Age-Dependent Shifts in Enzymatic Detoxification of Methylglyoxal in Normoglycemia and Prediabetes

Objective Experimental studies suggest that type 2 diabetes (T2D) may be promoted by an increase in methylglyoxal (MG) due to a decline in Glyoxalase 1 (Glo1) activity. These studies also propose that reduced Glo1 activity triggers a compensatory shift towards aldo-keto reductases (Akr) for MG detoxification. We investigated whether individuals with prediabetes already exhibit MG accumulation and reduced Glo1 activity, and whether this may be compensated by Akr-mediated detoxification.

Methodology We studied 72 individuals with normal glucose tolerance (NGT, n=35, 31F/4M, age 31–71) or prediabetes (PRED, n=37, 17F/20M, age 30–83). Biochemical assessments included fasting glucose, HbA1c, lipids, and markers of MG detoxification in red blood cells. These markers comprised Glo1 and Akr activity, measured spectrophotometrically, as well as MG, D-lactate, and hydroxyacetone levels, measured by mass spectrometry. Group comparisons were performed using unpaired t-tests.

Results PRED individuals exhibited elevated fasting glucose, HbA1c, triglycerides, and AUC of glucose during oral glucose tolerance tests (p<0.05). However, Glo1 and Akr activity, as well as MG levels, showed no significant differences between NGT and PRED but demonstrated high variability. Age emerged as a key driver of these variations, with Glo1 activity decreasing (NGT: r=-0.44, p<0.01; PRED: r=-0.66, p<0.0001), while Akr activity increased (NGT: r=0.70, p<0.0001; PRED: r=0.81, p<0.0001) over life time. Similarly, age-related trends were observed in Glo1 and Akr metabolic by-products: D-lactate levels (a Glo1 by-product) decreased (NGT: r=-0.56, p<0.001; PRED: r=-0.69, p<0.0001), whereas hydroxyacetone levels (an Akr by-product) increased with age (NGT: r=0.69, p<0.0001; PRED: r=0.74, p<0.0001). MG levels remained stable across age and glucose tolerance groups. While the age-related decline of Glo1 activity appeared steeper in PRED (-0.68) than NGT (-0.37), this difference was not statistically significant.

Conclusion Our findings demonstrate an age-related shift from Glo1- to Akr-mediated MG detoxification, maintaining stable MG levels irrespective of glucose tolerance status. This suggests that aging-related adaptations in MG handling are robust and occur independently of prediabetes. These enzymatic shifts may serve as a compensatory mechanism to mitigate the effects of MG and preserve metabolic stability during aging. Understanding these dynamics could provide insights into the interplay between aging, MG detoxification, and metabolic health, potentially informing strategies for metabolic disease prevention.

Publikationsverlauf

Artikel online veröffentlicht:
28. Mai 2025