近年來，隨著老齡化人口不斷增多，老化相關疾病也逐漸被重視。阿茲海默症為臨床上常見之神經退化疾病，流行病學研究發現，第二型糖尿病(Type 2 diabetes mellitus; T2DM)為阿茲海默症之風險因子之一，而胰島素阻抗為其主要表徵。本實驗探討咖啡胺衍生物K36對T2DM大鼠降血糖及改善認知功能之效果。Wistar大鼠以高脂飲食(脂肪含量佔總熱量60%)與STZ誘導為T2DM之動物模式後，每日管餵K36 (15 mg/kgBW) 13周，觀察K36對於胰島素訊息路徑與阿茲海默症生成途徑，所造成長期增益效應途徑、突觸表現改變之影響。結果顯示，K36可顯著降低T2DM大鼠血糖、胰島素阻抗，及改善血脂異常之效果(p <0.05)。莫式水迷宮結果顯示，K36顯著改善T2DM大鼠學習與記憶的能力(p <0.05)。西方墨點法結果顯示，於胰島素訊息路徑方面，K36能夠顯著增加大腦皮質之胰島素分解酵素(Insulin degrading enzyme; IDE)、胰島素受體(insulin receptor; IR)、胰島素受體基質1 (insulin receptor substrate-1; IRS-1)及葡萄糖轉運蛋白4 (glucose transporter 4; GLUT4)的蛋白表現 (p <0.05)；在突觸功能表現方面，K36能夠增加大腦皮質與海馬迴的突觸蛋白Drebrin、PSD-95 (p <0.05)；阿茲海默症風險因子β類澱粉樣蛋白(β-Amyloid; Aβ)的生成途徑方面，結果顯示K36可顯著降低大腦皮質與海馬迴BACE (β-site APP cleaving enzyme, BACE)與類澱粉樣前驅蛋白 (Amyloid-β precursor protein; APP)的表現(p <0.05)；在腦部神經之長期增益效應部分，K36能夠顯著增加大腦皮質與海馬迴N-甲基-D-天門冬胺酸(N-methyl-D-aspartate; NMDA)受體之次單位NMDAR1與NMDAR2B，以及海馬迴攜鈣素(Calmodulin; CaM)的表現，而K36也能增加皮質攜鈣素(CaM)及CaMKIIβ的表現量(p<0.05)。綜合以上結果顯示，K36能夠改善腦部胰島素訊息路徑、降低Aβ之生成、改善突觸後功能及長期增益效應，進而改善T2DM大鼠認知功能。

Currently, as the increasing in aging population, the aging-related diseases are noticed in the world. Alzheimer’s disease is one of the most common neurodegenerative diseases. Type 2 diabetes mellitus (T2DM) is a risk factor of Alzheimer’s disease characterized as insulin resistance. This study aims to investigate the effect of caffeamide K36 on hypoglycemia and improving cognitive impairment in T2DM rats. Wistar rats were fed with high fat diet (HFD; 60% of kcal) and STZ injection to induce T2DM, and then administrated with K36 (15 mg/kg BW) for 13 weeks. Results show that K36 reduces insulin resistance and improves dyslipidemia significantly in T2DM rats (p<0.05). The result from Morris Water Maze shows that K36 improves the ability of learning and memory in T2DM rats (p<0.05). Western blotting analysis reveals that K36 significantly increases the insulin signaling-related proteins expression, including insulin receptor (IR), insulin receptor substrate-1(IRS-1) and glucose transporter 4 (GLUT4) in cortex (p<0.05). In addition, K36 increases the synaptic function-related proteins expression, including postsynaptic density protein-95 (PSD-95) and drebrin in both cortex and hippocampus. Moreover, K36 decreases the expression of BACE (β-site APP cleaving enzyme) and amyloid-β precursor protein (APP) significantly (p<0.05). K36 increases LTP (long-term potential)-related proteins expression, including NMDA (N-methyl-D-aspartate) subunit NMDAR1 and NMDAR2B in cortex and hippocampus significantly. K36 enhances the expression of Calmodulin (CaM) in hippocampus. K36 also increases CaM and CalMKIIβ expression in cortex. Above observations demonstrate that K36 may alleviate cerebral insulin resistance, reduce the accumulation of Aβ, ameliorate postsynaptic function and LTP ability, and enhance the cognitive and memory ability in T2DM rats.

Alberti, K. G. M. M., & Zimmet, P. F. (1998). Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic medicine, 15(7), 539-553.
Alzheimer’s Association. (2016). Basics of Alzheimer’s Disease. Alzheimer’s Association.
Anand, P., & Singh, B. (2013). A review on cholinesterase inhibitors for Alzheimer’s disease. Archives of pharmacal research, 36(4), 375-399.
Arnold, S. E., Lucki, I., Brookshire, B. R., Carlson, G. C., Browne, C. A., Kazi, H., ... & Kim, S. F. (2014). High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiology of disease, 67, 79-87.
Barilar, J. O., Knezovic, A., Grünblatt, E., Riederer, P., & Salkovic-Petrisic, M. (2015). Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer’s disease. Journal of neural transmission, 122(4), 565-576.
Bellamy, L., Casas, J. P., Hingorani, A. D., & Williams, D. (2009). Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. The Lancet, 373(9677), 1773-1779.
Biessels, G. J., & Reagan, L. P. (2015). Hippocampal insulin resistance and cognitive dysfunction. Nature Reviews Neuroscience, 16(11), 660-671.
Bitner, R. S. (2012). Cyclic AMP response element-binding protein (CREB) phosphorylation: a mechanistic marker in the development of memory enhancing Alzheimer's disease therapeutics. Biochemical pharmacology, 83(6), 705-714.
Calvo‐Ochoa, E., & Arias, C. (2015). Cellular and metabolic alterations in the hippocampus caused by insulin signalling dysfunction and its association with cognitive impairment during aging and Alzheimer's disease: studies in animal models. Diabetes/metabolism research and reviews, 31(1), 1-13.
Diamant, M., & Heine, R. J. (2003). Thiazolidinediones in type 2 diabetes mellitus. Drugs, 63(13), 1373-1406.
Dominguez, R. O., Pagano, M. A., Marschoff, E. R., González, S. E., Repetto, M. G., & Serra, J. A. (2014). Alzheimer disease and cognitive impairment associated with diabetes mellitus type 2: Associations and a hypothesis. Neurología (English Edition), 29(9), 567-572.
Francis, P. T., Palmer, A. M., Snape, M., & Wilcock, G. K. (1999). The cholinergic hypothesis of Alzheimer’s disease: a review of progress. Journal of Neurology, Neurosurgery & Psychiatry, 66(2), 137-147.
Georgy, G. S., Nassar, N. N., Mansour, H. A., & Abdallah, D. M. (2013). Cerebrolysin ameloriates cognitive deficits in type III diabetic rats. PloS one, 8(6), e64847.
Gispen, W. H., & Biessels, G. J. (2000). Cognition and synaptic plasticity in diabetes mellitus. Trends in neurosciences, 23(11), 542-549.
Glenn E. Smith. (2014) Early-onset Alzheimer's: When symptoms begin before age 65. 取自http://www.mayoclinic.org/diseases-conditions/alzheimers-disease/in-depth/alzheimers/art-20048356?pg=1
Heni, M., Kullmann, S., Preissl, H., Fritsche, A., & Häring, H. U. (2015). Impaired insulin action in the human brain: causes and metabolic consequences. Nature reviews Endocrinology, 11(12), 701-711. Holbrook, M. B., & Hirschman, E. C. (1982). The experiential aspects of consumption: Consumer fantasies, feelings, and fun. Journal of consumer research, 9(2), 132-140.
Hölscher, C. (2011). Diabetes as a risk factor for Alzheimer's disease: insulin signalling impairment in the brain as an alternative model of Alzheimer's disease. Biochemical Society Transactions, 39(4), 891-897.
Hu, S. H., Jiang, T., Yang, S. S., & Yang, Y. (2013). Pioglitazone ameliorates intracerebral insulin resistance and tau-protein hyperphosphorylation in rats with type 2 diabetes. Experimental and Clinical Endocrinology & Diabetes, 121(04), 220-224.
Li, W., Wang, T., & Xiao, S. (2016). Type 2 diabetes mellitus might be a risk factor for mild cognitive impairment progressing to alzheimer’s disease. Neuropsychiatric Disease and Treatment, 12, 2489.
Liao, M. H., Xiang, Y. C., Huang, J. Y., Tao, R. R., Tian, Y., Ye, W. F., ... & Fukunaga, K. (2013). The disturbance of hippocampal CaMKII/PKA/PKC phosphorylation in early experimental diabetes mellitus. CNS neuroscience & therapeutics, 19(5), 329-336.
Lisman, J., Yasuda, R., & Raghavachari, S. (2012). Mechanisms of CaMKII action in long-term potentiation. Nature Reviews Neuroscience, 13(3), 169-182.
Liu, Y., Liu, F., Grundke‐Iqbal, I., Iqbal, K., & Gong, C. X. (2011). Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. The Journal of pathology, 225(1), 54-62.
Lu, D. Y., Huang, B. R., Yeh, W. L., Lin, H. Y., Huang, S. S., Liu, Y. S., & Kuo, Y. H. (2013). Anti-neuroinflammatory effect of a novel caffeamide derivative, KS370G, in microglial cells. Molecular neurobiology, 48(3), 863-874.
Ma, L., Shao, Z., Wang, R., Zhao, Z., Dong, W., Zhang, J., ... & Zhang, J. (2015). Rosiglitazone improves learning and memory ability in rats with type 2 diabetes through the insulin signaling pathway. The American journal of the medical sciences, 350(2), 121-128.
M de la Monte, S. (2012). Brain insulin resistance and deficiency as therapeutic targets in Alzheimer's disease. Current Alzheimer Research, 9(1), 35-66.
Mayeux, R., & Stern, Y. (2012). Epidemiology of Alzheimer disease. Cold Spring Harbor perspectives in medicine, 2(8), a006239.
McClean, P. L., Parthsarathy, V., Faivre, E., & Hölscher, C. (2011). The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. The Journal of Neuroscience, 31(17), 6587-6594.
Miao, Y., He, T., Zhu, Y., Li, W., Wang, B., & Zhong, Y. (2015). Activation of hippocampal CREB by rolipram partially recovers balance between TNF-α and IL-10 levels and improves cognitive deficits in diabetic rats. Cellular and molecular neurobiology, 35(8), 1157-1164.
Mittal, K., Mani, R. J., & Katare, D. P. (2016). Type 3 Diabetes: Cross Talk between Differentially Regulated Proteins of Type 2 Diabetes Mellitus and Alzheimer’s Disease. Scientific reports, 6.
Morgen, K., & Frölich, L. (2015). The metabolism hypothesis of Alzheimer’s disease: from the concept of central insulin resistance and associated consequences to insulin therapy. Journal of Neural Transmission, 122(4), 499-504.
Morris, R. (1984). Developments of a water-maze procedure for studying spatial learning in the rat. Journal of neuroscience methods, 11(1), 47-60.
NCD Risk Factor Collaboration. (2016). Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4· 4 million participants. The Lancet, 387(10027), 1513-1530.
Piroli, G. G., Grillo, C. A., Reznikov, L. R., Adams, S., McEwen, B. S., Charron, M. J., & Reagan, L. P. (2007). Corticosterone impairs insulin-stimulated translocation of GLUT4 in the rat hippocampus. Neuroendocrinology, 85(2), 71-80.
Qiu, W. Q., & Folstein, M. F. (2006). Insulin, insulin-degrading enzyme and amyloid-β peptide in Alzheimer's disease: review and hypothesis. Neurobiology of aging, 27(2), 190-198.
Reijmer, Y. D., van den Berg, E., Ruis, C., Jaap Kappelle, L., & Biessels, G. J. (2010). Cognitive dysfunction in patients with type 2 diabetes. Diabetes/metabolism research and reviews, 26(7), 507-519.
Reitz, C., & Mayeux, R. (2014). Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochemical pharmacology, 88(4), 640-651.
Seuring, T., Archangelidi, O., & Suhrcke, M. (2015). The economic costs of type 2 diabetes: a global systematic review. Pharmacoeconomics, 33(8), 811-831.
Sims-Robinson, C., Kim, B., Rosko, A., & Feldman, E. L. (2010). How does diabetes accelerate Alzheimer disease pathology? Nature Reviews. Neurology, 6(10), 551–559. http://doi.org/10.1038/nrneurol.2010.130
Steen, E., Terry, B. M., J Rivera, E., Cannon, J. L., Neely, T. R., Tavares, R., ... & de la Monte, S. M. (2005). Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease–is this type 3 diabetes?. Journal of Alzheimer's disease, 7(1), 63-80.
Suzanne, M. (2014). Type 3 diabetes is sporadic Alzheimer’s disease: Mini-review. European Neuropsychopharmacology, 24(12), 1954-1960.
Weng, Y. C., Chiu, H. L., Lin, Y. C., Chi, T. C., Kuo, Y. H., & Su, M. J. (2010). Antihyperglycemic effect of a caffeamide derivative, KS370G, in normal and diabetic mice. Journal of agricultural and food chemistry, 58(18), 10033-10038.
Whitmer, R. A., Karter, A. J., Yaffe, K., Quesenberry, C. P., & Selby, J. V. (2009). Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. Jama, 301(15), 1565-1572.
Winocur, G., Greenwood, C. E., Piroli, G. G., Grillo, C. A., Reznikov, L. R., Reagan, L. P., & McEwen, B. S. (2005). Memory impairment in obese Zucker rats: an investigation of cognitive function in an animal model of insulin resistance and obesity. Behavioral neuroscience, 119(5), 1389.
郭柏伶。(2013)。咖啡酸對高脂飼料誘導高胰島素血症大鼠海馬迴及皮質醣類代謝之研究。碩士論文，國立臺灣師範大學人類發展與家庭學系。
社團法人中華民國糖尿病學會。（2015）。2015糖尿病臨床照護指引【Adobe Reader版】。台北市：社團法人中華民國糖尿病學會。取自http://www.endo-dm.org.tw/
鄭勤巧。(2014)。咖啡酸預防高胰島素血症大鼠阿茲海默症之機制。碩士論文，國立臺灣師範大學人類發展與家庭學系。