题名：Interleukin-1beta hampers glucose stimulated insulin secretion in Cohen diabetic rat islets through mitochondrial cytochrome c oxidase inhibition by nitric-oxide.
作者：WEKSLER-ZANGEN S; AHARON-HANANEL G; MANTZUR C; AOUIZERA T; GURGUL-CONVEY E; RAZ I; SAADA A;
来源：Am J Physiol Endocrinol Metab. 2014 Jan 14. [ IF= 0.00 ] ]
摘要：Aims/hypothesis High-sucrose-low-copper-diet (HSD) induces inhibition of
glucose-stimulated-insulin-secretion (GSIS), pancreatic-acinar-cell apoptosis and
infiltration of interleukin-1beta 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-1beta 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-1beta and Nomega-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-1beta (2.5U/ml) reduced GSIS and COX-activity in CDs-islets. Exposure
to 10U/ml interleukin-1beta 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.
Nomega-nitro-L-arginine, and copper prevented the deleterious-effect of
interleukin-1beta 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 beta-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.