Figure 3.
Excessive AGEs impair insulin sensitivity in insulin-target tissues. In adipocytes, as in immune cells, AGE-mediated effects are normally controlled by AGER1, via ROS suppression, protecting SIRT1-dependent insulin functions. Excessive food-derived protein and lipid AGEs can suppress AGER1 and other host defenses, reversing this balance. For instance, exposure to AGEs reduces insulin receptor and IRS1 tyrosine phosphorylation and increases IRS1 serine phosphorylation, resulting in impaired insulin signaling and decreased glucose uptake. Enhanced NFκB p65 hyperacetylation of preadipocytes, endothelial cells and immune cells residing in adipose tissue can also promote inflammatory cytokine production, impair FOXO3α activity and further ROS production. Restored AGER1 and SIRT1, following AGE restriction in individuals with diabetes mellitus, coincides with markedly lower plasma insulin levels and higher adiponectin levels —evidence of a crucial crosstalk between host defenses and metabolic pathways in diverse tissues and cells. Abbreviations: Acl, acetylation; AGE, advanced glycation endproduct; AGER1, AGE receptor 1; ALE, advanced lipoxidation endproduct; FOXO3α, forkhead box protein O3 α; GLUT4, glucose transporter type 4; IR, insulin receptor; IRS, insulin receptor substrate; NFκB, nuclear factor κB; pAkt, phosphorylated serine/threonine-protein kinase AKT; pSer, serine phosphorylation; pTyr, tyrosine phosphorylation; ROS, reactive oxygen species; SIRT1, NAD-dependent deacetylase sirtuin-1; SOD2, mitochondrial superoxide dismutase 2 [Mn].