臺灣博碩士論文加值系統

台灣糖尿病人口逐年攀升，已躍居國人十大死因的第五位，其中糖尿病患者約有95 % 屬於第二型糖尿病，主因為胰島素阻抗而導致高血糖之症狀。酚酸廣泛存在於許多蔬果中，已有許多研究證實酚酸具有降血糖之生理活性，但目前仍未被完整的研究。本研究首先利用9種酚酸對小鼠肝臟上皮細胞株FL83B進行細胞存活率試驗，結果顯示，酚酸之最高安全使用劑量為12.5 μM，再以葡萄糖攝入試驗篩選具降血糖潛力之酚酸，香草酸在改善胰島素阻抗細胞葡萄糖攝入能力具有良好效果，接著以動物實驗探討香草酸對高脂飼料餵食大鼠之影響。實驗設計將雄性Sprague-Dawley大鼠隨機分為兩組，一組給予正常飲食 (脂肪佔總飲食熱量14 %)，另一組給予高脂飲食 (脂肪佔總飲食熱量60 %)，實驗期間定期監測大鼠禁食血糖變化；將餵食12週高脂飲食後成功誘導成高血糖動物模式之大鼠，再隨機分為負控制組、正控制組 (餵予pioglitazone) 及實驗組 (餵予香草酸)。結果顯示，以高脂飼料餵食大鼠12週後可成功誘發高血糖症狀，而每日餵食香草酸 (30 mg/kg b.w.) 4週後則能顯著改善高脂飲食大鼠高血糖、高血脂、高瘦體素血症及胰島素阻抗之現象。由上述結果顯示，香草酸可能具有改善胰島素阻抗及血脂異常之效果，有助於調節糖尿病前期之血糖異常，未來具有開發成健康食品及膳食補充劑之潛力。

Diabetes mellitus (DM) is the 5th leading cause of death in Taiwan, and the prevalence is still growing. More than 95 % among all the cases belong to type 2 diabetes and characterized as insulin resistance that resulted in hyperglycemia. Phenolic acids are widely distributed in vegetables and fruits. Although some studies have shown the effect of phenolic acids on anti-hyperglycemia, there has been no systematic study on DM yet. In this study, the insulin resistant mouse hepatocytes FL83B cell model was established and used as the screen platform. The cell viability test showed that the critical safe dosage of 9 phenolic acids is 12.5 μM. The result from glucose uptake test showed that vanillic acid exhibits the highest increment in glucose uptake in insulin resistant cells among tested samples. Animal model was then performed to assess the effect of vanillic acid in high fat diet-fed rats. Male Sprague-Dawley rats are randomly divided into two groups, including a control group (fed with chow diet containing 14 % kcal from fat), and a high-fat diet group (fed with high-fat diet containing 60 % kcal from fat) for the development of hyperglycemia. Furthermore, the high-fat diet group were further divided into three sub-groups, including the high-fat diet sub-group, positive control sub-group (orally administrated pioglitazone, 30 mg/kg b.w.) and treatment sub-group (orally administrated vanillic acid, 30 mg/kg b.w.). The results showed that vanillic acid significantly alleviated high-fat diet induced syndrome, including hyperglycemia, hyperlipidemia, hyperleptinemia and insulin resistance. We thus demonstrated the potential of vanillic acid in the development of health foods or dietary supplements for the prevention of hyperglycemia in prediabetes.

中文摘要 I
Abstract II
目 錄 III
圖 次 V
表 次 VII
第一章 前言 1
第二章 文獻回顧 2
第一節 糖尿病 2
一、糖尿病簡介 2
二、糖尿病流行病學 2
三、糖尿病分類 3
四、糖尿病診斷標準 7
五、常見抗糖尿病藥物治療 9
六、糖尿病前期 11
第二節 胰島素 13
一、胰島素簡介 13
二、胰島素訊息傳遞 15
三、胰島素阻抗 16
第三節 高脂飼料誘發高血糖之動物實驗模式 18
一、實驗模式簡介 18
二、高脂飲食與血糖及胰島素之關係 18
三、高脂飲食與血中瘦體素之關係 20
四、高脂飲食與肝臟脂質代謝之關係 21
五、高脂飲食與發炎反應之關係 22
第四節 酚酸與糖尿病 23
第三章 研究動機與實驗架構 26
第一節 研究動機與目的 26
第二節 實驗架構 27
第四章 材料與方法 28
第一節 胰島素阻抗細胞實驗模式 28
一、實驗材料 28
二、實驗方法 30
第二節 高脂飼料誘發高血糖動物實驗模式 34
一、實驗材料 34
二、實驗方法 37
第五章 結果與討論 45
第一節 以細胞模式篩選具有降血糖潛力之酚酸 45
第二節 香草酸 (Vanillic acid) 對高脂飼料大鼠生理、生化之影響 48
第三節 香草酸 (Vanillic acid) 對高脂飼料大鼠肝臟蛋白質表現量之影響 53
第六章 結論 75
第七章 參考文獻 77

行政院衛生署衛生統計資訊網。2013。http://www.doh.gov.tw.
何橈通。糖尿病與公共衛生。臨床醫學。1986。17：300-317。
吳俐瑩。衛生所第二型糖尿病患者照護滿意度及相關因素之探討─以溪口鄉為例。南華大學資訊管理學系碩士論文。2012。
吳寧容。番石榴萃出物對streptozotocin-nicotinamide 誘發第二型糖尿病大白鼠血糖之影響。國立台灣大學食品科技研究所碩士論文。2007。
沈德昌、顏兆熊。第二型糖尿病藥物治療新知。台灣醫界。2008。51：22-27。
林進丁。胰島素。藥學雜誌。1986。2：57-63。
施瑞雯。蓮霧幼果分離物 ─ Vescalagin 與 Gallic acid 對高果糖飼料誘導糖尿病前期大鼠之影響。國立臺灣師範大學人類發展與家庭學系碩士論文。2012。
張文昌。食用桃金孃科植物萃取物減輕小鼠肝臟細胞 (FL83B) 胰島素阻抗之探討。國立台灣大學食品科技研究所碩士論文。2010。
張巧俐。粉紅種蓮霧幼果水萃物減輕以腫瘤壞死因子 (TNF-α) 處理之小鼠肝臟細胞 (FL83B) 胰島素阻抗及改善醣類代謝之研究。國立台灣大學食品科技研究所碩士論文。2011。
郭熙文。飯後血糖值的控制是更理想的糖尿病治療之指標嗎。中華民國內分泌暨糖尿病會會訊。2001。14：31-33。
陳敏麗、黃松元。某社區民眾糖尿病篩檢中血糖值與糖尿病高危險因子及健康促進生活型態之探討。衛生教育學報。2005。24：1-24。
黃大維。咖啡酸及肉桂酸減輕小鼠肝臟細胞 (FL83B) 胰島素阻抗及改善碳水化合物代謝之研究。國立台灣大學食品科技研究所博士論文。2010。
鄭芳琪。番石榴葉水萃物降血糖作用及有效成分分離。國立台灣大學食品科技研究所博士論文。2009。
Adams, L. A.; Angulo, P.; Lindor, K. D. Nonalcoholic fatty liver disease. Can. Med. Assoc. J. 2005, 172, 899-905.
Adisakwattana, S.; Roengsamarn, S.; Hsu, W. H.; Yibchok-anun, S. Mechanisms of antihyperglycemic effect of p-methoxycinnamic acid in normal and streptozotocin-induced diabetic rats. Life Sci. 2005, 78, 406-412.
Aguirre, V.; Uchida, T.; Yenush, L.; Davis, R.; White, M. F. The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J. Biol. Chem. 2000, 275, 9047-9054.
Ahren, B.; Gudbjartsson, T.; Al-amin, A. N. Islet perturbations in rats fed a high-fat diet. Pancreas. 1999, 18, 75-83.
Arkan, M. C.; Hevener, A. L.; Greten, F. R.; Maeda, S.; Li, Z. W.; Long, J. M.; Wynshaw-Boris, A.; Poli, G.; Olefsky, J.; Karin, M. IKK-β links inflammation to obesity-induced insulin resistance. Nat. Med. 2005, 11, 191-198.
Bahorun, T.; Luximon-Ramma, A.; Crozier, A.; Aruoma, O.I. Total phenol, flavonoid, proanthocyanidin and Vitamin C levels and antioxidant activities of Mauritian vegetables. J. Sci. Food Agric. 2004, 84, 1553-1561.
Bjӧrnholm, M.; Zierath, J. R. Insulin signal transduction in human skeletal muscle: identifying the defects in type II diabetes. Biochem. Soc. Trans. 2005, 33, 354-357.
Bose, T.; Alvarenga, J. C.; Tejero, M. E.; Voruganti, V. S.; Proffitt, J. M.; Freeland-Graves, J. H. Association of monocyte chemoattractant protein-1 with adipocyte number, insulin resistance and liver function markers. J. Med. Primatol. 2009, 38, 418-424.
Buettner, R.; Scholmerich, J.; Bollheimer, L. C. High-fat diet: modeling the metabolic disorders of human obesity in rodents. Obesity. 2007, 15, 798-808.
Buettner, R.; Parhofer, K. G.; Woenckhaus, M.; Wrede, C. E.; Kunz-Schughart, L. A.; Scholmerich, J.; Bollheimer, L. C. Defining high-fat-diet rat models : metabolic and molecular effect of different fat types. Mol. Endocrinol. 2006, 36, 485-501.
Butler, A. A.; LeRoith, D. Tissue-specific versus generalized gene targeting of the igflr genes and their roles in insulin-like growth factor physiology. Endocrinology. 2001, 142, 1685-1688.
Cai, D.; Yuan, M.; Frantz, D. F.; Melendez, P. A.; Hansen, L.; Lee, j.; Shoelson, S. E. Local and systemic insulin resistance resulting from hepatic activation of IKKβ and NF-κB. Nat. Med. 2005, 11, 183-190.
Carlsson, C.; Borg, L. A.; Welsh, N. Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro. Endocrinology. 1999, 140, 3422-3428.
 
Caro, J. F.; Kolaczynski, J. W.; Nyce, M. R.; Ohannesian, J. P.; Opentanova, I.; Goldman, W. H.; Lynn, R. B.; Zhang, P. L.; Sinha, M. K.; Considine, R. V. Decreased cerebrospinal-fluid/serum leptin ratio in obesity : a possible mechanism for leptin resistance. Lancet. 1996, 348, 159-161.
Clarke W.L.; Larner J.; Pohn S.C. Methods in diabetes research. John Wiley and Sous, ENC. New York. 1986, 39-86.
Considine, R. V. Increased serum leptin indicates leptin resistance in obesity. Clin. Chem. 2011, 57, 1461-1462.
Considine, R. V.; Sinha, M. K.; Heiman, M. L.; Kriauciunas, A.; Stephens, T. W.; Nyce, M. R.; Ohannesian, J. P.; Marco, C. C.; Mckee, L. J.; Baur, T. L.; Caro, J. F. Serum immunoreative-leptin concentrations in normal weight and obese human. N. Engl. J. Med. 1996, 334, 292-295.
Dandona, P.; Aljada, A.; Chaudhuri, A.; Mohanty, P.; Garg, R. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation. 2005, 111, 1448-1454.
Dandona, P.; Aljada, A.; Mohanty, P.; Ghanim, H.; Hamouda, W.; Assian, E.; Ahmad, S. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J. Clin. Endocrinol. Metab. 2001, 86, 3257-3265.
Deji, N.; Kume, S.; Araki, S.; Soumura, M.; Sugimoto, T.; Isshiki, K. Structural and functional changes in the kidneys of high-fat diet-induced obese mice. Am. J. Physiol. Renal Physiol. 2009, 296, F118-126.
Esposito, E.; Iacono, A.; Bianco, G.; Autore, G.; Cuzzocrea, S.; Vajro, P.; Canani, R. B.; Calignano, A.; Raso, G. M.; Meli, R. Probiotics reduce the inflammatory response induced by a high-fat diet in the liver of young rats. J. Nutr. 2009, 139, 905-911.
Feinstein, R.; Kanety, H.; Papa, M. Z.; Lunenfeld, B.; Karasik, A. Tumor necrosis factor-alpha suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J. Biol Chem. 1993, 268, 26055-26058.
Feng, Y.; Carroll, A. R.; Addepalli, R.; Fechner, G. A.; Avery, V. M.; Quinn, R. J. Vanillic acid derivatives from the green algae Cladophora socialis as potent protein tyrosine phosphatase 1B inhibitors. J. Nat. Prod. 2007, 70, 1790-1792. 
Fraze, E.; Chiou, M.; Chen, Y.; Reaven, G. M. Age-related changes in postprandial plasma glucose, insulin, and free fatty acid concentrations in nondiabetic individuals. J. Am. Geriatr. Soc. 1987, 35, 224-228.
Gregoire, F. M.; Zhang, Q.; Smith, S. J. Diet-induced obesity and hepatic gene expression alterations in C57BL/6J and ICAM-1-deficient mice. Am. J. Physiol. Endocrinol. Metab. 2002, 282, 703-713.
Halaas, J. L.; Gajiwala, K. S.; Maffei, M.; Cohen, S. L.; Chait, B. T.; Rabinowitz, D.; Lallone, R. L.; Burley, S. K.; Friedman, J. M. Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995, 269, 543-546.
Huang B. W.; Chiang M. T.; Yao H. T.; Chiang W. The effect of high-fat and high-fructose diets on glucose tolerance and plasma lipid and leptin levels in rats. Diabetes Obes. Metab. 2004, 6, 120-126.
Huang, D. W.; Shen, S. C.; Wu, J. S. B. Effect of caffeic acid and cinnamic acid on glucose uptake in insulin-resistant mouse hepatocytes. J. Agric. Food Chem. 2009, 57, 7687-7692.
Huang, S. M.; Hsu, C. L.; Chuang, H. C.; Shih, P. H.; Wu, C. H.; Yen, G. C. Inhibitory effect of vanillic acid on methylglyoxal-mediated glycation in apoptotic Neuro-2A cells. Neurotoxicology. 2008, 29,1016-1022.
Inoue, M.; Suzuki, R.; Sakaguchi, N.; Li, Z.; Takeda, T.; Ogihara, Y.; Jiang, B. Y.; Chen, Y. Selective induction of cell death in cancer cells by gallic acid. Biol Pharm. Bull. 1995, 18, 1526-1530.
Iwata, M.; Haruta, T.; Usui, I.; Takata, Y.; Takano, A.; Uno, T.; Kawahara, J.; Ueno, E.; Sasaoka, T.; Ishibashi, O.; Kobayashi, M. Pioglitazone ameliorates tumor necrosis factor-α-induced insulin resistance by a mechanism independent of adipogenic activity of peroxisome proliferator-activated receptor-γ. Diabetes. 2001, 50, 1083-1092.
Johnson, A. B.; Webster, J. M.; Sum, C. F.; Heseltine, L.; Argyraki, M.; Cooper, B. G. The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type 2 diabetic patients. Metabolis. 1993, 42, 1217-1222.
Jensen, M. D.; Haymond, M.W.; Rizza, R. A.; Cryer, P. E.; Miles, J. M. Influence of body fat distribution on free fatty acid metabolism in obesity. J. Clin. Invest. 1989, 83, 1168-1173.
Jiang, T.; Wang, Z.; Proctor, G.; Moskowitz, S.; Liebman, S. E.; Rogers, T. Diet-induced obesity in C57BL/6J mice causes increased renal lipid accumulation and glomerulosclerosis via a sterol regulatory element-binding protein-1c-dependent pathway. J. Biol. Chem. 2005, 280,32317-32325.
Jornayvaz, F. R.; Shulman, G. I. Diacylglycerol activation of protein kinase Cε and hepatic insulin resistance. Cell. 2012, 15, 574-584.
Jung, U. J.; Lee, M. K.; Park, Y. B.; Jeon, S. M.; Choi, M. S. Antihyperglycemic and antioxidant properties of caffeic acid I db/db mice. J. Pharmaco. Experi. Therap. 2006, 318, 476-483.
Kaiyala, K. J.; Prigeon, R. L.; Kahn, S. E.; Woods, S. C.; Porte, D.; Schwartz, M. W. Reduced β-cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding. Am. J. Physiol. 1999, 277, E659-E667.
Keilson, L.; Mather, S.; Walter, Y. H. Synergistic effect of netegtlinide the meal administration on insulin secretion in patients with type 2 diabetic mellitus. J. Clin. Endocrinol. Metab. 2000, 85, 1081-1086.
Kendall, D. M.; Harmel, A. P. The metabolic syndrome, type 2 diabetes, and cardiovascular disease : understanding the role of insulin resistance. Am. J. Manag. Care. 2002, 8, S635-653.
Kilmartin, P. A.; Zou, H.; Waterhouse, A. L. A cyclic voltammetry method suitable for characterizing antioxidant properties of wine and wine phenolics. J. Agric. Food Chem. 2001, 49, 1957-1965.
Kraegen, E. W.; James, D. E.; Storlien, L. H.; Burleigh, K. M.; Chisholm, D. J. In vivo insulin resistance in individual peripheral tissues of the high fat fed rat: assessment by euglycaemic clamp plus deoxyglucose administration. Diabetologia. 1986, 29, 192-198.
Kroder, G.; Bossenmayer, B.; Kellerer, M.; Capp, E.; Stoyanov, B.; Muhlhofer, A.; Berti, L.; Horikoshi, H.; Ullrich, A.; Haring, H. Tumor necrosis factor-alpha and hyperglycemia-induced insulin resistance. J. Clin Invest. 1996, 97, 1471- 1477.
Lalli, C. A.; Pauli, J. R.; Prada, P. O.; Cintra, D. E.; Ropelle, E. R.; Velloso, L. A.; Saad, M. J. Statin modulates insulin signaling and insulin resistance in liver and muscle of rats fed a high-fat diet. Metabolism. 2008, 57, 57-65.
Leahy, J.L.; Halvan, P.A.; Weir, G.D. Relative hyperserection of proinsulin in rat model of NIDDM. Diabetes. 1991, 40, 985-989.
Liu, I. M.; Hsu, F. L.; Chen, C. F.; Cheng, J. T. Antihyperglycemic action of isoferulic acid in streptozotocin-induced diabetic rats. Br. J. Pharmacol. 2000, 129, 631-636.
Louzao, M. C.; Espina, B.; Vieytes, M. R.; Vega, F. V.; Rubiolo, J. A.; Baba, O.; Terashima, T.; Botana, L. M. “Fluorescent glycogen” formation with sensibility for in vivo and in vitro detection. Glycoconj. J. 2008, 25, 503–510.
Luximon-Ramma A.; Bahorun T; Crozier A. Antioxidant action sand phenolic and Vitamin C contents of common Mauritan exotic fruits. J. Sci. Food Agric. 2003, 83, 496-502.
Maffei, M.; Halaas, J.; Ravussin, E.; Pratley, R. E.; Fei, H.; Kim, S.; Lallone, R.; Ranganathan, S.; Kern, P. A.; Friedman, J. M. Leptin levels in human and rodent : measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat. Med. 1995, 1, 1155-1161.
Marchand-Brustel, Y. L.; Gual, P.; Gremeaux, T.; Gonzalez, T.; Barres, R.; Tanti, J. F. Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signaling. Biochem Soc Trans. 2003, 31, 1152-1156.
McGarry, J. D. Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes. 2002, 51, 7-18.
Moore, D. D. Nuclear receptors reverse McGarry’s vicious cycle to insulin resistance. Cell. 2012, 15, 615-622.
Munzberg, H.; Flier, J.S.; Bjorbaek, C. Region-specific leptin resistance within the hypothalamus of diet-induced obese mice. Endocrinology. 2004, 145, 4880-4889.
Ohnishi, M.; Matuo, T.; Tsuno, T.; Hosoda, A.; Normura, E.; Taniguchi, H.; Sasaki, H.; Morishita, H. Antioxidation activity and hypoglycemic effect of ferulic acid in STZ-induced diabetic mice and KK-Ay mice. Biofactors. 2004, 21, 315-319.
Okabayashi, Y.; Maddux, B. A.; Mcdonald, A. R.; Logsdon, C. D.; Williams, J. A.; Goldfine, I. D. Mechanisms of insulin-induced insulin-receptor downregulation : decrease of receptor biosynthesis and mRNA levels. Diabetes. 1989, 38, 182-187.
Okutan, H.; Ozcelikb, N.; Yilmazb, H. R.; Uzb, E. Effects of caffeic acid phenethyl ester on lipid peroxidation and antioxidant enzymes in diabetic rat heart. Clin. Biochem. 2005, 38, 191-196. 
Panunti, B.; Jawa, A. A.; Fonseca, V. A. Mechanisms and therapeutic targets in type 2 diabetes mellitus. Drug Discovery Today: Disease Mechanisms. 2004, 1, 151-157.
Paz, K.; Hemi, R.; Leroith, D.; Karasik, A.; Elhanany, E.; Kanety, H.; Zick, Y. A molecular basis for insulin resistance. J. Biol. Chem. 1997, 272, 29911-29918.
Pedersen, O.; Kahn, C. R.; Flier, J. S.; Kahn, B. B. High fat feeding causes insulin resistance and a marked decrease in the expression of glucose transporters (Glut 4) in fat cells of rats. Endocrinology. 1991, 129, 771-777.
Pelleymounter, M. A.; Cullen, M. J.; Baker, M. B.; Hecht, R.; Winters, D.; Boone, T.; Collins, F. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995, 269, 540-543.
Peraldi, P.; Hotamisligil, G. S.; Buurman, W. A.; White, M. F.; Spiegelman, B. M. Tumor necrosis factor (TNF-α) inhibits insulin signaling through stimulation of the p55 TNF receptor and activation of sphingomyelinase. J. Biol. Chem. 1996, 271, 13018–13022.
Pessin, J. E.; Saltiel, A. R. Signaling pathways in insulin action: molecular targets of insulin resistacne. J. Clin. Invest. 2000, 106, 165-169.
Prada, P. O.; Zecchin, H.G.; Gasparetti, A. L. Western diet modulates insulin signaling, c-Jun N-terminal kinase activity, and insulin receptor substrate-1ser307 phosphorylation in a tissue-specific fashion. Endocrinology. 2005, 146, 1576-1587.
Puigserver, P.; Rodgers, J. T. Foxa2, a novel transcriptional regulator of insulin sensitivity. Nature. 2006, 12, 38-39.
Punithavathi, V. R.; Prince, S. M.; Kumar, M. R.; Selvakumari, C. J. Protective effect of gallic acid on hepatic lipid peroxide metabolism, glycoprotein components and lipids in streptozotocin-induced type II diabetic wistar rats. J. Bio. Mol. Toxicology. 2010, 25, 68-76.
Qatanani, M.; Lazar, M. A. Mechanisms of obesity-associated insulin resistance: many choices on the menu. Gene. Dev. 2007, 21, 1443-1455.
Rangwala, S. M.; Lazar, M. A. Peroxisome proliferator-activated receptor γ in diabetes and metabolism. Trends Pharmacol. Sci. 2004, 25, 331-336.
Riddle, M. C. Tactics for type 2 diabetes. Endocrinol. Metab. Clin. 1997, 26, 659-677.
Rosen, O. M. After insulin binds. Science. 1987, 237, 1452-1457.
 
Saltiel, A. R.; Kahn, C. R. Insulin signaling and the regulation of glucose and lipid metabolism. Nuture, 2001, 414, 799-806.
Sargent, J.M. The use of the MTT assay to study drug resistance in fresh tumour samples. Recent Results Cancer Res. 2003, 161, 13-25.
Scalbert, A. R.; Johnson, I. T.; Saltmarsh, M. Polyphenols: antioxidants and beyond. Am. J. Clin. Nutr. 2005, 81, 215S-217S.
Scarsi, M.; Podvinec, M.; Roth, A.; Hug, H.; Kersten, S.; Albrecht, H.; Schwede, T.; Meyer, U. A.; Rucker, C. Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity : a combined virtual screening and biological assay approach. Mol. Pharmacol. 2007, 71, 398-406.
Senn, J. J.; Klover, P. J.; Nowak, I. A.; Mooney, R. A. Interleukin-6 induces cellular insulin resistance in hepatocytes. Diabetes. 2002, 51, 3391-3399.
Sharabi Y.; Oron-herman, M.; Kamari, Y.; Avni, I.; Peleg, E.; Shabtay, Z.; Grossman, E.; Shamiss, A. Effect of PPAR-γ agonist on adiponectin levels in the metabolic syndrome: lessons from the high fructose fed rat model. Am. J. Hypertens. 2007, 20, 206-210.
Shiba, T.; Higashi, N.; Nishimura, Y. Hyperglycaemia due to insulin resistance caused by interferon-gamma. Diabet. Med. 1998, 15, 435-436.
Shyamala, B. N.; Madhava, N. M.; Sulochanamma, G.; Srinivas, P. Studies on the anti-oxidant activities of natural vanilla extract and its constituent compounds through in vitro models. J. Agric. Food Chem. 2007, 55, 7738-7743.
Singh, J.; Rai, G. K.; Upadhyay, A. K.; Kumar, R.; Singh, K. P. Antioxidant phytochemicals in tomato (Lycopersicon esculentum). Ind. Agric. Sci. 2004, 74, 3-5.
Song, S.; Andrikopoulos, S.; Filippis, C.; Thorburn, A. W.; Khan, D.; Proietto, J. Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin. Am. J. Physiol. Endocrinol. Metab. 2001, 281, 275-282.
Steiner, D.; Bell, G.; Tagar, H. Chemistry and biosynthesis of pancreatic protein hormones. Endocrinology. 1995, 1296-1328.
Storlien, L. H.; James, D. E.; Burleigh, K. M.; Chisholm, D. J.; Kraegen, E. W. Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats. Am. J. Physiol. 1986, 251, E576-E583. 
Sun, X. J.; Rothenberq, P.; Kahn, C. R.; Backer, J. M.; Araki, E.; Wilden, P. A.; Cahill, D. A.; Goldstein, B. J.; White, M. F. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991, 352, 73-77.
Tilg, H.; Moschen, A. R. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nature. 2006, 6, 772-783.
Trout, D. L.; Conway, E. S.; Putney, J. D. Dietary influences on gastric emptying of carbohydrate versus fat in the rat J. Nutr. 1977, 107, 104-111.
Unger, R. H.; Orci, L. Lipotoxic diseases of nonadipose tissues in obesity. Int. J. Obes. Relat. Metab. Disord. 2000, 24, S28-S32.
Van de Laar, F. A.; Lucassen, P. L.; Akkermans, R. P.; Van de Lisdonk, E. H.; Rutten, G. E.; Van Weel, C. Alpha-glucosidase inhibitors for type 2 diabetes mellitus. Cochrane. Db. Sy. St. Rev. 2005, CD003639.
Vazquez-Vela, M. E.; Torres, N.; Tovar, A. R. White adipose tissue as endocrine organ and its role in obesity. Arch. Med. Res. 2008, 39, 715-728.
Watarai, T.; Kobayashi, M.; Takata, Y.; Sasaoka, T.; Iwasaki, M.; Shigeta, Y. Alteration of insulin-receptor kinase activity by high-fat feeding. Diabetes. 1988, 37, 1397-1404.
Weisberg, S. P.; Hunter, D.; Huber, R.; Lemieux, J.; Slaymaker, S.; Vaddi, K.; Charo, I.; Leibel, R. L.; Ferrante, A. W. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 2006, 116, 115-124.
Xu, H.; Barnes, G. T.; Yang, Q.; Tan, G.; Yang, D.; Chou, C. J.; Sole, J.; Nichols, A.; Ross, J. S.; Tartaglia, L. A. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 2003, 112, 1821-1830.
Yoshioka, K.; Oh, K. B.; Saito, M.; Nemoto, Y.; Matsuoka, H. Evaluation of 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D glucose, a new fluorescent derivative of glucose, for viability assessment of yeast. Candida albicans. Appl. Microbiol. Biotechnol. 1996, 46, 400–404.
Youngren, J. F.; Paik, J.; Barnard, R. J. Impaired insulin-receptor autophosphorylation is an early defect in fat-fed, insulin-resistant rats. J. Appl. Physiol. 2001, 91, 2240-2247. 
Yuan W.; Pei-Yu W.; Li-Qiang Q.; Ganmaa D.; Takashi K.; Jiaying X.; Shin-ichi M.; Ryohei K.; Akio S. The development of diabetes mellitus in wistar rats kept on a high-fat low-carbohydrate diet for long periods. Endocrine. 2003, 22, 85-92.
Zierath, J. R.; Houseknecht, K. L.; Gnudi, L.; Kahn, B. B. High-fat feeding impairs insulin-stimulation of glucose transport in muscle: functional evaluation of potential mechanisms. J. Biol.Chem. 1998, 273, 26157-26163.