title: IL-1β hampers glucose-stimulated insulin secretion in Cohen diabetic rat islets through mitochondrial cytochrome c oxidase inhibition by nitric oxide.
abstract: A high-sucrose, low-copper-diet (HSD) induces inhibition of glucose-sensitive rats (CDs) but not 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. We measured COX activity, ATP content, GSIS, iNOS expression, and nitrite production with and without IL-1β, N(ω)-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 < 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-1β (2.5 U/ml) reduced GSIS and COX activity in CDs islets. Exposure to 10 U/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 the HSD diet, which was reduced by copper supplementation. N(ω)-nitro-l-arginine and copper prevented the deleterious effect of interleukin-1β 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 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.
authors.affiliation: Diabetes Unit, Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel;
authors.forename: Sarah
authors.initials: S
authors.lastname: Weksler-Zangen
authors.forename: Genya
authors.initials: G
authors.lastname: Aharon-Hananel
authors.forename: Carmit
authors.initials: C
authors.lastname: Mantzur
authors.forename: Tzemach
authors.initials: T
authors.lastname: Aouizerat
authors.forename: Ewa
authors.initials: E
authors.lastname: Gurgul-Convey
authors.forename: Itamar
authors.initials: I
authors.lastname: Raz
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
mesh_terms: D000818:Animals; D003300:Copper / Q000172:deficiency / Q000378:metabolism / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control; D019422:Dietary Sucrose / Q000009:adverse effects; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism / Q000517:prevention & control; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D053583:Interleukin-1beta / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D009994:Osmolar Concentration; D051381:Rats; D011919:Rats, Inbred Strains; D046509:Tissue Culture Techniques
chemical_list: D019422:Dietary Sucrose; D004791:Enzyme Inhibitors; D007328:Insulin; D053583:Interleukin-1beta; D009569:Nitric Oxide; D003300:Copper; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D003576:Electron Transport Complex IV; D005947:Glucose
keywords: copper; cytochrome c oxidase; inducible nitrix oxide synthase; interleukin-1β; pancreatic β-cell