Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1

Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):15888-93. doi: 10.1073/pnas.1205847109. Epub 2012 Aug 20.


The epidemics of insulin resistance (IR) and type 2 diabetes (T2D) affect the first world as well as less-developed countries, and now affect children as well. Persistently elevated oxidative stress and inflammation (OS/Infl) precede these polygenic conditions. A hallmark of contemporary lifestyle is a preference for thermally processed nutrients, replete with pro-OS/Infl advanced glycation endproducts (AGEs), which enhance appetite and cause overnutrition. We propose that chronic ingestion of oral AGEs promotes IR and T2D. The mechanism(s) involved in these findings were assessed in four generations of C57BL6 mice fed isocaloric diets with or without AGEs [synthetic methyl-glyoxal-derivatives (MG(+))]. F3/MG(+) mice manifested increased adiposity and premature IR, marked by severe deficiency of anti-AGE advanced glycation receptor 1 (AGER1) and of survival factor sirtuin 1 (SIRT1) in white adipose tissue (WAT), skeletal muscle, and liver. Impaired 2-deoxy-glucose uptake was associated with marked changes in insulin receptor (InsR), IRS-1, IRS-2, Akt activation, and a macrophage and adipocyte shift to a pro-OS/inflammatory (M1) phenotype. These features were absent in F3/MG(-) mice. MG stimulation of 3T3-L1 adipocytes led to suppressed AGER1 and SIRT1, and altered InsR, IRS-1, IRS-2 phosphorylation, and nuclear factor kappa-light chain enhancer of activated B cells (Nf-κB) p65 acetylation. Gene modulation revealed these effects to be coregulated by AGER1 and SIRT1. Thus, prolonged oral exposure to MG-AGEs can deplete host-defenses AGER1 and SIRT1, raise basal OS/Infl, and increase susceptibility to dysmetabolic IR. Because exposure to AGEs can be decreased, these insights provide an important framework for alleviating a major lifestyle-linked disease epidemic.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / metabolism
  • Adipocytes / pathology
  • Administration, Oral
  • Animals
  • Deoxyglucose / genetics
  • Deoxyglucose / metabolism
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Glycation End Products, Advanced / adverse effects*
  • Glycation End Products, Advanced / pharmacology
  • Humans
  • Inflammation / drug therapy
  • Inflammation / genetics
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / metabolism
  • Macrophages / metabolism
  • Macrophages / pathology
  • Metabolic Syndrome / chemically induced
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism*
  • Metabolic Syndrome / pathology
  • Mice
  • Oxidative Stress / drug effects
  • Oxidative Stress / genetics
  • Proto-Oncogene Proteins c-akt
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism*


  • Glycation End Products, Advanced
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Deoxyglucose
  • Proto-Oncogene Proteins c-akt
  • Sirt1 protein, mouse
  • Sirtuin 1