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研究生:鄧如芳
研究生(外文):Teng, Ju-Fang
論文名稱:雲芝醣肽調節HepG2細胞葡萄糖汲取及胰島素訊息傳遞之影響
論文名稱(外文):The effects of Trametes versicolor derived polysaccharopeptides on glucose uptake and insulin signaling pathway in HepG2 cells
指導教授:羅慧珍
指導教授(外文):Lo Hui-Chen
口試委員:徐泰浩李建興
口試委員(外文):Hsu Tai-HaoLee Chien-Hsing
口試日期:2011-01-17
學位類別:碩士
校院名稱:輔仁大學
系所名稱:營養科學系
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:英文
論文頁數:144
中文關鍵詞:胰島素訊息傳遞路徑葡萄糖汲取HepG2細胞株降血糖活性胞外多醣肽雲芝
外文關鍵詞:glucose uptakeHepG2 cell linehypoglycemic activityextracellular polysaccharopeptideTrametes versicolorinsulin signaling pathway
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衛生署統計資料顯示,糖尿病是台灣十大死亡原因的第五位。世界衛生組織(WHO)亦預測,西元2030年時,全世界罹患糖尿病人口將超過3.6億人。近年來,國人利用膳食補充劑、營養製劑及功能性食品以預防高血糖及減緩糖尿病併發症的需求遽增。建立一有效及快速之體外篩選平台,將有助於產業界開發各種具血糖調節功能產品。許多富含多醣體的菇菌及菌絲體發酵的相關產品,已被證實具有降血糖的功效。雲芝LH-1為一種在台灣發現的特有雲芝新品種,其胞外多醣肽(ePSP)具有免疫調節之活性。本研究以人類肝臟細胞HepG2細胞株建立一降血糖活性成份之體外篩選平台,包括正常葡萄糖、高葡萄糖及高葡萄糖/高胰島素模式,利用細胞流式計數儀測定細胞汲取螢光標定葡萄糖類似物之效率,以探討雲芝LH-1 ePSP之調節細胞汲取葡萄糖功效,並以西方墨點法探討其對胰島素訊息傳遞之機制。結果顯示,細胞培養於正常葡萄糖環境時,胰島素顯著增加葡萄糖汲取量,但此現象於高葡萄糖及高葡萄糖/高胰島素環境時並不顯著。在正常葡萄糖、高葡萄糖及高葡萄糖/高胰島素之細胞模式中,葡萄糖汲取量隨LH-1 ePSP的劑量增加而顯著增加。在高葡萄糖模式中,而非正常葡萄糖及高葡萄糖/高胰島素模式,LH-1 ePSP顯著增加肝醣合成量。訊息傳導路徑方面,在正常葡萄糖模式中,胰島素顯著增加p-IR-beta、IR-beta、IRS-1、IRS-2、p-Akt、Akt、Glut-1、GSK3-beta、G6Pase及AMPK的蛋白質表現量,但顯著降低p-PI3K的蛋白質表現量;而給予LH-1 ePSP顯著增加Glut-2、G6Pase及AMPK的蛋白質表現量。在高葡萄糖模式中,胰島素顯著增加p-IR-beta。但LH-1 ePSP對高葡萄糖及高葡萄糖/高胰島素細胞模式的胰島素訊息傳遞路徑之分子皆無顯著影響。本實驗顯示,HepG2細胞培養於高葡萄糖及高葡萄糖/高胰島素環境時,細胞產生胰島素拮抗現象,且其胰島素訊息傳遞路徑產生缺陷。此外,LH-1 ePSP可顯著增加葡萄糖的汲取量,但對胰島素訊息傳遞路徑分子無顯著影響。以上結果建議LH-1 ePSP之作用並非藉由改變胰島素訊息傳遞路徑增加葡萄糖汲取量。本實驗利用HepG2細胞株所建立之體外篩選平台,與高葡萄糖及高葡萄糖/高胰島素細胞模式,可有效檢測受試物對細胞汲取葡萄糖之影響,將可應用於產業界以快速篩選具調節血糖功效之食品及藥品。
According to the results of Department of Health, Executive Yuan, ROC, diabetes mellitus is the fifth leading cause of death in Taiwan. World Health Organization indicated that there will be more than 360 million people suffering from diabetes in 2030 worldwide. Recently, the demands of dietary supplements, nutraceuticals and functional foods are greatly increased in preventing hyperglycemia and attenuating diabetes-associated complications in the population. To establish in vitro platforms will be helpful for industry to efficiently and rapidly screen for products with glucose regulatory activity. Several mushrooms and related fermented products of mycelia with copious of polysacchorides have been demonstrated to have hypoglycemic activity. Recently, a novel Trametes versicolor (TV) strain LH-1 was originally collected in Taiwan and its extracellular polysaccharopeptides (ePSP) has been found to have immunoregulatory activity. In this study, an in vitro model using human hepatoma HepG2 cells has been developed to screen for hypoglycemic activity, including the conditions of normal glucose, high glucose, and high glucose plus high insulin. In addition, the effects of TV LH-1 ePSP on modulating glucose uptake were investigated by measuring the fluorescent labeled deoxyglucose analog using flow cytometer. The effects of TV LH-1 ePSP on insulin signaling pathway were determined by western blots. The results showed that the efficacy of insulin on stimulating glucose uptake was significantly increased in HepG2 cells incubated with normal glucose, not with high glucose or high glucose plus high insulin. LH-1 ePSP significantly increased glucose uptake in a dose-dependent manner in all three conditions. When HepG2 cells were incubated with high glucose, not with normal glucose and high glucose plus high insulin, LH-1 ePSP significantly increased the glycogen synthesis. In signal transduction, insulin significantly increased the protein expression of p-IR-beta, IR-beta, IRS-1, IRS-2, p-Akt, Glut-1, GSK3-beta, G6Pase, and AMPK and significantly decreased p-PI3K in HepG2 cells with normal glucose. LH-1 ePSP significantly increased the protein expression of Glut-2, G6Pase, and AMPK. Insulin significantly increased protein expression of p-IR-beta in HepG2 cells with high glucose. However, LH-1 ePSP did not have significant impact on the molecules of insulin signaling pathway in cells with high glucose and high glucose plus high insulin. The result showed that HepG2 cells may have insulin resistance and defects in insulin signaling pathway when incubated with high glucose and high glucose plus high insulin. In addition, LH-1 ePSP may significantly increase glucose uptake, even though the molecules of insulin signaling pathway were not significantly affected. These results suggest that the LH-1 ePSP-induced increase in glucose uptake is not via the insulin signaling pathway. The results suggest that using this in vitro HepG2 cell platform with high glucose and high glucose plus high insulin may efficiently and rapidly examine the effects of candidates on glucose uptake, and may further help the industry to screen functional foods and pharmaceuticals with glucose regulatory activity.

ABSTRACT IN CHINESE…………………………………………………………i
ABSTRACT IN ENGLISH………………………………………………………iii
ACKNOWLEDGEMENTS……………………………………………………………v
LIST OF TABLES………………………………………………………………xi
LIST OF FIGURES……………………………………………………………xii
ABBREVIATION.................................................xv

CHAPTER 1 INTRODUCTION.................................1

CHAPTER 2 LITERATURE REVIEW............................3
I. Diabetes mellitus...................................3
A. Definition..........................................4
B. Classification......................................4
1. Typediabetes........................................4
a. Immune-mediated diabetes............................4
b. Idiopathicdiabetes..................................5
2. Type 2 diabetes.....................................5
3. Gestational diabetes mellitus…………………………….5
4. Other specific types of diabetes…………………………6
C. Diagnostic criteria………………………………………….6
D. Complications.......................................7
E. Oral antihyperglycemic therapy…………………………..8
1. alpha-Glucosidase inhibitors………………………………8
2. Biguanides…………………………………………………….11
3. Insulin secretagogues………………………………………11
a. Sulfonylureas………………………………………………..12
b. Non-sulfonylureas……………………………………………12
4. Insulin sensitizers……………………………….……….12
5. Intestinal lipase inhibitor………………………………13
F. Nonpharmacologic therapy……………………………….…14
1. Dietary control………………………………………………14
2. Physical activity……………………………………………14

3. Alternative approach: supplementation and functional foods…15
II. Trametes versicolor………………………………………15
A. Traditional uses……………………………………………16
B. Active ingredients…………………………………………16
C. Pharmacological actions………………………………….17
1. Immunoregulatory activity……………………………….17
2. Antitumor activity…………………………………………18
3. Antivirus activity……………………………...……….20
4. Other Pharmacological activity…………………………20
D. Adverse effects/Toxicity…………………………………21
III. Glucose metabolism in the liver.................21
A. Hepatic glucose homeostasis…………………………….23
1. Glycolysis……………………………………………………23
2. Glycogenesis/Glycogenolysis…………………………….25
3. Gluconeogenesis…………………………………………….27
B. Glucose transporters………………………………………28
C. Insulin signaling pathway……………………………….29
1. Insulin receptor……………………………………………32
2. Insulin receptor substrate………………………………32
3. Phosphatidyl inositol 3 kinase…………………………33
4. Akt/protein kinase B (PKB)………………………………34
D. AMP-activated protein kinase……………………………35
1. Structure and regulation of AMPK………………………36
2. The function of AMPK in the liver…………………….37
E. Hepatic insulin resistance………………………………37
IV. HepG2…………………………………………………………38
CHAPTER 3 AIMS AND HYPOTHESIS………………………………40
CHAPTER 4 MATERIALS AND METHODS……………………………41
I. Cell culture......................................41
II. Glucose uptake………………….....................41
III. Model setup……………………………………………….42
A. Normal model…………………………………………………42
B. Hyperglycemic model……………………………………….42
C. Hyperglycemic and hyperinsulinemic model……………43
IV. Analytic measurements……………………………………43
A. Cell viability assay………………………………………43
B. Assay of glucose uptake………………………………….43
C. Assay of glycogen synthesis…………………………….44
D. Western blotting……………………………………………45
VII. Statistical analysis……………………………………47
CHAPTER 5 RESULTS………………………………………………48

CHAPTER 6 DISCUSSION…………………………………………107
CHAPTER 7 CONCLUSIONS...............................109

CHAPTER 8 REFERENCES…………………………………………111

APPENDICES
APPENDIX I.Proof of patent applications………………138
APPENDIX III.Poster…………………………………………140

LIST OF TABLES

Table 1.The experimental design for glucose uptake a
ssay using normal, hyperglycemic, and hyperglycemic
and hyperinsulinemic models of HepG2 cells with different
doses of PSK, PSP, or LH-1 ePSP……………………....60
Table 2.The experimental design for glycogen synthesis
assay using normal, hyperglycemic, and hyperglycemic and
hyperinsulinemic models of HepG2 cells with different doses
of LH-1 ePSP or PSK…………………………............63
Table 3.The experimental design for western blotting
using normal, hyperglycemic, and hyperglycemic and
hyperinsulinemic models of HepG2 cells with different doses
of LH-1 ePSP or PSK…………………………………….....65

LIST OF FIGURES

Figure 1.Major target organs and actions of orally
administered antihyperglycemic agents in type 2 diabetes
mellitus…………………………………………..........10
Figure 2.Summary of glucose homeostatic pathways
in the hepatocyte…………….......................22
Figure 3.Substrate cycles in the glycolytic/gluconeogenic
and glycogenic/glycogenolytic pathways that are involved
in the regulation of glucose production by the liver…24
Figure 4.Insulin-mediated activation of glycogen
synthase…………………………......................26
Figure 5. Signal transduction in insulin action…31
Figure 6.The experimental scheme to determine
the incubation time and dose of 2-NBDG for
glucose uptake assay……………………………………67
Figure 7.The experimental scheme of glucose
uptake assay for HepG2 cells in DMEM with
5.5 mM glucose (normal model)………………………68
Figure 8.The experimental scheme of glucose
uptake assay for HepG2 cells in DMEM with high
glucose (hyperglycemicmodel)………………………69
Figure 9.The experimental scheme of glucose uptake
assay for HepG2 cells in DMEM with high glucose and
insulin (hyperglycemic and hyperinsulinemic model)
……………………………………………………………70
Figure 10.The experimental scheme of cell
viability for HepG2 cells with 5.5 mM glucose
and different doses of PSK, PSP, or LH-1 ePSP..71
Figure 11.The growth curve of HepG2 cells
in DMEM with 5.5 mM glucose for four days………72
Figure 12.The 2-NBDG uptake of HepG2 cells……73
Figure 13.Flow cytometry dot plots
of 104 HepG2 cells……………………………………74
Figure 14.Doses and time course of 2-NBDG
uptake in HepG2 cells………………………………75
Figure 15.2-NBDG uptake of HepG2 cells in
DMEM with 5.5 mM glucose (normal model)………76
Figure 16.2-NBDG uptake of HepG2 cells in
DMEM with 5.5 (normal model) or high
(hyperglycemic model) glucose…...……………77
Figure 17.2-NBDG uptake of HepG2 cells in
DMEM with 5.5 mM glucose (normal model), high glucose
(hyperglycemic model), or high glucose plus insulin
for 24 hours (hyperglycemic and hyperinsulinemic model)
and stimulated with or without insulin
for one hour…………………………………………78
Figure 18.Effects of PSK on cell
viability of HepG2 cells…………………………79
Figure 19.Effects of PSP on cell
viability of HepG2 cells……………………...80
Figure 20.Effects of LH-1 ePSP on cell
viability of HepG2 cells………………………81
Figure 21.Effects of PSK on
glucose uptake……………………………………82
Figure 22.Effects of PSP on
glucose uptake……………………………………84
Figure 23.Effects of LH-1 ePSP
on glucose uptake………………………………86
Figure 24.Effects of LH-1 ePSP
on glycogen synthesis…………………………88
Figure 25.Protein expression
of the p-IR-beta, total IR-betaand
the ratio of p-IR-beta to total IR-beta..90 
Figure 26.Protein expression of
the IRS-1 and IRS-2……...…………………92
Figure 27.Protein expression of
the p-PI3K………………………………………94
Figure 28.Protein expression of the
p-Akt, total Akt and ratio of
p-Akt to total Akt……………………………95
Figure 29.Protein expression of the
Glut-1 and Glut-2 in cytosol………………97
Figure 30.Protein expression of the
Glut-1 and Glut-2 in the cell membrane…99
Figure 31.Protein expression of the
GSK3-betain HepG2 cells……………………101
Figure 32.Protein expression of
the glucokinase………………………………102
Figure 33.Protein expression of the
PEPCK and G6Pase……………………………103
Figure 34.Protein expression of the
p-AMPK, total AMPK and ratio p-AMPK
to total AMPK………………………………105

CHAPTER 8
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