Abstract

Diabetes mellitus alters systemic metabolism and increases vulnerability to both environmental toxicants and 
neurodegenerative processes. Environmental chemicals-heavy metals, persistent organic pollutants, pesticides, and 
air pollutants-can exacerbate oxidative stress, mitochondrial dysfunction, inflammation, and impaired proteostasis, 
mechanisms that overlap with metabolic derangements in diabetes and with pathways leading to neurodegeneration. 
Natural compounds derived from plants, marine organisms, and fungi possess dual activities: they can modulate 
neuronal signaling (neuromodulation) and support metabolic detoxification pathways (phase I/II enzymes, 
antioxidant defenses, metal chelation). This review synthesizes mechanistic evidence linking environmental toxicant 
exposure and heightened neurodegenerative risk in diabetic settings, and examines how selected natural compounds 
(polyphenols, flavonoids, terpenoids, alkaloids, marine carotenoids, and omega-3 polyunsaturated fatty acids) act as 
mediators that simultaneously attenuate toxicant burden and preserve neuronal function. We discuss modes of 
action-Nrf2 activation, mitochondrial stabilization, modulation of cytochrome P450 and conjugating enzymes, metal 
chelation, anti-inflammatory and anti-aggregate effects, and direct modulation of ion channels and neurotransmitter 
systems. Preclinical and emerging clinical data supporting neuroprotective and detoxification roles are summarized, 
along with formulation, pharmacokinetic, and safety considerations. We conclude by outlining research priorities to 
translate dual-action natural compounds into integrative strategies for reducing neurodegenerative risk in people 
with diabetes who face environmental chemical exposures.