Obese mice (Umeå oblob) and their lean littermates 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 oblob 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 IAPPlinsulin molar ratio was similar in lean and obese mice until age 14 weeks. At 21 weeks, the ratio in the oblob 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 oblob mice was 25-fold higher than that in the lean mice. Immunohistochemically, a majority of the oblob mice displayed enlarged and more numerous pancreatic islets, compared with the lean mice, and the IAPP- and insulinlabeling intensity was equal for all animals. At the electronmicroscopic 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 oblob 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.