HMGB1, TLR and RAGE: a functional tripod that leads to diabetic inflammation

Expert Opin Ther Targets. 2011 Aug;15(8):1023-35. doi: 10.1517/14728222.2011.575360. Epub 2011 May 17.


Introduction: Despite advances in treatment of diabetes mellitus, its prevalence continues to rise globally. Medications available are unable to control the vascular complications. Proposals for new therapeutic targets must take into account the hyperglycemia-induced signaling pathways that give rise to the inflammatory profile of the disease.

Areas covered: How high-mobility-group box-1 (HMGB1) protein, acting as an activator of Toll-like receptors (TLR) and receptors for advanced glycation end products (RAGE), creates a functional tripod that contributes to increased production of pro-inflammatory mediators, and sustains the chronic inflammatory state associated with diabetes. The interaction of TLR2 and TRL4 with host-derived ligands, which links diabetic complications with the innate immune response, and the activation of RAGE, which induces a cascade of metabolic responses, leading to the production and secretion of pro-inflammatory cytokines.

Expert opinion: Considering the involvement of the innate immune system, in association with the role of HMGB1 as an activator of TLR and RAGE, diabetes should be considered and treated as a metabolic and immunological disease, triggered by hyperglycemia. HMGB1 plays a central role in mediating injury and inflammation, and interactions involving HMGB1-TLR-RAGE constitute a tripod that trigger NF-κB activation. Blockade or downregulation of HMGB1, and/or control of the inflammatory tripod, represent a promising therapeutic approach for the treatment of diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / pathology*
  • HMGB1 Protein / metabolism*
  • Humans
  • Inflammation / metabolism*
  • Receptor for Advanced Glycation End Products / metabolism*
  • Toll-Like Receptors / metabolism*


  • HMGB1 Protein
  • Receptor for Advanced Glycation End Products
  • Toll-Like Receptors