title: Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat.
abstract: BACKGROUND
  Inflammation followed by fibrosis is a component of islet dysfunction in both rodent and human type 2 diabetes. Because islet inflammation may originate from endothelial cells, we assessed the expression of selected genes involved in endothelial cell activation in islets from a spontaneous model of type 2 diabetes, the Goto-Kakizaki (GK) rat. We also examined islet endotheliuml/oxidative stress (OS)/inflammation-related gene expression, islet vascularization and fibrosis after treatment with the interleukin-1 (IL-1) receptor antagonist (IL-1Ra).
  
  
  RESULTS
  Gene expression was analyzed by quantitative RT-PCR on islets isolated from 10-week-old diabetic GK and control Wistar rats. Furthermore, GK rats were treated s.c twice daily with IL-1Ra (Kineret, Amgen, 100 mg/kg/day) or saline, from 4 weeks of age onwards (onset of diabetes). Four weeks later, islet gene analysis and pancreas immunochemistry were performed. Thirty-two genes were selected encoding molecules involved in endothelial cell activation, particularly fibrinolysis, vascular tone, OS, angiogenesis and also inflammation. All genes except those encoding angiotensinogen and epoxide hydrolase (that were decreased), and 12-lipoxygenase and vascular endothelial growth factor (that showed no change), were significantly up-regulated in GK islets. After IL-1Ra treatment of GK rats in vivo, most selected genes implied in endothelium/OS/immune cells/fibrosis were significantly down-regulated. IL-1Ra also improved islet vascularization, reduced fibrosis and ameliorated glycemia.
  
  
  CONCLUSIONS
  GK rat islets have increased mRNA expression of markers of early islet endothelial cell activation, possibly triggered by several metabolic factors, and also some defense mechanisms. The beneficial effect of IL-1Ra on most islet endothelial/OS/immune cells/fibrosis parameters analyzed highlights a major endothelial-related role for IL-1 in GK islet alterations. Thus, metabolically-altered islet endothelium might affect the beta-cell microenvironment and contribute to progressive type 2 diabetic beta-cell dysfunction in GK rats. Counteracting islet endothelial cell inflammation might be one way to ameliorate/prevent beta-cell dysfunction in type 2 diabetes.
authors.affiliation: Laboratory of Biology & Pathology of Endocrine Pancreas, Functional and Adaptive Biology Unit-CNRS EA 7059, University Paris-Diderot, Paris, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Lacraz
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Giroix
authors.forename: Nadim
authors.initials: N
authors.lastname: Kassis
authors.forename: Josiane
authors.initials: J
authors.lastname: Coulaud
authors.forename: Anne
authors.initials: A
authors.lastname: Galinier
authors.forename: Christophe
authors.initials: C
authors.lastname: Noll
authors.forename: Mélanie
authors.initials: M
authors.lastname: Cornut
authors.forename: Fabien
authors.initials: F
authors.lastname: Schmidlin
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Paul
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Irminger
authors.forename: Micheline
authors.initials: M
authors.lastname: Kergoat
authors.forename: Bernard
authors.initials: B
authors.lastname: Portha
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
authors.forename: Jan A
authors.initials: JA
authors.lastname: Ehses
authors.forename: Françoise
authors.initials: F
authors.lastname: Homo-Delarche
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology*; D008297:Male; D008954:Models, Biological; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000975:Antioxidants; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1