The secretion of islet amyloid polypeptide (IAPP) during the course of insulin-dependent diabetes mellitus (IDDM) is essentially unknown. In the present study we elucidated this issue by examining IAPP and insulin secretion from isolated pancreatic islets obtained from IDDM-prone female NOD mice aged 6-9 weeks and 12-15 weeks and from non-IDDM-prone male NMRI mice. Basal islet hormone secretion at 1.7 mM glucose and after stimulation with 17 mM glucose or with 17 mM glucose + 5 mM theophylline was studied acutely or after 1 week of tissue culture. The levels of glucose-stimulated insulin release from NOD mouse islets increased after tissue culture, whereas it remained unchanged in NMRI mouse islets. Overall changes in islet insulin secretion were accompanied by similar changes in IAPP secretion. Acute after isolation, islets from NMRI mice displayed a reduced IAPP/insulin secretion ratio in response to the stimulation, which could reflect a destabilized hormone release. When the NOD mouse islets at 6-9 weeks of age were exposed to secretory stimuli the molar ratio of IAPP/insulin secretion declined. At a later stage of advanced insulitis (12-15 weeks) also the basal IAPP/insulin secretory ratio at low glucose tended to decline. If extrapolated to the early prediabetic phase of human IDDM, this would mean that a relative hypersecretion of insulin in relation to IAPP might occur, due to an increased secretory demand for insulin or due to an intrinsic change in the biology of the secretory cells.