Obese mice (Umeå ob/ob) and their lean litter-mates were investigated from 7 to 52 weeks of age with respect to the plasma concentration of islet amyloid polypeptide (IAPP) and insulin. Plasma levels of IAPP were highly elevated in the ob/ob mice and remained unchanged until age 33 weeks, after which a sudden significant increase occurred at age 40 weeks. The plasma concentration of insulin gradually increased from start to end and reached extremely high levels. In the lean mice, there were no age-related differences in plasma levels of IAPP and insulin, being of the same magnitude as in normal NMRI mice. The plasma IAPP/insulin molar ratio was similar in lean and obese mice until age 14 weeks. At 21 weeks, the ratio in the ob/ob mice had decreased dramatically and remained markedly (sixfold) lower than in the lean mice until the end of the study. The IAPP concentration in the pancreata of 21-week-old ob/ob mice was 25-fold higher than that in the lean mice. Immunohistochemically, a majority of the ob/ob mice displayed enlarged and more numerous pancreatic islets, compared with the lean mice, and the IAPP- and insulin-labeling intensity was equal for all animals. At the electron-microscopic level, there was an increase in the number of IAPP- and insulin-immunoreactive gold particles per whole granule area as well as per core granule area. We conclude that the dramatically increased IAPP levels in severely hyperinsulinemic ob/ob mice may be of importance for the development of insulin resistance. Further, the disproportionate secretion of IAPP and insulin in the adult obese mouse might indicate a disturbed negative feedback effect of IAPP on insulin secretory mechanisms, resulting in very high plasma insulin levels.