Different Sensitivity of Glucose and Amino Acid Metabolism to Insulin in NIDDM

Abstract

NIDDM subjects are characterized by impaired glucose tolerance and insulin resistance with respect to glucose metabolism. To examine whether the defect in glucose utilization extends to amino acid metabolism, 6 NIDDM subjects (64 ± 4 yr of age; ideal body weight of 107 ± 3%) and 7 control subjects (58 ± 4 yr of age; ideal body weight of 105 ± 2%) were studied with the euglycemic insulin clamp technique, in combination with [1-14C]leucine and indirect calorimetry. All subjects participated in two studies. In study 1, after 3 h of tracer equilibration, a 3-h insulin clamp (40 mU · m−2 · min−1) was performed to define the effect of insulin on leucine kinetics and glucose metabolism. In study 2, subjects received a repeat 3-h insulin clamp, and a balanced amino acid solution was infused to increase the plasma amino acid concentrations ∼ 2-fold to examine the effect of combined physiological hyperinsulinemia-hyperaminoacidemia on the rate of leucine and glucose disposal. Insulin-mediated total body glucose uptake was significantly reduced in NIDDM during both study 1 (5.6 ± 0.4 vs. 6.9 ± 0.6 mg · kg−1 · min−1 P < 0.01) and study 2 (5.2 ± 0.4 vs. 6.8 ± 0.6, P < 0.01). Basal plasma leucine (120 ± 10 vs. 123 ± 11 μM) and α-ketoisocaproic acid concentrations (28 ± 3 vs. 25 ± 2 μM) were similar in NIDDM and control subjects, respectively. In contrast, the basal plasma glucose concentration (8.9 ± 0.8 vs. 4.7 ± 0.2 μM) and the HbA1c (8.5 ± 0.2 vs. 5.7 ± 0.2%) were significantly increased in NIDDM (P < 0.01). In the postabsorptive state, endogenous leucine flux, leucine oxidation, and nonoxidative leucine disposal were similar in NIDDM and control subjects. When insulin was infused without amino acids (study 1), the decrement in plasma leucine (53 ± 5 vs. 48 ± 4 μM), endogenous leucine flux (13 ± 2 vs. 11 ± 1 μmol · m−2 · min−1), leucine oxidation (1.6 ± 0.2 vs. 1.3 ± 0.1 μmol · m−2 · min−1), and nonoxidative leucine disposal (10 ± 1 vs. 8 ± 1 μmol · m−2 · min−1) was comparable in both groups. During combined insulin and amino acid infusion (study 2), plasma leucine concentration (185 ± 20 vs. 190 ± 15 μM) rose similarly in NIDDM and control subjects. In NIDDM, the increment in leucine oxidation (9.0 ± 0.7 vs. 8.5 ± 0.6 μmol · m−2 · min−1) and nonoxidative leucine disposal (9.3 ± 0.7 vs. 10.5 ± 0.9 μmol · m−2 · min−1) was similar to that observed in control subjects; the decrement in endogenous leucine flux (22.3 ± 2.1 vs. 20.2 ±1.9 μmol · m−2 · min−1) was comparable in both groups. We conclude that 1) insulin-mediated glucose disposal is significantly impaired in NIDDM and 2) the effect of insulin on endogenous leucine flux (protein degradation), nonoxidative leucine disposal (protein synthesis), and leucine oxidation is similar in NIDDM and control subjects. These results indicate a clear-cut dissociation between the effect of insulin on glucose and protein metabolism in NIDDM.