INS and type 2 diabetes mellitus: T2D animal model studies demonstrated that: (1) neuronal loss and neurite degeneration, associated with altered AβPP metabolism, hyper phosphorylation of tau protein, and impaired signalling of insulin and IGF-1, were more severe in rat models of T2D than in rat models of T1D [138]; and (2) in a T2D animal model, the major contributing factor to AD was hyperglycaemia-mediated proteolytic tau cleavage since the cleaved tau served as a nucleation centre for the pathological assembly of tau filaments [137].