Islet amyloid polypeptide and insulin relationship in a longitudinal studyof the genetically obese (ob/ob) mouse

Obese mice (Umea ob/ob) and their lean littermates were investigated from 7 to 52 weeks of age with respect: to the plasma concentration of islet amyl oid polypeptide (IAPP) and insulin. Plasma levels of IAPP were highly eleva ted in the ob/ob mice and remained unchanged until age 33 weeks, after whic h a sudden significant increase occurred at age 40 weeks. The plasma concen tration of insulin gradually increased from start to end and reached extrem ely 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 norma l NMRI mice. The plasma IAPP/insulin molar ratio was similar in lean and ob ese mice until age 14 weeks. At 21 weeks, the ratio in the ob/ob mice had d ecreased dramatically and remained markedly (sixfold) lower than in the lea n 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. I mmunohistochemically, a majority of the ob/ob mice displayed enlarged and m ore numerous pancreatic islets, compared with the lean mice, and the IAPP- and insulin-labeling intensity was equal for all animals. At the electron-m icroscopic level, there was an increase in the number of IAPP- and insulin- immunoreactive gold particles per whole granule area as well as per core gr anule area. We conclude that the dramatically increased IAPP levels in seve rely hyperinsulinemic ob/ob mice may be of importance for the development o f insulin resistance. Further, the disproportionate secretion of IAPP and i nsulin in the adult obese mouse might indicate a disturbed negative feedbac k effect of IAPP on insulin secretory mechanisms, resulting in very high pl asma insulin levels.