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Öz

Alzheimer's Disease (AD) is the most common cause of dementia. The term of 'type 3 diabetes' is constituted to point out the insulin deficiency and resistant in brain of people with AD. In postmortem studies about AD, it has ben detected that insulin receptors, insulin-like growth factor 1 and 2, insulin messenger ribonucleic acid are decreased in brain. Insulin can pass through brain-blood-barrier, besides it can be synthesized by a group of neuron internally. Gene expression of insulin is present in mature and immature neurons of mammals. Insulin has important effects on regulation of energy metabolism of neurons and neuronal recovery. Decreased glucose uptake and adenosine triphosphate production in the case of insulin deficiency, leads an impairment in neuronal homeostasis. Insulin can increase cognitive functions without changing plasma glucose and insulin levels when it applied intranasally. Insulin and its sub-pathways will maintain its current importance about improvement and protection of cognitive functions

Anahtar Kelimeler

• Alzheimer's disease; dementia; insulin; type 3 diabetes

Alzheimer hastalığı tip 3 diyabet midir?

Öz

Alzheimer hastalığı (AH) en sık g.rülen demanstır. Tip 3 diyabet terimi, AH’de beyinde oluşan insülin eksikliği ve direncine dikkat çekmek için kullanılan bir terimdir. Postmortem çalışmalarda AH hastalarının beyinlerinde insülin resept.rü, insülin benzeri büyüme fakt.rü 1 ve 2 ve insülin haberci ribonükleik asit düzeylerinde azalma vardır. İnsülin kan beyin bariyerine geçmekte ayrıca beyinde bir grup nöron tarafından internal olarak da sentez edilmektedir. İnsülin gen ekspresyonu matur ve immatur memeli nöronal hücrelerinde mevcuttur. İnsülin nöronlardaki enerji metabolizmasını düzenlemesi nöronal sağkalım üzerinde önemli etki yapar. İnsülin eksikliğinde oluşan azalmış glikoz alımı ve adenozin trifosfat üretimi nöronal homeostazın bozulmasına neden olur. Intranazal insülin plazma glikoz ve insülin konsantrasyonunda değişiklik olmadan kognitif fonksiyonlarda artma oluşturmuştur. İnsülin ve alt yolları gelecekte bellek fonksiyonlarının düzeltilmesinde ve korunmasında güncel önemini korumaya devam edecektir.

Anahtar sözcükler: Alzheimer hastalığı; demans; insülin; tip 3 diyabet.

Anahtar Kelimeler

• Alzheimer hastalığı; demans; insülin; tip 3 diyabet

Kaynakça

1. Pasquier F, Boulogne A, Leys D, Fontaine P. Diabetes mellitus and dementia. Diabetes Metab 2006;32:403-14.
2. de la Monte SM, Neusner A, Chu J, Lawton M. Epidemilogical trends strongly suggest exposures as etiologic agents in the pathogenesis of spo- radic Alzheimer’s disease, diabetes mellitus, and non-alcoholic steatohepatitis. J Alzheimers Dis 2009;17:519-29.
3. Sima AA, Zhang W, Kreipke CW, Rafols JA, Hoffman WH. Inflammation in Diabetic Encephalopathy is Prevented by C-Peptide. Rev Diabet Stud 2009;6:37-42.
4. Vendrell J, Broch M, Fernandez-Real JM, Gutiérrez C, Simón I, Megia A, et al. Tumour necrosis factor receptors (TNFRs) in Type 2 diabetes. Analysis of soluble plasma fractions and genetic variations of TNFR2 gene in a case-control study. Diabet Med 2005;22:387-92.
5. Lechleitner M, Herold M, Dzien-Bischinger C, Hoppichler F, Dzien A. Tumour necrosis factor-alpha plasma levels in elderly patients with Type 2 diabe- tes mellitus-observations over 2 years. Diabet Med 2002;19:949-53.
6. Shoham S, Bejar C, Kovalev E, Weinstock M. Intracerebroventricular injection of streptozoto- cin causes neurotoxicity to myelin that contributes to spatial memory deficits in rats. Exp Neurol 2003;184:1043-52.
7. Duelli R, Schröck H, Kuschinsky W, Hoyer S. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci 1994;12:737-43.
8. Hoyer S, Lee SK, Löffler T, Schliebs R. Inhibition of the neuronal insulin receptor. An in vivo model for sporadic Alzheimer disease? Ann N Y Acad Sci 2000;920:256-8.

9. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozo- tocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. J Alzheimers Dis 2006;9:13-33.
10. Santos TO, Mazucanti CH, Xavier GF, Torrão AS. Early and late neurodegeneration and memory dis- ruption after intracerebroventricular streptozotocin. Physiol Behav 2012;107:401-13.
11. Sakr HF. Effect of sitagliptin on the working memory and reference memory in type 2 diabetic Sprague- Dawley rats: possible role of adiponectin receptors 1. J Physiol Pharmacol 2013;64:613-23.
12. Trudeau F, Gagnon S, Massicotte G. Hippocampal synaptic plasticity and glutamate receptor regulati- on: influences of diabetes mellitus. Eur J Pharmacol 2004;490:177-86.
13. Skaper SD. Wnt-signalling: A new direction for alz- heimer disease? CNS Neurol Disord Drug Targets 2014;13:556.
14. Shruster A, Eldar-Finkelman H, Melamed E, Offen D. Wnt signaling pathway overcomes the disrupti- on of neuronal differentiation of neural progenitor cells induced by oligomeric amyloid b-peptide. J Neurochem 2011;116:522-9.
15. Schiöth HB, Craft S, Brooks SJ, Frey WH, Benedict C. Brain insulin signaling and Alzheimer’s disease: current evidence and future directions. Mol Neurobiol 2012;46:4-10.
16. Grilli M, Ferrari Toninelli G, Uberti D, Spano P, Memo M. Alzheimer’s disease linking neurodege- neration with neurodevelopment. Funct Neurol 2003;18:145-8.
17. Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, et al. Long-acting intra- nasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis 2015;44:897-906.
18. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal insulin the- rapy for Alzheimer disease and amnestic mild cog- nitive impairment: a pilot clinical trial. Arch Neurol 2012;69:29-38.
19. Stockhorst U, de Fries D, Steingrueber HJ, Scherbaum WA. Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans. Physiol Behav 2004;83:47-54.
20. Hoyer S. Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update. Exp Gerontol 2000;35:1363-72.
21. Frölich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm 1998;105:423-38.
22. Hong M, Lee VM. Insulin and insulin-like growth fac- tor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem 1997;272:19547-53.
23. Messier C, Teutenberg K. The role of insulin, insu- lin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer’s disease. Neural Plast 2005;12:311-28.
24. Chen GJ, Xu J, Lahousse SA, Caggiano NL, de la Monte SM. Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: potential strategies for neuroprotection. J Alzheimers Dis 2003;5:209-28.
25. Lyn-Cook LE Jr, Lawton M, Tong M, Silbermann E, Longato L, Jiao P, et al. Hepatic ceramide may medi- ate brain insulin resistance and neurodegeneration in type 2 diabetes and non-alcoholic steatohepatitis. J Alzheimers Dis 2009;16:715-29.
26. Contreras C, González-García I, Martínez-Sánchez N, Seoane-Collazo P, Jacas J, Morgan DA, et al. Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Rep 2014;9:366-77.
27. Ramirez T, Longato L, Dostalek M, Tong M, Wands JR, de la Monte SM. Insulin resistance, ceramide accumulation and endoplasmic reticulum stress in experimental chronic alcohol-induced steatohepatitis. Alcohol Alcohol 2013;48:39-52.
28. Orsatti CL, Petri Nahas EA, Nahas-Neto J, Orsatti FL, Giorgi VI, Witkin SS. Evaluation of Toll-Like receptor 2 and 4 RNA expression and the cytokine profile in postmenopausal women with metabolic syndrome. PLoS One 2014;9:109259.
29. Ye D, Li FY, Lam KS, Li H, Jia W, Wang Y, et al. Toll- like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice. Gut 2012;61:1058-67.
30. Trotta T, Porro C, Calvello R, Panaro MA. Biological role of Toll-like receptor-4 in the brain. J Neuroimmunol 2014;268:1-12.
31. Brito BE, Zamora DO, Bonnah RA, Pan Y, Planck SR, Rosenbaum JT. Toll-like receptor 4 and CD14 expression in human ciliary body and TLR-4 in human iris endothelial cells. Exp Eye Res 2004;79:203-8.
32. Zhu T, Meng Q, Ji J, Lou X, Zhang L. Toll-like receptor 4 and tumor necrosis factor-alpha as diag- nostic biomarkers for diabetic peripheral neuropathy. Neurosci Lett 2015;585:28-32.
33. Erba O, Sarac F, Aktu¤ H, Peker G. Detection of impaired cognitive function in rat with hepatostea- tosis model and improving effect of GLP-1 analogs (exenatide) on cognitive function in hepatosteatosis. Scientific World Journal 2014;2014:946265.
34. Erba O, Solmaz V, Aksoy D, Yavao¤lu A, Sa¤can M, Takıran D. Cholecalciferol (vitamin D 3) improves cognitive dysfunction and reduces inflammation in a rat fatty liver model of metabolic syndrome. Life Sci 2014;103:68-72.