The accumulation of methylglyoxal and acrolein impairs arginine homeostasis causing hyperglycemia and renal abnormalities in male zebrafish.

Reactive carbonyl species contribute to diabetes and its complications, but how the interconnections of carbonyl-detoxifying enzymes regulate metabolic homeostasis through arginine metabolism remains unclear. Here we generate zebrafish lacking both glyoxalase 1 and aldo-keto reductase 1A1A, two major enzymes that detoxify methylglyoxal and acrolein. Double deficiency causes carbonyl accumulation, suppresses arginine metabolism, and impairs insulin signaling, resulting in elevated glucose levels in larvae and in postprandial hyperglycemia in adult male zebrafish. These metabolic alterations are accompanied by glomerular basement membrane thickening and podocyte effacement, whereas retinal vasculature remains unaffected. Arginine supplementation restores Akt phosphorylation, improves insulin signaling, and attenuates renal pathology, indicating that disrupted arginine metabolism mediates the metabolic consequences of carbonyl stress. Our findings identify glyoxalase 1 and aldo-keto reductase 1A1A as cooperative regulators of carbonyl detoxification and reveal a carbonyl-arginine axis linking reactive carbonyl accumulation to impaired insulin signaling, hyperglycemia, and tissue-specific diabetic injury.