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Structural and functional changes in human insulin induced by methylglyoxal

Xuming Jia^*, Douglas J. H. Olson, Andrew R. S. Ross and Lingyun Wu^*,1

^* Department of Pharmacology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada and

National Research Council of Canada, Plant Biotechnology Institute, Saskatoon, Saskatchewan, Canada

¹Correspondence: Department of Pharmacology, College of Medicine, University of Saskatchewan, 107 Wiggins Rd., Saskatoon, SK S7N 5E5, Canada. E-mail: liw070{at}duke.usask.ca

ABSTRACT

Elevated methylglyoxal (MG) levels have been reported in insulin-resistance syndrome. The present study investigated whether MG, a highly reactive metabolite of glucose, induced structural and functional changes of insulin. Incubation of human insulin with MG in vitro yielded MG-insulin adducts, as evidenced by additional peaks observed on mass spectrometric (MS) analysis of the incubates. Tandem MS analysis of insulin B-chain adducts confirmed attachment of MG at an arginine residue. [³H]-2-deoxyglucose uptake by 3T3-L1 adipocytes was significantly and concentration-dependently decreased after the treatment with MG-insulin adducts, in comparison with the effect of native insulin at the same concentrations. A significant decrease of glucose uptake induced by MG-insulin adducts was also observed in L8 skeletal muscle cells. MG alone had no effect on glucose uptake or the transcriptional expression of insulin receptor. Unlike native insulin, MG-insulin adducts did not inhibit insulin release from pancreatic ß-cells. The degradation of MG-insulin through liver cells was also decreased. In conclusion, MG modifies insulin by attaching to internal arginine residue in ß-chain of insulin. The formation of this MG-insulin adduct decreases insulin-mediated glucose uptake, impairs autocrine control of insulin secretion, and decreases insulin clearance. These structural and functional abnormalities of insulin molecule may contribute to the pathogenesis of insulin resistance.—Jia, X., Olson, D. J. H., Ross, A. R. S., Wu, L. Structural and functional changes in human insulin induced by methylglyoxal.

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