Chronic hyperglycemia results in the accumulation of reactive α-dicarbonyls (α-DCs), such as methylglyoxal that leads to various diabetic complications. Conventional treatment regimens for long-term diabetics focus on lowering blood glucose levels with comparatively less focus on glucose derived by-products or the α-DCs. α-DCs are detoxified by the evolutionarily conserved glyoxalases; however their core biochemical regulation is still not clear. Using a Caenorhabditis elegans model with an impaired glyoxalase (glod-4/GLO1), we characterized a mechanism to broadly study α-DC-related stress. glod-4 animals display phenotypes such as hyperesthesia, neuronal damage and early mortality recapitulating diabetic neuropathy related pathologies in two weeks. Our results demonstrate TRPA-1/TRPA1 as a sensor for α-DCs, conserved between worms and mammals. Additionally, TRPA-1 activates SKN-1/Nrf2 via calcium-modulated kinase signaling that regulates the glutathione dependent (GLO1) and independent (DJ1) glyoxalases to detoxify α-DCs. Phenotypic drug screen using C. elegans identified podocarpic acid, a novel C. elegans TRPA-1 activator, that rescues the α-DC-induced pathologies both in C. elegans and mammalian cells. Using a combination of C. elegans and mammalian cells, we propose that amelioration of α-DC stress would help identify novel pharmacological leads that in principle would help overcome diabetic pathologies and associated neurodegenerative conditions like Alzheimer's, and Parkinson's disease without manipulating glucose levels.