| First Author | Sajan M | Year | 2016 |
| Journal | Diabetes | Volume | 65 |
| Issue | 7 | Pages | 1892-903 |
| PubMed ID | 26895791 | Mgi Jnum | J:249749 |
| Mgi Id | MGI:5923237 | Doi | 10.2337/db15-1428 |
| Citation | Sajan M, et al. (2016) Brain Insulin Signaling Is Increased in Insulin-Resistant States and Decreases in FOXOs and PGC-1alpha and Increases in Abeta1-40/42 and Phospho-Tau May Abet Alzheimer Development. Diabetes 65(7):1892-903 |
| abstractText | Increased coexistence of Alzheimer disease (AD) and type 2 diabetes mellitus (T2DM) suggests that insulin resistance abets neurodegenerative processes, but linkage mechanisms are obscure. Here, we examined insulin signaling factors in brains of insulin-resistant high-fat-fed mice, ob/ob mice, mice with genetically impaired muscle glucose transport, and monkeys with diet-dependent long-standing obesity/T2DM. In each model, the resting/basal activities of insulin-regulated brain protein kinases, Akt and atypical protein kinase C (aPKC), were maximally increased. Moreover, Akt hyperactivation was accompanied by hyperphosphorylation of substrates glycogen synthase kinase-3beta and mammalian target of rapamycin and FOXO proteins FOXO1, FOXO3A, and FOXO4 and decreased peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) expression. Akt hyperactivation was confirmed in individual neurons of anterocortical and hippocampal regions that house cognition/memory centers. Remarkably, beta-amyloid (Abeta1-40/42) peptide levels were as follows: increased in the short term by insulin in normal mice, increased basally in insulin-resistant mice and monkeys, and accompanied by diminished amyloid precursor protein in monkeys. Phosphorylated tau levels were increased in ob/ob mice and T2DM monkeys. Importantly, with correction of hyperinsulinemia by inhibition of hepatic aPKC and improvement in systemic insulin resistance, brain insulin signaling normalized. As FOXOs and PGC-1alpha are essential for memory and long-term neuronal function and regeneration and as Abeta1-40/42 and phospho-tau may increase interneuronal plaques and intraneuronal tangles, presently observed aberrations in hyperinsulinemic states may participate in linking insulin resistance to AD. |
