Insulin resistance is a characteristic finding in obesity and in non insulin dependent (Type II) diabetes mellitus. However, the interaction between diabetes and obesity has been poorly characterized and the metabolic disturbances contributing to the defect in insulin-mediated glucose uptake have not been defined. To examine these questions euglycemic and hyperinsulinemic clamp studies (40 mU/m2/min) were performed in 10 control non-obese subjects, 10 non diabetic obese subjects, 8 normal weight Type II diabetics, and 12 obese Type II diabetics. During the insulin clamp study total body glucose uptake in the obese non diabetics (157 +/- 18 mg/m2.min, p less than 0.01), the normal weight diabetics (159 +/- 21, p less than 0.01) and the obese diabetics (125 +/- 11, p less than 0.001) was significantly reduced compared to the non-obese non diabetic control group (249 +/- 22 mg/m2.min). The impairment in total body glucose uptake was the result mainly of a defect in non-oxidative glucose disposal. Indeed non-oxidative glucose disposal was blunted by 50% in the obese groups (p less than 0.01), somewhat less significantly in the non-obese diabetic group (p less than 0.05) but more when obesity and diabetes mellitus were combined (p less than 0.001). Total glucose oxidation was significantly diminished (p less than 0.01) in both diabetic groups but not in the obese non diabetic group when compared to lean control. A significant inverse correlation between the fasting free fatty acids levels and total glucose uptake (r = -0.453, p less than 0.001) and total glucose oxidation (r = -0.446, p less than 0.001) during the clamp was observed.(ABSTRACT TRUNCATED AT 250 WORDS)