The Influence of Graded Hyperglycemia with and without Physiological Hyperinsulinemia on Forearm Glucose Uptake and Other Metabolic Responses in Man*

We studied the influence of hyperglycemia on glucose homeostasis in man by determining the effect of graded hyperglycemia on peripheral glucose uptake and systemic metabolism in the presence of basal and increased serum insulin concentrations in 10 normal men. This was achieved by the simultaneous application of forearm and clamp techniques (euglycemic and hyperglycemic) during the combined iv infusion of somatostatin, glucagon, and insulin. While mean (±SE) basal serum insulin levels (14 ± 2 µU/ml) were maintained, the elevation of fasting arterial glucose concentrations (90 ± 1 mg/dl) to 146 ± 1 and 202 ± 1 mg/dl (each for 120 min) increased forearm glucose uptake (FGU) only modestly from 0.06 ± 0.01 to 0.15 ± 0.02 and then to 0.24 ± 0.03 mg/100 ml forearm-min, respectively. During physiological hyperinsulinemia (47 ± 3 µU/ml), the influence of similar graded hyperglycemia on FGU was considerably enhanced. At plasma glucose concentrations of 90 ± 1, 139 ± 1, and 206 ± 1 mg/dl, FGU rose to 0.33 ± 0.05, 0.59 ± 0.07, and 0.83 ± 0.12 mg/100 ml forearm-min, respectively. The glucose infusion rate required to maintain the glucose clamp with basal insulin levels was 1.08 ± 0.20 and 2.67 ± 0.39 mg/kg-min at glucose concentrations of 146 ± 1 and 202 ± 1 mg/dl, respectively. During physiological hyperinsulinemia, however, the glucose infusion rate required was 4.15±0.39, 9.45 ± 1.05, and 12.70 ± 0.81 mg/kg-min at glucose levels of 90 ± 1,139 ± 1, and 206 ± 1 mg/dl, respectively. Lactate concentrations rose significantly during hyperglycemia, but the rise in the presence of increased insulin concentrations (from 0.72 ± 0.06 to 1.31 ± 0.11 mmol/liter; P < 0.001) considerably exceeded the increment (from 0.74 ± 0.05 to 0.92 ± 0.03 mmol/liter) with basal insulin levels. While both FFA and glycerol concentrations were immediately reduced by euglycemic hyperinsulinemia, the fall in FFA during hyperglycemia in the presence of basal insulin levels preceded the decrease in glycerol concentrations by 45 min. Forearm oxygen consumption did not change throughout the study. We conclude that 1) the plasma glucose concentration is a major determinant of FGU and total glucose metabolism in the presence of basal and increased insulin levels; 2) the influence of hyperglycemia is small with normal basal serum insulin levels, but is markedly enhanced by physiological hyperinsulinemia; and 3) since the rise in blood lactate levels signifies increased splanchnic lactate output, homeostasis during hyperglycemic hyperinsulinemia may depend additionally on marked increments in glucose uptake by nonmuscle tissues, particularly the liver.