Figure 12.

Putative mechanism of tau hyperphosphorylation during insulin dysfunction. Injection of STZ induces immediate decrease of pancreatic insulin secretion and results in insulin-dependent diabetes mellitus. During the early phase of DM, when the adult mice are still normothermic, PP2A is inhibited, presumably through changes in the Bβ regulatory subunit, which leads to a mild hyperphosphorylation of tau specific to insulin deficiency, as demonstrated in Figures 7 and 10. In the later phase of DM, deficits in peripheral glucose/energy metabolism lead to hypothermia. This leads to a direct inhibition of PP2A activity by low temperatures, resulting in massive hyperphosphorylation of tau not specific to hypoinsulinemia. The early and mild tau hyperphosphorylation is still present at this stage, but is masked by the effects of hypothermia, as demonstrated in Figure 6.