title: Structural and functional changes in human insulin induced by methylglyoxal.
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 beta-cells. The degradation of MG-insulin through liver cells was also decreased. In conclusion, MG modifies insulin by attaching to internal arginine residue in beta-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.
authors.affiliation: Department of Pharmacology, University of Saskatchewan, 107 Wiggins Rd., Saskatoon, Saskatchewan S7N 5E5, Canada.
authors.forename: Xuming
authors.initials: X
authors.lastname: Jia
authors.forename: Douglas J H
authors.initials: DJ
authors.lastname: Olson
authors.forename: Andrew R S
authors.initials: AR
authors.lastname: Ross
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D022781:Hepatocytes; D006801:Humans; D007328:Insulin / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D007340:Insulinoma; D051379:Mice; D010190:Pancreatic Neoplasms; D011765:Pyruvaldehyde / Q000494:pharmacology*; D051381:Rats
chemical_list: D007328:Insulin; D011765:Pyruvaldehyde