In skeletal muscle advanced glycation end products (AGEs) inhibit insulin action and induce the formation of multimolecular complexes including the receptor for AGEs

Angela Cassese, Iolanda Esposito, Francesca Fiory, Alessia P.M. Barbagallo, Flora Paturzo, Paola Mirra, Luca Ulianich, Ferdinando Giacco, Claudia Iadicicco, Angela Lombardi, Francesco Oriente, Emmanuel Van Obberghen, Francesco Beguinot, Pietro Formisano, Claudia Miele

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79 Scopus citations

Abstract

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 Cα (PKCα). Here we show that HGA-induced PKCα activation is mediated by Src. Coprecipitation experiments showed that Src interacts with both the receptor for AGE (RAGE) and PKCα in HGA-treated L6 cells. A direct interaction of PKCα with Src and insulin receptor substrate-1 (IRS-1) has also been detected. In addition, silencing of IRS-1 expression abolished HGA-induced RAGE-PKCα 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 PKCα 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 PKCα. 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 PKCα.

Original languageEnglish (US)
Pages (from-to)36088-36099
Number of pages12
JournalJournal of Biological Chemistry
Volume283
Issue number52
DOIs
StatePublished - Dec 26 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Cassese, A., Esposito, I., Fiory, F., Barbagallo, A. P. M., Paturzo, F., Mirra, P., Ulianich, L., Giacco, F., Iadicicco, C., Lombardi, A., Oriente, F., Van Obberghen, E., Beguinot, F., Formisano, P., & Miele, C. (2008). In skeletal muscle advanced glycation end products (AGEs) inhibit insulin action and induce the formation of multimolecular complexes including the receptor for AGEs. Journal of Biological Chemistry, 283(52), 36088-36099. https://doi.org/10.1074/jbc.M801698200