Dicarbonyl stress and glyoxalase enzyme system regulation in human skeletal muscle

Jacob T. Mey, Brian K. Blackburn, Edwin R. Miranda, Alec B. Chaves, Joan Briller, Marcelo G. Bonini, Jacob M. Haus*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Skeletal muscle insulin resistance is a hallmark of Type 2 diabetes (T2DM) and may be exacerbated by protein modifications by methylglyoxal (MG), known as dicarbonyl stress. The glyoxalase enzyme system composed of glyoxalase 1/2 (GLO1/GLO2) is the natural defense against dicarbonyl stress, yet its protein expression, activity, and regulation remain largely unexplored in skeletal muscle. Therefore, this study investigated dicarbonyl stress and the glyoxalase enzyme system in the skeletal muscle of subjects with T2DM (age: 56 = 5 yr.; BMI: 32 = 2 kg/m2) compared with lean healthy control subjects (LHC; age: 27 = 1 yr.; BMI: 22 = 1 kg/m2). Skeletal muscle biopsies obtained from the vastus lateralis at basal and insulin-stimulated states of the hyperinsulinemic (40 mU·m-2·min-1)–euglycemic (5 mM) clamp were analyzed for proteins related to dicarbonyl stress and glyoxalase biology. At baseline, T2DM had increased carbonyl stress and lower GLO1 protein expression (Ƴ78.8%), which inversely correlated with BMI, percent body fat, and HOMA-IR, while positively correlating with clamp-derived glucose disposal rates. T2DM also had lower NRF2 protein expression (Ƴ31.6%), which is a positive regulator of GLO1, while Keap1 protein expression, a negative regulator of GLO1, was elevated (207%). Additionally, insulin stimulation during the clamp had a differential effect on NRF2, Keap1, and MG-modified protein expression. These data suggest that dicarbonyl stress and the glyoxalase enzyme system are dysregulated in T2DM skeletal muscle and may underlie skeletal muscle insulin resistance. Whether these phenotypic differences contribute to the development of T2DM warrants further investigation.

Original languageEnglish (US)
Pages (from-to)R181-R190
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume314
Issue number2
DOIs
StatePublished - Feb 2018
Externally publishedYes

Keywords

  • Hyperinsulinemic-euglycemic clamp
  • Keap1
  • Methylglyoxal
  • NRF2
  • Type 2 diabetes

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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