Effects of insulin excess and deficiency on glucose-dependent insulinotropic polypeptide (GIP) was examined in rats following insulinoma transplantation or streptozotocin (STZ) administration. Over 14 days, food intake was increased (p<0.001) in both groups of rats, with decreased body weight (p<0.01) in STZ rats. Non-fasting plasma glucose levels were decreased (p<0.01) and plasma insulin levels increased (p<0.001) in insulinoma-bearing rats, whereas STZ treatment elevated glucose (p<0.001) and decreased insulin (p<0.01). Circulating GIP concentrations were elevated (p<0.01) in both animal models. At 14 days, oral glucose resulted in a decreased glycaemic excursion (p<0.05) with concomitant elevations in insulin release (p<0.001) in insulinoma-bearing rats, whereas STZ-treated rats displayed similar glucose-lowering effects but reduced insulin levels (p<0.01). GIP concentrations were augmented in STZ rats (p<0.05) following oral glucose. Plasma glucose and insulin concentrations were not affected by oral fat, but fat-induced GIP secretion was particularly (p<0.05) increased in insulinoma-bearing rats. Exogenous GIP enhanced (p<0.05) glucose-lowering in all groups of rats accompanied by insulin releasing (p<0.001) effects in insulinoma-bearing and control rats. Both rat models exhibited increased (p<0.001) intestinal weight but decreased intestinal GIP concentrations. These data suggest that circulating insulin has direct and indirect effects on the synthesis and secretion of GIP.