Leucine Metabolism in IDDM: Role of Insulin and Substrate Availability

The effect of insulin on plasma amino acid concentrations and leucine metabolism was examined in 18 healthy nondiabetic young volunteers and in 7 subjects with insulin-dependent diabetes mellitus (IDDM) with the euglycemic insulin-clamp technique (40 mU · m⁻² · min⁻¹) in combination with [1-¹⁴C]leucine. All diabetic subjects were studied while in poor metabolic control (fasting glucose 13.3 ± 1.1 mM; HbA_1c 10.8 ± 0.2%) and again after 2 mo of intensified insulin therapy (fasting glucose 7.2 ± 0.5 mM; HbA_1c 8.0 ± 0.2%). Insulin-mediated total-body glucose uptake in poorly controlled diabetic subjects (3.6 ± 0.5 mg · kg⁻¹ · min⁻¹) was significantly reduced compared with control subjects (7.5 ± 0.2 mg · kg⁻¹ · min⁻¹; P < .001) and improved slightly after insulin therapy (4.8 ± 0.3 mg · kg⁻¹ · min⁻¹; P < .05), although it still remained significantly lower than in control subjects (P < .01). During the insulin-clamp study performed in subjects with poorly controlled IDDM, endogenous leucine flux (ELF), leucine oxidation (LO), and nonoxidative leucine disposal (NOLD) all decreased (50.1 ± 2.0 to 26.4 ± 0.4; 9.2 ± 0.4 to 6.0 ± 0.3; 40.9 ± 2.0 to 20.4 ± 2.0 μmol · m⁻² · min⁻¹, respectively) to the same extent as in control subjects. After 2 mo of intensified insulin therapy, the effect of acute hyperinsulinemia on ELF, LO, and NOLD was comparable to that of control subjects, whereas insulin-stimulated glucose metabolism was still impaired. To examine the effect of substrate availability on leucine turnover, well-regulated IDDM and control subjects underwent a repeat insulin-clamp study combined with a balanced amino acid infusion designed to increase circulating plasma amino acid levels approximately twofold. Under these conditions, NOLD was equally enhanced above baseline in both control and IDDM subjects (P < .01), whereas ELF was inhibited to a greater extent (P < .01) than during the insulin clamp performed without amino acid infusion (control vs. diabetic subjects, NS). In conclusion, insulin-mediated glucose metabolism is severely impaired in subjects with both poorly controlled and well-controlled IDDM, whereas the effect of acute insulin infusion on leucine turnover is normal, and combined hyperaminoacidemia/hyperinsulinemia stimulated NOLD to a similar extent in both IDDM and control subjects.