To evaluate the metabolic basis of gestational glucose intolerance (gestational diabetes), the response of normal pregnant women (N=6) and lean (N=23), and obese (N=12) gestational diabetics to the physiologic challenge of a 400-kcal mixed meal breakfast tolerance test was studied. Obese patients with gestational diabetes were more hyperglycemic than the lean gestational diabetics in both the fasting and postprandial periods. Women with gestational diabetes had a more prolonged glycemic response and a later insulin response to meal stimulation than normal control subjects. Fasting and postprandial insulin levels were higher in the obese gestational diabetes group, whereas those of lean subjects fell below the values of the control group. The percent specific binding of insulin to red blood cell receptors was lower in both gestational diabetes groups than in control subjects, with the most marked decrease in the obese group. Mean fasting plasma levels of total cholesterol and triglyceride and plasma glucagon levels during the meal tolerance test were not significantly different among the three groups. Obese gestational diabetics had significantly larger infants and placentas than lean gestational diabetics. These findings, taken together, suggest that the pathophysiology of gestational diabetes differs between obese and lean patients. Lean gestational diabetics appear to develop glucose intolerance on the basis of relative insulin deficiency in contrast to obese gestational diabetics who manifest glucose intolerance characterized by insulin resistance, hyperinsulinemia, and decreased insulin binding to red blood cell receptors.