Hypersecretion of immunoreactive gastric inhibitory polypeptide (IRGIP) has been reported previously in patients with diabetes mellitus (DM) and obesity. To ascertain the relative contribution of glucose intolerance and obesity to the abnormalities of IRGIP secretion, 114 subjects were studied during a standard oral glucose (75 g) tolerance test; responses of glucose, insulin, C-peptide, IRGIP, and glucagon were evaluated. The subjects were divided into six subgroups according to body weight and the degree of glucose intolerance. In normal weight subjects, the IRGIP response to oral glucose was significantly higher in the patients with impaired glucose tolerance (IGT) and DM than in the healthy control subjects (P less than 0.05). In the obese subjects, no significant differences in mean IRGIP responses could be detected among control, IGT, and DM subjects. In spite of similar IRGIP responses, the obese IGT patients did release more insulin than the obese control subjects, suggesting that incretin factors other than GIP may be operative in this condition. When obese and nonobese patients were compared, the obese subjects with normal glucose tolerance released a greater amount of IRGIP and insulin than the normal weight controls, whereas no significant difference between obese and nonobese could be found within the IGT and DM groups. We conclude that in the absence of obesity, glucose intolerance may induce IRGIP hypersecretion. On the other hand, obesity is associated with IRGIP hypersecretion, and glucose intolerance has no further effect, indicating a different pathogenetic mechanism for the IRGIP abnormalities. In both the obese and nonobese diabetic groups, IRGIP hypersecretion was associated with a failure of plasma glucagon levels to fall after oral glucose; this effect might be related to the glucagonotropic action of this peptide.