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^-1min^-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.