Insulin resistance and β-cell function were assessed by a continuous infusion of glucose in the following three groups of white subjects at risk of developing impaired glucose tolerance and diabetes: 41 subjects who were the offspring of patients with type II diabetes, 26 general-population subjects with an increased fasting plasma glucose level of at least 5.6 mmol/L on screening, and 22 subjects who had had gestational diabetes but were now nondiabetic. Subjects had a mean (± 1 SD) age of 43 ± 9 years and a body mass index (BMI) of 27 ± 5 kg/m 2. Subjects with previously increased fasting glucose levels were significantly more insulin resistant than a control group, taking into account BMI, age, and gender (% normal insulin sensitivity [%S], 59 [50 to 79] v 87 [73 to 96]; P < .005), and previously gestationally diabetic subjects showed greater impairment of β-cell function (% normal β-cell function [%β], 69 [60 to 87] v 97 [89 to 105]; P < .005). Diabetes (defined by World Health Organization criteria) or impaired glucose tolerance (defined as an achieved plasma glucose concentration [APG]>95th percentile of an age-and weight-matched population) was identified in 22% of family members, 31% of fasting hyperglycemic subjects, and 41% of previously gestationally diabetic subjects. Twenty-two subjects with impaired glucose tolerance from all the groups were compared with their normoglycemic counterparts and were characterized by greater obesity (29 ± 7 v 25 ± 3 kg/m 2, P < .05), impaired insulin sensitivity [%S, 46 [23 to 78] v 81 [51 to 128]; P < .001), impaired β-cell function (%β, 83 [63 to 110] v 95 [65 to 141]; P < .05), and decreased suppression of nonesterified fatty acids ([NEFA] 40 [38 to 50] v 66 [50 to 77] % decrease in NEFA, P < .001). After taking into account BMI, gender, and age, the decrease in β-cell function of the impaired-glucose tolerance group was more apparent ( P < .01) and there continued to be a difference in insulin sensitivity, implying non-obesity-associated insulin resistance in the impaired-glucose tolerance group ( P < .001). In conclusion, although subjects with impaired glucose tolerance from each of the three different at-risk groups showed similar phenotypic characteristics with obesity being a major feature, we have identified in a single study using a single investigative technique more marked impairment of β-cell function in previously gestationally diabetic subjects and more insulin resistance in subjects with a previously increased fasting plasma glucose level. Impaired glucose tolerance is thus a multifactorial disease in which genetic or environmental contributions vary between different at-risk groups and between different individuals.