PMID- 26895791 OWN - NLM STAT- MEDLINE DCOM- 20170605 LR - 20201209 IS - 1939-327X (Electronic) IS - 0012-1797 (Print) IS - 0012-1797 (Linking) VI - 65 IP - 7 DP - 2016 Jul TI - 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. PG - 1892-903 LID - 10.2337/db15-1428 [doi] AB - 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. CI - (c) 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. FAU - Sajan, Mini AU - Sajan M AD - Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL. FAU - Hansen, Barbara AU - Hansen B AD - Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL. FAU - Ivey, Robert 3rd AU - Ivey R 3rd AD - Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL. FAU - Sajan, Joshua AU - Sajan J AD - Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL. FAU - Ari, Csilla AU - Ari C AD - Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL. FAU - Song, Shijie AU - Song S AD - Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL. FAU - Braun, Ursula AU - Braun U AD - The Biotechnology Centre of Oslo, Oslo, Norway. FAU - Leitges, Michael AU - Leitges M AD - The Biotechnology Centre of Oslo, Oslo, Norway. FAU - Farese-Higgs, Margaret AU - Farese-Higgs M AD - Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL. FAU - Farese, Robert V AU - Farese RV AD - Medical, Neurology, Psychiatry, and Research Services, James A. Haley Veterans Hospital, Tampa, FL Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL rfarese@health.usf.edu. LA - eng GR - I01 BX001407/BX/BLRD VA/United States GR - R01 DK065969/DK/NIDDK NIH HHS/United States PT - Journal Article DEP - 20160219 PL - United States TA - Diabetes JT - Diabetes JID - 0372763 RN - 0 (Amyloid beta-Peptides) RN - 0 (Cell Cycle Proteins) RN - 0 (Forkhead Box Protein O1) RN - 0 (Forkhead Box Protein O3) RN - 0 (Forkhead Transcription Factors) RN - 0 (FoxO3 protein, mouse) RN - 0 (FoxO4 protein, mouse) RN - 0 (Insulin) RN - 0 (Peptide Fragments) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Ppargc1a protein, mouse) RN - 0 (amyloid beta-protein (1-40)) RN - 0 (tau Proteins) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.13 (PKC-3 protein) RN - EC 2.7.11.13 (Protein Kinase C) SB - IM MH - Alzheimer Disease/metabolism MH - Amyloid beta-Peptides/metabolism MH - Animals MH - Brain/drug effects/*metabolism MH - Cell Cycle Proteins MH - Diabetes Mellitus, Type 2/metabolism MH - Diet, High-Fat MH - Female MH - Forkhead Box Protein O1/*metabolism MH - Forkhead Box Protein O3/*metabolism MH - Forkhead Transcription Factors/*metabolism MH - Insulin/*metabolism/pharmacology MH - Insulin Resistance/*physiology MH - Macaca mulatta MH - Male MH - Mice MH - Neurons/drug effects/metabolism MH - Obesity/metabolism MH - Peptide Fragments/metabolism MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism MH - Phosphorylation MH - Protein Kinase C/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Signal Transduction/*physiology MH - tau Proteins/metabolism PMC - PMC4915579 EDAT- 2016/02/21 06:00 MHDA- 2017/06/06 06:00 PMCR- 2017/07/01 CRDT- 2016/02/21 06:00 PHST- 2015/10/14 00:00 [received] PHST- 2016/02/08 00:00 [accepted] PHST- 2016/02/21 06:00 [entrez] PHST- 2016/02/21 06:00 [pubmed] PHST- 2017/06/06 06:00 [medline] PHST- 2017/07/01 00:00 [pmc-release] AID - db15-1428 [pii] AID - 1428 [pii] AID - 10.2337/db15-1428 [doi] PST - ppublish SO - Diabetes. 2016 Jul;65(7):1892-903. doi: 10.2337/db15-1428. Epub 2016 Feb 19.