Mechanism of suppression of insulin signalling with lignocaine.
Lignocaine suppresses insulin-stimulated glucose transport into the cells and insulin-stimulated glycogenesis at doses equivalent to that used in the treatment of muscle pain disorder. We evaluated the direct effect of lignocaine on insulin receptor (IR) kinase activity. After lignocaine (40 mM, approximately equivalent to 1%) or an equal volume (100 microl) saline had been injected into the tibialis anterior muscle of rat, insulin (50 mM g-1 body weight) was administered into the portal vein in vivo. Immunoprecipitation and immunoblotting were used to detect insulin-mediated tyrosine phosphorylation of both IR-beta and insulin receptor substrate (IRS)-1, and insulin-stimulated binding of IRS-1 to p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3-K) in the extracted muscle. In the in vitro study, purified IR from rat liver and/or recombinant IRS-1 protein with adenosine triphosphate were incubated with lignocaine (4 or 40 mM). Lignocaine reduced insulin-stimulated tyrosine phosphorylation of IR-beta to 12.6+/-5.7% (P<0.001), and IRS-1 to 32.1+/-18.8% (P<0.01), and also reduced insulin-stimulated binding of IRS-1 to p85 to 27.4+/-12.7% (P<0.001) relative to control (100%) in muscle in vivo. The in vitro study revealed that lignocaine directly inhibited both basal and insulin-stimulated tyrosine phosphorylation of IR. These results indicate that clinically used doses of lignocaine inhibit insulin signalling in skeletal muscle. The inhibitory effect of lignocaine on tyrosine kinase activity of the IR underlies the suppression of insulin signalling with lignocaine.
Hirose
Munetaka
M
Department of Anaesthesiology, Kyoto Prefectural University of Medicine, Kamigyoku, Kyoto 602-8566, Japan. hirose@koto.kpu-m.ac.jp
Martyn
J A Jeevendra
JA
Kuroda
Yoshihiro
Y
Marunaka
Yoshinori
Y
Tanaka
Yoshifumi
Y
D000779:Anesthetics, Local / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D003864:Depression, Chemical; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D008012:Lidocaine / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry
D000779:Anesthetics, Local; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D014443:Tyrosine; D008012:Lidocaine; D011972:Receptor, Insulin