臺灣博碩士論文加值系統

隨著生活型態的改變，肥胖、糖尿病等代謝症候群已變成世紀流行病。代謝症候後群大多涉及胰島素阻抗，使調控葡萄糖恆定之組織臟器無法有效運作，其中肝臟為調控葡萄糖合成、儲存及分解的主要器官。有研究指出食用諾麗果可以保肝、降血糖及降血脂，有利於降低罹患第二型糖尿病及肥胖。本研究中，將雄性C57BL/6JNarl分為五組(n=5)，分別為空白組、30%高果糖誘導對照組、高果糖誘導胰島素阻抗並給予低中高三種劑量之諾麗果粉。結果顯示，諾麗果粉於高果糖誘導胰島素阻抗之小鼠中，可增加肝醣含量及脂聯素，降低血清中肝酵素ALT及AST、三酸甘油酯、膽固醇、抗素、果醣胺、發炎細胞激素TNF-α分泌，減少肝損傷及降低脂肪堆積，並使空腹血糖值可降至正常狀態。隨著劑量效應下可以刺激IR-β、GLUT2及PI3K之基因表現，提升AMPK及AKT磷酸化增強訊號，並降低FoxO1、GSK3β及PEPCK之基因表現。此外，肝臟組織學切片H&E和油紅染色中，觀察到高果糖誘導對照組有大量油滴堆積及組織排列混亂，餵食諾麗果粉後，有效改善此現象。綜合上述，諾麗果可以改善小鼠葡萄糖代謝調控，增加葡萄糖攝入，減輕胰島素阻抗性，降低小鼠罹患代謝症候群的風險。

With the changing lifestyle, diabetes mellitus and obesity both became common diseases in this century. Metabolic syndrome is largely linked to insulin resistance, which renders the target organs or tissues responsible for glucose homeostasis fail to function properly. Among them, liver play crucial roles in regulating the synthesis, storage and breakdown of glucose. Research shows that consumption of noni can nourish the liver, lower blood sugar and lipid, help to reduce risk of Type II diabetes and obesity. In this study, male C57BL / 6JNarl mice were divided into five groups, the naive group, high fructose fed (HF) control group, HF with supplementation of low, medium and high doses of noni fruits. Mice fed with showed noni fruits increased glycogen content and serum adiponectin, reduced serum liver enzymes, triglycerides, cholesterol, ALT, AST, resistin, fructosamine, inflammatory cytokines TNF-α secretion, and reduced liver damage and fat accumulation and fasting blood glucose levels . In a dose-dependent manner, noni fruits stimulated the expression and/or phosphorylation of IR-β, GLUT2, PI3K, AKT and AMPK, while reducing gene expression of FoxO1, GSK3β and PEPCK. In addition, the liver histological evaluation of H & E and oil-red-O stainings revealed the liver from HF control mice accumulated a large number of oil droplets and showed chaotic tissue organization, which could be significantly reversed by feeding noni fruits. In summary, noni fruits can improve the regulation of glucose metabolism in mice, increase glucose uptake, reduce insulin resistance, and thereby reduce the risk of metabolic syndrome.

摘要1
Abstract2
第一章、前言3
第二章、文獻回顧4
2-1 諾麗之簡介4
2-1-1諾麗(Noni)之簡介4
2-1-2諾麗果粉4
2-1-3諾麗之生理活性5
2-1-3.1抗微生物(antimicrobial)5
2-1-3.2抗氧化(antioxidant activity)5
2-1-3.3抗發炎和止痛活性5
2-1-3.4抗腫瘤及抗癌(anti-tumor and anti-carcinogenic)5
2-1-3.5保肝6
2-1-3.6降血脂6
2-1-3.7降血糖6
2-2胰島素阻抗與相關代謝症候群6
2-2-1果糖於肝臟之代謝7
2-2-2非酒精性脂肪肝(non-alcoholic fatty liver disease, NAFLD)8
2-2-3脂肪細胞產生之細胞激素9
2-2-3.1腫瘤壞死因子-α (tumor necrosis factor alpha, TNF-α)9
2-2-3.2介白素-6 (Interleukin 6, IL-6)9
2-2-3.3脂聯素(Adiponectin)9
2-2-3.4抗素(Resistin)10
2-2-4肝功能指標10
2-2-4.1天門冬胺酸轉胺酶(aspartate aminotransferase, AST)10
2-2-4.2丙胺酸轉胺酶(alanine aminotransferase, ALT)10
2-2-4.3鹼性磷酸酶(Alkaline phosphatase, ALP)11
2-2-4.4總膽紅素(Total bilirubin, T-BIL)11
2-2-4.5果糖胺(Fructosamine)11
2-3糖尿病11
2-3-1糖尿病分類12
2-3-1.1第一型糖尿病12
2-3-1.2第二型糖尿病12
2-3-1.3其他特異型 12
2-3-1.4妊娠糖尿病 12
2-3-2糖尿病診斷13
2-3-3糖尿病的治療 13
2-4體內血糖恆定13
2-4-1胰島素分泌與其功能14
2-4-2 胰島素傳訊15
2-4-2.1胰島素受體(Insulin receptor, IR)16
2-4-2.2胰島素受體基質(Insulin receptor substrate, IRS)16
2-4-2.3磷脂基醇-3-激酶(Phosphatidylinositol 3 kinase, PI3K)17
2-4-2.4蛋白質激酶B (Protein kinase B, PKB/Akt) 17
2-4-2.5磷酸腺苷激活蛋白激酶(AMP-actived protein kinase, AMPK)18
2-4-2.6磷酸烯醇丙酮酸羧化激酶(Phosphoenolpyruvate carboxykinase, PEPCK)18
2-5 葡萄糖轉運與代謝18
2-5-1葡萄糖轉運蛋白(Glucose transporter, GLUT)19
2-5-2肝糖合成激酶3 (Glycogen synthase kinase 3, GSK3)19
2-5-3高糖誘發胰島素阻抗20
第三章、研究目的與實驗架構21
一、研究目的21
二、實驗架構22
第四章、材料與方法 23
一、藥品材料23
4-1-1 實驗藥品與試劑23
4-1-2 設備與器材24
二、實驗方法25
4-2-1動物飼養與試驗分組25
4-2-1.1高血糖及胰島素阻抗之造型模式 26
4-2-2血清分離與分析項目26
4-2-2.1總膽固醇(Total cholesterol)濃度測定26
4-2-2.2三酸甘油酯(Triglyceride)濃度測定26
4-2-2.3 AST (Aspartate Aminotransferase)活性測定26
4-2-2.4 ALT (Alanine Aminotransferase) 活性測定27
4-2-2.5胰島素(Insulin)濃度測定27
4-2-2.6口服葡萄糖耐受試驗(Oral glucose tolerance test, OGTT)27
4-2-2.7 胰島素阻抗HOMA-IR值27
4-2-2.8果糖胺(Fructosamine)濃度測定27
4-2-2.9脂泌素Adiponetin、Resistin之測定28
4-2-3肝臟病理分析 28
4-2-3.1肝臟肝醣分析28
4-2-3.2肝臟組織H&E染色(Hematoxylin and Eosin stain, H&E stain)29
4-2-3.3肝臟組織Oil-Red- O染色(Oil-Red-O stain)29
4-2-4 肝臟蛋白質分析29
4-2-4.1蛋白質萃取 29
4-3-4.2蛋白質濃度測定29
4-2-4.3細胞激素TNF-α與IL-6之測定30
4-2-4.4西方轉漬30
4-2-5肝臟基因表現分析31
4-2-5.1肝臟RNA抽取與cDNA 製備31
4-2-5.2同步定量聚合酶連鎖反應31
4-2-6體脂肪重量32
4-2-7脾臟及腎臟重量32
4-2-8統計分析32
第五章、結果33
5-1諾麗果粉對以高果糖誘導高血糖症小鼠之影響33
5-1-1 小鼠之體重、攝食與飲水量33
5-1-2 小鼠之總增重、肝臟、脾臟、腎臟與脂肪重量33
5-1-3 小鼠之口服葡萄糖耐受性試驗及空腹血糖檢測33
5-1-4 胰島素阻抗性: HOMA-IR34
5-2-5 血清肝功能指標34
5-1-6 血清中膽固醇與三酸甘油酯之含量34
5-1-7 血清中脂聯素與抗素之含量34
5-1-8 血清中腫瘤壞死因子與果糖胺之含量35
5-1-9 肝臟中肝醣相對含量35
5-2肝臟外觀與病理切片分析36
5-2-1肝臟外觀病理型態圖36
5-2-2肝臟蘇木紫與伊紅染色36
5-2-3肝臟油紅(Oil-Red-O)染色36
5-3胰島素傳訊相關基因表現36
5-3-1 GLUT2 mRNA相對表現量36
5-3-2 PEPCK mRNA相對表現量37
5-3-3 GSK3 mRNA相對表現量37
5-3-4 FoxO1 mRNA相對表現量37
5-3-5 IR-β蛋白質相對表現量37
5-3-6 PI3K蛋白質相對表現量37
5-3-7 Akt蛋白質相對表現量38
5-3-8 pAkt蛋白質相對表現量38
5-3-9 AMPK蛋白質相對表現量38
5-3-10 pAMPK蛋白質相對表現量38
5-3-11 PEPCK蛋白質相對表現量38
第六章、討論79
附錄84
參考文獻88

周彥宏。2013。丹參中單一成份Dsh-003抑制前列腺素E2誘導HA22T肝癌細胞存活以及轉移能力探討。
趙樹銘與李祝全。2000。糖化血紅蛋白HbA1c測定與臨床意義。中國檢驗醫學與臨床。1:75~76。
羅宇展。2009。檄樹(諾麗) 果實自然發酵過程中果汁與乾燥果肉所含酚類化合物之變化。台灣大學 生物資源暨農學院園藝學研究所碩士論文。
Accili, D., Drago, J., Lee, E. J., Johnson, M. D., Cool M. H., Salvatore, P., Asico L. D., José, P. A., Taylor, S. I. and Westphal, H. (1996) Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nat. Genet.12:106-109.
Alberti, K. G., Zimmet, P., Shaw, J. and IDF Epidemiology Task Force Consensus Group. (2005) The metabolic syndrome--a new worldwide definition. Lancet. 366:1059-1062.
Alessi, D. R., Andjelkovic, M., Caudwell, B., Cron, P., Morrice, P., Cohen, P. and Hemmings, B. A. (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15:6541-6551.
Aller, M. A., Vara, E., Garcia, C., Palma, M. D., Arias, J. L., Nava, M. P. and Arias, J.(2005) Proinflammatory liver and antiinflammatory intestinal mediators involved in portal hypertensive rats. Mediators Inflamm.2005:101-11.
American Diabetes Association (ADA) . (2014) Standards of Medical Care in Diabetes-2014. Diabetes Care January 2014 vol. 37 no. Supplement 1, S14-80. Angulo, P. (2002) Nonalcoholic Fatty Liver Disease. N. Engl. J. Med. 346:1221-1231.
Armbruster, D. A. (1987) Fructosamine: structure, analysis, and clinical usefulness. Clin. Chem. 33:2153-2163.
Bablok, W., Passing, H., Bender, R. and Schneider, B. (1998) A general regression procedure for method transformation. Application of linear regression procedures for method comparison studies in clinical chemistry, Part III. J. Clin. Chem. Clin. Biochem. 26:783-790.
Banerjee, R. R., Rangwala, S. M., Shapiro, J. S., Rich, A. S., Rhoades, B., Qi, Y., Wang, J., Rajala, M. W., Pocai, A., Scherer, P. E., Steppan, C. M., Ahima, R. S., Obici, S., Rossetti, L. and Lazar, M. A. (2004) Regulation of fasted blood glucose by resistin. Science. 303:1195-1198.
Beck-Nielsen, H., Pedersen, O. and Lindskov, H. O. (1980) Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects. Am J Clin Nutr. 33:273-278.
Berg, A. H., Combs, T. P., Du, X., Brownlee, M. and Scherer, P. E. (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 7:947-953.
Berg, A. H., Combs, T. P. and Scherer, P. E. (2002) ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab.13:84-99
Bjornholm, M. and Zierath, J. R. (2005) Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes. Biochem Soc Trans. 33:354-357.
Blakely, S. R., Hallfrisch, J., Reiser, S. and Prather, E. S. (1981) Long-term effects of moderate fructose feeding on glucose tolerance parameters in rats. J . Nutr. 111:307-314.
Blyszczuk, P., Czyz, J., Kania, G., Wagner, M., Roll, U., St-Onge, L. and Wobus, A. M. (2003) Expression of Pax4 in embryonic stem cells promotes differentiation of nestin-positive progenitor and insulin-producing cells. Proc. Natl. Acad. Sci. U. S. A. 100:998-1003.
Bouche, C., Serdy, S., Kahn, C. R. and Goldfine, A. B. (2004) The cellular fate of glucose and its relevance in type 2 diabetes. Endocr. Rev. 25:807-830.
Bratanova-Tochkova, T. K., Cheng, H., Daniel, S., Gunawardana, S., Liu, Y. J., Mulvaney-Musa, J., Schermerhorn, T., Straub, S. G., Yajima, H. and Sharp, G. W. (2002) Triggering and augmentation mechanisms, granule pools, and biphasic.
Bonora, E., Targher, G., Alberiche, M., Bonadonna, R. C., Saggiani, F., Zenere, M. B.,
Monauni, T. and Muggeo, M. (2000) Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care. 23:57-63.
Brownlee, M. (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 54:1615-1625.
Calabrò, M. L., Tommasini, S., Donato, P., Stancanelli, R., Raneri, D., Catania, S., Costa, C., Villari, V., Ficarra, P. and Ficarra, R. (2005) The rutin/beta-cyclodextrin interactions in fully aqueous solution: spectroscopic studies and biological assays. J. Pharm. Biomed. Anal. 36:1019-1027.
Capasso, I., Esposito, E., Pentimalli, F., Montella, M., Crispo, A., Maurea, N., D’Aiuto1, M., Fucito, A., Grimaldi, M., Cavalcanti, E., Esposito, G., Brillante, G., Lodato, S., Pedicini, T., D’Aiuto1, G., Ciliberto, Gennaro. and Giordano, A. (2003) Homeostasis model assessment to detect insulin resistance and identify patients at high risk of breast cancer development: National Cancer Institute of Naples experience. Journal of Experimental and Clinical Cancer Res. 32:14.
Carling, D. (2004) The AMP-activated protein kinase cascade--a unifying system for energy control. Trends Biochem. Sci. 29:18-24.
Carroll, N. V, Longley, R. W. and Roe, J. H. (1959) The determination of glycogen in liver and muscle by use of anthrone reagent. J. Biol. Chem. 220:583-593.
Castro, G. S., Cardoso, J. F., Vannucchi, H., Zucoloto, S. and Jordão, A. A. (2011) Fructose and NAFLD: metabolic implications and models of induction in rats. Acta Cir Bras. 2:45-50.
Cave, M., Deaciuc, I., Mendez, C., Song, Z., Joshi-Barve, S., Barve, S. and McClain, C. (2007) Nonalcoholic fatty liver disease: predisposing factors and the role of nutrition. J Nutr Biochem.18:184-195.
Chang, Y. Y., Lin Y. L., Yang, D. J., Liu, C. W., Hsu, C. L., Tzang, B. S. and Chen, Y. C. (2013)Hepatoprotection of noni juice against chronic alcohol consumption: lipid homeostasis, antioxidation, alcohol clearance, and anti-inflammation. J Agric Food Chem. 61:11016-11024.
Chen, W. S. Xu, P-Z., Gottlob, K., Chen, M-L. Sokol, K., Shiyanova, T., Roninson, I., Weng, W., Suzuki, R., Tobe, K., Kadowaki, T. and Hay, N. (2001) Growth retardation and increased apoptosis in mice with homozygous disruption of the
akt1 gene. Genes Dev. 15:2203-2008.
Cheng, A. Y. and Fantus, I. G. (2005) Oral antihyperglycemic therapy for type 2
diabetes mellitus. CMAJ. 172:213-226.
Cho, H., Mu, J., Kim, J. K., Thorvaldsen, J. L., Chu, Q., Crenshaw, E. B., Kaestner, K. H., Bartolomei, M. S., Shulman, G. I. and Birnbaum, M. J. (2001a) I731.
Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F. and Birnbaum, M. J. (2001b) Akt1 /PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem. 276:38349-38352.
Collier, J. J. and Scott, D. K. ( 2004) Sweet changes: glucose homeostasis can be altered by manipulating genes controlling hepatic glucose metabolism. Mol. Endocrinol. 18:1051-1063.
Da Silva, R. C., Miranda, W. L., Chacra, A. R. and Dib, S. A. (2005) Metabolic syndrome and insulin resistance in normal glucose tolerant brazilian adolescents with family history of type 2 diabetes. Diabetes Care. 28:716-718.
Davidson, M. B. (2005) Glycemia and risk for cardiovascular disease. Ann Intern Med. 142:227-228.
Day, C.P. and James, O. F. (1998) Steatohepatitis: a tale of two "hits"? Gastroenterology. 114:842-845.
Dimitriadisa, G., Mitroub, P., Lambadiaria, V., Maratoub, E. and Raptisa, S. A. (2011) Insulin effects in muscle and adipose tissue. Diabetes Research and Clinical Practice. S1:52-59.
Dipl-Pharm, S. G. (2005) Tackling the Insulin-signalling Cascade. Canadian Journal of Diabetes. 29:239-245.
Dixon, A.R., McMillen, H. and Etkin, N. L. (1999) Ferment this: the transformation of Noni, a traditional Polynesian medicine(Morinda citrifolia, Rubiaceae) . Ecological Botony 53:51-68
Dodson, G. and Steiner, D. (1988) The role of assembly in insulin's biosynthesis. Curr. Opin. Struct. Biol. 8:189-194.
Dufour, J. F. and Clavien P. A. (2010) Signaling Pathways in Liver Diseases. Springer-Verlag Berlin Heidelberg.15:229-241.
Easton, R. M., Cho, H., Roovers, K., Shineman, D. W., Mizrahi, M., Forman, M. S., Lee, V. M., Szabolcs, M., Jong, R., Oltersdorf, T., Ludwig, T., Efstratiadis, A. and Birnbaum, M. J. (2005) Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol. 25:1869-1878.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. (2001) Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) . J. A. M. A. 285:2486-2497.
Fasshauer, M., Klein, J., Krahlisch, S., Lössner, U., Klier, M., Blüher, M. and Paschke, R. (2003) GH is a positive regulator of tumor necrosis factor alpha-induced adipose related protein in 3T3-L1 adipocytes. J. Endocrinol. 178:523-531.
Fasshauer, M., Klein, J., Lossner, U. and Paschke, R. (2003) Regulation of and insulin resistance. Diabetologia. 46:1594-1603.
Fasshauer, M. and Paschke, R. (2003) Regulation of adipocytokines and insulin resistance. Diabetologia. 46:1594-1603
Fayard. E., Xue, G., Parcellier. A., Bozulic. L. and Hemmings, B. A. (2010) Protein kinase B(PKB/Akt) , a key mediator of the PI3K signaling pathway. Curr Top Microbiol Immunol. 346:31-56.
Fruebis, J., Tsao, T. S., Javorschi, S., Ebbets-Reed, D., Erickson, M. R., Yen, F. T., Bihain, B. E. and Lodish, H. F. (2001) Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A. 98:2005-2010.
Fulop, T., Tessier. and Carpentier, A. (2006) The metabolic syndrome. Pathol Biol. 54:375-386.
Garofalo., R. S., Orena, S. J., Rafidi, K., Torchia, A. J., Stock, J. L., Hildebrandt, A. L., Coskran. T., Black, S. C., Brees, D. J., Wicks, J. R., McNeish, J. D. and Coleman, K. G. (2003) Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBβ. J. Clin. Invest. 112:197-208.
Gates, R. E. (1991) Elimination of interfering substances in the presence of detergent in the bicinchoninic acid protein assay. Anal. Biochem. 196:290-295.
Gerstein, H. C. (2004) Glycosylated hemoglobin: finally ready for prime time as a
cardiovascular risk factor. Ann Intern Med. 141:475-460.
Glick, M. R., Ryder, K. W., Jackson, S. A. (1986) Graphical comparisons of
interferences in clinical chemistry instrumentation. Clin. Chem. 32:470-475.
Halaas, J. L., Gajiwala, K. S., Maffei, M., Cohen, S. L., Chait, B. T., Rabinowitz, D., Lallone, R. L., Burley, S. K. and Friedman, J. M. (1995) Weight-reducing effects of the plasma protein encoded by the obese gene.Science. 269:543-546.
Hirazumi, A., Furusawa, E., Chou, S. C. and Hokama , Y. (1994) Anticancer activity of Morinda citrifolia on intraperitoneally implanted Lewis lung carcinoma in syngenic mice. Proc West Pharmacol Soc. 37:145-146.
Hirazumi, A., Furusawa, E., Chou, S. C. and Hokama, Y. (1996)Immunomodulation contributes to the anticancer activity if Morinda citrifolia(Noni) fruit juice. Proc West Pharmacol Soc. 39:7-9.
Hirazumi, A. and Furusawa, E. (1999) An immunomodulatory polysaccharide-rich substance from the fruit juice of Morinda citrifolia(Noni)with antitumor activity.Phytother Res. 13:380-387.
Horsfall, A. U., Olabiyi, O., Aiyegbusi, A., Noronha, C. C. and Okanlawon, A. O. (2008) Morinda citrifolia fruit juice augments insulin action in Sprague-Dawley rats with experimentally induced diabetes. Nig Q J Hosp Med.18:162-165 .
Hotamisligil, G. S., Shargill, N. S. and Spiegelman, B. M. (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 259:87-91.
Hotamisligil, G. S., Peraldi, P., Budavari, A., Ellis, R., White, M. F. and Spiegelman B. M. (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science.
271:665-668.
Holst, D., and Grimaldi, P. A. (2002) New factors in the regulation of adipose differentiation and metabolism. Curr. Opin. Lipidol. 13:241-245.
Hu, P., Mondino, A., Skolnik, E. Y. and Schlessinger, J. (1993) Cloning of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase and identification of its binding site on p85. Mol. Cell. Biol. 13:7677-7688.
Hu, E., Liang, P. and Spiegelman, B. M. (1996) AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem. 271:10697-10703.
Huang, C., Thirone, A. C., Huang, X. and Klip, A. (2005) Differential contribution of insulin receptor substrates 1 versus 2 to insulin signaling and glucose uptake in l6 myotubes. J. Biol. Chem. 280:19426-19435.
Huang, P. L. (2009) A comprehensive definition for metabolic syndrome. Dis Model Mech. 2: 231-237.
International Diabetes Federation. (2004) The IDF consensus worldwide definition of the metabolic syndrome. Brussels, Belgium: International Dia-betes Federation.Jayaraman, S. K., Manoharan, M. S. and Illanchezian, S. (2008) Antibacterial,
Antifungal and Tumor cell suppression potential of Morinda citrifolia fruit extract. Int. J. Integr. Biol. 3:44-49.
Ju, T., Brewer, K., D'Souza, A., Cummings, R. D and Canfield, W. M. (2002) Cloning and expression of human core 1 beta1,3-galactosyltransferase. J. Biol. Chem. 277:178-186.
Kanuri, G., Spruss, A., Wagnerberger, S., Bischoff, S. C. and Bergheim, I. (2011 ) Role of tumor necrosis factor α (TNFα) in the onset of fructose-induced nonalcoholic fatty liver disease in mice. J Nutr Biochem. 22:527-534.
Kaplan, L. M. (1998) Leptin, obesity, and liver disease. Gastroenterology. 115:997-1001
Karlsson, H. K. and Zierath, J. R. (2007) Insulin signaling and glucose transport in insulin resistant human skeletal muscle. Cell Biochemistry and Biophysics. 48:103-113.
Katsuki, A., Sumida, Y., Gabazza, E. C., Murashima, S., Furuta, M., Araki-Sasaki, R., Hori, Y., Yano, Y. and Adachi, Y. (2001) Homeostasis model assessment is a reliable indicator of insulin resistance during follow-up of patients with type 2 diabetes. Diabetes Care. 24:362-365.
Kennedy, L., Mehl, T. D., Riley, W. J. and Merimee, T. J. (1981) Non-enzymatically glycosylated serum protein in diabetes mellitus: an index of short-term glycaemia. Diabetologia. 21:94-98.
Khamzina, L., Gruppuso, P. A. and Wands, J. R. (2003) Insulin signaling through insulin receptor substrate 1 and 2 in normal liver development. Gastroenterology. 125:572-585.
Kitamura, T., Kitamura, Y. I., Kobayashi, M., Kikuchi, O., Sasaki, T., Depinho, R. A. and Accili, D. (2009) Regulation of pancreatic juxtaductal endocrine cell formation by FoxO1. Mol Cell Biol. 29:4417-4430.
Kitamura T. ( 2013) The role of FOXO1 in β-cell failure and type 2 diabetes mellitus. Nat Rev Endocrinol. 9:615-623.
Kleiner, D. E., Brunt, E. M., Van, Natta, M., Behling, C., Contos, M. J., Cummings, O. W., Ferrell, L. D., Liu, Y. C., Torbenson, M. S., Unalp,A. A., Yeh, M,. McCullough, A. J. and Sanyal, A. J. (2005) Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 41:1313-1321.
Krook, A., Bjornholm, M., Galuska, D., Jiang, X. J., Fahlman, R., Myers, M. G., Wallberg-Henriksson, H. and Zierath, J. R. (2000) Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes. 49:284-92.
Le, L. S., Boucher, J., Rey, A., Castan-Laurell, I., Krief, S., Ferré, P., Valet, P　and Dugail, I. (2001) Decreased resistin expression in mice with different sensitivities to a high-fat diet. Biochem Biophys Res Commun. 289:564-567.
Lee, S.Y., Park, S. L., Hwang, J. T., Yi, S. H., Nam, Y. D. and Lim, S. I. (2012) Antidiabetic Effect of Morinda citrifolia (Noni) Fermented by Cheonggukjang in KK-Ay DiabeticMice. Evid Based Complement Alternat Med. 163280-163288.
Li, R. W., Myers, S. P., Leach, D. N., Lin, G. D. and Leach, G. (2003) A cross-cultural
study: anti-infammatory activity of Astralian and Chinese plants. J. Ethnopharmacol. 85:25-32.
Li, Y. C. and Hsieh, C. C. (2014) Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model. PLoS One. 9:e97341.
Lin, C. L. and Lin, J. K. (2008) Epigallocatechin gallate (EGCG) attenuates high glucose-induced insulin signaling blockade in human hepG2 hepatoma cells. Mol. Nutr. Food Res. 52:930-939.
Lin, Y. L., Chou, C. H., Yang, D. J., Chen, J. W., Tzang, B.S. and Chen, Y. C. ( 2012) Hypolipidemic and antioxidative effects of noni (Morinda citrifolia L.) juice on high- fat/cholesterol-dietary hamsters. Plant Foods Hum Nutr. 67:294-302.
Lin, Y. L., Chang, Y. Y., Yang, D. J., Tzang, B. S. and Chen, Y. C. (2013) Beneficial effects of noni(Morinda citrifolia L.)juice on livers of high-fat dietary hamsters. Food Chem. 140:31-38.
Livak, K. J. and Schmittgen, T. D. (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-Delta Delta C (T) ) Method. Methods. 25:402-408.
Locher, A,, Vanden Berghe, D. A. and Vlietinck, A. J. (1995) Anti-microbial activoity and anti-complement activity of extracts obtained from selected Hawaiianmedicinal plants. J. Ethnopharmacol. 49:23-32.
Lochhead, P.A., Salt, I. P., Walker, K. S., Hardie, D. G. and Sutherland, C. (2000) 5-aminoimidazole-4-carboxamide riboside mimics the effects of Insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes. 49:896-903.
Long, Y. C. and Zierath, J. R. (2006) AMP-activated protein kinase signaling in metabolic regulation. J. Clin. Invest. 116:1776-1783.
Maher, J. J. (1997) Exploring alcohol's effects on liver function. Alcohol Health Res World. 21:5-12.
Manning, P. J., Sutherland, W. H., McGrath, M.M., de Jong, S, A,, Walker, R. J. and Williams, M. J. (2008) Postprandial cytokine concentrations and meal composition in obese and lean women. Obesity (Silver Spring). 16:2046-2052.
Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F. and Turner, R. C. (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Endocrinol. Diabetologia. 28:412-419.
Mckoy, M. L. G., Thomas, E. A. and Simon, O. R. (2002) Preliminary investigation of the anti-inflammatory properties of an aqueous extract from Morinda citrifolia (Noni). Pharmacol Soc. 45:76-78.
Meigs, J. B., Wilson, P. W., Nathan, D. M., D'Agostino, R. B. Sr., Williams, K., Haffner, S. M. (2003) Prevalence and characteristics of the metabolic syndrome in the San Antonio Heart and Framingham Offspring Studies. Diabetes. 52:2160-2167.
Miyake, K., Ogawa, W., Matsumoto, M., Nakamura, T., Sakaue, H. and Kasuga, M. (2002) Hyperinsulinemia, glucose intolerance, and dyslipidemia induced by acute inhibition of phosphoinositide 3-kinase signaling in the liver. J. Clin. Invest. 110:1483-1491.
Mohamed-Ali, V., Pinkney J. H. and Coppack, S. W. (1998) Adipose tissue as an endocrine and paracrine organ. Int J Obes Relat Metab Disord. 22:1145-1158.
Moller, D. E. (2001) New drug targets for type 2 diabetes and the metabolic syndrome. Nature. 414:821-827.
Morton, J. F. (1992) The ocean-going Noni, or Indian mulberry(Morinda citrifolia,
Rubiaceae)and some of its ”colourful” relatives. Ecological Botony. 46:241-256.
Nayak, B. S., Marshall, J. R., Isitor, G. and Adogwa, A. (2011) Hypoglycemic and Hepatoprotective Activity of Fermented Fruit Juice of Morinda citrifolia (Noni) in Diabetic Rats. Evid Based Complement Alternat Med. 875293-875298.
Nelson, S. C. and Elevitch C. R. (2006) Noni: The complete guide for comsumers and growers. 1st ed. Permanent Agriculture Resources, Holualoa, Hawaii.
Nseir, W., Nassar, F. and Assy, N. (2010) Soft drinks consumption and nonalcoholic fatty liver disease. World. J. Gastroenterol. 16:2579-2588.
Ouchi, N., Kihara, S., Arita, Y., Maeda, K., Kuriyama, H., Okamoto, Y., Hotta, K.,
Nishida, M., Takahashi, M., Nakamura, T., Yamashita, S., Funahashi, T. and Matsuzawa, Y. (1999) Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation. 100:2473-2476.
Petlevski, R., Hadzija, M., Slijepcevic, M. and Juretic, D. (2001) Effect of 'antidiabetis' herbal preparation on serum glucose and fructosamine in NOD mice. J Ethnopharmacol. 75:181-184.
Pilkis, S. J. and Granner, D. K. (1992) Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu. Rev. Physiol. 54:885-909.
Pourteymour Fard Tabrizi, F., Alipoor, B., Mehrzad Sadaghiani, M. Ostadrahimi, A. and Malek Mahdavi, A. (2013) Metabolic Syndrome and Its Characteristics among Reproductive-Aged Women with Polycystic Ovary Syndrome: A Cross-sectional Study in Northwest Iran. Int J Fertil Steril. 6: 244-249.
Preitner, F., Ibberson, M., Franklin, I., Binnert, C., Pende, M., Gjinovci, A., Hansotia, T., Drucker, D. J., Wollheim, C., Burcelin, R. and Thorens, B. (2004) Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J. Clin. Invest. 113:635-45.
Prentki, M. and Nolan, C. J. (2006) Islet beta cell failure in type 2 diabetes. J Clin Invest. 116:1802-1812.
Putnam, A. L., Brusko, T. M., Lee, M. R., Liu, W., Szot, G. L., Ghosh, T., Atkinson, M. A. and Bluestone, J. A. (2009) Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes. 58:652-662.
Ram J. (2002) Noni processing and quality control: protecting the image of Hawaiian. Proc. 2002 Hawaii noni conf. p.25-28.
Rajala, M.W., Qi, Y., Patel, H. R., Takahashi, N., Banerjee, R., Pajvani, U. B., Sinha, M. K., Gingerich, R. L., Scherer, P. E. and Ahima, R. S. (2004) Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes. 53:1671-1679.
Reagan-Shaw, S., Nihal, M. and Ahmad, N. (2007) Dose translation from animal to human studies revisited. F. A. S. E. B. J. 22:659-61.
Reaven, G. M. (1988) Role of Insulin Resistance in Human Disease. Disease.
37:1595-1607.
Rotter, V., Nagaev, I. and Smith, U. (2003) Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem. 278:45777-45784.
Round, J. A., Jacklin, P., Fraser, R. B., Hughes, R. G., Mugglestone, M. A. and Holt, R. I. (2011) Screening for gestational diabetes mellitus: cost-utility of different screening strategies based on a woman's individual risk of disease. Diabetologia. 54:256-263..
Saini, V. (2010) Molecular mechanisms of insulin resistance in type 2 diabetes mellitus. World Journal of Diabetes. 1:68-75.
Saito, T., Misawa, K. and Kawata, S. (2007) Fatty liver and non-alcoholic steatohepatitis. Intern. Med. 46:101-103.
Saltiel, A. R. and Kahn, C. R. (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 414:799-806.
Satoh, H., Nguyen, M. T., Miles, P. D., Imamura, T., Usui, I. and Olefsky, J. M.(2004) Adenovirus-mediated chronic "hyper-resistinemia" leads to in vivo insulin resistance in normal rats. J. Clin. Invest. 114:224-231.
Schinner, S., Scherbaum, W. A., Bornstein, S. R. and Barthel, A. (2005) Molecular mechanisms of insulin resistance. Diabet Med. 22:674-682.
Schwartz, M. W., Dallman, M. F. and Woods, S. C. (1995) Hypothalamic response to starvation: implications for the study of wasting disorders. Am. J. Physiol. 1995 269:949-957.
Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P. and Baskin, D. G. (1996 ) Identification of targets of leptin action in rat hypothalamus. J Clin Invest. 98:1101-1106.
Senn, J. J., Klover, P. J., Nowak, I. A. and Mooney, R. A. (2002) Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes. Diabetes. 12:3391-3399.
Senn, J. J., Klover P. J., Nowak, I. A., Zimmers, T. A., Koniaris, L. G., Furlanetto, R. W. and Mooney, R. A. (2003) Suppressor of cytokine signaling-3 (SOCS-3) , a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. J. Biol. Chem. 278:13740-13746.
Sesti, G., Federici, M., Hribal, M. L., Lauro, D., Sbraccia, P. and Lauro, R. (2001) Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J. 15:2099-2111.
Shepherd, P. R., Withers, D. J. and Siddle, K. (1998) Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J. 333:471-490.
Shoelson, S. E., Jongsoon L. and Goldfine, A. B. (2006) Inflammation and insulin resistance. J. Clin. Invest. 116:1793-1801.
Smith, P. K., Krohn, R. I., Hermanson, G. T., Mallia, A. K., Gartner, F. H., Provenzano, M. D., Fujimoto, E. K., Goeke, N. M., Olson, B. J. and Klenk, D. C(1985) Measurement of protein using bicinchoninic acid. Anal. Biochem. 150:76-85.
Smith, U. (2002) Impaired diabetic insulin signaling and action occur in fat cells long before glucose in tolerance is insulin resistance initiated in the adipose tissue? Int. J. Obes. Relat. Metab. Disord. 26:897-904.
Sorbi, D., Boynton, J. and Lindor, K. D. (1999) The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am. J. Gastroenterol. 94:1018-1022.
Sorensen, K. (1992) One reagent simultaneously identifies the salt and the protein peaks on desalting column. Biotechniques. 12:235-236.
Stephens, T. W., Basinski, M., Bristow, P. K., Bue-Valleskey, J. M., Burgett, S. G., Craft, L., Hale, J., Hoffmann, J., Hsiung, H. M., Kriauciunas, A., Mackellar, W., Rosteck, P. R., Schomer, B., Smith, D., Tinsley, F, C., Zhang, X. Y. and Heiman, M. (1995) The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature. 377:530-532.
Steppan, C. M., Bailey, S. T., Bhat, S., Brown, E. J., Banerjee, R. R., Wright, C. M., Patel, H. R., Ahima, R. S. and Lazar, M. A. (2001) The hormone resistin links obesity to diabetes. Nature. 409:307-312.
Tahara, Y. and Shima, K. (1995) Kinetics of HbA1c, glycated albumin, and fructosamine and analysis of their weight functions against preceding plasma glucose level. Diabetes Care. 18:440-447.
Tao, R., Gong, J., Luo, X., Zang, M., Guo, W., Wen, R. and Luo, Z. (2010) AMPK exerts dual regulatory effects on the PI3K pathway. J. Mol. Signal. 5:1-9.
Thanyarat, W., Manee, R., Pichai, L., Suchada, I., Kitirat, T., Surasak, A., Prasong, T. and Chongdee Dangrat. (2012) The Usefulness of Homeostatic Measurement Assessment-Insulin Resistance (HOMA-IR) for Detection of Glucose Intolerance in Thai Women of Reproductive Age with Polycystic Ovary Syndrome. International Journal of Endocrinology. Volume 2012 6 pages
Thararat, N., Pleumchitt R., Wandee G., Seong, H. L., Darunee L. and Seung J. B., (2012) Damnacanthal, a noni component, exhibits antitumorigenic activity in human colorectal cancer cells. J Nutr Biochem 23:915–923.
Templeton, M. (1996) Microdetermination of glycogen with anthrone reagent.Journal of Histochemistry and Cytochemistry 9:670-672.
Thorens, B. and Mueckler, M. (2010) Glucose transporters in the 21st Century. Am. J. Physiol. Endocrinol. Metab. 298:E141-E145.
Thorburn, A. W., Storlien, L. H., Jenkins, A. B., Khouri, S. and Kraegen, E. W. (1989)Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats. Am. J. Clin. Nutr. 49:1155-1163.
Thirone, A. C., Huang, C. and Klip, A. (2006) Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Trends Endocrinol. & Metab. 17:72-78.
Tilg, H. and Moschen, A. R. (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 6:772-783.
Tiniakos, D. G. and Elizabeth, M. B. (2010) Histopathology of nonalcoholic fatty liver disease. World. J. Gastroenterol. 16:5286-5296.
Tschopp, O., Yang, Z. Z., Brodbeck, D., Dummler, B. A., Hemmings-Mieszczak, M., Watanabe, T., Michaelis, T., Frahm, J. and Hemmings, B. A. (2005) Essential role of protein kinase B gamma (PKB gamma/Akt3) in postnatal brain development but not in glucose homeostasis. Development. 132:2943-2954.
Tsigos, C., Papanicolaou, D. A., Kyrou, I., Defensor, R., Mitsiadis, C. S. and Chrousos G. P. (1997) Dose-dependent effects of recombinant human interleukin- 6 on glucose regulation. J Clin Endocrinol Metab. 82:4167-4170.
Tsuchiya, S. (1978) A simple method for hematoxylin-eosin staining of epoxy-embedded ocular tissue. Nihon. Ganka. Gakkai. Zasshi. 82:555-560.
Tsuruzoe, K., Emkey, R., Kriauciunas, K. M., Ueki, K. and Kahn, C. R. (2001)Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Mol. Cell. Biol. 21:26-38.
Tuszynski, G. P. and Murphy, A. (1990) Spectrophotometric quantitation of anchorage-dependent cell numbers using the bicinchoninic acid protein assay reagent. Anal. Biochem. 184:189-191.
Tyllianakis, P. E., Kakabakos, S. E., Evangelatos, G. P. and Ithakissios, D. S. (1994)Direct colorimetric determination of solid-supported functional groups and ligands using bicinchoninic acid. Anal. Biochem. 219:335-340.
Uysal, K. T., Wiesbrock, S. M., Marino, M. W. and Hotamisligil, G. S. (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature. 389:610-614.
Varman, T. S., Kitt, F. P. and Gerald, I. S. (2010) Lipid-induced insulin resistance: unravelling the mechanism. Lancet. 375:2267-2277.
Vies, J. V. D. (1954) Two methods for the determination of glycogen in liver. Biochem. J. 57: 410-416.
Wang, M. Y., West, B. J., Jensen, C. J., Nowicki, D., Che, S., Palu, A. K. and Anderson, G. (2002) Morinda citrifolia (noni): a literature review and recentadvances in Noni research. Acta.Pharmacol. Sin. 23:1127-1141.
Way, J. M., Görgün, C. Z., Tong, Q., Uysal, K.T., Brown, K. K., Harrington, W. W., Oliver, WR Jr., Willson, T. M., Kliewer, S. A. and Hotamisligil, G. S. (2001) Adipose tissue resistin expression is severely suppressed in obesity and
stimulated by peroxisome proliferator-activated receptor gamma agonists. J Biol Chem. 27:25651-25653.
White, M. F. (2002) IRS proteins and the common path to diabetes. Am. J. Physiol. Endocrinol. Metab. 283:E413-E422.
Williams, A. L. and Hoofnagle, J. H. (1988) Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology. 95:734-739.
Wong, W. P., Scott, D. W., Chuang, C. L., Zhang, S., Liu, H., Ferreira, A., Saafi, E. L., Choong, Y. S. and Cooper, G. J. (2008) Spontaneous Diabetes in Hemizygous Human Amylin Transgenic Mice That Developed Neither Islet Amyloid nor Peripheral Insulin Resistance. Diabetes. 57: 2737-2744.
Yadav, H., Jain, S. and Sinha, P. R. (2007) Antidiabetic effect of probiotic dahi containing Lactobacillus acidophilus and Lactobacillus casei in high fructose fed rats. Nutrition. 23:62-68.
Yamada, Y. and Fausto, N. (1998) Deficient liver regeneration after carbon tetrachloride injury in mice lacking type 1 but not type 2 tumor necrosis factor receptor. Am J Pathol.152:1577-1589.
Yamauchi, T., Tobe, K., Tamemoto, H., Ueki, K., Kaburagi, Y., Yamamoto-Honda, R., Takahashi, Y., Yoshizawa, F., Aizawa, S., Akanuma, Y., Sonenberg, N., Yazaki, Y. and Kadowaki, T. (1996) Insulin signaling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol. 16:3074-3084.
Yamauchi, T., Kamon, J., Waki, H., Terauchi, Y., Kubota, N., Hara, K., Mori, Y., Ide, T., Murakami, K., Tsuboyama-Kasaoka, N., Ezaki, O., Akanuma, Y., Gavrilova, O., Vinson, C.,Reitman, M, L., Kagechika, H., Shudo, K., Yoda, M., Nakano, Y., Tobe, K., Nagai, R., Kimura, S., Tomita, M., Froguel, P. and Kadowaki, T.(2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 7:941-946.
Yamauchi, T., Kamon, J., Minokoshi, Y., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., Ueki, K., Eto, K., Akanuma, Y., Froguel, P., Foufelle, F., Ferre, P., Carling, D., Kimura, S., Nagai, R., Kahn, B. B. and Kadowaki, T.
(2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Med. 11:1288-1295.
Yu, H., Li, S., Huang, M. T. and Ho, C. T. (2008) Anti-inflammatory constituents in Noni(Morinda citrifolia)fruits. Dietary Supplements 12:179-190.
Zierath, J. R., Krook, A. and Wallberg-Henriksson, H. (2000) Insulin action and insulin resistance in human skeletal muscle. Diabetologia. 43:821-835.
Zierath, J. R. and Kawano, Y. (2003) The effect of hyperglycaemia on glucose disposal and insulin signal transduction in skeletal muscle. Best Pract. Res. Clin. Endocrinol. Metab. 17:385-398.
Zin, Z. M. Abdul-Hamid, A., Osan, A. and Saari N. (2006) Antioxidative activity of chromatographic fractions obtained from root, fruit and leaf of Mengkudu (Morinda citrifolia L.) Food Chem. 94:169-178.