To investigate the possibility that an abnormality of the entero-insular axis is responsible for the hyperinsulinaemia of obesity, serum immunoreactive gastric inhibitory polypeptide (IR-GIP) and insulin (IRI) were measured after the ingestion of a liquid mixed test meal, glucose or fat, in normal weight and obese subjects. The latter were divided into a group with normal oral glucose tolerance (nOGT) and a group with pathological glucose tolerance (pOGT). Fasting levels of IR-GIP were significantly elevated in the obese group with pOGT. After the mixed meal the overweight subjects showed a significantly greater response of IR-GIP than the controls, with highest levels in the pOGT group. Simultaneously, the IRI response was significantly greater in the obese subjects than in the controls. The increases of IR-GIP and IRI after an oral load of 100 g glucose were normal in the obese subjects, but showed a significantly greater integrated response in the obese patients with pOGT. The ingestion of 100 g fat induced no IRI release but a significantly greater release of IR-GIP in the obese subjects, irrespective of their glucose tolerance. It is concluded that fat is a stronger releaser of IR-GIP than glucose. The effect of a combined load of glucose (30 g) and fat (100 g) was also compared in obese and normal weight subjects with the effect of either alone. Fat but not glucose released significantly more IR-GIP in obese subjects. In normal weight controls, but not in obese subjects, the IR-GIP release after fat plus glucose became significantly smaller than after fat alone. Since only the combined ingestion of glucose and fat and not fat alone releases insulin it is suggested that endogenous insulin inhibits GIP release and that this feedback control between insulin and GIP is defective in patients with obesity.