Islet amyloid polypeptide (IAPP) is synthesized in islet beta cells and has been implicated in diabetes pathogenesis because it can inhibit insulin secretion and action and form fibrils leading to islet amyloidosis. Its physiological function has, however, not been established. We therefore examined insulin secretion and glucose elimination after i.v. or gastric gavage of glucose in transgenic mice overexpressing human IAPP (hIAPP) resulting in considerably increased circulating IAPP concentrations. The insulin response to and the glucose elimination after i.v. glucose (1 g/kg) were not different in transgenic mice compared with wild type animals, neither in males nor in females. In contrast, the insulin response to gastric glucose (150 mg/mouse) was reduced and the glucose elimination was inhibited in both male and female transgenic mice. The area under the 30 min insulin curve (AUCinsulin) was 21 +/- 2 nmol/l in 30 min in transgenic males (n = 24) vs 43 +/- 3 nmol/l in 30 min in wild type males (n = 26; p < 0.001) and the respective areas under the glucose curve (AUCglucose) were 1.90 +/- 0.12 and 1.62 +/- 0.09 mol/l in 120 min (p < 0.05). Similarly, in females, the AUCinsulin was 17 +/- 2 nmol/l in 30 min in transgenic mice vs 25 +/- 3 nmol/l in 30 min in wild type mice (p < 0.05) and the respective AUCglucose was 1.62 +/- 0.7 and 1.12 +/- 0.07 mol/l in 120 min (p < 0.001). Hence, endogenous hIAPP inhibits insulin secretion and glucose elimination after gastric glucose gavage in both male and female mice, indicating that overexpression of hIAPP could be a diabetogenic factor, via effects on the intestinal tract or the gut-islet axis or both.