The accumulation of methylglyoxal and acrolein leads to arginine depletion causing hyperglycemia and renal abnormalities
There is growing evidence to support the idea that the accumulation of reactive carbonyl species plays a significant causal role in the pathogenesis of ageing, cardiovascular diseases, diabetes and its complications. Among reactive carbonyl species, methylglyoxal and acrolein, detoxified by Glyoxalase 1 and Aldo-keto reductase 1A1A, could modify arginine residues to form the advanced glycation end products and acrolein-derived guanidino adducts that alter protein structure and function. However, it remained unclear whether the combined loss of Glyoxalase 1 and AKR1A1A impairs arginine metabolism and exacerbates hyperglycemia and its complications. In this study, we generated Glyoxalase 1 and Aldo-keto reductase 1A1A double knockout zebrafish to explore the interplay between carbonyl detoxification and arginine metabolism. Loss of both enzymes led to accumulation of methylglyoxal and acrolein, suppression of the arginine metabolic pathway, and downregulation of insulin signaling. Double mutants exhibited elevated whole-body glucose in larvae and postprandial hyperglycemia in adults, accompanied by glomerular basement membrane thickening, while retinal vasculature remained unaffected. Remarkably, arginine supplementation restored Akt phosphorylation, improved insulin sensitivity, and alleviated renal pathology. Together, these findings identify Glyoxalase 1 and Aldo-keto reductase 1A1A as cooperative regulators of carbonyl detoxification and metabolic homeostasis. Disruption of this dual detoxification system links carbonyl stress to impaired insulin signaling and organ-specific damage through dysregulated arginine metabolism. These results uncover a carbonyl–arginine metabolic axis through which reactive carbonyl species, shaped by the synergistic activity of GLO1 and AKR1A1A, drive glucose dysregulation and tissue-specific injury, highlighting potential targets for metabolic intervention in diabetes and metabolic diseases. Overall design: glo1-/-akr1a1a-/-zebrafish were generated using CRISPR/Cas9 technology.  Multiple experiments are performed regarding vasculature and organ alterations, glucose homeostasis, transcriptome, and metabolomics in Tg(fli1:EGFP) zebrafish.