Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 52, Pages 36088-36099Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M801698200
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Funding
- European Foundation
- GlaxoSmithKline Programme
- Consiglio Nazionale delle Ricerche Grant RSLT
- European Community FP6 EUGENE2 [LSHM-CT-2004-512013]
- PRE-POBEDIA
- Associazione Italiana per la Ricerca sul Cancro
- Ministero dell'Universitae della Ricerca Scientifica [PRIN, FIRB RBNE0155LB]
- INSERM
- Universite de Nice-Sophia-Antipolis
- Conseil Regional PACA
- Conseil General des Alpes-Maritimes
- Fondation de France
- PRND
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Chronic hyperglycemia promotes insulin resistance at least in part by increasing the formation of advanced glycation end products (AGEs). We have previously shown that in L6 myotubes human glycated albumin (HGA) induces insulin resistance by activating protein kinase C alpha(PKC alpha). Here we show that HGA-induced PKC alpha activation is mediated by Src. Coprecipitation experiments showed that Src interacts with both the receptor for AGE (RAGE) and PKC alpha in HGA-treated L6 cells. A direct interaction of PKC alpha with Src and insulin receptor substrate-1 (IRS-1) has also been detected. In addition, silencing of IRS-1 expression abolished HGA-induced RAGE-PKC alpha co-precipitation. AGEs were able to induce insulin resistance also in vivo, as insulin tolerance tests revealed a significant impairment of insulin sensitivity in C57/BL6 mice fed a high AGEs diet (HAD). In tibialis muscle of HAD-fed mice, insulin-induced glucose uptake and protein kinase B phosphorylation were reduced. This was paralleled by a 2.5-fold increase in PKC alpha activity. Similarly to in vitro observations, Src phosphorylation was increased in tibialis muscle of HAD-fed mice, and co-precipitation experiments showed that Src interacts with both RAGE and PKC alpha. These results indicate that AGEs impairment of insulin action in the muscle might be mediated by the formation of a multimolecular complex including RAGE/IRS-1/Src and PKC alpha
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