臺灣博碩士論文加值系統

隨著飲食習慣的改變，高血壓、高血脂、高膽固醇、高血糖與肥胖等慢性疾病開始趨向年輕化。研究指出長期高果糖與飽和脂肪酸飲食會透過產生活性氧原子 (reactive oxygen species, ROS) 促進 c-Jun N-terminal kinase (JNK) 活性進而抑制胰島素接受器活性導致胰島素阻抗 (insulin resistance) 與葡萄糖耐受性 (glucose tolerance) 不良，而胰島素阻抗更被認為是第二型糖尿病的典型特徵。紅麴、monascin (MS) 與ankaflavin (AK) 已被證實具有抗氧化發炎之能力，但是尚未有任何關於 MS 與 AK 改善由高果糖及高油脂飲食 (high fructose and high fat diet, HFFD) 所造成的血糖調控與脂質代謝能力異常之研究，因此本實驗第一部分期望透過以MS 及AK 抗氧化發炎與降低體脂肪等功效，進而探討 MS 與 AK 對 HFFD 誘發高血糖大鼠血糖調控之影響與機制；若是 MS 與 AK 能有效改善 HFFD 誘發血糖調控異常，這可能意味著紅麴黃色素也具有降血糖之功效。第二部份以黃色素粗萃取物 (yellow pigment crude extract,YPCE) 餵食高果糖與高油脂誘發高血糖大鼠，並且以 MS+AK 做為對照，評估是否總黃色素萃取物具有更佳改善血糖調控之能力，以推測黃色素是否具有其他降血糖物質之可能性。高血糖大鼠之誘發皆為利用含果糖 30％(w/v) 之飲用水合併高油脂飼料誘發，實驗進行 10 週，並於第 8 週進行 oral glucose tolerance test(OGTT)、空腹血糖、胰島素阻抗與果糖胺測定，犧牲後則進行血液生化分析、肝臟危險因子分析與脂肪危險因子分析進而探討餵食 MS、AK 與 YPCE 對血糖調控之影響；結果顯示，HFFD 組除了造成血糖調控能力異常與脂肪肝外，體脂肪重、空腹血糖、胰島素阻抗、果糖胺、triglyceride (TG)、total cholesterol (TC) 與肝臟、脂肪 ROS 生成量也被提升，然而，這些現象均可經由餵食 MS 與 AK 而獲得改善，並由肝臟血糖調控相關蛋白 insulin receptor substrate-1、glucose transporters-2 與脂肪血糖調控相關蛋白 (glucose transporters-4、hypoxia-inducible factor 1-α、interlukin-1β、tumor necrosis factor-α 與 interlukin-6) 表現證明高果糖高油脂飲食所形成之血糖耐受性不良都可透過餵食 MS 與 AK 而獲得改善，同時隨著劑量的提升而有較佳的效果，相較於 MS 與 AK，MS 在血糖調控能力以及降低胰島素阻抗、果糖胺有較佳的效果，而AK 則在抗脂肪細胞發炎與降低總膽固醇含量上有較佳的效果。根據 YPCE 改善血糖調控之結果顯示 YPCE 能顯著改善 OGTT、空腹血糖、胰島素阻抗與果糖胺之能力 (p<0.05)，同時在抗氧化發炎、改善血糖調控相關蛋白與降低體脂肪率、TG、TC 及非酒精性脂肪肝等肥胖和心血管疾病因子均顯示有良好的效果，由此可知黃色素也具有改善 HFFD 誘發之血糖與脂質代謝能力異常；本研究也發現，YPCE-1X 組相較於每日餵食 MS+AK 顯示出有更好的血糖調控能力與改善血糖調控及發炎相關蛋白之表現，由於 YPCE-1X 組所含之 MS 與 AK 含量等同於 MS+AK 組(MS 3 mg + AK 1.5 mg)，因此 YPCE 可能含有其他具有血糖調控能力之成分，也顯示 YPCE 為紅麴中具降血糖功效之萃取物。

Since the custom changes in nutrient composition, the chronic disease such as hypertension, hyperlipidemia, hypercholesterolemia, hyperglycemia and obesity were tending to younger. Some study had indicated that reactive oxygen species (ROS) were produced by long-term high fructose and saturated fatty acid diet, which may lead to insulin resistance and glucose tolerant by promoting c-Jun N-terminal kinase (JNK) activity to inhibit insulin receptor activity. However, insulin resistance had also been considered as typical syndrome of type 2 diabetic mellitus. Monascus-fermented, monascin (MS) and ankaflavin (AK) were proven two perform antioxidant and anti-inflammatory abilities. But the study about MS and AK improving the disorder of blood glucose regulation and lipid metabolism inducedby high fructose and high fat diet (HFFD)has never been reported. Consequently, in the first, MS and AK with antioxidative effect, anti-inflammatory and antiobesity effect should improve the metabolic disorder in blood glucose regulation and mechanism in HFFD-induced high blood glucose rat. If MS and AK could effectively improve blood glucose regulation induced by HFFD. The yellow pigment of red mold discorea may also had more hypoglycemia function. Second, we further use yellow pigment crude extract (YPCE) to treat HFFD-induced high blood glucose rat, and use MS+AK as control to examine weather total yellow pigment crude extract had better blood glucose regulation ability. Furthermore, we also investigated weather yellow pigment containing other substance with hypoglycemia effect. High blood glucose rat was induced by 30% fructose drink and high calorie diet for 10 weeks. The blood glucose regulation effect of MS, AK and YPCE on OGTT, fasting blood glucose, insulin resistance and fructosamine were evaluated in 8thweek, and then blood biochemical, hepatic risk factor and adipocyte risk factor analysis were estimated after experiment animal sacrifice. Data showed that HFFD groups not only had weak the blood glucose regulation ability and obviousfatty liver but also performed high body fat ratio, fasting blood glucose, insulin resistance, fructosamine, triglyceride, total cholesterol, and hepatic and adipocyte ROS content. According to hepatic blood glucose regulation related proteins (insulin receptor substrate-1, glucose transporters-2) and adipocyte blood glucose regulation related proteins (glucose transporters-4, hypoxia-inducible factor 1-

縮寫表.............................................................................I
中文摘要.........................................................................III
目錄.............................................................................VII
前言...............................................................................1
第一章 文獻回顧.....................................................................3
第一節 高血糖.......................................................................3
第二節 高油與高糖飲食對血糖調控相關因子之影響...........................................5
第三節 高血糖動物模式誘發...........................................................12
第四節 降血糖臨床用藥簡介...........................................................16
第五節 紅麴菌簡介與功效.............................................................17
第六節 MS 與 AK 對高油脂與高果糖飲食誘發之高血糖之血糖調控之可行性......................23
第二章 研究動機、目的與架...........................................................25
第一節 研究動機....................................................................25
第二節 研究目的....................................................................26
第三節 研究架構....................................................................26
第三章 材料與方法..................................................................28
第一節 實驗材料....................................................................28
第二節 實驗藥劑....................................................................28
第三節 體內動物試驗.................................................................29
第四章 研究結果....................................................................45
第一節 RMD、MS 與 AK 對高果糖與高油脂誘發之高血糖大鼠血糖調控能力之影響.................45
第二節 MS+AK 與 YPCE 對高果糖與高油脂誘發之高血糖大鼠血糖調控能力之影響.................68
第五章 討論........................................................................92
第六章 結論.......................................................................104
第七章 未來研究方向................................................................106
第八章 參考文獻...................................................................107

行政院衛生署(2013)。認識糖尿病。
玉田英明(1988). 紅麴各種調味料之應用。食品及科學，30，96～99。
苗明三(1997).實驗動物和實驗動物技術。中國人民出版社，127-132。
陳彥霖(2003).紅麴中桔黴素之生成及安全性。食品工業，35，30-37。
陳彥霖、李昭蓉、陳健州、袁國芳(1998).紅麴菌種的開發與應用。食品工業月刊，30，1-9。
蘇遠志(1999). 應用微生物學。國立編譯館，華香園出版，945-960。
Anthony, W. N., Gerald, L. (1997). Hormones, Second Edition.7:197-227
Adams, L. A., Angulo, P. & Lindor, K. D. (2005). Nonalcoholic fatty liver disease. CMAJ172:899-905.
Ahn, Y. H., Yoon, D. J., Han, G. S. & Lee, B. G. (1993). Cloning and expression of rat liver type glucose transporter and translocation by insulin in Chinese hamster ovary cells. Yonsei Med J34:117-125.
Amiri, I., Karimi, J., Piri, H., Goodarzi, M. T., Tavilani, H., Khodadadi, I. & Ghorbani, M. (2011). Association between nitric oxide and 8-hydroxydeoxyguanosine levels in semen of diabetic men. Syst Biol Reprod Med57:292-295.
Aniya, Y., Ohtani, II, Higa, T., Miyagi, C., Gibo, H., Shimabukuro, M., Nakanishi, H. & Taira, J. (2000). Dimerumic acid as an antioxidant of the mold, Monascus anka. Free Radic Biol Med28:999-1004.
Aniya, Y., Yokomakura, T., Yonamine, M., Shimada, K., Nagamine, T., Shimabukuro, M. & Gibo, H. (1999). Screening of antioxidant action of various molds and protection of Monascus anka against experimentally induced liver injuries of rats. Gen Pharmacol32:225-231.
Arunkumar, E., Bhuvaneswari, S. & Anuradha, C. V. (2012). An intervention study in obese mice with astaxanthin, a marine carotenoid--effects on insulin signaling and pro-inflammatory cytokines. Food Funct3:120-126.
Bellomo, G., Mirabelli, F., DiMonte, D., Richelmi, P., Thor, H., Orrenius, C. & Orrenius, S. (1987). Formation and reduction of glutathione-protein mixed disulfides during oxidative stress. A study with isolated hepatocytes and menadione (2-methyl-1,4-naphthoquinone). Biochem Pharmacol36:1313-1320.
Bensellam, M., Duvillie, B., Rybachuk, G., Laybutt, D. R., Magnan, C., Guiot, Y., Pouyssegur, J. & Jonas, J. C. (2012). Glucose-induced O2 consumption activates hypoxia inducible factors 1 and 2 in rat insulin-secreting pancreatic beta-cells.PLoS One7:e29807.
Boden, G. (2011). Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes18:139-143.
Bortell, R. & Yang, C. (2012). The BB rat as a model of human type 1 diabetes. Methods Mol Biol933:31-44.
Brouwers, M. C., van Greevenbroek, M. M., Stehouwer, C. D., de Graaf, J. & Stalenhoef, A. F. (2012). The genetics of familial combined hyperlipidaemia. Nat Rev Endocrinol8:352-362.
Brunton, S. A. (2012). Hypoglycemic potential of current and emerging pharmacotherapies in type 2 diabetes mellitus. Postgrad Med124:74-83.
Castro, M. C., Francini, F., Schinella, G., Caldiz, C. I., Zubiria, M. G., Gagliardino, J. J. & Massa, M. L. (2012). Apocynin administration prevents the changes induced by a fructose-rich diet on rat liver metabolism and the antioxidant system. Clin Sci (Lond)123:681-692.
Caton, P. W., Nayuni, N. K., Kieswich, J., Khan, N. Q., Yaqoob, M. M. & Corder, R. (2010). Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5. J Endocrinol205:97-106.
Chakraborty, D., Samadder, A., Dutta, S. & Khuda-Bukhsh, A. R. (2012). Antihyperglycemic potentials of a threatened plant, Helonias dioica: antioxidative stress responses and the signaling cascade. Exp Biol Med (Maywood)237:64-76.
Chawla, A., Nguyen, K. D. & Goh, Y. P. (2011). Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol11:738-749.
Chen, W. P., Ho, B. Y., Lee, C. L., Lee, C. H. & Pan, T. M. (2008). Red mold rice prevents the development of obesity, dyslipidemia and hyperinsulinemia induced by high-fat diet. Int J Obes (Lond)32:1694-1704.
Cheng, M. J., Chen, J. J., Wu, M. D., Yang, P. S. & Yuan, G. F. (2010). Isolation and structure determination of one new metabolite isolated from the red fermented rice of Monascus purpureus. Nat Prod Res24:979-988.
Chuang, C. Y., Shi, Y. C., You, H. P., Lo, Y. H. & Pan, T. M. (2011). Antidepressant effect of GABA-rich monascus-fermented product on forced swimming rat model. J Agric Food Chem59:3027-3034.
Cnop, M., Havel,P. J., Utzschneider, K. M., Carr, D. B., Sinha, M. K., Boyko, E. J., Retzlaff, B. M., Knopp, R. H., Brunzell, J. D. & Kahn, S. E. (2003). Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia46:459-469.
Daly, A. K., Ballestri, S., Carulli, L., Loria, P. & Day, C. P. (2011). Genetic determinants of susceptibility and severity in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol5:253-263.
Davidson, A. L. & Arion, W. J. (1987). Factors underlying significant underestimations of glucokinase activity in crude liver extracts: physiological implications of higher cellular activity. Arch Biochem Biophys253:156-167.
Du, D., Shi, Y. H. & Le, G.W. (2010). Oxidative stress induced by high-glucose diet in liver of C57BL/6J mice and its underlying mechanism. Mol Biol Rep37:3833-3839.
Endo, A. (1979). Monacolin K, a new hypocholesterolemic agent produced by a Monascusspecies. J Antibiot (Tokyo)32:852-854.
Farmer, D. G. & Kennedy, S. (2009). RAGE, vascular tone and vascular disease. Pharmacol Ther124:185-194.
Flood, J. F., Morley, J. E. & Roberts, E. (1991). Amnestic effects in mice of four synthetic peptides homologous to amyloid beta protein from patients with Alzheimer disease. Proc Natl Acad Sci U S A88:3363-3366.
Gniuli, D., Dalla Libera, L., Caristo, M. E., Calvani, R., Castagneto, M. & Mingrone, G. (2008). High saturated-fat diet induces apoptosis in rat enterocytes and blunts GIP and insulin-secretive response to oral glucose load. Int J Obes (Lond)32:871-874.
Goustin, A. S., Derar, N. & Abou-Samra, A. B. (2013). Ahsg-fetuin blocks the metabolic arm of insulin action through its interaction with the 95 kD beta-subunit of the insulin receptor. Cell Signal. (on line )
Guilherme, A., Virbasius, J. V., Puri, V. & Czech, M. P. (2008). Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol9:367-377.
Hage, C., Brismar, K., Efendic, S., Lundman, P., Ryden, L. & Mellbin, L. (2013). Sitagliptin improves beta-cell function in patients with acute coronary syndromes and newly diagnosed glucose abnormalities: the BEGAMI study. J Intern Med. (on line )
Hawkins, M. A., Koppaka, S., Kehlenbrink, S., Li, W., Zhang, K., Sanchez, E., Lee, D. E., Lee, H., Carrasco, E., Kishore, P., Carey, M. & Chen, J. (2013). Reduced adipose tissue macrophage content is associated with improved insulin sensitivity in thiazolidinedione-treated diabetic humans. Diabetes. (on line )
Hebert, P. L., Geiss, L. S., Tierney, E. F., Engelgau, M. M., Yawn, B. P. & McBean, A. M. (1999). Identifying persons with diabetes using Medicare claims data. Am J Med Qual14:270-277.
Ho, B. Y., Wu, Y. M.,Chang, K. J. & Pan, T. M. (2011). Dimerumic acid inhibits SW620 cell invasion by attenuating H(2) O(2)-mediated MMP-7 expression via JNK/C-Jun and ERK/C-Fos activation in an AP-1-dependent manner. Int J Biol Sci7:869-880.
Hsu, L. C., Hsu, Y. W., Liang, Y.H., Kuo, Y. H. & Pan, T. M. (2011). Anti-tumor and anti-inflammatory properties of ankaflavin and monaphilone A from monascus purpureus NTU 568. J Agric Food Chem59:1124-1130.
Hsu, L. C., Hsu, Y. W., Liang, Y. H., Liaw, C. C., Kuo, Y. H. & Pan, T. M. (2012a). Induction of apoptosis in human breast adenocarcinoma cells MCF-7 by monapurpyridine A, a new azaphilone derivative from Monascus purpureus NTU 568. Molecules17:664-673.
Hsu, L. C., Hsu, Y. W., Liang, Y. H., Lin, Z. H., Kuo, Y. H. & Pan, T. M. (2012b). Protective effect of deferricoprogen isolated from Monascus purpureus NTU 568on citrinin-induced apoptosis in HEK-293 cells. J Agric Food Chem60:7880-7885.
Hsu, W. H., Lee, B. H., Hsu, Y. W. & Pan, T. M. (2013a). PPAR-gamma activators monascin and rosiglitazone attenuate carboxymethyllysine-induced fibrosis in hepatic stellate cells through regulating oxidative stress pathway but independent on RAGE signaling. J Agric Food Chem. (on line )
Hsu, W. H., Lee, B. H., Huang, Y. C., Hsu, Y. W. & Pan, T. M. (2012c). Ankaflavin, a novel Nrf-2 activator for attenuating allergic airway inflammation. Free Radic Biol Med53:1643-1651.
Hsu, W. H., Lee, B. H., Li, C. H., Hsu, Y. W. & Pan, T. M. (2013b). Monascin and AITC Attenuate methylglyoxal-induced PPARgamma phosphorylation and degradation through inhibition of the oxidative stress/PKC pathway depending on Nrf2 activation. J Agric Food Chem. (on line )
Hsu, W. H., Liao, T. H., Lee, B. H., Hsu, Y. W. &Pan, T. M. (2013c). Ankaflavin regulates adipocyte function and attenuates hyperglycemia caused by high-fat diet via PPAR-gamma activation. Journal of Functional Foods. (on line )
Hsu, W. H., Lee, B. H., Liao, T. H., Hsu, Y. W. & Pan, T. M. (2012d). Monascus-fermented metabolite monascin suppresses inflammation via PPAR-gamma regulation and JNK inactivation in THP-1 monocytes. Food Chem Toxicol50:1178-1186.
Hsu, W. H., Lee, B. H., Lu, I. J. & Pan, T. M. (2012e). Ankaflavin and monascin regulate endothelial adhesion molecules and endothelial NO synthase (eNOS) expression induced by tumor necrosis factor-alpha (TNF-alpha) in human umbilical vein endothelial cells (HUVECs). J Agric Food Chem60:1666-1672.
Inoue, N., Inafuku, M., Shirouchi, B., Nagao, K. & Yanagita, T. (2013). Effect of Mukitake mushroom (Panellus serotinus) on the pathogenesis of lipid abnormalities in obese, diabetic ob/ob mice. Lipids Health Dis12:18.
Islam, M. S. & Indrajit, M. (2012). Effects of xylitol on blood glucose, glucose tolerance, serum insulin and lipid profile in a type 2 diabetes model of rats. Ann Nutr Metab61:57-64.
Jackson, K. G., Maitin, V., Leake, D. S., Yaqoob, P. & Williams, C. M. (2006). Saturated fat-induced changes in Sf 60-400 particle composition reduces uptake of LDL by HepG2 cells. J Lipid Res47:393-403.
Jaidane, H., Sane, F., Gharbi, J., Aouni, M., Romond, M. B. & Hober, D. (2009). Coxsackievirus B4 and type 1 diabetes pathogenesis: contribution of animal models. Diabetes Metab Res Rev25:591-603.
Jeon, T., Hwang, S. G., Hirai, S., Matsui, T., Yano, H., Kawada, T., Lim, B. O. & Park, D. K. (2004). Red yeast rice extracts suppress adipogenesis by down-regulating adipogenic transcription factors and gene expression in 3T3-L1 cells. Life Sci75:3195-3203.
Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S. & Drachman, D. A. (2000). Statins and the risk of dementia. Lancet356:1627-1631.
Jou, P. C., Ho, B. Y., Hsu, Y. W. & Pan, T. M. (2010). The effect of Monascus secondary polyketide metabolites, monascin and ankaflavin, on adipogenesis and lipolysis activity in 3T3-L1. J Agric Food Chem58:12703-12709.
Juzlova, P., Martinkova, L. & Kren V. (1996). Secondary metabolites of the fungus Monascus: a review. J Ind Microbiol 16: 163-170.
Kaufman, R. J. (2011). Beta-cell failure, stress, and type 2 diabetes. N Engl J Med365:1931-1933.
Kim, B., Backus, C., Oh, S. & Feldman, E. L. (2012a). Hyperglycemia-Induced Tau Cleavage in vitroand in vivo: A Possible Link Between Diabetes and Alzheimer`s Disease. J Alzheimers Dis.
Kim, M. Y., Jo, S. H., Park, J. M., Kim, T. H., Im, S. S. & Ahn, Y. H. (2012b). Adenovirus-mediated overexpression of Tcfe3 ameliorates hyperglycaemia in a mouse model of diabetes by upregulating glucokinase in the liver. Diabetologia. (on line )
Kolka, C. M. & Bergman, R. N. (2013). The endothelium in diabetes: Its role in insulin access and diabetic complications. Rev Endocr Metab Disord. (on line )
Koo, H. Y., Wallig, M. A., Chung, B. H., Nara, T. Y., Cho,B. H. & Nakamura, M. T. (2008). Dietary fructose induces a wide range of genes with distinct shift in carbohydrate and lipid metabolism in fed and fasted rat liver. Biochim Biophys Acta1782:341-348.
Large, V., Peroni, O., Letexier, D., Ray, H. & Beylot, M. (2004). Metabolism of lipids in human white adipocyte. Diabetes Metab30:294-309.
Lee, B. H., Hsu, W. H., Chang, Y. Y., Kuo, H. F., Hsu, Y. W. & Pan, T. M. (2012). Ankaflavin: a natural novel PPARgamma agonist upregulates Nrf2 to attenuate methylglyoxal-induced diabetes in vivo. Free Radic Biol Med53:2008-2016.
Lee, B. H., Hsu, W. H., Hsu, Y. W. & Pan, T. M. (2013a). Dimerumic acid attenuates receptor for advanced glycation endproducts signal to inhibit inflammation and diabetes mediated by Nrf2 activation and promotes methylglyoxal metabolism into d-lactic acid. Free Radic Biol Med. (on line )
Lee, B. H., Hsu, W. H., Huang, T., Chang, Y. Y., Hsu, Y. W. & Pan, T. M. (2013b). Monascin improves diabetes and dyslipidemia by regulating PPARgamma and inhibiting lipogenesis in fructose-rich diet-induced C57BL/6 mice. Food Funct. (on line )
Lee, B. H., Hsu, W. H., Liao, T. H. & Pan, T. M. (2011). The Monascus metabolite monascin against TNF-alpha-induced insulin resistance via suppressing PPAR-gamma phosphorylation in C2C12 myotubes. Food Chem Toxicol49:2609-2617.
Lee, C. L., Hung, H. K., Wang, J. J. & Pan, T. M. (2007a). Red mold dioscorea has greater hypolipidemic and antiatherosclerotic effect than traditional red mold rice and unfermented dioscorea in hamsters. J Agric Food Chem55:7162-7169.
Lee, C. L., Hung, Y. P., Hsu, Y. W. &Pan, T. M. (2013c). Monascin and ankaflavin have more anti-atherosclerosis effect and less side effect involving increasing creatinine phosphokinase activity than monacolin K under the same dosages. J Agric Food Chem61:143-150.
Lee, C. L., Kung, Y. H., Wu, C. L., Hsu, Y. W. & Pan, T. M. (2010). Monascin and ankaflavin act as novel hypolipidemic and high-density lipoprotein cholesterol-raising agents in red mold dioscorea. J Agric Food Chem58:9013-9019.
Lee, C. L., Kuo, T. F., Wang, J. J. & Pan, T. M. (2007b). Red mold rice ameliorates impairment of memory and learning ability in intracerebroventricular amyloid beta-infused rat by repressing amyloid beta accumulation. J Neurosci Res85:3171-3182.
Lee, C. L., Tsai, T. Y., Wang, J. J. & Pan, T. M. (2006a). In vivo hypolipidemic effects and safety of low dosage Monascus powder in a hamster model of hyperlipidemia. Appl Microbiol Biotechnol70:533-540.
Lee, C. L., Wang, J. J., Kuo, S. L. & Pan, T. M. (2006b). Monascus fermentation of dioscorea for increasing the production of cholesterol-lowering agent--monacolin K and antiinflammation agent--monascin. Appl Microbiol Biotechnol72:1254-1262.
Lee, C. L., Wang, J. J. &Pan, T. M. (2008). Red mold rice extract represses amyloid beta peptide-induced neurotoxicity via potent synergism of anti-inflammatory and antioxidative effect. Appl Microbiol Biotechnol79:829-841.
Lee, C. L., Wen, J. Y., Hsu, Y. W. & Pan, T. M. (2013d). Monascus-Fermented Yellow Pigments Monascin and Ankaflavin Showed Antiobesity Effect via the Suppression of Differentiation and Lipogenesis in Obese Rats Fed a High-Fat Diet. J Agric Food Chem61:1493-1500.
Lee, J. Y. & Carr, T. P. (2004). Dietary fatty acids regulate acyl-CoA: cholesterol acyltransferase and cytosolic cholesteryl ester hydrolase in hamsters. J Nutr134:3239-3244.
Li, X., Choi, Y., Yanakawa, Y. & Park, T. (2013). Piperonal prevents high-fat diet-induced hepatic steatosis and insulin resistance in mice via activation of adiponectin/AMPK pathway. Int J Obes (Lond). (on line)
Lim, J. S., Mietus-Snyder, M., Valente, A., Schwarz, J. M. & Lustig, R. H. (2010). The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol7:251-264.
Lin, C. P., Lin, Y. L., Huang, P. H., Tsai, H. S. & Chen, Y. H. (2011). Inhibition of endothelial adhesion molecule expression by Monascus purpureus-fermented rice metabolites, monacolin K, ankaflavin, and monascin. J Sci Food Agric91:1751-1758.
Malandrucco, I., Pasqualetti, P., Giordani, I., Manfellotto, D., De Marco, F., Alegiani, F., Sidoti, A. M., Picconi, F., Di Flaviani, A., Frajese, G., Bonadonna, R. C. & Frontoni, S. (2012). Very-low-calorie diet: a quick therapeutictool to improve beta cell function in morbidly obese patients with type 2 diabetes. Am J Clin Nutr95:609-613.
Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F. & Turner, R. C. (1985). Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia28:412-419.
Mossine, V. V. & Mawhinney, T. P. (2010). 1-Amino-1-deoxy-D-fructose (&auot;fructosamine&auot;) and its derivatives. Adv Carbohydr Chem Biochem64:291-402.
Muoio, D. M. & Newgard, C. B. (2008). Fatty acid oxidation and insulin action: when less is more. Diabetes57:1455-1456.
Nakagawa, T., Yokozawa, T., Kim, H. J. & Shibahara, N. (2005). Protective effects of gamma-aminobutyric acid in rats with streptozotocin-induced diabetes. J Nutr Sci Vitaminol (Tokyo)51:278-282.
Nicolosi, R. J., Stucchi, A. F., Kowala, M. C., Hennessy, L. K., Hegsted, D. M. & Schaefer, E. J. (1990). Effect of dietary fat saturation and cholesterol on LDL composition and metabolism. In vivo studies of receptor and nonreceptor-mediated catabolism of LDL in cebus monkeys. Arteriosclerosis10:119-128.
Ozdemir, G., Ozden, M., Maral, H., Kuskay, S., Cetinalp, P. & Tarkun, I. (2005). Malondialdehyde, glutathione, glutathione peroxidase and homocysteine levels in type 2 diabetic patients with and without microalbuminuria. Ann Clin Biochem42:99-104.
Panchal,S. K., Poudyal,H., Iyer,A., Nazer,R., Alam,M. A., Diwan,V., Kauter,K., Sernia,C., Campbell,F., Ward,L., Gobe,G., Fenning,A. &Brown,L.(2011). High-carbohydrate, high-fat diet-induced metabolic syndrome and cardiovascular remodeling in rats. J Cardiovasc Pharmacol57:611-624.
Peng, C. H., Chyau, C. C., Chan, K. C., Chan, T. H., Wang, C. J. & Huang, C. N. (2011). Hibiscus sabdariffa polyphenolic extract inhibits hyperglycemia, hyperlipidemia, and glycation-oxidative stress while improving insulin resistance. J Agric Food Chem59:9901-9909.
Puri, D., Prabhu, K. M. & Murthy, P. S. (2012). Antidiabetic Effect of GII Compound Purified from Fenugreek (Trigonella foenum graecum Linn) Seeds in Diabetic Rabbits. Indian J Clin Biochem27:21-27.
Ragheb, R., Shanab, G. M., Medhat, A. M., Seoudi, D. M., Adeli, K. & Fantus, I. G. (2009). Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: evidence for PKC activation and oxidative stress-activated signaling pathways. Biochem Biophys Res Commun389:211-216.
Rasineni, K., Bellamkonda, R., Singareddy, S. R. &Desireddy, S. (2013). Abnormalities in carbohydrate and lipid metabolisms in high-fructose dietfed insulin-resistant rats: amelioration by Catharanthus roseus treatments. J Physiol Biochem. (on line)
Rasouli, N. & Kern, P. A. (2008). Adipocytokines and the metabolic complications of obesity. J Clin Endocrinol Metab93:S64-73.
Retnakaran, R., Hanley, A. J., Raif, N., Connelly, P. W., Sermer, M. & Zinman, B. (2003). C-reactive protein and gestational diabetes: the central role of maternal obesity. J Clin Endocrinol Metab88:3507-3512.
Rhyu, M. R., Kim, D. K., Kim, H. Y. & Kim, B. K. (2000). Nitric oxide-mediated endothelium-dependent relaxation of rat thoracic aorta induced by aqueous extract of red rice fermented with Monascus ruber. J Ethnopharmacol70:29-34.
Rivera-Ramirez, F., Escalona-Cardoso, G. N., Garduno-Siciliano, L., Galaviz-Hernandez, C. & Paniagua-Castro, N. (2011). Antiobesity and hypoglycaemic effects of aqueous extract of Ibervillea sonorae in mice fed a high-fat diet with fructose. J Biomed Biotechnol2011:968984.
Shen, Q., Lal, R., Luellen, B. A., Earnheart, J. C., Andrews, A. M. & Luscher, B. (2010). gamma-Aminobutyric acid-type A receptor deficits cause hypothalamic-pituitary-adrenal axis hyperactivity and antidepressant drug sensitivity reminiscent of melancholic forms of depression. Biol Psychiatry68:512-520.
Shen, Y., Luche, R., Wei, B., Gordon, M. L., Diltz, C. D. & Tonks, N. K. (2001). Activation of the Jnk signaling pathway by a dual-specificity phosphatase, JSP-1. Proc Natl Acad Sci US A98:13613-13618.
Shi, Y. C., Liao, V. H. & Pan, T. M. (2012). Monascin from red mold dioscorea as a novel antidiabetic and antioxidative stress agent in rats and Caenorhabditis elegans. Free Radic Biol Med52:109-117.
Shi, Y. C. & Pan, T. M. (2010a). Anti-diabetic effects of Monascus purpureus NTU 568fermented products on streptozotocin-induced diabetic rats. J Agric Food Chem58:7634-7640.
Shi, Y. C. & Pan, T. M. (2010b). Antioxidant and pancreas-protective effect of red mold fermented products on streptozotocin-induced diabetic rats. J Sci Food Agric90:2519-2525.
Sivakumar, A. S. & Anuradha, C. V. (2011). Effect of galangin supplementation on oxidative damage and inflammatory changes in fructose-fed rat liver. Chem Biol Interact193:141-148.
Srinivasan, K. & Ramarao, P. (2007). Animal models in type 2 diabetes research: an overview. Indian J Med Res125:451-472.
Stephens, J. M. & Pilch, P. F. (1995). The metabolic regulation and vesicular transport of GLUT4, the major insulin-responsive glucose transporter. Endocr Rev16:529-546.
Su, N. W., Lin, Y. L., Lee, M. H. & Ho, C. Y. (2005). Ankaflavin from Monascus-fermented red rice exhibits selective cytotoxic effect and induces cell death on Hep G2 cells. J Agric Food Chem53:1949-1954.
Sun, L., Zeng, X., Yan, C., Sun, X., Gong, X., Rao, Y. & Yan, N. (2012). Crystal structure of a bacterial homologue of glucose transporters GLUT1-4. Nature490:361-366.
Suresh, S., Prithiviraj, E., Venkata Lakshmi, N., Karthik Ganesh, M., Ganesh, L. & Prakash, S. (2013). Effect of Mucuna pruriens(Linn.) on mitochondrial dysfunction and DNA damage in epididymal sperm of streptozotocin induced diabetic rat. J Ethnopharmacol145:32-41.
Targher, G., Bertolini, L., Rodella, S., Zoppini, G., Lippi, G., Day, C. &Muggeo, M. (2008). Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia51:444-450.
Thyfault, J. P., Hedberg, E. M., Anchan, R. M., Thorne, O. P., Isler, C. M., Newton, E. R., Dohm, G. L. & deVente, J. E. (2005). Gestational diabetes is associated with depressed adiponectin levels. J Soc Gynecol Investig12:41-45.
Tournier, C., Dong, C., Turner, T. K., Jones,S. N., Flavell, R. A. & Davis, R. J. (2001). MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev15:1419-1426.
Trayhurn, P. & Beattie, J. H. (2001). Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc60:329-339.
Tseng, K. C., Fang, T. J., Chiang, S. S., Liu, C. F., Wu, C. L. & Pan, T. M. (2012). Immunomodulatory activities and antioxidant properties of polysaccharides from Monascus-fermented products in vitro. J Sci Food Agric92:1483-1489.
Tsuji, K., Ichikawa, T., Tanabe, N., Abes., Tarui, S. & Nakagwa, Y. (1992). Antihypertensive activities of beni-Koji extracts and r-amiobutyric acid in Spontaneously hypertensive rates. Jpn J Nutr50:285-291.
Tuch, B. E., Beynon, S., Tabiin, M. T., Sassoon, R., Goodman, R. J. & Simpson, A. M. (1997). Effect of beta-cell toxins on genetically engineered insulin-secreting cells. J Autoimmun10:239-244.
van Uden, P., Kenneth, N. S. & Rocha, S. (2008). Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J412:477-484.
Vangoitsenhoven, R., Mathieu, C. & Van der Schueren, B. (2012). GLP1 and cancer: friend or foe? Endocr Relat Cancer19:F77-88.
Varela-Rey, M., Embade, N., Ariz, U., Lu, S. C., Mato, J. M. & Martinez-Chantar, M. L. (2009). Non-alcoholic steatohepatitis and animal models: understanding the human disease. Int J Biochem Cell Biol41:969-976.
Wang, J., Song, Y., Wang, Q., Kralik, P. M.& Epstein, P. N. (2006a). Causes and characteristics of diabetic cardiomyopathy. Rev Diabet Stud3:108-117.
Wang, J. J., Shieh, M. J., Kuo, S. L., Lee, C. L. & Pan, T. M. (2006b). Effect of red mold rice on antifatigue and exercise-related changes in lipid peroxidation in endurance exercise. Appl Microbiol Biotechnol70:247-253.
Wei, W., Li, C., Wang, Y., Su, H., Zhu, J. & Kritchevsky, D. (2003). Hypolipidemic and anti-atherogenic effects of long-term Cholestin (Monascus purpureus-fermented rice, red yeastrice) in cholesterol fed rabbits. J Nutr Biochem14:314-318.
Wei, Y., Wang, D., Topczewski, F. & Pagliassotti, M. J. (2007). Fructose-mediated stress signaling in the liver: implications for hepatic insulin resistance. J Nutr Biochem18:1-9.
Wiecek, A., Adamczak, M. & Chudek, J. (2007). Adiponectin--an adipokine with unique metabolic properties. Nephrol Dial Transplant22:981-988.
Wong, R. K., Pettit, A. I., Quinn, P. A., Jennings, S. C., Davies, J. E. & Ng, L. L. (2003). Advanced glycation end products stimulate an enhanced neutrophil respiratory burst mediated through the activation of cytosolic phospholipase A2 and generation of arachidonic Acid. Circulation108:1858-1864.
Wu, C. L., Lee, C. L. & Pan, T. M. (2009). Red mold dioscorea has a greater antihypertensive effect than traditional red mold rice in spontaneously hypertensive rats. J Agric Food Chem57:5035-5041.
Yadav, H., Jain, S. & Sinha, P. R. (2007). Antidiabetic effect of probiotic dahi containing Lactobacillus acidophilusand Lactobacillus caseiin high fructose fed rats. Nutrition23:62-68.
Yamashiro, J., Shiraishi, S., Fuwa, T. & Horie, T. (2008). Dimerumic acid protected oxidative stress-induced cytotoxicity in isolated rat hepatocytes. Cell Biol Toxicol24:283-290.
Yasukawa, K., Akihisa, T., Oinuma, H., Kaminaga, T., Kanno, H., Kasahara, Y., Tamura, T., Kumaki, K., Yamanouchi, S. & Takido, M. (1996). Inhibitory effect of taraxastane-type triterpenes on tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in two-stage carcinogenesis in mouse skin. Oncology53:341-344.
Zavalza-Gomez, A. B., Anaya-Prado, R., Rincon-Sanchez, A. R. & Mora-Martinez, J. M. (2008). Adipokines and insulin resistance during pregnancy. Diabetes Res Clin Pract80:8-15.
Zheng, F., Yin, X., Lu, W., Zhou, J., Yuan, H. & Li, H. (2013). Improved Postprandial Ghrelin Response by Nateglinide or Acarbose Therapy Contributes to Glucose Stability in Type 2 Diabetic Patients. J Endocrinol Invest. (on line)