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

Chronic hyperglycaemia 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 PKCalpha. Here we show that HGA-induced PKCalpha activation is mediated by Src. Co-precipitation experiments showed that Src interacts with both RAGE and PKCalpha in HGA-treated L6 cells. A direct interaction of PKCalpha with Src and IRS-1 has also been detected. In addition, silencing of IRS-1 expression abolished HGA-induced RAGE-PKCalpha 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 PKB phosphorylation were reduced. This was paralleled by a 2.5-fold increase in PKCalpha 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 PKCalpha. 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 PKCalpha.