To quantitate the degree of whole body insulin resistance in patients with myotonic dystrophy, three separate euglycemic insulin infusions were given to ambulatory patients and the results compared with findings in normal control subjects. Basal glucose and insulin values were similar for the two groups. There was no significant difference in insulin clearance rates between normal subjects and patients at the three insulin infusion rates used. A highly significant decrease in the whole body glucose disposal rate was seen during the 120-minute insulin infusion in the patients with myotonic dystrophy compared with normal subjects at all three insulin dosages (20 mU/m2/min: 2.18 * 0.29 [standard error] versus 5.49 2 1.72 mg/kg/min, p < 0.0001; 80 mU/m2/min: 4.16 -t 0.34 versus 8.49 k 0.45 mg/kg/min, p < 0.0001; 200 mU/m2/min: 5.22 ? 0.53 versus 10.06 -t 0.50 mg/kg/min, p < 0.0001). These marked decreases in glucose disposal rates for the patients were adjusted in accordance with their 24-hour urinary creatinine excretion rate to correct for the difference in muscle mass between patients and controls. This adjusted glucose disposal rate was 15 to 25% lower (p < 0.02) in the patients with myotonic dystrophy at insulin infusion rates of 20 and 80 mu. During the 200 mU insulin infusions, the adjusted glucose disposal rate remained lower than that in normal subjects but was of borderline statistical significance. These studies suggest that moderately severe whole body insulin resistance is responsible for the postprandial hyperinsulinemia typically seen in patients with myotonic dystrophy.