Faculty Collaboration Database

Dicarbonyl stress and glyoxalase enzyme system regulation in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol 2018 Feb 01;314(2):R181-R190

Date

10/20/2017

Pubmed ID

29046313

Pubmed Central ID

PMC5867671

DOI

10.1152/ajpregu.00159.2017

Scopus ID

2-s2.0-85043582559 (requires institutional sign-in at Scopus site)   28 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 (-78.8%), 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 (-31.6%), 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.

Author List

Mey JT, Blackburn BK, Miranda ER, Chaves AB, Briller J, Bonini MG, Haus JM

MESH terms used to index this publication - Major topics in bold

Adult
Aldehyde Reductase
Blood Glucose
Case-Control Studies
Diabetes Mellitus, Type 2
Female
Glyceraldehyde-3-Phosphate Dehydrogenases
Humans
Insulin
Insulin Resistance
Kelch-Like ECH-Associated Protein 1
Lactoylglutathione Lyase
Male
Middle Aged
NF-E2-Related Factor 2
Protein Carbonylation
Quadriceps Muscle
Triose-Phosphate Isomerase