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Division for Physiology, Department of Biomedicine, University of Bergen, Bergen, Norway

In this study we present a novel function of insulin in rat dermis. We investigated local effects of insulin on interstitial fluid pressure (P_if), and capillary albumin leakage and pro-inflammatory cytokine production in skin and serum after intravenous lipopolysaccharide (LPS), tumour necrosis factor- (TNF-) and interleukin-1ß (IL-1ß) challenge treated with a glucose–insulin–potassium regimen (GIK). The main objective for this study was to investigate anti-inflammatory effects of insulin. Work by others shows that insulin stimulates cell adhesion, and that this effect is dependent upon phosphatidylinositol 3-kinase (PI3K) activity. Cytokines like platelet-derived growth factor BB (PDGF-BB) attenuate lowering of P_if, possibly via PI3K. LPS and pro-inflammatory cytokines contribute to oedema development during acute inflammation by lowering the P_if. Intravenous injection of LPS, TNF- or IL-1ß to Wistar Møller rats caused a lowering of P_if, but after local injection of insulin in the paw, P_if increased back to control values. IL-1ß caused a lowering in control from –0.5 ± 0.2 mmHg to –3.0 ± 0.2 mmHg after 20 min (mean ± S.E.M.) (P < 0.05). Within 50 min after insulin injection the pressure was increased to –0.6 ± 0.2 mmHg (P > 0.05 compared with control). Insulin was given together with a PI3K inhibitor (wortmannin) locally in the skin, almost abolishing the effect of insulin on P_if. A GIK regimen was given as a continuous intravenous infusion, significantly attenuating the oedema formation after LPS or TNF-/IL-1ß challenge. The same GIK regimen caused a significant reduction in pro-inflammatory cytokines in serum and in interstitial fluid in skin of endotoxaemic rats. These experiments show a possible role for insulin in the interstitium during inflammation induced by LPS and TNF-/IL-1ß. Insulin can attenuate a lowering of P_if possibly via PI3K, and it has an anti-inflammatory effect by inhibiting production of pro-inflammatory cytokines.

(Received 6 May 2004; accepted after revision 28 June 2004; first published online 2 July 2004)
Corresponding author T. Nedrebø: Division for Physiology, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway. Email: torbjorn.nedrebo{at}fys.uib.no

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