In conclusion, we have demonstrated that limited early exposure to sub-mutagenic doses of NDEA causes T2DM and neurodegeneration with impairments in insulin/IGF signaling mechanisms, and deficits in cholinergic and neuronal cytoskeletal gene and protein expression in brain, whereas chronic HFD feeding alone produces more restrictive deficits in insulin/IGF signaling mechanisms with reduced ChAT expression and increased oxidative stress. This evidence concerns the gene INS and type 2 diabetes mellitus.