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研究生: 林士翔
Lin, Shih-Xiang
論文名稱: α-硫辛酸改善高脂飲食及STZ誘導高胰島血症大鼠肌肉萎縮之研究
Effect of α-lipoic acid on muscle atrophy in hyperinsulinemic rats induced by high-fat diet plus streptozotocin
指導教授: 沈賜川
Shen, Szu-Chuan
吳瑞碧
Wu, JamesSwi-Bea
丁俞文
Ting, Yu-Wen
學位類別: 碩士
Master
系所名稱: 人類發展與家庭學系
Department of Human Development and Family Studies
論文出版年: 2018
畢業學年度: 106
語文別: 中文
論文頁數: 88
中文關鍵詞: 糖尿病肌肉萎縮胰島素阻抗硫辛酸抗氧化劑
英文關鍵詞: T2DM, muscle atrophy, insulin resistance, alpha-lipoic acid, Antioxidants
DOI URL: http://doi.org/10.6345/THE.NTNU.DHDFS.036.2018.A06
論文種類: 學術論文
相關次數: 點閱:187下載:8
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  • 流行病學研究顯示糖尿病患者罹患肌少症(sarcopenia)的比率比一般人高出三倍。第2型糖尿病的蛋白質合成和降解不平衡會造成患者肌肉萎縮,而肌肉萎縮是導致肌少症的主要症狀之一。文獻指出,高脂肪飲食會誘導周邊組織,例如肌肉產生氧化壓力與胰島素阻抗(insulin resistance)。胰島素阻抗被認為是影響肌肉蛋白流失的主要因素之一,因此推測其與肌肉萎縮之發生有關。α-硫辛酸(ALA)是一種生物抗氧化劑,研究指出其可緩解胰島素抵抗。
    本研究的目的是探討ALA對HFD與鏈脲佐菌素(STZ)誘導的高胰島素血症大鼠肌肉萎縮的影響及其機制。雄性Wistar大鼠餵食HFD 4週後以腹膜內注射STZ,然後連續8週給予HFD以誘導高胰島素血症,之後給予高胰島素血症大鼠ALA每日一次,連續13週。大鼠犧牲後摘取比目魚肌並稱重,另以H&E染色觀察肌纖維的形態學,並使用西方墨點法分析胰島素信號傳遞、發炎、肌肉再生與分解相關的蛋白質表現。
    結果顯示,高脂飲食大鼠之比目魚肌肌肉量顯著增加,而H&E染色分析顯示,ALA處理的高胰島素血症大鼠肌肉纖維截面長度顯著增加48.6%,表示ALA處理可以維持較好的肌肉纖維。Western bolt分析顯示,ALA上調高胰島素血症大鼠比目魚肌胰島素信號傳遞相關蛋白質和肌肉再生相關蛋白質的表現,其同時也下調了發炎與肌肉分解相關蛋白質之表現。
    由以上結果顯示,ALA具有改善糖尿病患者肌肉中胰島素阻抗和肌肉萎縮的潛力,期望未來ALA可以開發為治療糖尿病引起的肌肉萎縮的藥物或膳食補充劑。

    Epidemiological studies revealed three fold higher risk of sarcopenia in diabetes mellitus (DM) patients. One of the symptoms of sarcopenia , muscle atrophy,is caused by an imbalance in protein synthesis and degradation which can be triggered by Type 2 Diabetes Mellitus. High fat diet (HFD) was reported to induce oxidative stress and insulin resistance in peripheral tissues, including muscle, of animals. Alpha-lipoic acid (ALA) which is a potent biological antioxidant would alleviate insulin resistance.
    The purpose of this study was to investigate the effects of ALA on alleviate muscle atrophy in HFD plus streptozotocin (STZ)-induced hyperinsulinemic rats and to explore the underlying mechanisms. The male Wistar rats fed HFD for 4 weeks were intraperitoneally (ip) injected STZ and then served HFD continuously for 8 weeks to induce hyperinsulinemia. The hyperinsulinemic rats were then orally administered with ALA for 13 weeks. After sacrifice, the soleus muscle was weighed and H&E staining was performed for morphological observation of muscle fibers. The protein expression of insulin signaling, inflammation, muscle regeneration and catabolic related signal proteins were analyzed by western blotting.
    The results show that administration of ALA significantly increased soleus muscle mass in hyperinsulinemic rats. H&E staining image analysis reveals that muscle fibers significantly increased by 48.6% in ALA-treated hyperinsulinemic rats. The western bolt analysis indicates that ALA up-regulated expression of insulin signaling、muscle regeneration related proteins, and down-regulated expression of inflammation、muscle protein breakdown related proteins.
    Above observations demonstrates that ALA has the potential on improving the insulin resistance and muscle atrophy in muscle of DM patients. In the future, ALA may become a possible alternative therapy to treat muscle atrophy caused by diabetes.

    第一章. 前言 1 第二章. 文獻回顧 2 第一節. 糖尿病 2 一、 糖尿病定義及其合併症 2 二、 糖尿病流行病學 2 三、 糖尿病分類 3 四、 糖尿病診斷 5 第二節. 胰島素阻抗 6 一、 胰島素簡介 6 二、 胰島素訊息傳遞及作用 6 三、 胰島素阻抗簡介 8 四、 肥胖與胰島素阻抗形成 8 五、 高胰島素血症與胰島素阻抗 10 第三節. 氧化壓力與發炎 11 一、 氧化壓力 11 二、 發炎路徑 11 三、 胰島素阻抗與發炎 13 第四節. 肌少症 14 一、 肌少症簡介 14 二、 肌少症流行病學 14 三、 肌少症與高胰島素血症的關聯性 15 四、 肌少症、肥胖與胰島素阻抗的關聯 16 第五節. 肌肉生成 17 一、 骨骼肌分類 17 二、 肌肉生成途徑 18 三、 胰島素阻抗與肌肉再生 21 第六節. 肌肉分解 22 一、 肌肉分解路徑 22 二、 胰島素阻抗與肌肉分解 23 第七節. 硫辛酸 25 一、 硫辛酸簡介 25 二、 硫辛酸與氧化壓力 26 三、 硫辛酸與胰島素阻抗 26 第三章. 實驗目的與架構 27 第一節. 實驗動機與目的 27 第二節. 實驗架構 28 第四章. 實驗材料與方法 29 第一節. 樣品製備之材料 29 一、 實驗材料 29 二、 實驗動物來源 32 三、 實驗動物飼料 32 第二節. 試驗方法 33 一、 實驗樣品配置 33 二、 實驗藥品配置 33 三、 實驗動物誘導及分組 34 四、 試驗方法 35 五、 儀器設備 43 六、 統計分析 44 第五章. 實驗結果 45 第一節. α –硫辛酸對高脂肪飲食併合STZ藥物誘導高胰島素血症大鼠血液生理生化值之影響 45 一、 體重與飲水、食物攝取量 45 二、 血液血糖、胰島素值 45 三、 血液生化值 46 第二節. α –硫辛酸對高脂肪飲食併合STZ藥物誘導高胰島素血症大鼠肌肉發炎與肌肉纖維長度之影響 50 一、 肌肉腫瘤壞死因子-α值 50 二、 肌肉質量與纖維長度 50 第三節. α –硫辛酸對高脂肪飲食併合STZ藥物誘導高胰島素血症大鼠細胞傳訊蛋白質之影響 56 一、 胰島素傳訊路徑 56 二、 發炎相關路徑 56 三、 肌肉再生路徑 57 四、 肌肉分解路徑 57 第六章. 討論 68 第一節. 生理血液生化 68 第二節. 肌肉纖維長度與質量 69 第三節. 胰島素傳訊系統 70 第四節. 發炎與相關傳訊系統 71 第五節. 肌肉相關傳訊系統 72 第六節. 硫辛酸減緩高胰島素血症大鼠肌肉萎縮的可能機制 73 第七章. 結論 76 第八章. 附錄 77 第九章. 參考資料 81

    一、中文文獻:

    吳易謙、熊昭、陳慶餘、吳名祥、許志成。(2014)。台灣社區老人肌少症流行病學初探。台灣醫學期刊 201405 (18:3期) 209-302。
    吳雅汝、周怡君、詹鼎正(2014)。文獻回顧-肌少症與衰弱症。內科學誌,25(3),131-136。
    吳佩芩。(2017)。咖啡胺衍生物K36改善高脂飲食及STZ誘發第二型糖尿病大鼠認知功能之探討。碩士論文,國立臺灣師範大學人類發展與家庭學系。
    涂孟萱。(2017)。硫辛酸抑制NLRP3發炎體活化而減緩高脂飲食及STZ誘發第二型糖尿病大鼠內臟脂肪組織發炎反應之研究。碩士論文,國立臺灣師範大學人類發展與家庭學系。
    林家羽。(2016)。消渴草粗萃物減緩高脂飲食及STZ誘發第二型糖尿病大鼠肝臟脂肪變性及發炎反應之探討。碩士論文,國立臺灣師範大學人類發展與家庭學系。
    陳奕安。(2010)。探討重組豬肌肉生長抑制素前胜肽對C2C12肌原母細胞及小鼠模式動物之肌肉生成的影響。碩士論文,國立中興大學生命科學系碩士論文。
    施玉惠。(2015)。中鏈三酸甘油酯有效抑制C57BL/6腫瘤小鼠的肌肉萎縮。碩士論文,中山醫學大學營養學研究所碩士論文
    行政院衛生署。(2017)。中華民國一○五年死因統計。

    二、英文文獻:

    ADA. (2017). Standards of medical care in diabetes—2017(Vol.Volume40): American Diabetes Associaion.
    Asmat, U., Abad, K., & Ismail, K. (2016). Diabetes mellitus and oxidative stress—A concise review. Saudi Pharmaceutical Journal, 24(5), 547-553.
    Bellacosa A, Testa Staal S, Tsichlis P. (1991). A retroviral oncogene, Akt, encoding a serine-threonine kinase containing an SH2-like region. Science, 254(5029): 274-277.
    Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, Zlotchenko E, Scrimgeour A, Lawrence JC, Glass DJ, Yancopoulos GD. (2001). Akt/mTOR pathway is acrucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy. In vivo. Nat. Cell Biol. 3: 1014-1019.
    Beaudart C, Rizzoli R, Bruye`re O, Reginster JY, Biver E. (2014). Sarcopenia: burden and challenges for public health. Arch Public Health 72:45.
    Bellacosa A, Testa JR, Staal SP, Tsichlis PN. (1991). retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254: 274–277
    Benomar, Y., Gertler, A., De Lacy, P., Crépin, D., Ould Hamouda, H., Riffault, L., & Taouis, M. (2013). Central Resistin Overexposure Induces Insulin Resistance Through Toll-Like Receptor 4. Diabetes, 62(1), 102.
    Carotenuto F, Costa A, Albertini MC, Rocchi MB, Rudov A, Coletti D, Teodori L. (2016). Dietary Flaxseed Mitigates Impaired Skeletal Muscle Regeneration: in Vivo, in Vitro and in Silico Studies. Int J Med Sci, 13(3): 206-219.
    Clarke W, Larner J, Pohn S. (1986). Methods in diabetes research (Vol. 2, pp. 39-86). New York: John Wiley and Sous, ENC.
    Clarke, B. A., Drujan, D., Willis, M. S., Murphy, L. O., Corpina, R. A., Burova, E., Rakhilin ,SV ., Stitt, TN ., Patterson, C ., Latres ,E ., Glass, D. J. (2007). The E3 Ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle. Cell Metab, 6(5), 376-385.
    Cleasby, M.E., Jamieson, P.M., & Atherton, P.J. (2016). Insulin resistance and sarcopenia: mechanistic links between common co-morbidities. J Endocrinol, 229(2), R67-81.
    Cornelison DD, Olwin BB, Rudnicki MA, Wold BJ. (2000). MyoD(-/-) satellite cells insingle-fiber culture are differentiation defective and MRF4 deficient. Dev. Biol. 224: 122-137.
    Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM, Topinková E, Vandewoude M, Zamboni M. (2010). Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 39(4):412-23.
    De la Fuente, M., & Miquel, J. (2009). An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des, 15(26), 3003-3026.
    Dicter N, Madar Z, Tirosh O. (2002). Alpha-lipoic acid inhibits glycogen synthesis in rat soleus muscle via its oxidative activity and the uncoupling of mitochondria. J Nutr 132(10): 3001-3006.
    Diz-Chaves Y, Gil-Lozano M, Toba L, Fandino J, Ogando H, Gonzalez-Matias LC, Mallo F. (2016). Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis. J Endocrinol, 230(2):R77-94.
    Doody, N. E., Dowejko, M. M., Akam, E. C., Cox, N. J., Bhatti, J. S., Singh, P., & Mastana, S. S. (2017). The Role of TLR4, TNF-alpha and IL-1beta in Type 2 Diabetes Mellitus Development within a North Indian Population. Ann Hum Genet, 81(4), 141-146.
    Endo, M., Yamamoto, H., Setsu, N., Kohashi, K., Takahashi, Y., Ishii, T., Iida, K ., Matsumoto, Y .,Hakozaki, M .,Aoki, M .,Iwasaki, H .,Dobashi, Y ., Nishiyama, K .,Iwamoto, Y ., Oda, Y. (2013). Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors. Clinical Cancer Research, 19(2), 450.
    Fanzani, A., Conraads, V. M., Penna, F., & Martinet, W. (2012). Molecular and cellular mechanisms of skeletal muscle atrophy: an update. J Cachexia Sarcopenia Muscle, 3(3), 163-179.
    Foletta, V. C., White, L. J., Larsen, A. E., Leger, B., & Russell, A. P. (2011). The role and regulation of MAFbx/atrogin-1 and MuRF1 in skeletal muscle atrophy. Pflugers Arch, 461(3), 325-335.
    Freychet P, Roth J, Neville DM, Jr. (1971). Insulin receptors in the liver: specific binding of (125 I) insulin to the plasma membrane and its relation to insulin bioactivity. Proc. Natl. Acad. Sci. USA 1971, 68:1833–1837.
    Gordillo-Moscoso, A., Ruiz, E., Carnero, M., Reguillo, F., Rodriguez, E., Tejerina, T., & Redondo, S. (2013). Relationship between serum levels of triglycerides and vascular inflammation, measured as COX-2, in arteries from diabetic patients: a translational study. Lipids Health Dis, 12, 62.
    Graber, C. D., O'neal, R. M., & Rabin, E. R. (1965). Effect of high fat diets on intestinal microflora and serum cholesterol in rats. J bacteriol, 89, 47-51.
    Guo, J., Gao, S., Liu, Z., Zhao, R., & Yang, X. (2016). Alpha-Lipoic Acid Alleviates Acute Inflammation and Promotes Lipid Mobilization During the Inflammatory Response in White Adipose Tissue of Mice. Lipids, 51(10), 1145-1152.
    Jacob, S., Streeper, RS., Fogt, DL., Hokama, JY., Tritschler, HJ., Dietze, GJ., & Henriksen,EJ.(1996). The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. Diabetes, 45(8), 1024-1029.
    Karalaki, M., Fili, S., Philippou, A., & Koutsilieris, M. (2009). Muscle regeneration: cellular and molecular events. In Vivo, 23(5), 779-796.
    Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M. (2006). MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest, 116(6), 1494-1505
    Kaneto, H., Nakatani, Y., Kawamori, D., Miyatsuka, T., & Matsuoka, T. (2004). Involvement of Oxidative Stress and the JNK Pathway in Glucose Toxicity. Rev Diabet Stud, 1(4), 165-174.
    Kato, G. J., McGowan, V., Machado, R. F., Little, J. A., Taylor, J., Morris, C. R., Nichols, J. S. ,Wang, X. ,Poljakovic, M. ,Morris, S. M.. Gladwin, M. T. (2006). Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood, 107(6), 2279-2285.
    Kim, S. W., Jung, H. W., Kim, C. H., Kim, K. I., Chin, H. J., & Lee, H. (2016). A New Equation to Estimate Muscle Mass from Creatinine and Cystatin C. PLoS One, 11(2), e0148495.
    Kitess, SM, Abeywardena MY. (2016). Lipid-Induced Insulin Resistance in Skeletal Muscle: The Chase for the Culprit Goes from Total Intramuscular Fat to Lipid Intermediates, and Finally to Species of Lipid Intermediates. Nutrients, 8(8).
    Lawrence, T. (2009). The Nuclear Factor NF-κB Pathway in Inflammation. Cold Spring Harb Perspect Biol, 1(6).
    Lietzke SE, Bose S, Cronin T, Klarlund J, Chawla A, Czech M P, Lambright DG. (2000). Structural Basis of 3-Phosphoinositide Recognition by Pleckstrin Homology Domains. Mol Cell, 6(2), 385-394.
    Liu, T. W., Heden, T. D., Matthew Morris, E., Fritsche, K. L., Vieira-Potter, V. J., & Thyfault, J. P. (2015). High-Fat Diet Alters Serum Fatty Acid Profiles in Obesity Prone Rats: Implications for In Vitro Studies. Lipids, 50(10), 997-1008.
    Locksley, R. M., Killeen, N., & Lenardo, M. J. (2001). The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell, 104(4), 487-501.
    Lu, S.-Y., Wang, C.-Y., Jin, Y., Meng, Q., Liu, Q., Liu, Z, Liu, K-X, Sun H-J. ,Liu, M.-Z. (2017). The osteogenesis-promoting effects of alpha-lipoic acid against glucocorticoid-induced osteoporosis through the NOX4, NF-kappaB, JNK and PI3K/AKT pathways. Scientific Reports, 7(1), 3331.
    Mudaliar S, Chang, Anna R, Henry, Robert R. (2003). Thiazolidinediones, peripheral edema, and type 2 diabetes: incidence, pathophysiology, and clinical implications. Endocr Pract. 2003 Sep-Oct;9(5):406-16.
    Muroya, S., Nakajima, I., & Chikuni, K. (2002). Related expression of MyoD and Myf5 with myosin heavy chain isoform types in bovine adult skeletal muscles. Zoolog Sci, 19(7), 755-761.
    Okanovic, A., Prnjavorac, B., Jusufovic, E., & Sejdinovic, R. (2015). Alpha-lipoic acid reduces body weight and regulates triglycerides in obese patients with diabetes mellitus. Med Glas (Zenica), 12(2), 122-127.
    Patel, S. S., Molnar, M. Z., Tayek, J. A., Ix, J. H., Noori, N., Benner, D., Kovesdy, C. P. , Kalantar-Zadeh, K. (2013). Serum creatinine as a marker of muscle mass in chronic kidney disease: results of a cross-sectional study and review of literature. J Cachexia Sarcopenia Muscle, 4(1), 19-29.
    Pelosi, M., De Rossi, M., Barberi, L., & Musaro, A. (2014). IL-6 impairs myogenic differentiation by downmodulation of p90RSK/eEF2 and mTOR/p70S6K axes, without affecting AKT activity. Biomed Res Int, 2014, 206026
    Rosen OM. (1987). After insulin binds. Science, 237(4281), 1452-1458.
    Reaven GM, Banting L. (1988). Role of insulin resistance in human disease. Diabetes 1988, 37, 1595–1607.
    Sandri, M., Sandri, C., Gilbert, A., Skurk, C., Calabria, E., Picard, A., . . . Goldberg, A. L. (2004). Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell, 117(3), 399-412.
    Samuel VT, Petersen KF, Shulman GI. (2010). Lipid-Induced insulin resistance: Unravelling the mechanism. Lancet, 375, 2267–2277.
    Schroder, K., & Tschopp, J. (2010). The Inflammasomes. Cell, 140(6), 821–832.
    Shaw, SC., Dennison, EM., & Cooper, C. (2017). Epidemiology of Sarcopenia: Determinants Throughout the Lifecourse. Calcif Tissue Int, 101(3), 229-247.
    Shay KP, Moreau RF, Smith EJ, Smith AR, Hagen TM. (2009). Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Biochim Biophys Acta, 1790(10), 1149-1160.
    Soon Jib Yoo, Oak Kee Hong, Do Man Kim, Hyuk Sang Kwon, Ho Young Son, Sung Koo Kang & Dong-Sun Kim(2009). The effect of [alpha]-lipoic acid on myostatin and myosin heavy chain isoform profile of skeletal muscle of OLETF rats. Endocrine Abstracts (2009) 20 P498
    Susan M. Abmayr, Grace K. Pavlath. (2012). Myoblast fusion: lessons from flies and mice. Development, 139: 641-656.
    Tisdale, M. J. (2002). Cachexia in cancer patients. Nat Rev Cancer, 2(11), 862-871.
    Tisdale, M. J. (2009). Mechanisms of cancer cachexia. Physiol Rev, 89(2), 381-410.
    Tomás E, Lin YS, Dagher Z, Saha A, Luo Z, Ido Y, Ruderman NB. (2002). Hyperglycemia and insulin resistance: possible mechanisms. Ann N Y Acad Sci. 967, 43-51.
    Vida, C., Gonzalez, E. M., & De la Fuente, M. (2014). Increase of oxidation and inflammation in nervous and immune systems with aging and anxiety. Curr Pharm Des, 20(29), 4656-4678.
    Walro, J. M., & Kucera, J. (1999). Why adult mammalian intrafusal and extrafusal fibers contain different myosin heavy-chain isoforms. Trends Neurosci, 22(4), 180-184.
    Wertz, Ingrid E, & Dixit, Vishva M. (2010). Signaling to NF- B: Regulation by Ubiquitination Cold Spring Harb Perspect Biol. 2010 Mar;2(3):a003350
    Xu Q, Wu Z. (2000). The insulin-like growth factor-phosphatidylinositol 3-kinase-Akt signaling pathway regulates myogenin expression in normal myogenic cells but not in rhabdomyosarcoma-derived RD cells. J Biol Chem, 275(47), 36750-36757.
    Umegaki H. (2015). Sarcopenia and diabetes: Hyperglycemia is a risk factor for age-associated muscle mass and functional reduction. J Diabetes Investig 6(6), 623-624.

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