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We measured COX activity, ATP content, GSIS, iNOS expression, and nitrite production with and without IL-1\u03b2, N<jats:sup>\u03c9<\/jats:sup>-nitro-l-arginine, copper, or potassium cyanide in isolated islets of CDs and CDr fed different diets. We found reduced COX activity, ATP content, and GSIS in isolated islets of CDs rats fed a regular diet. These were severely reduced following HSD and were restored to regular diet levels on copper-supplemented HSD ( P &lt; 0.01 vs. CDr islets). Potassium cyanide chemically reduced COX activity, decreasing GSIS and thus reinforcing the link between islet COX activity and GSIS. Interleukin-1\u03b2 (2.5 U\/ml) reduced GSIS and COX activity in CDs islets. Exposure to 10 U\/ml interleukin-1\u03b2 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 the HSD diet, which was reduced by copper supplementation. N<jats:sup>\u03c9<\/jats:sup>-nitro-l-arginine and copper prevented the deleterious effect of interleukin-1\u03b2 on COX activity and GSIS. We conclude that reduced islet COX activity renders vulnerability to GSIS inhibition on low-copper HSD through two interrelated pathways: 1) by further reducing the activity of COX that is essential for \u03b2-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.<\/jats:p>","DOI":"10.1152\/ajpendo.00451.2013","type":"journal-article","created":{"date-parts":[[2014,1,15]],"date-time":"2014-01-15T06:42:24Z","timestamp":1389768144000},"page":"E648-E657","source":"Crossref","is-referenced-by-count":13,"title":["IL-1\u03b2 hampers glucose-stimulated insulin secretion in Cohen diabetic rat islets through mitochondrial cytochrome<i>c<\/i>oxidase inhibition by nitric oxide"],"prefix":"10.1152","volume":"306","author":[{"given":"Sarah","family":"Weksler-Zangen","sequence":"first","affiliation":[{"name":"Diabetes Unit, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Genya","family":"Aharon-Hananel","sequence":"additional","affiliation":[{"name":"Diabetes Unit, Department of Internal Medicine, Hadassah-Hebrew 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