详细记录  
题名:IL-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; AOUIZERAT T; GURGUL-CONVEY E; RAZ I; SAADA A;
来源:Am J Physiol Endocrinol Metab. 2014 Mar;306(6):E648-57. doi: [ IF= 0.00 ] ]
URL :10.1152/ajpendo.00451.2013
日期:20140408
摘要: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-1beta 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-1beta, N(omega)-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-1beta (2.5
U/ml) reduced GSIS and COX activity in CDs islets. Exposure to 10 U/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 the
HSD diet, which was reduced by copper supplementation. N(omega)-nitro-l-arginine
and copper prevented the deleterious effect of interleukin-1beta 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 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.

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