Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat.
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.
Lacraz
Grégory
G
Laboratory of Biology & Pathology of Endocrine Pancreas, Functional and Adaptive Biology Unit-CNRS EA 7059, University Paris-Diderot, Paris, France.
Giroix
Marie-Hélène
MH
Kassis
Nadim
N
Coulaud
Josiane
J
Galinier
Anne
A
Noll
Christophe
C
Cornut
Mélanie
M
Schmidlin
Fabien
F
Paul
Jean-Louis
JL
Janel
Nathalie
N
Irminger
Jean-Claude
JC
Kergoat
Micheline
M
Portha
Bernard
B
Donath
Marc Y
MY
Ehses
Jan A
JA
Homo-Delarche
Françoise
F
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
D000975:Antioxidants; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1