Diabetes Mellitus’un Alzheimer İle Olası İlişkisi

Yıl 2018, Cilt: 1 Sayı: 2, 1 - 12, 15.10.2018

Duygu Şahin

Öz

Diabetes Mellitus, pankreasın insülin salgısının tam ya da kısmi yetersizliği ya da insülin etkisinin

yetersizliği ile oluşan, kendini hiperglisemi ile belli eden, karbonhidrat, lipid ve protein metabolizma

bozukluğu ile de karakterize bir endokrin ve metabolizma hastalığıdır. Beyinde insülin reseptörlerinin

keşfi ile insülinin beyin fizyolojisinde önemli bir rol oynadığı, serebral insülin sinyalinde ve glukoz

homeostazında meydana gelen bozuklukların beyin patolojisine katkıda bulunduğu belirtilmektedir.

İnsülin, reseptörü aracılığıyla kan-beyin bariyerini aşarak santral sinir sistemine girmekte, beyin

glukoz metabolizmasında regülatör etkisine ek olarak, nöromodülatör ve nöroendokrin bir molekül

gibi davranmakta, nöronal gelişim ve sağkalımda önemli bir rol almaktadır. İnsülin periferde olduğu

gibi, beyinde de etkilerini, reseptörü aracılığıyla, insülin reseptör substrat/fosfotidilinozitol 3-kinaz

(IRS/PI3K) ve mitojen aktive protein kinaz (MAPK) sinyal yolu aracılığıyla göstermektedir. PI3K

sinyal yolağının aktivasyonu, protein kinaz B (Akt) aracılığı ile, Alzheimer’ın en belirgin iki

patolojik karakteristiği olan, tau hiperfosforilasyonu ile oluşan intraselüler nörofibriler yumaklar ve

β-amiloid agregatlarının oluşturduğu ekstraselüler senil plakların metabolizmasının regülasyonunda

etkili olmaktadır. Son yıllarda yapılan çalışmalarla, Alzheimer, Merkezi Sinir Sisteminde insülin

reseptör duyarlılığının ve sinyal iletiminin bozulmasından kaynaklanan insülin rezistansının

gelişimine bağlı olarak meydana gelen tau ve Aβ metabolizmasındaki değişiklikleri içerdiğinden,

Diabetes Mellitus’un beyin spesifik formu (Tip 3 DM) olarak tanımlanmaktadır.

Anahtar Kelimeler

Diabetes Mellitus, Insülin, Tau hiperfosforilasyonu, Alzheimer

Kaynakça

• 1. de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimers Dis 2005; 7(1): 45-61. 2. S Roriz-Filho J, Sá-Roriz TM, Rosset I et al. (Pre)diabetes, brain aging, and cognition.Biochim Biophys Acta 2009; 1792(5): 432-43. 3. Peter FH, Karam JH, Saler PR. Pancreatic Hormones and Diabetes Mellitus in “Basic and Clinical Endocrinology”. 3 rd ed. Toronto: Prentice Hall International Inc; 1992. 4. Biessels GJ, Bravenboer B, Gispen WH. Glucose, insulin and the brain: modulation of cognition and synaptic plasticity in health and disease: a preface. Eur J Pharmacol 2004; 490(1-3): 1-4. 5. Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 1978; 272: 827- 829. 6. Cardoso S, Correia S, Santos RX et al. Insulin is a two-edged knife on the brain. J Alzheimers Dis 2009; 18: 483-507. 7. Gasparini L, Xu H. Potential roles of insulin and IGF-1 in Alzheimer’s disease. Trends Neurosci 2003; 26(8): 404-6. 8. Nelson TJ, Sun MK, Hongpaisan J, Alkon DL. Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. Eur J Pharmacol 2008; 585: 76-87. 9. Banks WA, Owen JB, Erickson MA. Insulin in the brain: there and back again. Pharmacol Ther 2012; 136(1): 82-93. 10.Niswender KD, Morrison CD, Clegg DJ et al. Insulin activation of phosphatidylinositol 3-kinase in the hypothalamic arcuate nucleus: a key mediator of insulin-induced anorexia. Diabetes 2003; 52: 227-231. 11. Plum L, Belgardt BF, Bruning JC. Central insulin action in energy and glucose homeostasis. J. Clin Invest 2006; 116: 1761-1766. 12. Hoyer S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 2004; 490(1-3): 115-25. 13. de la Monte SM. Brain insulin resistance and deficiency as therapeutic targets in Alzheimer’s disease. Curr Alzheimer Res 2012; 9(1): 35-66. 14. Hong M, Lee VM. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem 1997; 272: 19547-19553. 15. Frolich L. et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm 1998; 105, 423-438. 16. Frolich L. et al. A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer’s disease. Ann NY Acad Sci 1999; 893, 290-293. 17. Correia SC, Santos RX, Perry G, et al. Insulinresistant brain state: the culprit in sporadic Alzheimer’s disease? Ageing Res Rev 2011; 10(2): 264-73. 18. Gasparini L, Gouras GK, Wang R et al. Stimulation of b-amyloid precursor protein trafficking by insulin reduces intraneuronal b-amyloid and requires mitogen-activated protein kinase signalling. J Neurosci 2001; 21: 2561-2570. 19. Carro E, Trejo JL, Gomez-Isla T et al. Serum insulin growth factor 1 regulates brain amyloid-b levels. Nat Med 2002; 8: 1390-1397. 20. Burtis CA, Ashwood ER. Tietz Textbook of Clinical Chemistry. 3rd ed. WB Saunders Company; 1999. 21. Sack BS. Implications of the Revised Criteria for Diagnosis and Classification of Diabetes Mellitus. Clinical Chemistry 1997; 43: 2230-32. 22. Berne RM, Levy MN. Principles of phsiology. USA. 1990. 23. Bloom A, Ireland J. A colour atlas of diabetes. 2nd ed. Spain: Wolfe publishing; 1992. 24. Bothwell TH, Charlton RW. A general approach to the problems of iron deficiency and iron overload in the population at large. Semin Hematol 1982; 19: 54-67. 25. Bingöl G. Biyokimya. 4. Baskı. Ankara: Taş kitabevi; 1983. 26. Gerozissis K. Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol 2008; 585(1): 38-49. 27. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414(6865): 799-806. 28. McEwen BS, Reagan LP. Glucose transporter expression in the central nervous system: Relationship to synaptic function. Eur J Pharmacol 2004; 490: 13-24. 29. Margolis RU, Altszuler N. Insulin in the cerebrospinal fluid. Nature 1967; 215: 1375-1376. 30. Plum L, Schubert M, Brüning JC. The role of insulin receptorsignaling in the brain. Trends Endocrinol Metab 2005; 16(2): 59-65. 31. Banks WA. The source of cerebral insulin. Eur J Pharmacol 2004; 490(1-3): 5-12. 32. Schechter R, Beju D, Gaffney T et al. Preproinsulin I and II mRNAs and insulin electron microscopic immunoreaction are present within the rat fetal nervous system. Brain Res 1996; 736: 16- 27. 33. Wozniak M, Rydzewski B, Baker SP, Raizada MK. The cellular and physiological actions of insulin in the central nervous system. Neurochem Int 1993; 22: 1-10. 34. Belfiore A, Frasca F, Pandini G et al. Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease. Endocr Rev 2009; 30(6): 586-623. 35. Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK- 3alpha regulates production of Alzheimer’s disease amyloid-beta peptides. Nature 2003; 423: 435-439. 36. Ishiguro K, Shiratsuchi A, Sato S et al. Glycogen synthase kinase 3 beta is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett 1993; 325: 167-172. 37. Zhao WQ, Chen H, Quon MJ, Alkon DL. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 2004; 490(1-3): 71-81. 38. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s Disease: Progress and problems on the road to therapeutics. Science 2002; 297: 353-356. 39. Vetrivel KS, Thinakaran G. Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments. Neurology 2006; 66: 69-73. 40. Vardy ER, Catto AJ, Hooper NM. Proteolytic mechanisms in amyloid-metabolism: therapeutic implications for Alzheimer’s disease. Trends in Molecular Medicine 2005; 11: 464-472. 41. Watanabe A, Hasegawa M, Suzuki T et al. In vivo phosphorylation sites in fetal and adult rat tau. J Biol Chem 1993; 268: 25712-25717. 42. Johnson GVW, Stoothoff WH. Tau phosphorylation in neuronal cell function and dysfunction. Journal of Cell Science 2004; 117: 5721-5729. 43. Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau protein in both physiological and pathological conditions. Physiological Review 2004; 84: 361- 384. 44. Schubert M, Gautam D, Surjo D et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci USA 2004; 101(9): 3100-3105. 45. De Ferrari GV, Inestrosa NC. Wnt signaling function in Alzheimer’s disease. Brain Res Brain Res Rev 2000; 33(1): 1-12. 46. Lucas JJ, Hernández F, Gómez-Ramos P et al. Decreased nuclear b-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3b conditional transgenic mice. EMBO J 2001; 20: 27-39. 47. Miles WR, Root HF. Psychologic tests applied to diabetic patients. Arch Intern Med 1922; 30: 767- 777. 48. Kodl CT, Seaquist ER. Cognitive dysfunction and diabetes mellitus. Endocr Rev 2008; 29(4): 494-511. 49. Biessels GJ, Van der Heide LP, Kamal A et al. Ageing and diabetes: implications for brain function. Eur J Pharmacol 2002; 441: 1-14. 50. Sredy J, Sawicki DR, Notvest RR. Polyol pathway activity innervous tissues of diabetic and galactose-fed rats: effect of dietary galactose withdrawal or tolrestat intervention therapy. J Diabet Complications 1991; 5: 42-47. 51. Toth C, Schmidt AM, Tuor UI et al. Diabetes, leukoencephalopathy and rage. Neurobiol Dis 2006; 23: 445-461. 52. Welsh B, Wecker L. Effects of streptozotocininduced diabetes on acetylcholine metabolism in rat brain. Neurochem Res 1991; 16: 453-460. 53. Biessels GJ, Kappelle AC, Bravenboer B et al. Cerebral function in diabetes mellitus. Diabetologia 1994; 37: 643-650. 54. Steen E, Terry BM, Rivera EJ et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s diseaseis this type 3 diabetes? J Alzheimers Dis 2005; 7: 63-80. 55. Hak AE, Pols HA, Stehouwer CD et al. Markers of inflammation andcellular adhesion molecules in relation to insulin resistance in nondiabeticelderly: the Rotterdam study. J Clin Endocrinol Metab 2001; 86: 4398-4405. 56. Lee ZS, Chan JC, Yeung VT et al. Plasma insulin, growth hormone, cortisol, and central obesity among young Chinese type 2 diabetic patients. Diabetes Care 1999; 22: 1450-1457. 57. Tojo C, Takao T, Nishioka T et al. Hypothalamicpituitary- adrenal axis in WBN/Kob rats with noninsulin dependent diabetes mellitus. Endocr J 1996; 43: 233-239 58. Craft S, Peskind E, Schwartz MW et al. Cerebrospinal fluid and plasma insulin levels in Alzheimer’s disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 1998; 50: 164-168. 59. Craft S, Asthana S, Cook DG et al. Insulin dose-response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology 2003; 28: 809-822. 60. Ott A, Stolk RP, Hofman A et al. Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia 1996; 39(11): 1392-7. 61. den Heijer T, Vermeer SE, van Dijk EJ et al. Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI. Diabetologia 2003; 46(12): 1604-10. 62. Lin L, Hölscher C. Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Res Rev 2007; 56(2): 384-402. 63. Churcher I. Tau therapeutic strategies for the treatment of Alzheimer’s disease. Curr Top Med Chem 2006; 6: 579-595. 64. Glabe CG. Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol Aging 2006; 27: 570-575. 65. Ristow M. Neurodegenerative disorders associated with diabetes mellitus. J Mol Med (Berl). 2004; 82(8): 510-29. 66. Stolk RP, Breteler MM, Ott A et al. Insulin and cognitive function in an elderly population. The Rotterdam Study. Diabetes Care 1997; 20: 792-795. 67. Watson GS, Peskind ER, Asthana S et al. Insulin increases CSF Abeta42 levels in normal older adults. Neurology 2003; 60: 1899-19