Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-20373
Ehses, J A; Lacraz, G; Giroix, M H; Schmidlin, F; Coulaud, J; Kassis, N; Irminger, J C; Kergoat, M; Portha, B; Homo-Delarche, F; Donath, M Y (2009). IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 106(3):13998-14003.
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-1beta. In the periphery, increased expression of IL-1beta 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-1beta 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-1beta, IL-6, TNFalpha, KC, MCP-1, and MIP-1alpha) 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-1beta activity in the GK rat promotes cytokine and chemokine expression, leading to the recruitment of innate immune cells. Rather than being directly cytotoxic, IL-1beta may drive tissue inflammation that impacts on both beta cell functional mass and insulin sensitivity in type 2 diabetes.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > University Hospital Zurich > Clinic for Endocrinology and Diabetology|
04 Faculty of Medicine > Center for Integrative Human Physiology
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Date:||18 August 2009|
|Deposited On:||25 Aug 2009 14:11|
|Last Modified:||27 Nov 2013 22:27|
|Publisher:||National Academy of Sciences|
|Additional Information:||Copyright: National Academy of Sciences USA - Free full text article|
|Citations:||Web of Science®. Times Cited: 95|
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