Patients with cystic fibrosis (CF) frequently have impaired glucose tolerance and progression to diabetes (DM) with clinical features of both insulin-dependent and non-insulin-dependent diabetes. One feature of non-insulin-dependent DM is decreased insulin sensitivity, also known as insulin resistance. The goal of this study was to determine whether patients with CF exhibit insulin resistance and to determine the potential effect of insulin resistance on clinical status. We also sought to determine whether insulin resistance is associated with a specific CF genotype. We studied 18 patients with CF (8 with normal glucose tolerance, 5 with impaired glucose tolerance, 5 with DM), and 20 lean control subjects matched for age, weight, and sex. All control subjects had normal glucose tolerance. The clinical status for each CF patients was determined according to a modified National Institutes of Health scoring system. Each subject underwent a three-step hyperinsulinemic euglycemic clamp (insulin doses of 10, 40, 120 mU/m2 per minute). Results from the 120 mU/m2 per minute infusion defined maximal glucose disposal rate (defined in milligrams per kilogram body weight per minute) at steady state with peripheral insulin levels 195 +/- 20 mU/ml. Subjects with CF demonstrated insulin resistance (control subjects = 13.6 +/- 1.1, patients with CF = 10.2 +/- 1.6 mg/kg per minute; p = 0.003). When each subgroup was compared separately with control subjects, all subgroups were statistically insulin resistant (glucose disposal rate, patients with CF and normal glucose tolerance = 10.8; those with impaired glucose tolerance = 8.4; those with DM = 10.1 mg/kg per minute), and the patients with CF with impaired glucose tolerance were the most insulin resistant. When plotted versus glucose disposal rate, a striking positive correlation between worsened clinical status and insulin resistance (r = 0.85) is demonstrated. Furthermore, there is no correlation between insulin resistance and fasting blood glucose, subject age, or percent ideal body weight (all r values not significant). In conclusion, patients with CF exhibit insulin resistance that is associated with worsened clinical status. We believe it is the combination of insulin resistance and decreased insulin secretion that is responsible for the high incidence of CF-related diabetes.