Twenty-five newly presenting, untreated, white, non-insulin-dependent diabetic (NIDDM) subjects were studied within 72 hours of diagnosis. They were allocated to three groups according to their body mass index [BMI] (lean BMI less than 25.0, n = 9; overweight BMI 25.0 to 30.0, n = 6; obese BMI greater than .30.0 kg/m2, n = 10). All three groups exhibited equivalent hyperglycemia. Eleven normal control subjects were also studied. The degree of activation of skeletal muscle glycogen synthase (GS) was used as an intracellular marker of insulin action, before and during a 240-minute insulin infusion (100 mU/kg/h). Fractional GS activity did not increase in the lean (change, -0.9 +/- 3.3%), the overweight (-1.9 +/- 2.7%), or the obese (+2.2 +/- 1.6%) NIDDM subjects during the insulin infusion and was markedly decreased compared with the control subjects (change, +14.6 +/- 2.4%, all P less than .001). Glucose requirement was also significantly decreased in all three NIDDM groups (103 +/- 23 v 81 +/- 14 v 53 +/- 14 mg/m2/min, respectively) compared with the control subjects (319 +/- 18 mg/m2/min, all P less than .001). There was a significant negative correlation with BMI (r = -.51, P less than .01), but the difference in glucose requirement between the lean and obese NIDDM groups was not significant. Muscle GS activity at the end of the euglycemic clamp correlated with glucose requirement (r = .53, P less than .001), and a similar correlation was observed between the insulin-induced change in muscle GS activity from basal and glucose requirement (r = .47, P less than .005).(ABSTRACT TRUNCATED AT 250 WORDS)