Role of impaired intracellular glucose metabolism in the insulin resistance of aging

Abstract

The insulin resistance of aging is characterized by both reduced glucose uptake and impaired intracellular glucose metabolism. The aim of this study was to determine whether impaired intracellular glucose metabolism contributes to insulin resistance in the elderly independent of reduced glucose uptake. To address this question, glucose uptake in non-obese elderly males was matched to controls using the glucose clamp technique, and intracellular glucose mtabolism was assessed in vivo by indirect calorimetry and in vitro by skeletal muscle biopsy for glycogen synthase activity. When elderly subjects were compared with controls at an equivalent basal glucose uptake of approximately 2.5 mg/kg fat-free mass (FFM)/min, muscle glycogen synthase activity was similar (fractional velocity of glycogen synthase at 0.1 mmol/L glucose-6-phosphate [FV 0.1], 0.06 ± 0.1 and 0.07 ± 0.1), but whole-body rates of glucose oxidation were reduced (1.36 ± 0.12 v 1.90 ± 0.11 mg/kg FFM/min, P < .05). During 40-mU/m 2/min hyperinsulinemic clamps at matched rates of glucose uptake (∼10.7 mg/kg FFM/min in both groups), glycogen synthase activity was again similar (FV 0.1, 0.15 ± 0.02 and 0.14 ± 0.02), and glucose oxidation remained reduced in the elderly (4.18 ± 0.25 v 4.77 ± 0.17 mg/kg FFM/min, P < .05). Only during clamps in the maximal range of glucose uptake (∼29.5 mg/kg FFM/min) was glucose oxidation between the groups comparable (5.97 ± 0.50 and 5.75 ± 0.31 mg/kg FFM/min). Plasma free fatty acid (FFA) concentrations, fat oxidation, and protein oxidation were similar under all study conditions. In summary, when glucose uptake in the elderly was normalized, (1) glucose oxidation remained reduced in the submaximal but not maximal range of glucose uptake, and (2) skeletal muscle glycogen synthase activity was similar to that of controls. In conclusion, impaired intracellular glucose metabolism contributes to the insulin resistance of aging independent of the defect in glucose uptake through decreased sensitivity of whole-body glucose oxidation to insulin stimulation. In contrast, skeletal muscle glycogen synthase is normal and does not contribute to the insulin resistance of aging.