 2O production) were also decreased in the uncontrolled group compared with the insulin-treated group (1.73 ± 0.30 v 5.57 ± 1.26 μmol/min/g dry weight, respectively; P < .05). During low-flow ischemia, glucose-oxidation rates markedly decreased in both groups (23.9 ± 8.7 and 38.3 ± 25.2 nmol/min/g dry weight in the uncontrolled and insulin-treated diabetic rats, respectively). Glycolytic rates during ischemia decreased slightly, but remained significantly depressed in the uncontrolled group compared with the insulin-treated group (1.28 ± 0.28 v 2.15 ± 0.25 μmol/min/g dry weight, respectively; P < .05). During reperfusion, glucose oxidation recovered to preischemic values in hearts from uncontrolled diabetic rats, and remained depressed compared with the insulin-treated diabetic rats (84.7 ± 9.2 and 366.9 ± 81.3 nmol/min/g dry weight, respectively, P < 0.05). Glycolytic rates also returned to preischemic values and remained depressed in these hearts (2.27 ± 0.42 and 4.71 ± 0.91 μmol/min/g dry weight, respectively, P < .05). Combined with our previous studies, these data suggest that poor control of insulin-dependent diabetic BB rats increases the sensitivity of the heart to ischemia, possibly by decreasing the ability of hearts to maintain high glycolytic rates during ischemia.