Effect of Chronic Diabetes on Myocardial Fuel Metabolism and Insulin Sensitivity

Abstract

To assess the effect of chronic insulin-deficient diabetes on myocardial fuel substrate metabolism in vivo, we measured the myocardial balance of glucose, free fatty acids (FFAs), and amino acids in nine postabsorptive conscious dogs 4–6 wk after treatment with streptozocin. The acute effect of insulin on the myocardial balance of these same substrates was measured in six dogs by use of the euglycemic insulin clamp technique. To further examine the effect of insulin on heart amino acid balance, we studied three additional dogs given a constant infusion of amino acids during the insulin clamp to blunt the insulin-induced hypoaminoacidemia. In these dogs, the fasting plasma glucose concentration was markedly elevated (258 ± 3 mg/dl). In the basal period, there was no significant glucose uptake by the heart [arterial vs. coronary sinus concentration difference (Δ) = 1.0 ± 2.0 mg/dl]; furthermore, physiologic hyperinsulinemia did not stimulate glucose uptake (Δ = 2.0 ± 2.5 mg/dl). Postabsorptively, arterial FFAs were elevated (1550 ± 320 μμ) in diabetic animals, and there was a significant net extraction of FFAs by the heart (net uptake 26 ± 9 μmol/min; extraction ratio 30 ± 8%). During the insulin clamp, arterial FFAs declined (645 ± 240 μM), as did heart FFA uptake (11 ± 6 μmol/min), and the net extraction ratio for FFAs was unchanged (30 ± 7%). Similarly, the arterial branched-chain amino acid (BCAA) concentration was elevated in the postabsorptive state, and there was a significant myocardial uptake of these amino acids and of alanine. With infusion of insulin alone or a combination of insulin and amino acids, there was a highly significant linear correlation between the arterial BCAA concentration and myocardial BCAA uptake (r = .80, P < .02). Glutamine is the dominant amino acid released by the diabetic myocardium, both in the basal period and during insulin infusion (0.4 ± 0.4 and 1.1 ± 0.4 μmol/min, respectively). We conclude that when compared with myocardium of normal dogs, the myocardium of diabetic dogs is severely resistant to the action of insulin to promote glucose uptake.