Plasma glucose, FFA, and insulin responses to an oral glucose challenge, plasma lipid and lipoprotein concentrations, and the ability of insulin to stimulate glucose disposal were measured in 35 nondiabetic sedentary and overweight subjects. The subjects were divided into 2 groups on the basis of the presence (n = 19) or absence (n = 16) of a history of a first degree relative with noninsulin-dependent diabetes. The 2 groups were similar in age, body mass index, waist to hip ratio, and maximal aerobic capacity. The results demonstrated that the ability of insulin to stimulate disposal of a glucose load was significantly reduced in the subjects with a positive family history of noninsulin-dependent diabetes. In addition, these individuals had significantly higher plasma triglyceride and very low density lipoprotein cholesterol concentrations. Since all environmental factors known to modify insulin action and very low density lipoprotein metabolism were equal in the 2 groups, these data suggest that the metabolic differences noted are likely to be genetic in origin.