Dicarbonyl stress in clinical obesity

Abstract

The glyoxalase system in the cytoplasm of cells provides the primary defence against glycation by methylglyoxal catalysing its metabolism to D-lactate. Methylglyoxal is the precursor of the major quantitative advanced glycation endproducts in physiological systems - arginine-derived hydroimidazolones and deoxyguanosine-derived imidazopurinones. Glyoxalase 1 of the glyoxalase system was linked to anthropometric measurements of obesity in human subjects and to body weight in strains of mice. Recent conference reports described increased weight gain on high fat diet-fed mouse with lifelong deficiency of glyoxalase 1 deficiency, compared to wild-type controls, and decreased weight gain in glyoxalase 1-overexpressing transgenic mice, suggesting a functional role of glyoxalase 1 and dicarbonyl stress in obesity. Increased methylglyoxal, dicarbonyl stress, in white adipose tissue and liver may be a mediator of obesity and insulin resistance and thereby a risk factor for development of type 2 diabetes and non-alcoholic fatty liver disease. Increased methylglyoxal formation from glyceroneogenesis on adipose tissue and liver and decreased glyoxalase 1 activity in obesity likely drives dicarbonyl stress in white adipose tissue increasing the dicarbonyl proteome and related dysfunction. The clinical significance will likely emerge from on-going clinical evaluation of inducers of glyoxalase 1 expression in overweight and obese subjects. Increased transcapillary escape rate of albumin and increased total body interstitial fluid volume in obesity likely makes levels of glycation of plasma protein unreliable indicators of glycation status in obesity as there is a shift of albumin dwell time from plasma to interstitial fluid, which decreases overall glycation for a given glycemic exposure.

Isocaloric Fructose Restriction Reduces Serum d-Lactate Concentration in Children With Obesity and Metabolic Syndrome

“…Masania et al reported higher fasting serum levels of MG and D-lactate in subjects with obesity compared to non-obese adults following an isocaloric diet for 2 weeks (26). These findings are in line with the current literature suggestive of plasma D-lactate level as a surrogate marker for MG flux, which is increased in obesity (26,(32)(33)(34). Furthermore, in a cross-sectional study, we previously demonstrated that serum D-lactate levels were higher in obese Latino adolescents and correlated with serum triglycerides and small dense LDL levels (27).…”

“…The limit of detection was 1 µmol/L, and the reaction was linear up to 15 µmol/L. To further ensure specificity, we ran the reaction with and without 1 mmol/L L-lactate (upper limit of reference range in serum) and found <5% interference (p < 0.05), in agreement with data on the literature (26,28). The intraassay coefficient of variation was 5% at 2 µmol/L and 3% at 10 µmol/L.…”

“…Consistent with this, we found that the reduction in serum D-lactate correlated with reduction in DNL and reduction in serum triglycerides over the 9 days of isocaloric fructose restriction. The role of MG in the pathogenesis of metabolic syndrome has been recently postulated (26). MG is a particularly reactive intermediate because of its α-dicarbonyl moiety.…”

“…D-lactate was measured by kinetic spectrophotometric assay, in which D-lactate is specifically oxidized by bacterial D-lactate dehydrogenase, using the D-lactate Colorimetric Assay kit MAK058 from Sigma (St.Louis, MO, USA). Serum samples were ultra-filtered to eliminate interference by the reaction of serum LDH with L-lactate and then incubated at 37 °C, and the reaction was followed kinetically to achieve maximal sensitivity and linearity (26). The <10-kDa fractions were separated by ultrafiltration through 0.5 mL Amicon ultra centrifugal filters spun at 14,000g for 30 min in a refrigerated centrifuge at 4 °C; the ultrafiltrate was employed to measure D-lactate (27).…”

Protein oxidation, nitration and glycation biomarkers for early-stage diagnosis of osteoarthritis of the knee and typing and progression of arthritic disease

“…This effect is lost when marked increase in protein glycation, oxidation and nitration in the joints in advanced disease outweighs the effects of increased protein residence time at interstitial sites. Albumin TER has been described previously as a confounding factor in the diagnostic use of plasma protein glycation [52]. …”