糖尿病是全球性流行的慢性疾病，根據統計目前全世界之糖尿病盛行率約為5％，患者將近1.94億人。近十幾年來糖尿病患者人數更是急速增加，預計西元2010年之糖尿病患者將增加到2.2億人，而西元2025年則將增加到近3.3億人。糖尿病主要可分為兩類，第一型糖尿病(type 1 diabetes mellitus, T1DM)主要是器官特異性自體免疫疾病，而第二型糖尿病(type 2 diabetes mellitus, T2DM)的主要特徵則為胰島素阻抗性(insulin resistance)。本論文分為二大部分探討糖尿病，第一部分分析T1DM病人自體抗體表現的情形，第二部分探討T2DM與Th2細胞激素基因多型性以及胰島素啟動子因子-1(insulin promoter factor-1, IPF-1)基因點突變之間的關聯性。麩胺酸脫羧酶(glutamic acid decarboxylase, GAD)、第二型去氧核糖核酸拓撲異構酶(type II topoisomerase, TopII)以及類酥胺酸磷酸酶分子(protein tyrosine phosphatase [PTP]-like molecules, IA-2)是引發T1DM胰島β細胞自體免疫反應的主要自體抗原。為了解自體抗體和台灣本土T1DM的關係，本論文分析GAD自體抗體(GADA)、TopII自體抗體(TopIIA)以及IA-2自體抗體(IA-2A)等抗體的盛行率，以及這些抗體和病人臨床表徵的關聯性。實驗結果顯示T1DM患者IA-2A、GADA與TopIIA的盛行率分別是23.6%、47.1%與55.2%。GADA 的盛行率與患者平均發病年齡有顯著相關性(GADA+患者10.82 ± 0.76 歲，GADA－患者8.38 ± 0.77歲， p=0.026)；青春期發病患者的GADA 盛行率較高，而且胰島β細胞分泌胰島素的殘餘功能也較佳。此外，本論文利用聚合酶連鎖反應與限制片段長度多型性技術分別分析T2DM患者之Th2細胞激素介白質素-6(interleukin-6, IL-6)、介白質素-10(IL-10)之基因多型性與IPF-1基因C18R、Q59L、D76N 與 R197H等四種基因點突變情形，並探討他們與T2DM患者臨床表徵之間的相關性。結果顯示所有參與本研究的T2DM病人以及對照組個體的IL-6 C-174G均為同合子G對偶基因型，而IL-10啟動子基因型的分佈在T2DM病人與對照組之間雖然無統計差異，但是較多T2DM病人帶有高分泌能力之IL-10 -592＊C對偶基因(34.28%, p＝0.027)。另外，實驗結果並未發現台灣T2DM病人之IPF-1基因的C18R、Q59L、D76N 與 R197H有突變發生。整體而言，由於台灣本土T1DM患者TopIIA與GADA盛行率比IA-2A高，而且在病程中持續出現的時間也比較長，因此本論文認為TopIIA與GADA比較適合作為預測台灣本土T1DM之發病、糖尿病的診斷與病情追蹤的標記。雖然白種人之IL-6與IL-10基因多型性與T2DM發病有關，但上述相關性並不適用於台灣本土之糖尿病患者，不過較多之台灣T2DM病人帶有IL-10分泌能力較高的-592＊C對偶基因，此外，實驗結果也證明IPF-1基因突變則並非是引發台灣本土T2DM的重要因子。綜合上述研究結果，本論文最重要之發現為不論是T1DM或T2DM，台灣本土之糖尿病患都有與西方人不同之獨特基因型與免疫反應。本論文希望能提供並建立台灣本土糖尿病免疫反應與基因型等之相關資訊與資料，期以更深入瞭解糖尿病之發病機制以提供研發預防與治療策略之參考資訊。

Diabetes mellitus (DM) is an important global chronic disease, and with increased incidence during the last decade. Currently approximately 5% of worldwide population, which corresponds to 194 million, suffer from diabetes. It is estimated that 220 and 330 million people worldwide, respectively, will have diabetes in year 2010 and 2025. DM is mainly classified into 2 types: Type 1 diabetes mellitus (T1DM) is a chronic disease associated with the selectively destruction of pancreatic β-cells, and type 2 diabetes mellitus (T2DM) is a disease characterized by insulin resistance. This study is devided into 2 sections: The first one focused on the investigation of autoantibody prevalences in T1DM patients, and the second, association between Th2 cytokine gene polymorphisms and insulin promoter factor-1 (IPF-1) point mutations with T2DM. In the first section, the prevalence of autoantibodies against glutamic acid decarboxylase (GADA), type II topoisomerase (TopIIA) and protein tyrosine phosphatase (PTP)-like molecules (IA-2A) in Taiwanese T1DM patients were investigated to explore the association of autoantibodies with T1DM. Our results showed that prevalence of IA-2A, GADA and TopIIA in our patients was 23.6%, 47.1% and 55.2%, respectively. Presence of GADA was correlated with the mean age of onset (10.82 ± 0.76 vs. 8.38 ± 0.77 years for GADA+ and GADA- patients, p=0.026). Patients with adolescent onset have higher GADA prevalence and better residual β-cell functions. In the second section, genetic polymorphisms of Th2 cell-secreted cytokine genes, including interleukin-6 (IL-6, C-174G) and Interleukin-10 (IL-10, A-592C and T-819C), and IPF-1 point mutations (C18R, Q59L, D76N and R197H) were examined to explore putative correlation of the above gene variations with T2DM. All of our T2DM patients and non-diabetic healthy individuals carried homologous G alleles at IL-6 -174 position. Though no significant association was detected between either IL-10 A-592C (p=0.088) or T-819C (p=0.160) polymorphisms and T2DM, significant more T2DM subjects carried -592*C (34.27%, p=0.027) which were associated with high levels of IL-10 production. Nevertheless, no association was found between the above polymorphisms with biochemical markers for T2DM. No IPF-1 C18R, Q59L, D76N and R197H mutations were found among Taiwanese patients with common late-onset T2DM. In summary, our results suggested that TopIIA and GADA might be better markers for prediction of diabetic onset, disease diagnosis and follow-up among Taiwanese T1DM patients because of their higher prevalence and persistence. Besides, the conclusion that IL-6 and IL-10 genetic polymorphisms are correlated with T2DM in Caucasian study might not be applied to Taiwanese T2DM, neither is the conclusion in regard to IPF-1 mutations. Nevertheless, our study demonstrated that significantly more T2DM patients carried the alleles with higher IL-10 secretion ability. This study revealed that Taiwanese DM patients show certain unique characteristics of immune responses and genotypes, compared to Caucasian subjects. Hopefully, this study can provide information and establish data bank regarding immune responses and genotypes of Taiwanese DM patients for further understanding of diabetic pathogenesis and development of strategies for diabetic prevention and treatment.

壹、中文摘要..............................................1
貳、英文摘要..............................................3
參、縮寫檢索表............................................5
肆、第一部分 糖尿病基本簡介...............................7
伍、第二部分 第一型糖尿病自體抗體之盛行率的研究(摘要)....13
第一節 緒論(Introduction)..........................14
第二節 材料與方法(Materials and Methods)...........19
第三節 實驗結果(Results)...........................23
第四節 討論(Discussion)............................26
陸、第三部分 第二型糖尿病與細胞激素基因多型性之間的關聯性
第一章 緒論(Introduction)...........................30
第二章 介白質素-6基因多型性與第二型糖尿病之關聯性
的研究(摘要).................................33
第一節 緒論(Introduction)..........................34
第二節 材料與方法(Materials and Methods)...........38
第三節 實驗結果(Results)...........................42
第四節 討論(Discussion)............................43
第三章 介白質素-10基因多型性與第二型糖尿病之關聯性
的研究(摘要).................................46
第一節 緒論(Introduction)..........................47
第二節 材料與方法(Materials and Methods)...........50
第三節 實驗結果(Results)...........................53
第四節 討論(Discussion)............................55
第四章 人類胰島素啟動子因子-1(insulin promoter
factor-1, IPF-1)基因點突變與第二型糖尿病之關
聯性的研究(摘要).............................58
第一節 緒論(Introduction)..........................59
第二節 材料與方法(Materials and Methods)...........63
第三節 實驗結果(Results)...........................66
第四節 討論(Discussion)............................67
柒、結語.................................................69
捌、參考文獻.............................................71
玖、圖與表...............................................90
(一)圖：Figure 1.- Figure 9. .....................90-98
(二)表：Table 1. - Table 8. ....................99-106
拾、附表................................................107
附表一 - 附表八.................................107-117
拾壹、相關論文發表......................................118

1.Slack JM. Developmental biology of the pancreas. Development 121（1995）1569-1580.
2.Lu M, Miller C, Habener JF. Functional regions of the homeodomain protein IDX-1 required for transactivation of the rat somatostatin gene. Endocrinology 37（1996）2959-2967.
3.Wang H, Maechler P, Ritz-Laser B, Hagenfeldt KA, Ishihara H, Philippe J, Wollheim CB. Pdx1 level defines pancreatic gene expression pattern and cell lineage differentiation. J Biol Chem. 276（2001）25279-25286.
4.Schuster DP, Duvuuri V. Diabetes mellitus. Clin Podiatr Med Surg. 19（2002）79-107.
5.Bate, KL, Jerums G: 3: Preventing complications of diabetes. The Medical journal of Australia. 179（2003）498-503.
6.Chelliah A, Burge MR: Hypoglycaemia in elderly patients with diabetes mellitus: causes and strategies for prevention. Drugs Aging 21（2004）511-530.
7.Pinero-Pilona A, Raskin P. Idiopathic Type 1 diabetes. J Diabetes Complications 15（2001）328-335.
8.The American Diabetes Association: Report of Expert Committer on the diagnosis and Classification of diabetes mellitus. Diabetes Care 20（1997）1183-1197.
9.American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 27（2004）s5-s10.
10.Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H, Ilanne- Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344（2001）1343-1350.
11.Kelly MA, Rayner ML, Mijovic CH, Barnett AH. Molecular aspects of type I diabetes. Mol Pathol 56（2003）1-10.
12.American Diabetes Association: Standards of Medical Care in Diabetes. Diabetes Care 29（2006）S4-S42.
13.Karvonen M. Tuomilehto J. Libman I. LaPorte R. Group of the World Health Organization DIAMOND Project Group: A review of the recent epidemiological data on the worldwide incidence of type 1 (insulin-dependent) diabetes mellitus. Diabetologia 36 (1993) 883-892.
14.Green A, Gale E.A.M, Patterson C. The EURODIAB ACE Study Group: Incidence of childhood-onset insulin-dependent diabetes mellitus: the EURODIAB ACE Study. Lancet 339 (1992) 905-909.
15.Chuang LM. Lin CY. Wu HP. Tsai WY. Tai TY. Lin BJ. Anti-GAD65 autoantibody in Taiwanese patients with insulin-dependent diabetes mellitus: effect of HLA on anti-GAD65 positivity and clinical characteristics. Clin. Endocrinol. 47 (1997) 455-461.
16.Devendra D. Liu E. Eisenbarth GS. Type 1 diabetes: recent developments. British Medical Journal 328（2004）750-754.
17.Atkinson MA, George S Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 358（2001）221-229.
18.Lo FS, Yang MH, Chang LY, Ou YC, Van YH. Clinical and laboratory features of type 1 diabetic children at initial diagnosis. Acta Pediatr Tw 45（2004）218-223.
19.Thai A, Eisenbarth GS. Natural history of IDDM. Diabetes Rev. 1 (1993) 1-14.
20.Endl J, Rosinger S, Schwarz B, Friendrich SO, Rothe G, Karges W, Schlosser M, Eiermann T, Schendel DJ, Boehm BO. Coexpression of CD25 and OX40（CD134） receptors delineates autoreactive T-cell in type 1 diabetes. Diabetes 55（2006）50-60.
21.Shoenfeld Y, Gershwin M.E., Meroni P.L. eds. Autoantibodies 2nd ed. Krueger C, Stocker W, and Schlosser M. 2007, pp.369-378.
22.Park Y, Eisenbarth GS. Chapter 34 The nature history of autoimmunity in type 1A diabetes mellitus. In LeRoith D, Taylor SI, Olefsky JM, eds. Diabetes mellitus-A fundamental and clinical text. 2nd ed. Lippincott Williams & Wilkins: Philadelphia. 2000, pp.347-363.
23.Shoenfeld Y, Gershwin M.E., Meroni P.L. eds. Autoantibodies 2nd ed. Pietropaolo M, Sperling M.A. 2007, pp.379-387.
24.Bottazzo GF, Florin-Christensen A, Doniach D. Islet cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2 (1974) 1279-1283.
25.Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, Camilli PD. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347 (1990) 151-156.
26.Jones DB, N.R. NR, Duff GW. Heat-shock protein 65 as a B-cell antigen of insulin-dependent diabetes. Lancet 336 (1990) 583-585.
27.Lu J, Li Q, Xie H, Chen ZJ, Borovitskaya AE, Maclaren NK, Notkins AL, Lan MS. Identification of a second transmembrane protein tyrosine phosphatase, IA-2β , as an autoantigen in insulin-dependent diabetes mellitus: precursor of the 37kDa tryptic fragment. Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 2307-2311.
28.Lan MS, Wasserfall C, Maclaren NK, Notkins AL. IA-2, a transmembrane protein of the protein tyrosine phosphatase family, is a major autoantigen in insulin-dependent diabetes mellitus. Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 6367-6370.
29.Chang YH, Hwang J, Shang HF, Tsai ST. Characterization of human DNA topoisomerase II as an autoantigen recognized by patients with IDDM. Diabetes 45 (1996) 408-414.
30.Pietropaolo M, Peakman M, Pietropaolo SL, ZanoneMM, Foley TPJr, Becker DJ, Trucco M. Combined analysis of GAD65 and ICA512(IA-2) autoantibodies in organ and non-organ-specific autoimmune diseases confers high specificity for insulin-dependent diabetes mellitus. J. Autoimmun. 11 (1998) 1-10.
31.Wiest-Ladenburger U, Hartmann R, Hartmann U, Berling K, Böhm BO, Richter W. Combined analysis and single-step detection for GAD65 and IA2 autoantibodies in IDDM can replace the histochemical islet cell antibody test. Diabetes 46 (1997) 565-571.
32.Hawa M, Rowe R, Lan MS, Notkins AL, Pozzilli P, Christie MR, Leslie RD. Value of antibodies to islet protein tyrosine phosphatase-like molecule in predicting type 1 diabetes. Diabetes 48 (1997) 1270-1275.
33.Hagopian WA, Sanjeevi CB, Kockum I, Landin-Olssen M, Karlsen AE, Sundkvist G, Dahlquist G, Palmer J, Lernmark A. Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children. J. Clin. Invest. 95 (1995) 1505-1511.
34.Velloso LA, Kampe O, Hallberg A, Christmanson L, Betsholtz C, Karlson GA. Demonstration of Gad-65 as the main immunogenic isoform of glutamate decarboxylase in type I diabetes and determination of autoantibodies using a radioligand produced by Eukaryotic expression. J. Clin. Invest. 91 (1993) 2084-2090.
35.Atkinson MA, Kaufman DL, Newman D, Tobin AJ, Maclaren NK. Islet cell cytoplasmic autoantibody reactivity to glutamate decarboxylase in insulin-dependent diabetes. J. Clin. Invest. 91 (1993) 350-356.
36.Zimmet PZ, Rowley MJ, Mackay IR, Knowles WJ, Chen QY, Chapman LH, Serjeantson SW. The ethnic distribution of antibodies to glutamic acid decarboxylase: presence and levels of insulin-dependent diabetes mellitus in Europid and Asian subjects. J. Diabetes Compli. 7 (1993) 1-7.
37.Tuomi T, Zimmet P, Rowley MJ, Min HK, Vichayanrat A, Lee HK, Rhee BD, Vannasaeng S, Humphrey AR, Mackay IR. Differing frequency of autoantibodies to glutamic acid decarboxylase among Koreans, Thais, and Australians with diabetes mellitus. Clin. Immunol. Immunopathol. 74 (1995) 202-206.
38.Thai AC, Ng WY, Loke KY, Lee WRW, Lui KF, Cheah JS. Anti GAD antibodies in Chinese patients with youth and adult-onset IDDM and NIDDM. Diabetologia 40 (1997) 1425-1430.
39.Rattarasam C, Aguilar-Diosdado M, Soonthornpun S, Patarakijvanich N, Jaruratanasirikul S. GAD antibodies in IDDM in Thailand. Diabetes Care 19 (1996) 674-685.
40.Sanjeevi CB, Shtauvere A, Ramachandran A, Snehalatha C, Falorni A. Prevalence of GAD65 autoantibodies in South Indian patients with insulin-dependent diabetes mellitus, and in their parents. Idab. Nutr. Metab. 10 (1997) 60-66.
41.Ozawa Y, Kasuga A, Marayuma T, Kitamura Y, Amemiya S, Ishihara Y, Suzuki R, Saruta T. Antibodies to the 37,000-Mr tryptic fragment of islet antigen were detected in Japanese insulin dependent diabetes mellitus patients. Endocr. J. 43 (1996) 615-620.
42.Akamine H, Komiya I, Shimabokuro T, Asawa T, Tanaka H, Yagi N, Taira T, Nagata K, Arakaki K, Wakugami T, Takasu N, Powell MJ, Furmaniak J, Smith BR. High prevalence of GAD65 (and IA-2) antibodies in Japanese IDDM patients by a new immunoprecipitation assay based on recombinant human GAD65. Diabetic Med. 14 (1997) 778-784.
43.Verge CF, Gianani R, Kawasaki E, Yu L, Pietropaolo M, Jackson RA, Chase HP, Eisenbarth GS. Prediction of type 1 diabetes in first-degree relatives using a combination of insulin, GAD and ICA512bdc/IA-2 autoantibodies. Diabetes 45 (1996) 926-933.
44.Bingley PJ, Bonifacio E, Williams AJK, Genovese S, Bottazzo GF, Gale EAM. Prediction of IDDM in the general population: strategies based on combination of autoantibody markers. Diabetes 46 (1997) 1701-1710.
45.Seissler J, Morgenthaler NG, Achenback P, Lampeter EF, Glawe D, Payton M, Christie M, Scherbaum WA. Combined screening for autoantibodies to IA-2 and antibodies to glutamic acid decarboxylase in first degree relatives of patients with IDDM. Diabetologia 39 (1996) 1351-1356.
46.Medici F, Hawa MI, Giorgini A, Panelo A, Solfelix CM, Leslie RD, Pozzilli P. Antibodies to GAD65 and a tyrosine phosphatase-like molecule IA-2ic in Filipino type 1 diabetic patients. Diabetes Care 22 (1999) 1458-1461.
47.Kasuga A, Ozawa Y, Maruyama T, Ishihara T, Amemiya S, Saruta T. Autoantibody against IA-2 improves the test sensitivity for insulin-dependent diabetes mellitus in Japanese patients of child onset. Endocr. J. 44 (1997) 485-491.
48.Leslie RDG, Atkinson MA, Notkins AL. Autoantigens IA-2 and GAD in Type 1 (insulin-dependent) diabetes. Diabetologia 42 (1999) 3-14.
49.Nishino M, Ikegami H, Kawaguchi Y, Fujisawa T, Kawabata Y, Shintani M, Ono M, Horiki M, Kawasaki E. Polymorphism in gene for islet autoantigen, IA-2, and type 1 diabetes in Japanese subjects. Human Immunol. 62 (2001) 518-522.
50.Hermitte L, Atlan-Gepner C, Mattei C, Dufayet D, Jannot MF, Christofilis MA, Nervi S, Vialettes B. Diverging evolution of anti-GAD and anti-IA-2 antibodies in long-standing diabetes mellitus as a function of age at onset: no association with complications. Diabet. Med. 15 (1998) 586-591.
51.Grubin CE, Daniels T, Toivola B, Landin-Olsson M, Hagopian WA, Li L, Karlsen AE, Boel E, Michelsen B, Lernmark A. A novel radioligand binding assay to determine diagnostic accuracy of isoform-specific glutamic acid decarboxylase antibodies in childhood IDDM. Diabetologia 37 (1994) 344-350.
52.Shiau MY, Tsai ST, Hwang J, Wu CY, Chang YH. Relationship between autoantibodies against glutamic acid decarboxylase, thyroglobulin/thyroid microsome and DNA topoisomerase II in the clinical manifestation of patients with type 1 diabetes mellitus in Taiwan. Eur. J. Endocrinol. 142 (2000) 577-585.
53.Zhang B, Lan MS, Notkins AL. Autoantibodies to IA-2 in IDDM: location of major antigenic determinants. Diabetes 46 (1997) 40-43.
54.Nakamoto S, Kasuga A, Maruyama T, Ozawa Y, Amemiya S, Saruta T. Age of onset, not type of onset, affects the positivity and evanescence of IA-2 antibody. Diabetes Res. Clin. Practice 50 (2000) 147-152.
55.Yokota I, Ito M, Matsuda J, Shima K, Naito E, Kuroda Y. Comparison of GAD and ICA512/IA-2 antibodies at and after the onset of IDDM. Diabetes Care 21 (1998) 49-52.
56.Ohta M, Ohta K, Obayashi H, Nakamura N, Shigeta H, Nakano K, Hasegawa G, Fukui M, Kitagawa, Nishimura YM, Itoh N. Clinical evaluation of a radioimmunoprecipitation assay for IA-2 antibody and comparison of GAD antibody in type 1 diabetes mellitus. Autoimmunity 32 (2000) 79-88.
57.Jun HS, Khil LY, Yoon JW. Role of glutamic acid decarboxylase in the pathogenesis of type 1 diabetes. Cell Mol Life Sci 59（2002）1892-1901.
58.Seissler J, deSonnaville JJ, Norgenthaler NG, Stenbrenner H, Glawe D, Khoo-Morgenthaler UT, Lan MS, Notkins AL, Heine RJ., Scherbaum WA. Immunological heterogeneity in type 1 diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive diseases. Diabetologia 41 (1998) 891-897.
59.Kaufman DL, Clare-Salzler M, Tian J, Forsthuber T, Ting GS, Robinson P, Atkinson MA, Sercarz EE, Tobin AJ, Lehmann PV. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366 (1993) 69-72.
60.Tisch R, Yang XD, Singer SM, Liblau RS, Fugger L, McDevitt HO. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366 (1993) 72-75.
61.Trembleau S, Penna G, Gregori S, Magistrelli G, Isacchi A, Adorini L. Early Th1 response in unprimed nonobese diabetic mice to the tyrosine phosphatase-like insulinoma-associated protein 2, an autoantigen in type 1 diabetes. J. Immunol. 165 (2000) 6748-6755.
62.Kaufman DL, Houser CR, Tobin AJ. Two forms of the gamma-aminobutyric acid synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J. Neurochem. 56 (1991) 720-723.
63.Honeyman MC, Stone NL, Harrison LC. T-cell epitopes in type 1 diabetes autoantigen tyrosine phosphatase IA-2: potential for mimicry with rotavirus and other environmental agents. Mol. Med. 4 (1998) 231-239.
64.Kallan AA, Roep BO, Arden SD, Jutton JC, deVries RRP. T-cell clones from newly diagnosed type 1 patients define novel B-cell antigens cross-reactive with neuroendocrine tissue. Autoimmunity 15 (1993) 73.
65.Leslie RD, Atkinson MA, Notkins AL. Autoantigens IA-2 and GAD in Type I (insulin-dependent) diabetes. Diabetologia 42 (1999) 3-14.
66.Pihoker C, Gilliam LK, Hampe CS, Lernmark A. Autoantibodies in diabetes. Diabetes 54（2005）S52-61.
67.Hansen BC. The metabolic syndrome-X. Ann N Y Acad Sci 892（1999）1-24.
68.Ahren B. Type 2 diabetes, insulin secretion and beta-cell mass. Curr Mol Med 5(2005) 75-86.
69.Jun HS and Yoon JW. Approaches for the cure of type 1 diabetes by cellular and genetherapy. Curr Gene Ther 5 (2005) 249-62.
70.Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 414（2001）782-787.
71.Caro JJ, Salas M, O''Brien JA, Ishak K, Sung J, Raggio G. Modeling the efficiency of reaching a target intermediate end point: a case study in type 2 diabetes in the United States. Value Health 7（2004）13-21.
72.Wei JN, Sung FC, Lin CC, Lin RS, Chiang CC, Chuang LM. National surveillance for type 2 diabetes mellitus in Taiwanese children. JAMA 290（2003）1345-1350.
73.Fagot-Campagna A, Pettitt DJ, Engelgau MM, Burrows NR, Geiss LS, Valdez R, Beckles GL, Saaddine J, Gregg EW, Williamson DF, Narayan KM. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. Journal of Pediatrics 136（2000）664-672.
74.Fagot-Campagna A. Emergence of type 2 diabetes mellitus in children: epidemiological evidence. Journal of Pediatric Endocrinology & Metabolism 13（2000）1395-1402.
75.Henry RR. Insulin resistance: from predisposing factor to therapeutic target in type 2 diabetes. Clin. Ther. 25（2003）B47-63.
76.Jermendy G. Is type-2 diabetes mellitus preventable. Orv. Hetil. 144（2003）1909-1917.
77.Shirai K. Obesity as the core of the metabolic syndrome and the management of coronary heart disease. Curr.Med. Res. Opin. 20（2004）295-304.
78.Walder K, Segal D, Jowett J, Blangero J, Collier GR. Obesity and diabetes gene discovery approaches. Curr.Pharm. Des. 9（2003）1357-1372.
79.Hotamisligil GS and Shargill NS. Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259（1993）87-91.
80.Kern PA,. Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. Journal of Clinical Investigation. 95（1995）2111-2119.
81.Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T. Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. J. Clin. Endocrinol. Metab. 83（1998）2907-2910.
82.Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler. Thromb. Vasc. Biol. 19（1999）972-978.
83.Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J. Clin. Endocrinol. Metab. 82（1997）4196-4200.
84.Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and IL-6 with metabolic syndrome X. Diabetologia 40（1997）1286-1292.
85.Crook MA, Tutt P, Pickup JC. Elevated serum sialic acid concentration in NIDDM and its relationship to blood pressure and retinopathy. Diabetes Care 16（1993）57-60.
86.Zimmet P, Alberyi K. The changing face of macrovascular disease in non-insulin dependent diabetes mellitus in different culture: an epidemic in progress. Lancet 350（1997）S1-S4.
87.Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25（2004）4-7.
88.Schmidt MI, Duncan BB, Sharrett AR, Lindberg G., Savage PJ. Offenbacher S. Azambuja MI. Tracy RP. Heiss G. Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet. 353（1999）1649-1652.
89.Duncan BB, Schmidt MI, Pankow JS, Ballantyne CM, Couper D, Vigo A. Hoogeveen R. Folsom AR. Heiss G. Atherosclerosis Risk in Communities Study. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes. 52（2003）1799-1805.
90.Kubaszek A, Pihlajamaki J, Komarovski V, Lindi V, Lindstrom J, Eriksson J, Valle TT, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Tuomilehto J, Uusitupa M, Laakso M. Finnish Diabetes Prevention Study. Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study. Diabetes. 52（2003）1872-1876.
91.Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med. 128(1998) 127-137.
92.Orban Z, Remaley A, Sampson M, Trajanoski Z, Chrousos GP. The differential effect of food intake and ß-adrenergic stimulation on adipose derived hormones and cytokines in man. J Clin Endocrinol Metab. 84(1999) 2126-2133.
93.Fernandez-Real J-M, Broch M, Vendrell J, Richart C, Ricart W. Interleukin-6 gene polymorphism and lipid abnormalities in healthy subjects J Clin Endocrinol Metab. 85(2000) 1334-1339.
94.Monzillo LU, Hamdy O, Horton ES. Effect of lifestyle modification on adipokine levels in obese subjects with insulin resistance Obes Res. 11(2003) 1048-1054.
95.Pickup JC, Chusney GD, Thomas SM, Burt D. Plasma IL-6, tumour necrosis factorαand blood cytokine production in type 2 diabetes. Life Sci. 67（2000）291-300.
96.Eggesbø JB, Hjermann I, Lund PK, Joø GB, Øvstebø R, Kierulf P. LPS-induced release of IL-1 beta, IL-6, IL-8, TNF-alpha and sCD14 in whole blood and PBMC from persons with high or low levels of HDL-lipoprotein. Cytokine 6（1994）521-529.
97.Makino T, Noguchi Y, Yoshikawa T, Doi C, Nomura K. Circulating interleukin 6 concentrations and insulin resistance in patients with cancer. Br. J. Surg. 85（1998）1658-1662.
98.Fernández-Real JM, Broch M, Vendrell J, Gutierrez C, Casamitjana R, Pugeat M, Richart C, Ricart W. IL-6 Gene polymorphism and insulin sensitivity. Diabetes 49（2000）517-520.
99.Vozarova B, Fernández-Real J-M, Knoler WC, Gallart L, Hanson RL, Gruber JD, Ricart W, Vendrell J, Richart C, Tataranni PA, Wolford JK. The interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians. Hum. Genet. 112（2003）409-413.
100.Kubaszek A, Pihlajamäki J, Punnonen K, Karhapää P, Vauhkonen I, Laakso M. The C-174G promoter polymorphism of the IL-6 gene affects energy expenditure and insulin sensitivity. Diabetes 52（2003）558-561.
101.Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P. The effect of novel polymorphisms in the interleukin 6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J. Clin. Invest. 102（1998）1369-1376.
102.Georges JL, Loukaci V, Poirier O, Evans A, Luc G, Arveiler D, Ruidavets JB, Cambien F, Tiret L.. IL-6 gene polymorphisms and susceptibility to myocardial infarction: the ECTIM study. Etude Cas-Temoin de l''Infarctus du Myocarde. J. Mol. Med. 79（2001）300-305.
103.Villuendas G, San Millan JL, Sancho J, Escobar-Morreale HF. The -597 G-->A and -174 G-->C polymorphisms in the promoter of the IL-6 gene are associated with hyperandrogenism. J. Clin. Endocrinol. Metab. 87（2002）1134-1141.
104.Knowler WC, Pettitt DJ, Saad MF, Bennett PH. Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. Diabetes Metab. Rev. 6（1990）1-27.
105.Pankow JS, Folsom AR, Cushman M, Borecki IB, Hopkins PN, Eckfeldt JH, Tracy RP. Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study. Atherosclerosis 154（2001）681-689.
106.Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 170(1989) 2081-2095.
107.van Exel E, Gussekloo J, de Craen AJM, Frölich M, Bootsma-van der Wiel A, Westendorp RGJ. Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes. The Leiden 85-plus study. Diabetes 51（2002）1088-1092.
108.Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 147（1991）3815-3822.
109.De Waal Malefyt R, Abrams J, Bennett B, Figdor CG, DeVries JE. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 174（1991）1209-1220.
110.Del Prete G, DeCarli M, Almerigogna F, Giudizi MG, Biagiotti R, Romagnani S. Human IL-10 is produced by both type 1 helper (Th1) and type 2 helper (Th2) T cell clones and inhibits their antigen-specific proliferation and cytokine production. J Immunol. 150（1993）353-356.
111.Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendrotp RG, Huizinga TW. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci. U.S.A 95（1998）9465-9470.
112.Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology 30（1999）526-530.
113.Mok CC, Lanchbury JS, Chan DW, Lau CS. Interleukin-10 promoter polymorphisms in southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum. 41（1998）:1090-1095.
114.Lim S, Crawley E, Woo P, Barnes PJ. Haplotype associated with low interleukin-10 production in patients with severe asthma. Lancet 352（1998）113.
115.Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet. 24（1997）1-8.
116.Koch W, Kastrati A, Böttiger C, Mehilli J, von Beckerath N, Schömig A. Interleukin-10 and tumor necrosis factor gene polymorphisms and risk of coronary artery disease and myocardial infarction. Atherosclerosis 159（2001）137-144.
117.Tegoshi H, Hasegawa G, Obayashi H, Nakano K, Kitagawa Y, Fukui M, Matsuo S, Deguchi M, Ohta M, Nishimura M, Nakamura N, Yoshidawa T. Polymorphisms of interferon-γ gene CA-repeat and interleukin-10 promoter region (-592A/C) in Japanese type 1 diabetes. Hum Immunol. 63（2002）121-128.
118.Chang YH, Huang CN, Lee YL, Shiau MY. The C-174G promoter polymorphism of the IL-6 gene that affects insulin sensitivity in Caucasians is not involved in the pathogenesis of Taiwanese type 2 diabetes mellitus. Eur Cytokine Netw. 15（2004）117-119.
119.Shiau MY, Wu CY, Huang CN, Hu SW, Lin SJ, Chang YH. Analysis of TNF-αG-238A and G-308A promoter polymorphism in Taiwanese patient with type 2 diabetes mellitus. Tissue Antigens 61（2003）393-397.
120.Hattersley AT. Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity. Diabet Med. 15（1998）15-24.
121.Fajans SS. Scope and heterogeneous nature of MODY. Diabetes Care 13（1990）49-64.
122.Wang H, Hagenfeldt-Johansson K, Otten LA, Gauthier BR, Herrera PL, Wollheim CB. Experimental models of transcription factor-associated maturity-onset diabetes of the young. Diabetes 51（2002）S333-342.
123.Doria A, Plengvidhya N. Recent advances in the genetics of maturity-onset diabetes of the young and other forms of autosomal dominant diabetes. Curr Opin Endocrinol Diabetes 7（2000）203-210.
124.Shimomura H, Sanke T, Hanabusa T, Tsunoda K, Furuta H, Nanjo K. Nonsense mutation of Islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history. Diabetes 49（2000）1597-1600.
125.Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM, Boriraj VV, Chen X, Cox NJ, Oda Y, Yano H, Le Beau MM, Yamada S, Nishigori H, Takeda J, Fajans SS, Hattersley AT, Iwasaki N, Hansen T, Pedersen O, Polonsky KS, Bell GI, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384（1996）455-8.
126.Thomas H, Jaschkowitz K, Bulman M, Frayling TM, Mitchell SM, Roosen S, Lingott-Frieg A, Tack CJ, Ellard S, Ryffel GU, Hattersley AT. A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young. Hum Mol Genet. 10（2001）2089-2097.
127.Vionnet N, Stoffel M, Takeda J, Yasuda K, Bell GI, Zouali H, Lesage S, Velho G, Iris F, Passa P, et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 356（1992）721-722.
128.Watada H, Kajimoto Y, Umayahara Y, Matsuoka T, Kaneto H, Fujitani Y, Kamada T, Kawamori R, Yamasaki Y. The human glucokinase gene beta-cell-type promoter: an essential role of insulin promoter factor 1/PDX-1 in its activation in HIT-T15 cells. Diabetes 45（1996）1478-1488.
129.Wang H, Maechler P, Hagenfeldt KA, Wollheim CB. Dominant-negative suppression of HNF-1alpha function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic beta-cell line. EMBO J. 17（1998）6701-6713.
130.Stoffers DA, Ferrer J, Clarke WL, Habener JF. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat Genet. 17（1997）138-139.
131.Weng J, Macfarlane WM, Lehto M, Gu HF, Shepherd LM, Ivarsson SA, Wibell L, Smith T, Groop LC. Functional consequences of mutations in the MODY4 gene (IPF1) and coexistence with MODY3 mutations. Diabetologia 44（2001）249-258.
132.Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Iwamoto Y, Bell GI. Mutation in the hepatocyte nuclear factor-1[beta] gene (TCF2) associated with MODY. Nature Genet. 17（1997）384–385.
133.Tamimi R, Steingrimsson E, Copeland NG, Dyer-Montgomery K, Lee JE, Hernandez R, Jenkins NA, Tapscott SJ. The NEUROD gene maps to human chromosome 2q32 and mouse chromosome 2. Genomics 34（1996）418-421.
134.Malecki MT, Jhala US, Antonellis A, Fields L, Doria A, Orban T, Saad M, Warram JH, Montmiy M, Krolewski AS. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nature Genet. 23（1999）323-328.
135.Velho G, Robert JJ. Maturity-Onset Diabetes of the Young (MODY). Genetic and Clinical Characteristics. Horm Res. 57（2002）29-33.
136.Inoue H, Riggs AC, Tanizawa Y, Ueda K, Kuwano A, Liu L, Donis-Keller H, Permutt MA. Isolation, characterization, and chromosomal mapping of the human insulin promoter factor 1 (IPF-1) gene. Diabetes 45（1996）789-794.
137.Bonner-Weir S, Smith FE. Islet cell growth and the growth factors involved. Trends Endocrinol Metab. 5（1994）60-64.
138.Hung Hp, Tsai MJ. Transcription factors involved in pancreatic islet development. J Biomed Sci. 7（2000）27-34.
139.Kajimoto Y, Watada H, Matsuoka Ta. Suppression of transcription factor PDX-1/IPF1/ STF-1/ IDX-1 causes decrease in insulin mRNA in MIN6 cells. J Clin Invest. 100（1997）1840-1846.
140.Peshavaria M, Henderson E, Sharma A, Wright CV, Stein R. Functional characterization of the transactivation properties of the PDX-1 homeodomain protein. Mol Cell Biol. 17（1997）3987-3996.
141.Ohlsson H, Karlsson K, Edlund T. IPF1, a homeodomain-containing transactivator of the insulin gene. EMBO J. 12（1993）4251-4259.
142.Melloul D, Ben-Neriah Y, Cerasi E. Glucose modulates the binding of an islet-specific factor to a conserved sequence within the rat I and the human insulin promoters. Proc Natl Acad Sci. U.S.A 90（1993）3865-3869.
143.Macfarlane WM, Read ML, Gilligan M, Bujalska I, Docherty K. Glucose modulates the binding activity of the beta-cell transcription factor IUF1 in a phosphorylation-dependent manner. Biochem J. 303（1994）625-631.
144.Marshak S, Totary H, Cerasi E, Melloul D. Purification of the β-cell glucose-sensitive factor that transactivates the insulin gene differentially in normal and transformed islet cells. Proc Natl Acad Sci. U.S.A 93（1996）15057-15062.
145.Melloul D, Marshak S, Cerasi E. Regulation of pdx-1 gene expression. Diabetes 51（2002）S320-325.
146.Macfarlane WM, McKinnon CM, Felton-Edkins ZA, Cragg H, James RF, Docherty K. Glucose stimulates translocation of the homeodomain transcription factor PDX1 from the cytoplasm to the nucleus in pancreatic beta-cells. J Biol Chem. 274（1999） 1011-1016.
147.Stoffers DA, Zinkin NT, Stanojevic V, Clarke WL, Habener JF. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 15（1997）106-110.
148.Habener JF, Stoffers DA. A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus. Proc Assoc Am Physicians 110（1998）12-21.
149.Macfarlane WM, Frayling TM, Ellard S, Evans JC, Allen LI, Bulman MP, Ayres S, Shepherd M, Clark P, Millward A, Demaine A, Wilkin T, Docherty K, Hattersley AT. Missense mutations in the insulin promoter factor-1 gene predispose to type 2 diabetes. J Clin Invest. 104（1999）R33-39.
150.Hani EH, Stoffers DA, Chevre JC, Durand E, Stanojevic V, Dina C, Habener JF, Froguel P. Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus. J Clin Invest. 104（1999）R41-48.
151.Reis AF, Ye WZ, Dubois-Laforgue D, Bellanne-Chantelot C, Timsit J, Velho G. Mutations in the insulin promoter factor-1 gene in late-onset type 2 diabetes mellitus. Eur J Endocrinol. 143（2000）511-513.
152.Hansen L, Urioste S, Petersen HV, Jensen JN, Eiberg H, Barbetti F, Serup P, Hansen T, Pedersen O. Missense mutations in the human insulin promoter factor-1 gene and their relation to maturity-onset diabetes of the young and late-onset type 2 diabetes mellitus in Caucasians. J Clin Endocrinol Metab. 85（2000）1323-1326.
153.Hara M, Lindner TH, Paz VP, Wang X, Iwasaki N, Ogata M, Iwamoto Y, Bell GI. Mutations in the coding region of the insulin promoter factor 1 gene are not a common cause of maturity-onset diabetes of the young in Japanese subjects. Diabetes 47（1998）845-846.
154.Baier LJ, Permana PA, Traurig M, Dobberfuhl A, Wiedrich C, Sutherland J, Thuillez P, Luczy-Bachman G, Hara M, Horikawa Y, Hinokio Y, Hanson RL, Bogardus C. Mutations in the genes for hepatocyte nuclear factor (HNF)-1α, -4α, -1β, and -3β; the dimerization cofactor of HNF-1; and insulin promoter factor 1 are not common causes of early-onset type 2 diabetes in Pima Indians. Diabetes Care 23（2000）302-304.
155.Dutta S, Bonner-Weir S, Montminy M, Wright C. Regulatory factor linked to late-onset diabetes? Nature 392（1998）560.
156.Clocquet AR, Egan JM, Stoffers DA, Muller DC, Wideman L, Chin GA, Clarke WL, Hanks JB, Habener JF, Elahi D. Impaired insulin secretion and increased insulin sensitivity in familial maturity-onset diabetes of the young 4 (Insulin Promoter Factor 1 Gene). Diabetes 49（2000）1856-1864.