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Structural and functional changes in human insulin induced by methylglyoxal
Xuming Jia1, Douglas J H Olson, Andrew R S Ross
1Department of Pharmacology, University of Saskatchewan, 107 Wiggins Rd., Saskatoon, Saskatchewan S7N 5E5, Canada.
Summary
Methylglyoxal (MG) modifies human insulin by attaching to arginine residues, forming adducts. These MG-insulin adducts reduce glucose uptake and contribute to insulin resistance pathogenesis.
Area of Science:
- Biochemistry
- Metabolic Research
- Endocrinology
Background:
- Elevated methylglyoxal (MG) levels are linked to insulin resistance.
- MG is a highly reactive glucose metabolite.
Purpose of the Study:
- To investigate if MG induces structural and functional changes in insulin.
- To determine the impact of MG-modified insulin on glucose uptake and insulin signaling.
Main Methods:
- In vitro incubation of human insulin with MG.
- Mass spectrometry (MS) and tandem MS analysis to identify MG-insulin adducts.
- Measurement of [3H]-2-deoxyglucose uptake in 3T3-L1 adipocytes and L8 skeletal muscle cells.
Main Results:
- MG formed adducts with human insulin, primarily at an arginine residue in the B-chain.
- MG-insulin adducts significantly reduced glucose uptake in adipocytes and muscle cells compared to native insulin.
- MG alone did not affect glucose uptake or insulin receptor expression.
- MG-insulin adducts did not inhibit insulin release from pancreatic beta-cells and showed decreased degradation by liver cells.
Conclusions:
- MG modifies insulin structure by adduct formation.
- MG-induced insulin modification impairs insulin's function in glucose uptake.
- These alterations in insulin structure and function may contribute to the development of insulin resistance.