The present study was undertaken to compare the effect of hyperglycemia and euglycemia during identical hyperinsulinemic conditions on glucose metabolism in NIDDM subjects. Eight NIDDM subjects participated in a 4 h hyperglycemic (12.1 +/- 0.7 mmol/l), hyperinsulinemic (475 +/- 43 pmol/l) and in a 4 h euglycemic (5.5 +/- 0.5 mmol/l), hyperinsulinemic (468 +/- 36 pmol/l) insulin clamp in combination with indirect calorimetry and [3H]-3-glucose. Six non-diabetic subjects were studied during euglycemia (5.1 +/- 0.2 mmol/l) and hyperinsulinemia (474 +/- 35 pmol/l) and served as controls. In NIDDM patients the rate of insulin-stimulated glucose disposal was 57% greater during hyperglycemia compared with euglycemia throughout the 4 h clamp (p less than 0.01). The major part of the increase in glucose metabolism during hyperglycemia was due to an increase in the non-oxidative glucose metabolism (89%). Whereas glucose metabolism could not be normalized during the prolonged euglycemic hyperinsulinemic clamp in NIDDM patients (49.9 +/- 6.8 vs 57.5 +/- 5.4 mumol.(kgLBM)-1.min-1 in controls) the addition of hyperglycemia resulted in complete normalization of the glucose disposal rates (78.3 +/- 5.8 mumol.(kgLBM)-1.min-1). The effect of hyperglycemia was apparent already at 60 min of the clamp. The data thus suggest that glucose metabolism in NIDDM is insulin resistant, but that the defect in insulin-stimulated glucose uptake can be overcome by increasing the glucose concentration.