Aims/hypothesis High-sucrose-low-copper-diet (HSD) induces inhibition of glucose-stimulated-insulin-secretion (GSIS), pancreatic-acinar-cell apoptosis and infiltration of interleukin-1β expressing-macrophages in hyperglycemic-Cohen-diabetes-sensitive rats (CDs), but not in Cohen-diabetes-resistant rats (CDr). Copper-supplemented-HSD increased activity of the copper-dependent mitochondrial-respiratory-chain-enzyme, cytochrome-c-oxidase (COX) and reversed hyperglycemia. This study examined the mechanism by which interleukin-1β modulates GSIS and the role of COX in this process. Methods We measured COX-activity, ATP-content, GSIS, iNOS expression and nitrite-production in isolated-islets of CDs and CDr fed different-diets, +/- interleukin-1β and N-nitro-L-arginine, copper or potassium-cyanide. Results A parallel reduction in COX-activity, ATP-content and GSIS was exhibited by isolated-islets of CDs-rats, fed regular-diet. These were severely-reduced following HSD and were restored to regular-diet levels on copper-supplemented-HSD (p<0.01 vs. CDr-islets). Potassium-cyanide chemically reduced COX-activity, decreasing GSIS, thus, reinforcing the link between islet-COX-activity and GSIS. Interleukin-1β (2.5U/ml) reduced GSIS and COX-activity in CDs-islets. Exposure to 10U/ml interleukin-1β decreased GSIS and COX-activity in both CDs and CDr islets inducing a similar nitrite production. Nevertheless, the effect on GSIS was more marked in CDs-islets. A significant iNOS expression was detected in CDs on HSD diet, which was reduced by copper-supplementation. N-nitro-L-arginine, and copper prevented the deleterious-effect of interleukin-1β on COX-activity and GSIS. Conclusions/interpretation Reduced islets-COX-activity renders vulnerability to GSIS-inhibition on low-copper-HSD through two interrelated pathways, 1) by further reducing the activity of COX essential for β-cell ATP-production and insulin-secretion, and, 2) by inducing the expression of iNOS and nitric-oxide-mediated COX-inhibition. We suggest, that islet COX-activity must be maintained above a critical-threshold to sustain adequate-GSIS with exposure to low-copper-HSD.