第二型糖尿病與阿茲海默氏症的關聯性

Link between type 2 diabetes and Alzheimer's disease

10.6647/CN.24.01.08

黃雅祺(Ya-chi Huang)；雷若莉(Ruoh-lih Lei)；謝東呈(Dong-chen Shieh)

第二型糖尿病 ； 阿茲海默氏症 ； 認知障礙 ； 第三型糖尿病 ； Type 2 diabetes mellitus ； Alzheimer's disease ； Cognitive impairment ； Type 3 diabetes

彰化護理

24卷1期（2017 / 03 / 01）

17 - 25

繁體中文

流行病學研究證實，第二型糖尿病（Type 2 diabetes mellitus, T2DM）與阿茲海默氏症（Alzheimer's disease, AD）之間確實存有生理病理性的關聯，此類糖尿病病人具有較高之認知障礙的發生率，也因此具有較高罹患AD的風險，因此，T2DM已成為AD的危險因子之一。T2DM與AD的共同致病因子包含慢性高血糖、高胰島素血症、胰島素阻抗、突發性的急性低血糖（尤其在老人患者）、纖維性的沈積（AD病人的腦部及T2DM病人的胰臟）、胰島素訊息傳導的改變、發炎、肥胖及APOE4基因等。此外，AD病人併發T2DM者（又稱第三型糖尿病）可加重其臨床疾病表現。本文於分子、生化及組織病理層面，整理歸納T2DM和AD可能之關聯性的存在證據。藉由這些資訊盼能進一步描述這兩個疾病之間較具體的致病機轉，期望能在未來對治療第三型糖尿病的藥物研發有所助益。

Epidemiological studies have proved that there are pathophysiological connections between Type 2 Diabetes Mellitus (T2DM) and Alzheimer's disease (AD). Diabetic patients have higher incidences of cognitive impairment and hence they are more at the risk of developing AD. Therefore, T2DM is a risk factor for AD, although AD pathological marker studies have not provided sufficient evidence. Common pathogenic factors in both conditions including chronic hyperglycemia, hyperinsulinemia, insulin resistance, acute hypoglycemia episodes, especially in the elderly, fibrillar deposits (in brain in AD and in pancreas in T2DM), altered insulin signaling, inflammation, obesity and APOE4 carrier status. In addition, comorbid T2DM can worsen the clinical presentations of patients with AD. This review summarizes the evidences which establish the possible links between the two pathologies on the account of molecular, biochemical and at histopathological level. The information regarding their interactions will clearly establish the link between the two pathologies and will be helpful in the future for the development of drugs for Type 3 Diabetes.

1. Ando, K.,Oishi, M.,Takeda, S.,Iijima, K.,Isohara, T.,Nairn, A. C.,Suzuki, T.(1999).Role of phosphorylation of Alzheimer's amyloid precursor protein during neuronal differentiation.The Journal of Neuroscience,19(11),4421-4427.
2. Baglietto-Vargas, D.,Shi, J.,Yaeger, D. M.,Ager, R.,LaFerla, F. M.(2016).Diabetes and Alzheimer's disease crosstalk.Neuroscience and Biobehavioral Reviews,64,272-287.
3. Biessels, G. J.,Staekenborg, S.,Brunner, E.,Brayne, C.,Scheltens, P.(2006).Risk of dementia in diabetes mellitus: a systematic review.The Lancet Neurology,5(1),64-74.
4. Chatterjee, S.,Peters, S. A. E.,Woodward, M.,Arango, S. M.,Batty, G. D.,Beckett, N.,Huxley, R. R.(2015).Type 2 diabetes as a risk factor for dementia in women compared with Men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia.Diabetes Care,39(2),300-307.
5. Cheng, P. Y.,Sy, H. N.,Wu, S. L.,Wang, W. F.,Chen, Y. Y.(2012).Newly diagnosed type 2 diabetes and risk of dementia: a population-based 7-year follow-up study in Taiwan.Journal of Diabetes and its Complications,26(5),382-387.
6. Claxton, A.,Baker, L. D.,Hanson, A.,Trittschuh, E. H.,Cholerton, B.,Morgan, A.,Craft, S.(2015).Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia.Journal of Alzheimer's Disease,44(3),897-906.
7. Convit, A.(2005).Links between cognitive impairment in insulin resistance: an explanatory model.Neurobiology of Aging,26(1),31-35.
8. Craft, S.,Watson, G. S.(2004).Insulin and neurodegenerative disease: shared and specific mechanisms.The Lancet Neurology,3(3),169-178.
9. Fei, M.,Yan, P. Z.,Ru, J. M.,Ning, N. L.,Lin, G.(2013).Risk factors for dementia with type 2 diabetes mellitus among elderly people in China.Age Ageing,42(3),398-400.
10. Felice, F. G.,Wu, D.,Lambert, M. P.,Fernandez, S. J.,Velasco, P. T.,Lacor, P. N.,Klein, W. L.(2008).Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers.Neurobiology of Aging,29(9),1334-1347.
11. Gao, Y.,Xiao, Y.,Miao, R.,Zhao, J.,Cui, M.,Huang, G.,Fei, M.(2016).The prevalence of mild cognitive impairment with type 2 diabetes mellitus among elderly people in China: a cross-sectional study.Archives of Gerontology and Geriatrics,62,138-142.
12. Goodpaster, B. H.,Krishnaswami, S.,Harris, T. B.,Katsiaras, A.,Kritchevsky, S. B.,Simonsick, E. M.,Newman, A. B.(2005).Obesity, regional body fat distribution, and the metabolic syndrome in older men and women.Archives of Internal Medicine,165(7),777-783.
13. Guo, Y.,Wang, L.,Zhu, M.,Zhang, H.,Hu, Y.,Han, Z.,Wang, D.(2016).Detection of hyperphosphorylated tau protein and α-synuclein in spinal cord of patients with Alzheimer's disease.Neuropsychiatric Disease and Treatment,12,445-452.
14. Haan M. N.,Mungas, D. M.,Gonzalez, H. M.,Ortiz, T. A.,Acharya, A.,Jagust, W. J.(2003).Prevalence of dementia in older latinos: the influence of type 2 diabetes mellitus, stroke and genetic factors.Journal of the American Geriatrics Society,51(2),169-177.
15. Haan, M. N.(2006).Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease.Nature Clinical Practice Neurology,2(3),159-166.
16. Han, W.,Li, C.(2010).Linking type 2 diabetes and Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America,107(15),6557-6558.
17. Hotamisligil, G. S.(2003).Inflammatory pathways and insulin action.International Journal of Obesity,27,53-55.
18. Kamboh, M. I.(1995).Apolipoprotein E polymorphism and susceptibility to Alzheimer's disease.Human Biology,67(2),195-215.
19. Kimura, N.(2016).Diabetes Mellitus Induces Alzheimer's disease pathology: histopathological evidence from animal models.International Journal of Molecular Sciences,17(4),503-513.
20. Leibson, C. L.,Rocca, W. A.,Hanson, V. A.,Cha, R.,Kokmen, E.,O'Brien, P. C.,Palumbo, P. J.(1997).Risk of dementia among persons with diabetes mellitus: a population-based cohort study.American Journal of Epidemiology,145(4),301-308.
21. Lin, C. H.,Sheu, W. H.(2013).Hypoglycaemic episodes and risk of dementia in diabetes mellitus: 7-year follow-up study.Journal of Internal Medicine,273(1),102-110.
22. Lina, R. A.,Carolina, S. L.,Amero, C.,Quintanar, L.(2015).Structural basis for the inhibition of truncated islet amyloid polypeptide aggregation by Cu(II): insights into the bioinorganic chemistry of type II diabetes.Inorganic Chemistry,54(8),3788-3796.
23. Lovestone, S.(1999).Diabetes and dementia: is the brain another site end-organ damage?.Neurology,53(9),1907.
24. Mayeda, E. R.,Haan, M. N.,Neuhaus, J.,Yaffe, K.,Knopman, D. S.,Sharrett, A. R.,Mosley, T. H.(2014).Type 2 diabetes and cognitive decline over 14 years in middle-aged African Americans and whites: the ARIC brain MRI Study.Neuroepidemiology,43(3-4),220-227.
25. Mittal, K.,Katare, D. P.(2016).Shared links between type 2 diabetes mellitus and Alzheimer's disease: a review.Diabetes & Metabolic Syndrome,10(2),144-149.
26. Mittal, K.,Mani, R. J.,Katare, D. P.(2015).Type 3 diabetes: cross talk between differentially regulated proteins of type 2 diabetes mellitus and Alzheimer's Disease.Scientific Reports,6,1-8.
27. Monte, S. M.,Tong, M.,Lester, C. N.,Plater, M. J.,Wands, J. R.(2006).Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer's disease.Journal of Alzheimer's Disease,10(1),89-109.
28. Moreira, P. I.,Santos, M. S.,Seica, R.,Oliveira, C. R.(2007).Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes.Journal of the Neurological Sciences,257(1-2),206-214.
29. Ohara, T.,Doi, Y.,Ninomiya, T.,Hirakawa, Y.,Hata, J.,Iwaki, T.,Kiyohara, Y.(2011).Glucose tolerance status and risk of dementia in the community: the Hisayama study.Neurology,77(12),1126-1134.
30. Ott, A.,Stolk, R. P.,Van, H. F.,Pols, H. A.,Hofman, A.,Breteler, M. M.(1999).Diabetes mellitus and the risk of dementia: the Rotterdam study.Neurology,53(9),1937-1942.
31. Pedros, I.,Petrov, D.,Allgaier, M.,Sureda, F.,Barroso, E.,Beas, Z. C.,Camins, A.(2014).Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease.Biochimica Et Biophysica Acta,1842(9),1556-1566.
32. Percy, M.,Somerville, M. J.,Hicks, M.,Garcia, A.,Colelli, T.,Wright, E.,Wong, M. K.(2014).Risk factors for development of dementia in a unique six-year cohort study. I. An exploratory, pilot study of involvement of the E4 allele of apolipoprotein E, mutations of the hemochromatosis-HFE gene, type 2 diabetes, and stroke.Journal of Alzheimer's Disease,38(4),907-922.
33. Prince, M.,Bryce, R.,Albanese, E.,Wimo, A.,Ribeiro, W.,Ferri, C. P.(2013).The global prevalence of dementia: a systematic review and meta-analysis.Alzheimer's & dementia,9(1),63-75.
34. Reddy, V. P.,Zhu, X.,Perry, G.,Smith, M. A.(2009).Oxidative stress in diabetes and Alzheimer's Disease.Journal of Alzheimer's Disease,16(4),763-774.
35. Reiman, E. M.,Chen, K.,Alexander, G. E.,Caselli, R. J.,Bandy, D.,Osborne, D.,Hardym, J.(2004).Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia.Proceedings of the National Academy of Sciences of the United States of America,101(1),284-289.
36. Rivera, E. J.,Goldin, A.,Fulmer, N.,Tavares, R.,Wands, J. R.,Monte, S. M.(2005).Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine.Journal of Alzheimer's Disease,8(3),247-268.
37. Schilling, M. A.(2016).Unraveling Alzheimer's: making sense of the relationship between diabetes and Alzheimer's disease.Journal of Alzheimer's Disease,51(4),961-977.
38. Simic, G.,Leko, M. B.,Wray, S.,Harrington, C.,Delalle, I.,Milosevic, N. J.,Hof, P. R.(2016).Tau protein hyperphosphorylation and aggregation in Alzheimer's disease and other tauopathies, and possible neuroprotective strategies.Biomolecules,6(1),1-28.
39. Sridhar, G. R.,Lakshmi, G.,Nagamani, G.(2015).Emerging links between type 2 diabetes and Alzheimer's disease.World Journal of Diabetes,6(5),744-751.
40. Stadtman, E. R.(2006).Protein oxidation in aging and age-related diseases.Annals of the New York Academy of Sciences,928(1),22-38.
41. Strachan, M. W.,Price, J. F.,Frier, B. M.(2008).Diabetes, cognitive impairment, and dementia.BMJ,336(7634),6.
42. Sultana, R.,Butterfield, D. A.(2010).Role of oxidative stress in the progression of Alzheimer's disease.Journal of Alzheimer's Disease,19(1),341-353.
43. Takeuchi, M.,Sato, T.,Takino, J.,Kobayashi, Y.,Furuno, S.,Kikuchi, S.,Yamagishi, S.(2007).Diagnostic utility of serum or cerebrospinal fluid levels of toxic advanced glycation end-products (TAGE) in early detection of Alzheimer's disease.Medical Hypotheses,69(6),1358-1366.
44. Takeuchi, M.,Yamagishi, S.(2008).Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer's disease.Current Pharmaceutical Design,14(10),973-978.
45. Takeuchi, M.,Yamagishi, S.(2004).Alternative routes for the formation of glyceraldehyde-derived AGEs (TAGE) in vivo.Medical Hypotheses,63(3),453-455.
46. Vandal, M.,White, P. J.,Tremblay, C.,St-Amour, I.,Chevrier, G.,Emond, V.,Calon, F.(2014).Insulin reverses the high-fat diet-induced increase in brain Aβ and improves memory in an animal model of Alzheimer disease.Diabetes,63(12),4291-4301.
47. Veurink, G.,Fuller, S. J.,Atwood, C. S.,Martins, R. N.(2003).Genetics, lifestyle and the roles of amyloid beta and oxidative stress in Alzheimer's disease.Annals of Human Biology,30(6),639-667.
48. West, R. K.,Ravona, S. R.,Heymann, A.,Schmeidler, J.,Leroith, D.,Koifman, K.,Beeri, M. S.(2015).Shorter adult height is associated with poorer cognitive performance in elderly men with type II diabetes.Journal of Alzheimer's Disease,44(3),927-935.
49. Wiklund, O.,Haversen, L.,Pettersson, C.,Hulten, L.(2007).How can we prevent cardiovascular disease in diabetes.Journal of Internal Medicine,262(2),199-207.
50. Woods, S. C.,Seeley, R. J.,Baskin, D. G.,Schwartz, M. W.(2003).Insulin and the blood-brain barrier.Current Pharmaceutical Design,9(10),795-800.
51. Yan, S. F.,Barile, G. R.,Agati, V. D.,Yan, S. D.,Ramasamy, R.,Schmidt, A. M.(2007).The biology of RAGE and its ligands: uncovering mechanisms at the heart of diabetes and its complications.Current Diabetes Reports,7(2),146-153.
52. Yan, S.,Chen, X.,Walker, D. G.,Schmidt, A. M.,Arancio, O.,Lue, L. F.(2007).RAGE: A potential target for Aβ-mediated cellular perturbation in Alzheimer's disease.Current Molecular Medicine,7(8),735-742.
53. Yoshitake, T.,Kiyohara, Y.,Kato, I.,Ohmura, T.,Iwamoto, H.,Nakayama, K.,Ueda, K.(1995).Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study.Neurology,45(6),1161-1168.