Pioglitazone Ameliorate Insulin Resistance And Alzheimer-like Hyperphosphorylation Of Tau Protein In The Hippocampus Of Rats With Type2Diabetes

Objective Brain insulin could accelerate the memory and cognition. Decreased insulinlevel and/or dysfunction of insulin signal transduction may be one of the mechanisms ofAlzheimer’s disease (AD). In order to clarify the underlying mechanism, we determinatedCSF insulin level, hippocampus insulin signal transduction activity and Tau proteinphosphorylation in type2diabetes rats(T2D).We also administered T2D ratsintragastrically insulin sensitizer Pioglitazone and determinated the former items before andafter Pioglitazone intervention,to observe the effect of Pioglitazone in ameliorating T2Drats brain Alzheimer-like changes and to clarify the underlying mechanisms.Materials and Methods The models of T2D rats were fed with a high protein, highglucose and high fat diet for3months, as well as treated with a streptozocin (STZ)injection. Pioglitazone was administered intragastrically for4weeks. Plasma insulin levelwas measured by RIA method, and the plasma glucose by glucose-oxidase method. Theactivities of PI3K/AKT and glycogen synthase kinase-3β (GSK-3β) in insulin signaltransduction, in brain and liver were analyzed by western blots. Phosphorylation of tau inbrain was also investigated by Western blot. The insulin resistant(IR) degree was valued byHOMA-IR.Results Our data showed that plasma insulin level in T2D was significantly higher and CSFinsulin level sinificantly lower than in control(CTL) group. The PI3K/AKT activity was significantly lower and GSK-3β activity significantly higher than in CTL group both inbrain and in liver. The level of phosphorylated tau protein at site Ser199and Ser396inhippocampus of T2DM rats was found to be notably raised as compared to CTL. For thepioglitazone group, palsma insulin level was evidently lower than that in T2D group, butstill higher than CTL; glycemia level and the IR degree decreased significantly as comparedto T2D group, no significant chang as compared to CTL. No significant difference of braininsulin level between this group and T2D group. The PI3K/AKT activitity in both brainand liver was significantly up-regulated than in T2D group, with GSK-3β activitydown-regulated. The level of phosphorylated tau protein at site Ser199and Ser396inhippocampus of T2DM rats was found to be notably decreased as compared to T2D group.Conclusions In T2D rats there is insulin resistance both in periphere tissue and in brian,and plasm insulin level was higher and CSF insulin level was lower than in controls.Meanwhile, tau protein in hippocampus was hyperphosphorylated in T2D. Pioglitazoneinterventin ameoliorated cerebral insulin resistance and decreased tau proteinhyperphosphorylation, but not increased brain insulin level. Our data suggested that insulinresistance, not insulin level in brain was responsible for Alzheimer-like changes, namelytau protein hyperphosphorylation.