Effect of insulin on the soluble receptor for advanced glycation end products (RAGE)

• Published in: Diabetic medicine Vol. 30; no. 6; pp. 702 - 709
• Main Authors: Lam, J. K. Y., Wang, Y., Shiu, S. W. M., Wong, Y., Betteridge, D. J., Tan, K. C. B.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.06.2013; Blackwell; Wiley Subscription Services, Inc
• Subjects: Adult; Biological and medical sciences; Biomarkers - blood; Biomarkers - chemistry; Biomarkers - metabolism; Cell Line; Cell Membrane - drug effects; Cell Membrane - metabolism; China; Cross-Sectional Studies; Culture Media, Conditioned - chemistry; Diabetes; Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - drug therapy; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin - pharmacology; Insulin - therapeutic use; Macrophages - drug effects; Macrophages - metabolism; Male; Matrix Metalloproteinase Inhibitors - pharmacology; Medical sciences; Middle Aged; Protein Isoforms - blood; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Proteolysis - drug effects; Receptor for Advanced Glycation End Products; Receptors, Immunologic - blood; Receptors, Immunologic - chemistry; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Solubility; Up-Regulation - drug effects; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Obesity; Advanced glycation end products; Nutrition; Receptor for advanced glycation endproducts; Nutrition disorder; Metabolic diseases; Soluble form; Endocrinology; Nutritional status; Hormonal receptor
• ISSN: 0742-3071; 1464-5491; 1464-5491
• DOI: 10.1111/dme.12166

Aims The receptor for advanced glycation end products (RAGE) plays an important role in the pathogenesis of diabetic complications. RAGE transcript splicing generates a number of isoforms, including a full‐length membrane‐bound receptor and a soluble isoform, endogenous secretory RAGE (esRAGE). Soluble forms of the receptor (sRAGE) can also be formed by ectodomain shedding of the membrane‐associated receptor. We have evaluated serum levels of sRAGE and esRAGE in Chinese patients with Type 1 diabetes and investigated the effect of insulin on the generation of esRAGE and sRAGE in vitro. Methods Serum sRAGE and esRAGE were measured by ELISA. The in vitro effect of insulin was investigated by incubating THP‐1 macrophages with insulin and RAGE isoforms in cell lysate and conditioned media determined. Results In patients with diabetes, both serum esRAGE and sRAGE were significantly higher than in age‐matched healthy subjects without diabetes. In vitro, insulin increased esRAGE and total RAGE isoform expression in cell lysate on a western blot, and reverse transcription–polymerase chain reaction showed an increase in esRAGE and full‐length RAGE mRNA. This was accompanied by an increase in esRAGE and sRAGE in cell conditioned media. Pretreatment of THP‐1 cells with a general metalloproteinase inhibitor GM6001 significantly reduced the production of sRAGE, suggesting that insulin also increased the cleavage of full‐length cell surface RAGE to form sRAGE. Conclusions Chinese patients with Type 1 diabetes have higher serum levels of esRAGE and sRAGE. In vitro, insulin not only increases both full‐length RAGE and esRAGE expression, but can also stimulate the shedding of sRAGE from the membrane‐bound receptor.