IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat

被引：294

作者：

Ehses, J. A. ^{[1
,2
]}

Lacraz, G. ^{[3
]}

Giroix, M. -H. ^{[3
]}

Schmidlin, F. ^{[4
]}

Coulaud, J. ^{[3
]}

Kassis, N. ^{[3
]}

Irminger, J. -C. ^{[5
]}

Kergoat, M. ^{[4
]}

Portha, B. ^{[3
]}

Homo-Delarche, F. ^{[3
]}

Donath, M. Y. ^{[1
,2
]}

机构：

[1] Univ Zurich Hosp, Div Endocrinol Diabet & Nutr, CH-8045 Zurich, Switzerland

[2] Univ Zurich Hosp, Ctr Integrated Human Physiol, CH-8045 Zurich, Switzerland

[3] Univ Paris Diderot, CNRS, EAC 7059, Unit Funct & Adapt Biol, F-75205 Paris, France

[4] Merck Sante, F-91380 Chilly Mazarin, France

[5] Ctr Med Univ Geneva, Dept Genet Med & Dev, CH-1211 Geneva, Switzerland

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 33期

基金：

瑞士国家科学基金会;

关键词：

interleukin-1; metabolic stress; pancreatic islet; insulin resistance; beta cells; HUMAN PANCREATIC-ISLETS; HIGH-FAT DIET; BETA-CELL; INSULIN-SECRETION; RECEPTOR ANTAGONIST; INTERLEUKIN-1; FAMILY; FOOD-INTAKE; GLUCOSE; EXPRESSION; IL-1-BETA;

D O I：

10.1073/pnas.0810087106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Recent studies suggest an inflammatory process, characterized by local cytokine/chemokine production and immune cell infiltration, regulates islet dysfunction and insulin resistance in type 2 diabetes. However, the factor initiating this inflammatory response is not known. Here, we characterized tissue inflammation in the type 2 diabetic GK rat with a focus on the pancreatic islet and investigated a role for IL-1. GK rat islets, previously characterized by increased macrophage infiltration, displayed increased expression of several inflammatory markers including IL-1 beta. In the periphery, increased expression of IL-1 beta was observed primarily in the liver. Specific blockade of IL-1 activity by the IL-1 receptor antagonist (IL-1Ra) reduced the release of inflammatory cytokines/chemokines from GK islets in vitro and from mouse islets exposed to metabolic stress. Islets from mice deficient in IL-1 beta or MyD88 challenged with glucose and palmitate in vitro also produced significantly less IL-6 and chemokines. In vivo, treatment of GK rats with IL-1Ra decreased hyperglycemia, reduced the proinsulin/insulin ratio, and improved insulin sensitivity. In addition, islet-derived proinflammatory cytokines/chemokines (IL-1 beta, IL-6, TNF alpha, KC, MCP-1, and MIP-1 alpha) and islet CD68(+), MHC II+, and CD53(+) immune cell infiltration were reduced by IL-1Ra treatment. Treated GK rats also exhibited fewer markers of inflammation in the liver. We conclude that elevated islet IL-1 beta activity in the GK rat promotes cytokine and chemokine expression, leading to the recruitment of innate immune cells. Rather than being directly cytotoxic, IL-1 beta may drive tissue inflammation that impacts on both beta cell functional mass and insulin sensitivity in type 2 diabetes.

引用

页码：13998 / 14003

页数：6

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