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Mechanisms of Disease: advanced glycation end-products and their receptor in inflammation and diabetes complications

Nature Clinical Practice Endocrinology & Metabolism volume 4, pages 285–293 (2008)Cite this article

Abstract

Many important biochemical mechanisms are activated in the presence of high levels of glucose, which occur in diabetes. Elevated levels of glucose accelerate the formation of advanced glycation end-products (AGEs). Via their chief signaling receptor—the AGE-specific receptor (commonly abbreviated as RAGE)—AGEs generate reactive oxygen species and activate inflammatory signaling cascades. Consequently, AGEs have key roles in the pathogenesis of diabetic complications. Two discoveries have advanced our knowledge of the roles of RAGE in inflammation. First, this receptor has multiple ligands and binds not only AGEs but also proinflammatory, calcium-binding S100 proteins (also known as calgranulins) and nuclear high mobility group protein box-1. Second, RAGE is expressed on T lymphocytes, monocytes and macrophages; RAGE expression on T lymphocytes is essential for effective priming of immune responses in vivo. In this Review, we chronicle roles for RAGE in the pathogenesis of diabetic complications and develop the hypothesis that, in addition to RAGE's central role in the inflammatory response, it is critically linked to the pathogenesis of types 1 and 2 diabetes.

Key Points

  • Elevated levels of glucose accelerate the formation of advanced glycation end-products (AGEs)

  • AGEs, via their chief signaling receptor—the AGE-specific receptor (RAGE)—generate reactive oxygen species, activate inflammatory signaling cascades and, consequently, have key roles in the pathogenesis of diabetic complications

  • RAGE is a multiligand receptor which, as well as AGEs, binds proinflammatory S100 proteins and high mobility group protein box-1

  • RAGE is also expressed on T lymphocytes, monocytes and macrophages; RAGE expression on T lymphocytes is essential for effective priming in vivo

  • Inflammatory mechanisms have critical roles in the pathogenesis of and complications associated with types 1 and 2 diabetes

  • Blockade of RAGE might provide a novel therapeutic target to suppress the complications of diabetes, and, in turn, mitigate injury triggered by the adaptive immune response

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Figure 1: Roles of RAGE and its ligands in the pathogenesis and complications of diabetes.

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Acknowledgements

We gratefully acknowledge the Juvenile Diabetes Research Foundation and the United States Public Health Service for their support of this work. AM Schmidt is a recipient of a Juvenile Diabetes Research Foundation Scholar Award.

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Authors and Affiliations

  1. SF Yan and R Ramasamy are Research Scientists and AM Schmidt is a Professor in the Division of Surgical Science, Department of Surgery, Columbia University Medical Center, New York, NY, USA.,

    Shi Fang Yan, Ravichandran Ramasamy & Ann Marie Schmidt

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  1. Shi Fang Yan
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Correspondence to Ann Marie Schmidt.

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Competing interests

Ann Marie Schmidt has declared that she is a consultant and receives grants/research support from Transtech Pharma. The other authors declared no competing interests.

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Yan, S., Ramasamy, R. & Schmidt, A. Mechanisms of Disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat Rev Endocrinol 4, 285–293 (2008). https://doi.org/10.1038/ncpendmet0786

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