IRS1 and Cognitive impairment: In the central nervous system, the involvement of non-activated AMPK with/without phosphorylation of IRS1 at mSer307 accompanied by p70S6K activation or different combinations of alterations in Akt and GSK3β activity (i.e., increased or decreased phosphorylation) in cognitive impairment in 40–45% HFD-fed and STZ mice has been reported [21,22,27,28,32,34,39,40], whereas the monotonous levels of phosphorylation of IRS1 at Ser sites and of downstream kinases including Akt, AMPK, GSK3β, and p70S6K are observed in 45% HFD-induced cognitive deficits [41].