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
REFERENCES
1.Aden DP, Vogel A, Plotkin S, Damjanov I, Knowles B. Controlled synthesis of HBS Ag in a differentiated human liver carcinoma-derived cell line. Nature. 1979;282: 615–616.
2.Agius L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J. 2008;414:1-18.
3.Aldhahi W, Hamdy O. Adipokines, inflammation and the endothelium in diabetes. Curr Diab Rep. 2003;3:293-8.
4.American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2011;34 Suppl 1:S62-9.
5.Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, Witters LA, Kemp BE, Means AR. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 2008;7:377-88.
6.Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP Jr, Roth RA. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem. 1999;274:20281-6.
7.Barthel A, Schmoll D. Novel concepts in insulin regulation of hepatic gluconeogenesis. Am J Physiol Endocrinol Metab. 2003;285:E685-92.
8.Basu A, Basu R, Shah P, Vella A, Johnson CM, Jensen M, Nair KS, Schwenk WF, Rizza RA. Type 2 diabetes impairs splanchnic uptake of glucose but does not alter intestinal glucose absorption during enteral glucose feeding: additional evidence for a defect in hepatic glucokinase activity. Diabetes. 2001;50:1351-62.
9.Basu A, Basu R, Shah P, Vella A, Johnson CM, Nair KS, Jensen MD, Schwenk WF, Rizza RA. Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism: evidence for a defect in hepatic glucokinase activity Diabetes. 2000;49:272-83.
10.Bell GI, Kayano T, Buse JB, Burant CF, Takeda J, Lin D, Fukumoto H, Seino S. Molecular biology of mammalian glucose transporters. Diabetes Care. 1990;13:198-208.
11.Bergeron R, Ren JM, Cadman KS, Moore IK, Perret P, Pypaert M, Young LH, Semenkovich CF, Shulman GI. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Endocrinol Metab. 2001;281:E1340-6.
12.Bouche C, Serdy S, Kahn CR, Goldfine AB. The cellular fate of glucose and its relevance in type 2 diabetes. Endocr Rev. 2004;25:807-30.
13.Boule N, Haddad E, Kenny G, Wells G, Sigal R. Effects of exercice on glycaemic control and body mass in type 2 diabetes mellitus. A metaanalysis of controlled clinical trials. JAMA. 2001;286:1218-27.
14.Boulton TG, Nye SH, Robbins DJ, Ip NY, Radziejewska E, Morgenbesser SD, DePinho RA, Panayotatos N, Cobb MH, Yancopoulos GD.ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell. 1991;65:663-75.
15.Brazil DP, Hemmings BA. Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci. 2001;26:657-64.
16.Brocklehurst KJ, Payne VA, Davies RA, Carroll D, Vertigan HL, Wightman HJ, Aiston S, Waddell ID, Leighton B, Coghlan MP, Agius L.Stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators. Diabetes. 2004 Mar;53(3):535-41.
17.Carling D. The AMP-activated protein kinase cascade--a unifying system for energy control. Trends Biochem Sci. 2004;29:18-24.
18.Centers for Disease Control and Prevention.gov [Internet] Atlanta: Department of Health and Human Services, Centers for Disease Control and Prevention; 2008 [cited 2011 Jan 6]. Available from: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2007.pdf
CHAPTER 8
19.Chen WL, Lin CT, Li JW, Hu FR, Chen CC. ERK1/2 activation regulates the wound healing process of rabbit corneal endothelial cells. Curr Eye Res. 2009;34:103-11.
20.Chen YF, Matsubayashi Y, Sakagami Y. Peptide growth factor phytosulfokine-alpha contributes to the pollen population effect. Planta. 2000;211:752-5.
21.Cheng AY, Fantus IG. Oral antihyperglycemic therapy for type 2 diabetes mellitus. CMAJ. 2005;172:213-26.
22.Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB 3rd, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science. 2001;292:1728-31.
23.Chow LW, Lo CS, Loo WT, Hu XC, Sham JS. Polysaccharide peptide mediates apoptosis by up-regulating p21 gene and down-regulating cyclin D1 gene. Am J Chin Med. 2003;31:1–9.
24.Chu KK, Ho SS, Chow AH. Coriolus versicolor: a medicinal mushroom with promising immunotherapeutic values. J Clin Pharmacol. 2002;42:976-84.
25.Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 1998;335:1-13.
26.Colville CA, Seatter MJ, Jess TJ, Gould GW, Thomas HM. Kinetic analysis of the liver-type (GLUT2) and brain-type (GLUT3) glucose transporters in Xenopus oocytes: substrate specificities and effects of transport inhibitors. Biochem J. 1993;290:701-6.
27.Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995;378:785-9.
28.Cross DA, Alessi DR, Vandenheede JR, McDowell HE, Hundal HS, Cohen P. the inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. Biochem J. 1994;303:21-6.
29.Cross DA, Watt PW, Shaw M, van der Kaay J, Downes CP, Holder JC, Cohen P. Insulin activates protein kinase B, inhibits glycogen synthase kinase-3 and activates glycogen synthase by rapamycin-insensitive pathways in skeletal muscle and adipose tissue. FEBS Lett. 1997;406:211-5.
30.Cui J, Chisti Y. Polysaccharopeptides of Coriolus versicolor: physiological activity, uses, and production. Biotechnol Adv. 2003;21:109-22.
31.Dearfield KL, Jacobson-Kram D, Buenaventura SK, Williams JR. In vitro assays of in vivo exposure to cyclophosphamide: induction of sister-chromatid exchanges in peripheral lymphocytes, bone-marrow cells and in cultured cells exposed to plasma. Mutat Res. 1985;158:97-104.
32.Department of Health.gov [Internet] Taiwan: Department of Health; 2010 [updated 2010 Dec 13; cited 2011 Jan 5]. Available from: http://www.doh.gov.tw/CHT2006/DM/DM2_2_p02.aspx?class_no=440&now_fod_list_no=11397&level_no=-1&doc_no=76512
33.Di Paola R, Caporarello N, Marucci A, Dimatteo C, Iadicicco C, Del Guerra S, Prudente S, Sudano D, Miele C, Parrino C, Piro S, Beguinot F, Marchetti P, Trischitta V, Frittitta L. ENPP1 Affects Insulin Action and Secretion: Evidences from In Vitro Studies. PLoS One.2011;6:e19462.
34.Donato J Jr, Frazão R, Elias CF. The PI3K signaling pathway mediates the biological effects of leptin. Arq Bras Endocrinol Metabol. 2010;54;591-602.
35.Dong X, Park S, Lin X, Copps K, Yi X, White MF. Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Invest. 2006;116:101-14.
36.Dong Y, Kwan CY, Chen ZN, Yang MP. Anti-tumor effects of a refined polysaccharide peptide fraction isolated from Coriolus versicolor in vitro and in vivo studies. Res Commun Mol Pathol Pharmacol. 1996;92:140–8.
37.Dong Y, Yang MP, Kwan CY. In vitro inhibition of proliferation of HL-60 cells by tetrandrine and Coriolous versicolor peptide derived from Chinese medicinal herbs. Life Sci. 1997;60:135–40.
38.Duthie SJ, Coleman CS, Grant MH. Status of reduced glutathione in the human hepatoma cell line, HEP G2. Biochem Pharmacol. 1988;37:3365-8.
39.Dzamko NL, Steinberg GR. .AMPK-dependent hormonal regulation of whole-body energy metabolism. Acta Physiol (Oxf). 2009;196:115-27.
40.Ebina Y, Ellis L, Jarnagin K, Edery M, Grat L, Clauser E, Ou J-H, Masiarz F, Kan YW, Goldfine ID, Roth RA, Rutter WJ: The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signaling. Cell. 1985;40:747–758.
41.Farese RV, Sajan MP, Standaert ML. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp Biol Med (Maywood). 2005;230:593-605.
42.Fayard E, Xue G, Parcellier A, Bozulic L, Hemmings BA Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. Curr Top Microbiol Immunol. 2010;346:31-56.
43.Firth R, Bell P, Rizza R. Insulin action in non-insulin-dependent diabetes mellitus: the relationship between hepatic and extrahepatic insulin resistance and obesity. Metabolism. 1987;36:1091-5.
44.Fisher JS, Gao J, Han DH, Holloszy JO, Nolte LA. Activation of AMP kinase enhances sensitivity of muscle glucose transport to insulin. Am. J. Physiol. Endocrinol. Metab. 2002;282:E18–E23.
45.Fisher M, Yang LX. Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy. Anticancer Res. 2002;22:1737-54.
46.Folli F, Saad MJ, Backer JM, Kahn CR. Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. J Clin Invest. 1993;92;1787-94.
47.Foretz M, Carling D, Guichard C, Ferre P, Foufelle F.. AMP-activated protein kinase inhibits the glucose-activated expression of fatty acid synthase gene in rat hepatocytes. J. Biol. Chem. 1998;273:14767–14771.
48.Foti D, Chiefari E, Fedele M, Iuliano R, Brunetti L, Paonessa F, Manfioletti G, Barbetti F, Brunetti A, Croce CM, Fusco A, Brunetti A. Lack of the architectural factor HMGA1 causes insulin resistance and diabetes in humans and mice. Nat Med. 2005;11:765-73.
49.Fujii T, Saito K, Matsunaga K, Oguchi Y, Ikuzawa M, Furusho T, Taguchi T. Prolongation of the survival period with the biological response modifier PSK in rats bearing N-methyl-N-nitrosourea-induced mammary gland tumors. In Vivo. 1995;9:55-7.
50.Galetic I, Andjelkovic M, Meier R, Brodbeck D, Park J, Hemmings BA. Mechanism of protein kinase B activation by insulin/insulin-like growth factor-1 revealed by specific inhibitors of phosphoinositide 3-kinase--significance for diabetes and cancer. Pharmacol Ther. 1999;82:409-25.
51.Garofalo RS, Orena SJ, Rafidi K, Torchia AJ, Stock JL, Hildebrandt AL, Coskran T, Black SC, Brees DJ, Wicks JR, McNeish JD, Coleman KG. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta. J Clin Invest. 2003;112:197-208.
52.Ge TF, Law PY, Wong HY, Ho YY. Gatifloxacin affects GLUT1 gene expression and disturbs glucose homeostasis in vitro. Eur J Pharmacol. 2007;573:70-4.
53.Giorgetti S, Ballotti R, Kowalski-Chauvel A, Tartare S, Van Obberghen E. The insulin and insulin-like growth factor-I receptor substrate IRS-1 associates with and activates phosphatidylinositol 3-kinase in vitro. J Biol Chem. 1993;268;7358-64.
54.Go P, Chung CH. Adjuvant PSK immunotherapy in patients with carcinoma of the nasopharynx. J Int Med Res. 1989;17:141–9.
55.Gómez-Valadés AG, Vidal-Alabró A, Molas M, Boada J, Bermúdez J, Bartrons R, Perales JC. Overcoming diabetes-induced hyperglycemia through inhibition of hepatic phosphoenolpyruvate carboxykinase (GTP) with RNAi. Mol Ther. 2006;13:401-10.
56.Gomperts BD, Kramer IM, Tatham PER. (2nd ed.) 2003. Signal Transduction.In: Phosphoinositide 3-kinases, protein kinase B and signalling through the insulin receptor, pp.308, Massachusetts. USA.
57.Gould GW, Thomas HM, Jess TJ, Bell GI. Expression of human glucose transporters in Xenopus oocytes: kinetic characterization and substrate specificities of the erythrocyte, liver, and brain isoforms. Biochemistry. 1991;30:5139-45.
58.Grant MH, Duthie SJ, Gray AG, Burke MD. Mixed function oxidase and UDP-glucuronyltransferase activities in the human Hep G2 hepatoma cell line. Biochem Pharmacol. 1988;37:4111-6.
59.Guerciolini R. Mode of action of orlistat. Int J Obes. 1997;2:S12-S23.
60.Guo W, Huang N, Cai J, Xie WS, Hamilton JA. Fatty acid transport and metabolism in HepG2 cells. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2006;290:528-534.
61.Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT--a major therapeutic target. Biochim Biophys Acta. 2004;11;1697:3-16.
62.Hanson RW, Reshef L. Glyceroneogenesis revisited. Biochimie. 2003;85:1199-205.
63.Hardie DG, Carling D. The AMP-activated protein kinase--fuel gauge of the mammalian cell? Eur J Biochem. 1997;246:259-73.
64.Hardie DG. The AMP-activated protein kinase pathway--new players upstream and downstream. J Cell Sci. 2004;117:5479-87.
65.Hardie, DG. Minireview. The AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology. 2003;144:5179–5183.
66.Harhaji Lj, Mijatović S, Maksimović-Ivanić D, Stojanović I, Momcilović M, Maksimović V, et al. Anti-tumor effect of Coriolus versicolor methanol extract against mouse B16 melanoma cells: in vitro and in vivo study. Food Chem Toxicol. 2008;46:1825-33.
67.Hatorpe V. Clinical pharmacokinetics and pharmacodynamics of repaglinide.Clin Pharmacokinet. 2002;41:471-83.
68.Hayakawa K, Mitsuhashi N, Saito Y, Takahashi M, Katano S, Shiojima K, et al. Effect of krestin (PSK) as adjuvant treatment on the prognosis after radical radiotherapy in patients with non-small cell lung cancer. Anticancer Res. 1993;13:1815–20.
69.Ho CY, Kim CF, Leung KN, Fung KP, Tse TF, Chan H, Lau CB. Differential anti-tumor activity of coriolus versicolor (Yunzhi) extract through p53- and/or Bcl-2-dependent apoptotic pathway in human breast cancer cells. Cancer Biol Ther. 2005;4:638-44.
70.Ho CY, Lau CB, Kim CF, Leung KN, Fung KP, Tse TF, Chan HH, Chow MS. Differential effect of Coriolus versicolor (Yunzhi) extract on cytokine production by murine lymphocytes in vitro. Int. Immunopharmacol. 2004;15:49–1557
71.Ho JC, Konerding MA, Gaumann A, Groth M, Liu W.K. Fungal polysaccharopeptide inhibits tumor angiogenesis and tumor growth in mice. Life Sci. 2004;75:1343–1356.
72.Holmes BF, Kurth-Kraczek EJ, Winder WW. Chronic activation of 5’-AMPactivated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J Appl Physiol 1999;87:1990-5.
73.Horike N, Sakoda H, Kushiyama A, Ono H, Fujishiro M, Kamata H, Nishiyama K, Uchijima Y, Kurihara Y, Kurihara H, Asano T.AMP-activated protein kinase activation increases phosphorylation of glycogen synthase kinase 3beta and thereby reduces cAMP-responsive element transcriptional activity and phosphoenolpyruvate carboxykinase C gene expression in the liver. J Biol Chem. 2008;283:33902-10.
74.Hsieh TC, Kunicki J, Darzynkiewicz Z, Wu JM. Effects of extracts of Coriolus versicolor (I'm-Yunity) on cell-cycle progression and expression of interleukins-1 beta,-6, and -8 in promyelocytic HL-60 leukemic cells and mitogenically stimulated and nonstimulated human lymphocytes. J Altern Complement Med. 2002;8:591-602.
75.Hsieh TC, Wu JM. Cell growth and gene modulatory activities of Yunzhi (Windsor Wunxi) from mushroom Trametes versicolor in androgen-dependent and androgen-insensitive human prostate cancer cells. Int J Oncol. 2001;18:81–8.
76.Hsieh TC, Wu P, Park S, Wu JM. Induction of cell cycle changes and modulation of apoptogenic/anti-apoptotic and extracellular signaling regulatory protein expression by water extracts of I'm-Yunity (PSP). BMC Complement Altern Med. 2006;6:30.
77.Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem. 2005;280:29060-6.
78.Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA. 2002;287:360-72.
79.Jarvi AE, Karlstrom BE, Granfeldt YE, Bjorck IE, Asp NG, Vessby BO. Improved glycemic control and lipid profile and normalized fibrinolytic activity on a low-glycemic index diet in type 2 diabetic patients. Diabet Care. 1999; 22:10-18.
80.Javitt NB. Hep-G2 Cells as a Resource for Metabolic Studies -Lipoprotein, Cholesterol, and Bile-Acids. Faseb Journal. 1990;4:161-168.
81.Jiménez-Medina E, Berruguilla E, Romero I, Algarra I, Collado A, Garrido F, et al. The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis. BMC Cancer. 2008;24;8:78.
82.Jungermann K, Katz N. Functional specialization of different hepatocyte populations. Physiol Rev. 1989;69:708-64.
83.Kahn, B.B., Alquier, T., Carling, D., and Hardie, D.G.. AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005;1:15–25.
84.Kamtchouing P, Sokeng SD, Moundipa PF, Watcho P, Jatsa HB, Lontsi D. Protective role of Anacardium occidentale extract against streptozotocin-induced diabetes in rats. J Ethnopharmacol. 1998;62:95-9.
85.Kemp BE, Stapleton D, Campbell DJ, Chen ZP, Murthy S, Walter M, Gupta A, Adams JJ, Katsis F, van Denderen B, Jennings IG, Iseli T, Michell BJ, Witters LA AMP-activated protein kinase, super metabolic regulator. Biochem Soc Trans. 2003;31:162-8.
86.Khatib OM. Guidelines for the prevention, management and care of diabetes mellitus. World Health Organization;2006.
87.Kidd PM. The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev. 2000;5:4–27.
88.Kiho T, Itahashi S, Sakushima M, Matsunaga T, Usui S, Ukai S, Mori H, Sakamoto H, Ishiguro Y. Polysaccharides in fungi. XXXVIII. Anti-diabetic activity and structural feature of a galactomannan elaborated by Pestalotiopsis species. Biol Pharm Bull. 1997;20:118-21.
89.Kiho T, Ookubo K, Usui S, Ukai S, Hirano K. Structural features and hypoglycemic activity of a polysaccharide (CS-F10) from the cultured mycelium of Cordyceps sinensis. Biol Pharm Bull. 1999;22:966-70.
90.Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002;137:25-33.
91.Klover PJ, Mooney RA. Hepatocytes: critical for glucose homeostasis. Int J Biochem Cell Biol. 2004;36:753-8.
92.Knasmüller S, Parzefall W, Sanyal R, Ecker S, Schwab C, Uhl M, Mersch-Sundermann V, Williamson G, Hietsch G, Langer T, Darroudi F, Natarajan AT. Use of metabolically competent human hepatoma cells for the detection of mutagens and antimutagens. Mutat Res. 1998;402:185-202.
93.Knowles BB, Howe CC, Aden DP. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science 1980;209: 497–499.
94.Kodama Y, Kano T, Tamada R, Kumashiro R, Okamura T, Inokuchi K. Combined effect of prophylactic lymphadenectomy and long term combination chemotherapy for curatively resected carcinoma of the stomach. Jpn J Surg. 1982;12:244–8.
95.Kohn AD, Barthel A, Kovacina KS, Boge A, Wallach B, Summers SA, Birnbaum MJ, Scott PH, Lawrence JC Jr, Roth RA. Construction and characterization of a conditionally active version of the serine/threonine kinase Akt. J Biol Chem. 1998;273:11937-43.
96.Kratochvil CJ, Heiligenstein JH, Dittmann R, Spencer TJ, Biederman J, Wernicke J, Newcorn JH, Casat C, Milton D, Michelson D. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry. 2002;41:776-84.
97.Krssak M, Brehm A, Bernroider E, Anderwald C, Nowotny P, Dalla Man C, Cobelli C, Cline GW, Shulman GI, Waldhäusl W, Roden M. Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes. Diabetes. 2004;53:3048-56.
98.Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW. 5' AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes. 1999;48:1667-71.
99.Lau CB, Ho CY, Kim CF, Leung KN, Fung KP, Tse TF, et al. Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis. Life Sci. 2004;75:797-808.
100.Lavan BE, Fantin VR, Chang ET, Lane WS, Keller SR, Lienhard GE. A novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family. J Biol Chem. 1997;272:21403-7.
101.Lavan BE, Lane WS, Lienhard GE. The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate family. J Biol Chem. 1997;272:11439-43
102.Lebovitz HE. Alpha-glucosidase inhibitors. Endocrinol Metab Clin North Am. 1997;26:539-51.
103.Lee CL, Sit WH, Jiang PP, So IW, Wan JM. Polysaccharopeptide mimics ciclosporin-mediated Th1/Th2 cytokine balance for suppression of activated human T cell proliferation by MAPKp38 and STAT5 pathways. J Pharm Pharmacol. 2008;60:1491-9.
104.Leighton B, Atkinson A, Coghlan MP. Small molecule glucokinase activators as novel anti-diabetic agents. Biochem Soc Trans. 2005;33(Pt 2):371-4.
105.Li X, Bijur GN, Jope RS. Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar Disord. 2002;4:137-44.
106.Lin CL, Lin JK. Epigallocatechin gallate (EGCG) attenuates high glucose-induced insulin signaling blockade in human hepG2 hepatoma cells. Mol Nutr Food Res. 2008;52:930-9.
107.Lin FY, Lai YK, Yu HC, Chen NY, Chang CY, Lo HC, et al. Effects of Lycium barbarum extract on production and immunomodulatory activity of the extracellular polysaccharopeptides from submerged fermentation culture of Coriolus versicolor. Food Chem 2008;110:446-53.
108.Liu JX, Zhou JY, Liu TF, Phase III clinical trial for the Yun Zhi polysacchride (PSP) capsules. In: Yang, Q.Y. (Ed.), Advanced Research in PSP 1999. The Hong Kong Association for Health Care Limited, Hong Kong, pp. 1999. 295–303.
109.Liu Z, Barrett EJ, Dalkin AC, Zwart AD, Chou JY. Effect of acute diabetes on rat hepatic glucose-6-phosphatase activity and its messenger RNA level. Biochem Biophys Res Commun. 1994;205:680-6.
110.Lloyd PG, Hardin CD, Sturek M. Examining glucose transport in single vascular smooth muscle cells with a fluorescent glucose analog. Physiol Res. 1999;48:401-10.
111.Lo HC, Hsu TH, Chen CY. Submerged culture mycelium and broth of Grifola frondosa improve glycemic responses in diabetic rats. Am J Chin Med. 2008;36:265-85.
112.Lo HC, Tsai FA, Wasser SP, Yang JG, Huang BM. Effects of ingested fruiting bodies, submerged culture biomass, and acidic polysaccharide glucuronoxylomannan of Tremella mesenterica Retz.:Fr. on glycemic responses in normal and diabetic rats. Life Sci. 2006;78:1957-66.
113.Lo HC, Tu ST, Lin KC, Lin SC. The anti-hyperglycemic activity of the fruiting body of Cordyceps in diabetic rats induced by nicotinamide and streptozotocin. Life Sci. 2004;74:2897-908.
114.Lo S, Russell JC, Taylor AW. Determination of glycogen in small tissue samples. J Appl Physiol. 1970;28:234-6.
115.Lochhead PA, Salt IP, Walker KS, Hardie DG, Sutherland C. 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. 2000;49:896–903.
116.Maffucci T, Brancaccio A, Piccolo E, Stein RC, Falasca M. Insulin induces phosphatidylinositol-3-phosphate formation through TC10 activation. EMBO J. 2003;22:4178-89.
117.Mallon L, Broman J-E, Hetta J. High incidence of diabetes in men with sleep complaints or short sleep duration: a 12-year follow-up study of a middleaged population. Diabetes Care 2005;28:2762–7.
118.Maruyama S, Akasaka T, Yamada K, Tachibana H. Protein-bound polysaccharide-K (PSK) directly enhanced IgM production in the human B cell line BALL-1.Biomed Pharmacother. 2009;63:409-12.
119.Matschinsky FM, Zelent B, Doliba NM, Kaestner KH, Vanderkooi JM, Grimsby J, Berthel SJ, Sarabu R. Research and development of glucokinase activators for diabetes therapy: theoretical and practical aspects. Handb Exp Pharmacol. 2011;(203):357-401.
120.Matschinsky FM. Glucokinase as glucose sensor and metabolic signal generator in pancreatic beta-cells and hepatocytes. Diabetes. 1990;39:647-52.
121.McLeod JF. Clinical pharmacokinetics of nateglinide. Clin Pharmacokinet. 2004;43:97-120.
122.Meier R, Hemmings BA. Regulation of protein kinase B. J Recept Signal Transduct Res. 1999;19:121-8.
123.Merrill GF, Kurth EJ, Hardie DG, Winder WW. AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol. 1997;273:E1107-12.
124.Meshkani R, Adeli K. Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Clin Biochem. 2009;42:1331-46.
125.Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell. 2000;6:87-97.
126.Mitomi T, Tsuchiya S, Iijima N, Aso K, Suzuki K, Nishiyama K, et al. Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. The Cooperative Study Group of Surgical Adjuvant Immunochemotherapy for Cancer of Colon and Rectum (Kanagawa). Dis Colon Rectum. 1992;35:123–30.
127.Monma Y, Kawana T, Shimizu F. In vitro inactivation of herpes simplex virus by a biological response modifier, PSK. Antiviral Res. 1997;35:131-8.
128.Morimoto T, Ogawa M, Orita K, Sugimachi K, Toge T, Dohi K, et al. Postoperative adjuvant randomised trial comparing chemoendocrine therapy, chemotherapy and immunotherapy for patients with stage II breast cancer: 5-year results from the Nishinihon Cooperative Study Group of Adjuvant Chemoendocrine Therapy for Breast Cancer (ACETBC) of Japan. Eur J Cancer 1996;32A:235-42.
129.Myers MG Jr, Backer JM, Sun XJ, Shoelson S, Hu P, Schlessinger J, Yoakim M, Schaffhausen B, White MF. IRS-1 activates phosphatidylinositol 38-kinase by associating with src homology 2 domains of p85. Proc. Natl Acad. Sci. 1992;89: 10350–10354.
130.Nakajima K, Yamauchi K, Shigematsu S, Ikeo S, Komatsu M, Aizawa T, Hashizume K. Selective attenuation of metabolic branch of insulin receptor down-signaling by high glucose in a hepatoma cell line, HepG2 cells. J Biol Chem. 2000;275:20880-6.
131.Nakazato H, Koike A, Saji S, Ogawa N, Sakamoto J: Efficacyof immunochemotherapyas adjuvant treatment after curative resection of gastric cancer. Lancet 1994;343:1122-6.
132.Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003. Circulation. 2003;108:2941-8.
133.Newgard CB, Brady MJ, O'Doherty RM, Saltiel AR.Organizing glucose disposal: emerging roles of the glycogen targeting subunits of protein phosphatase-1. Diabetes. 2000 ;49:1967-77.
134.Ng T.B. A review of research on the protein-bound polysaccharide (polysaccharopeptide, PSP) from the mushroom Coriolus versicolor (Basidiomycetes: Polyporaceae). Gen. Pharmacol. 1998;30:1–4.
135.Ng TB, Chan WY. Polysaccharopeptide from the mushroom Coriolus versicolor possesses analgesic activity but does not produce adverse effects on female reproductive or embryonic development in mice. Gen Pharmacol. 1997;29:269-73.
136.NHS Highland Diabetes Managed Clinical Network [Internet]. Available from: http://www.diabetes-highland.scot.nhs.uk/Guidelines/02Diagnosis/ogtt.pdf.
137.Nield L, Summerbell CD, Hooper L, Whittaker V, Moore H. Dietary advice for the prevention of type 2 diabetes mellitus in adults. Cochrane Database Syst Rev. 2008;16:CD005102.
138.Nordlie RC, Foster JD, Lange AJ. Regulation of glucose production by the liver. Annu Rev Nutr. 1999;19:379-406.
139.Ogoshi K, Satou H, Isono K, Mitomi T, Endoh M, Sugita M. Possible predictive markers of immunotherapy in esophageal cancer: retrospective analysis of a randomized study. Cancer Invest. 1995;13:363–9.
140.Olson AL, Pessin JE. Structure, function, and regulation of the mammalian facilitative glucose transporter gene family. Annu Rev Nutr. 1996;16:235-56.
141.O'Neil RG, Wu L, Mullani N. Uptake of a fluorescent deoxyglucose analog (2-NBDG) in tumor cells. Mol Imaging Biol. 2005;7:388-92.
142.Ooi VE, Liu F. Immunomodulation and anti-cancer activity of polysaccharide-protein complexes. Curr Med Chem. 2000;7:715–29.
143.Pang ZJ, Chen Y, Zhou M, Wan J. Effect of polysaccharide krestin on glutathione peroxidase gene expression in mouse peritoneal macrophages. Br J Biomed Sci. 2000;57:130-6.
144.Patti ME, Kahn CR. The insulin receptor—a critical link in glucose homeostasis and insulin action. J. Basic Clin. Physiol. Pharmacol. 1998;9:89–109.
145.Pessin JE, Bell GI. Mammalian facilitative glucose transporter family: structure and molecular regulation. Annu Rev Physiol. 1992;54:911-30.
146.Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med. 2006;119:10S–6S.
147.Pilkis SJ, Granner DK. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annual Review of Physiology. 1992;54:885–909.
148.Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, Shelton KD, Lindner J, Cherrington AD, Magnuson MA. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. J Biol Chem. 1999;274:305-15.
149.Qian ZM, Xu MF, Tang PL. Polysaccharide peptide (PSP) restores immunosuppression induced by cyclophosphamide in rats. Am J Chin Med. 1997;25: 27–35.
150.Quinn PG, Yeagley D.Insulin regulation of PEPCK gene expression: a model for rapid and reversible modulation. Curr Drug Targets Immune Endocr Metabol Disord. 2005;5:423-37.
REFERENCES
151.Robinson MJ, Cobb MH. Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997;9:180-6.
152.Sakamoto K, McCarthy A, Smith D, Green KA, Grahame Hardie D, Ashworth A, Alessi DR. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction. EMBO J. 2005;24:1810-20.
153.Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414:799-806.
154.Sassa S, Sugita O, Galbraith RA, Kappas A. Drug metabolism by the human hepatoma cell, Hep G2. Biochem Biophys Res Commun. 1987;143:52-7.
155.Scheepers A, Joost HG, Schurmann A. The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function. JPEN J Parenter Enteral Nutr. 2004;28:364-71.
156.Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett. 2003;546:108-12.
157.Schmoll D, Walker KS, Alessi DR, Grempler R, Burchell A, Guo S, Walther R, Unterman TG. Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity. J Biol Chem. 2000;275:36324-33.
158.Sciacchitano S, Taylor SI. Cloning, tissue expression, and chromosomal localization of the mouse IRS-3 gene. Endocrinology. 1997;138:4931-40.
159.Shaw RJ, Lamia KA, Vasquez D, Koo S.H, Bardeesy N, Depinho, RA, Montminy M, Cantley, LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310:1642–1646.
160.Shepherd PR, Withers DJ, Siddle K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J. 1998;333;471-90.
161.Shepherd PR, Withers DJ, Siddle K: Phosphoinositide 3-kinase: the key switch mechanism in insulin signaling. Biochem J 1998;333:471– 490.
162.Shrago E, Lardy HA, Nordlie RC, Foster DO. Metabolic and hormonal control of phosphoenolpyruvate carboxykinase and malic enzyme in rat liver. J Biol Chem. 1963;238:3188-92.
163.Sigal RJ, Kenny GP, Boulé NG, Wells GA, Prud'homme D, Fortier M, e. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Ann Intern Med. 2007;147:357-69.
164.Standaert ML, Galloway L, Karnam P, Bandyopadhyay G, Moscat J, Farese RV. Protein kinase C-z as a downstream effector of phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes. Potential role in glucose transport. J. Biol. Chem. 1997;272:30075–30082.
165.Standaert ML, Sajan MP, Miura A, Kanoh Y, Chen HC, Farese RV Jr, Farese RV. Insulin-induced activation of atypical protein kinase C, but not protein kinase B, is maintained in diabetic (ob/ob and Goto-Kakizaki) liver. J Biol Chem. 2004;279:24929–24934.
166.Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA, Kemp BE. Mammalian AMP-activated protein kinase subfamily. Biol Chem. 1996;271:611-4.
167.Steyn NP, Mann J, Bennett PH, Temple N, Zimmet P, Tuomilehto J, et al. Diet, nutrition and prevention of type 2 diabetes. Public Health Nutr. 2004;7:147–65
168.Sullivan JE, Brocklehurst KJ, Marley AE, Carey F, Carling D, Beri RK. Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett. 1994;353:33-6.
169.Sun XJ, Wang LM, Zhang Y, Yenush L, Myers MG Jr, Glasheen E, Lane WS, Pierce JH, White MF. Role of IRS-2 in insulin and cytokine signaling. Nature. 1995;377:173-7.
170.Takata M, Ogawa W, Kitamura T, Hino Y, Kuroda S, Kotani K, Klip A, Gingras AC, Sonenberg N, Kasuga M. Requirement for Akt (protein kinase B) in insulin-induced activation of glycogen synthase and phosphorylation of 4E-BP1 (PHAS-1). J Biol Chem. 1999;274:20611-8.
171.Taniguchi CM, Ueki K, Kahn R. Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J Clin Invest. 2005;115:718-27.
172.Tappy L, Dussoix P, Iynedjian P, Henry S, Schneiter P, Zahnd G, Jéquier E, Philippe J. Abnormal regulation of hepatic glucose output in maturity-onset diabetes of the young caused by a specific mutation of the glucokinase gene. Diabetes. 1997;46:204-8.
173.Thirone AC, Huang C, Klip A. Tissue-specific roles of IRS proteins in insulin signaling and glucose transport. Trends Endocrinol Metab. 2006;17:72-8.
174.Tiedge M, Richter T, Lenzen S. Importance of cysteine residues for the stability and catalytic activity of human pancreatic beta cell glucokinase. Arch Biochem Biophys. 2000;375:251-60.
175.Toker A, Cantley LC. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature. 1997;387:673-6.
176.Tsang KW, Lam CL, Yan C, Mak JC, Ooi GC, Ho JC, et al. Coriolus versicolor polysaccharide peptide slows progression of advanced non-small cell lung cancer. Respir Med. 2003;97:618-24.
177.Tsukagoshi S, Hashimoto Y, Fujii G, Kobayashi H, Nomoto K, Orita K.Krestin (PSK). Cancer Treat Rev. 1984;11:131-55.
178.UK HealthCare.edu [Internet]. Kentucky: University of Kentucky; [updated 2008 May 26; cited 2011 Jan 6]. Available from: http://ukhealthcare.uky.edu/content/content.asp?pageid=P00353
179.Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli IM, Dull TJ, Gray A, Coussens L, Liao Y-C, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM, Ramachandran J: Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature. 1985;313:756 –761.
180.Varma S, Lal BK, Zheng R, Breslin JW, Saito S, Pappas PJ, Hobson RW 2nd, Durán WN. Hyperglycemia alters PI3k and Akt signaling and leads to endothelial cell proliferative dysfunction. Am J Physiol Heart Circ Physiol. 2005;289;H1744-51.
181.Velho G, Robert JJ. Maturity-onset diabetes of the young (MODY): genetic and clinical characteristics. Horm Res. 2002;57:29-33.
182.Viana AY, Sakoda H, Anai M, Fujishiro M, Ono H, Kushiyama A, Fukushima Y, Sato Y, Oshida Y, Uchijima Y, Kurihara H, Asano T. Role of hepatic AMPK activation in glucose metabolism and dexamethasone-induced regulation of AMPK expression. Diabetes Res Clin Pract. 2006;73:135-42.
183.Vogel HG, editor. Drug Discovery and Evaluation: Pharmacological Assays. 3rd ed. New York: Springer Verlag; 2008.
184.Wang HX, NG TB, Liu WK, Ooi VE, Chang ST. Polysaccharide-peptide complexes from the cultured mycelia of the mushroom Coriolus versicolor and their culture medium activate mouse lymphocytes and macrophages. Int J Biochem Cell Biol. 1996;28:601-7.
185.Wang HX, Ng TB, Liu WK, Ooi VE, Chang ST..Polysaccharide-peptide complexes from the cultured mycelia of the mushroom Coriolus versicolor and their culture medium activate mouse lymphocytes and macrophages. Int J Biochem Cell Biol. 1996;28:601–7.
186.Wei WS, Tan JQ, Guo F, Ghen HS, Zhou ZY, Zhang ZH, Gui L. Effects of Coriolus versicolor polysaccharides on superoxide dismutase activities in mice. Zhongguo Yao Li Xue Bao. 1996;17:174-8.
187.White MF, Maron R, Kahn CR. Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells. Nature. 1985;14-20;318:183-6.
188.Wild S, Roglic G, Green A, Sicree R, King H. Global Prevalence of Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27: 1047-53.
189.Winder WW, Hardie DG..Inactivation of acetyl-CoA carboxylase and activation of AMPactivated protein kinase in muscle during exercise. Am. J. Physiol. Endocrinol. Metab. 1996;270:E299–E304.
190.Winder WW, Wilson HA, Hardie DG, Rasmussen BB, Hutber CA, Call GB, Clayton RD, Conley LM, Yoon S, Zhou B. Phosphorylation of rat muscle acetyl-CoA carboxylase by AMP-activated protein kinase and protein kinase A.J Appl Physiol. 1997;82:219-25.
191.Wolever TM, Jenkins DJ, Vuksan V, Jenkins AL, Buckley GC, Wong GS et al. Beneficial effect of a low glycaemic index diet in type 2 diabetes. Diabet Med. 1992; 9:451-458.
192.Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005;2:21-33.
193.World Diabetes Day.org [Internet]. [cited 2011 Jan 5]. Available from: http://www.hmc.org.qa/DiabetesDay/speaker.htm
194.World Health Organization.int [Internet]. [cited 2011 Jan 5]. Available from: http://www.who.int/mediacentre/factsheets/fs312/en/
195.Xie P, Liu ML, Gu YP, Lu J, Xu X, Zeng WM, Song HP. Oestrogen improves glucose metabolism and insulin signal transduction in HepG2 cells. Clin Exp Pharmacol Physiol. 2003;30:643-8.
196.Yamashita R, Saito T, Satoh S, Aoki K, Kaburagi Y, Sekihara H. Effects of dehydroepiandrosterone on gluconeogenic enzymes and glucose uptake in human hepatoma cell line, HepG2. Endocr J. 2005;52:727-33.
197.Yang BK, Kim GN, Jeong YT, Jeong H, Mehta P, Song CH. Hypoglycemic Effects of Exo-biopolymers Produced by Five Different Medicinal Mushrooms in STZ-induced Diabetic Rats. Mycobiology. 2008;36:45-9.
198.Yoshioka K, Takahashi H, Homma T, Saito M, Oh KB, Nemoto Y, Matsuoka H. A novel fluorescent derivative of glucose applicable to the assessment of glucose uptake activity of Escherichia coli. Biochim Biophys Acta. 1996;1289:5-9.
199.Yuan C, Mei Z, Liu S, Yi L. PSK protects macrophages from lipoperoxide accumulation and foam cell formation caused by oxidatively modified low-density lipoprotein. Atherosclerosis. 1996;124:171-81.
200.Zdychová J, Komers R. Emerging role of Akt kinase/protein kinase B signaling in pathophysiology of diabetes and its complications. Physiol Res. 2005;54:1-16.
201.Zeller WP, The SM, Sweet M, Goto M, Gottschalk ME, Hurley RM, Filkins JP, Hofmann C Altered glucose transporter mRNA abundance in a rat model of endotoxic shock. Biochem Biophys Res Commun. 1991;176:535-40.
202.Zeng F, Hon CC, Sit WH, Chow KY, Hui RK, Law IK, et al. Molecular characterization of Coriolus versicolor PSP-induced apoptosis in human promyelotic leukemic HL-60 cells using cDNA microarray. Int J Oncol. 2005;27:513-23.
203.Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y, Royo I, Vilella D, Díez MT, Pelaez F, Ruby C, Kendall RL, Mao X, Griffin P, Calaycay J, Zierath JR, Heck JV, Smith RG, Moller DE. Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. Science. 1999;284:974-7.
204.Zhang H, Wei J, Xue R, Wu JD, Zhao W, Wang ZZ, Wang SK, Zhou ZX, Song DQ, Wang YM, Pan HN, Kong WJ, Jiang JD.Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism. 2010;59:285-92.
205.Zhang WY, Lee JJ, Kim IS, Kim Y, Park JS, Myung CS. 7-o-methylaromadendrin stimulates glucose uptake and improves insulin resistance in vitro. Biol Pharm Bull. 2010;33:1494-9.
206.Zhang X, Liang W, Mao Y, Li H, Yang Y, Tan H. Hepatic glucokinase activity is the primary defect in alloxan-induced diabetes of mice. Biomed Pharmacother. 2009;63:180-6.
207.Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167-74.
208.Zhou M, Chen Y, Liu S, Ding Z, Pang Z, Wan J. Oxidative and malondialdehyde modification of low-density lipoprotein: a comparative study of binding and degradation by macrophages and endothelial cells. Br J Biomed Sci. 1998;55:192-8.
209.Zimmerman BR. Sulfonylureas. Endocrinol Metab Clin North Am. 1997;26:511-21.
210.Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001;414:782–7
211.Zjawiony JK. Biologically active compounds from Aphylloporales (polypore) fungi. J Nat Prod. 2004;67:300–10.
212.Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A. 2002;99:15983-7.
213.Zou C, Wang Y, Shen Z. 2-NBDG as a fluorescent indicator for direct glucose uptake measurement. J Biochem Biophys Methods. 2005;64:207-15
214.Zou W, Li ZY, Li CL, Cui ZC. Protein kinase B and its role in the signal transduction pathway mediated by phosphoinositide 3-kinase. Sheng Li Ke Xue Jin Zhan. 2000;31:120-4.