1. Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2013 年 4 月 11 日 8:30-8:55 ８階 医局 Moran A, Bundy B, Becker DJ, Dimeglio LA, Gitelman SE, Goland R, Greenbaum CJ, Herold KC, Marks JB, Raskin P, Sanda S, Schatz D, Wherrett DK, Wilson DM, Krischer JP, Skyler JS; for the Type 1 Diabetes TrialNet Canakinumab Study Group, Pickersgill L, de Koning E, Ziegler AG, Böehm B, Badenhoop K, Schloot N, Bak JF, Pozzilli P, Mauricio D, Donath MY, Castaño L, Wägner A, Lervang HH, Perrild H, Mandrup-Poulsen T; for the AIDA Study Group. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet. 2013 Apr 4. doi:pii: S0140-6736(13)60023-9. 10.1016/S0140-6736(13)60023-9. McMullan CJ, Schernhammer ES, Rimm EB, Hu FB, Forman JP. Melatonin secretion and the incidence of type 2 diabetes. JAMA. 2013 Apr 3;309(13):1388-96.

2. Diabetes Metab. Rev. 14, 3–29 (1998)

3. Dorota B. Schranz, Åke Lernmark Department of Medicine, University of Washington, Seattle, U.S.A.

4. The strongest susceptibility to Type 1 diabetes is with HLA-DQ alleles. Caucasian susceptibility is more strongly associated with DQA1* 0501– DQB1*0201/DQA1*0301–DQB1*0302 than with DRB1*03/DRB1*04. DRB1*03 and DRB1* 04 are in strong linkage disequilibrium with class I molecules B8 and B15, respectively. Conversely, the DRB1*04 allele is in linkage disequilibrium with the DQB1*0302 allele. Negative association with Type 1 diabetes was observed for DQA1*0102– DQB1*0602–DRB1*1501 genotype. The DQB1*0602 allele is probably immunodominant over susceptibility DQB1 alleles and may be protective even among islet cell autoantibody positive first-degree relatives to patients with Type 1 diabetes. Among people with the DQA1*0501–DQB1*0201/DQA1*0301– DQB1*0302 genotype protection may be associated with the DRB1*0403 allele, while the DRB1*0401 allele is susceptible. This negative association may, however, not be detected in all populations. Also, the DQA1*0301–DQB1*0301 haplotype may be protective, in spite of the small sequence differences between this molecule and the susceptible DQA1*0301– DQB1*0302 molecule. The association of the DQ alleles with diabetes is correlated with amino acid residue on the  chain and amino acid residue on the  chain. However, these individual amino acids do not solely explain susceptibility or protection. Many individuals develop Type 1 diabetes despite the presence of Asp- 57 on the DQ  chain. The presence of negatively charged aspartic acid at position 57 of DQ  is associated with unique peptide binding capacity which may influence disease etiology, pathogenesis or both processes. Diabetes Metab. Rev. 14, 3–29 (1998)

5. Susceptibility genes for type 1 diabetes Major gene ： HLA(IDDM1)  -cell specificity ： INS(IDDM2) negative regulator ： CTLA4(IDDM12) SUMO4(IDDM5) PTPN22

6. JapaneseDRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) CaucasiansDRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4) HLA haplotypes associated with type 1 diabetes KoreanDRB1*0301-DQB1*0201 (DR3) DRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9)

7. JapaneseDRB1*0405-DQB1*0401 (DR4) DRB1*0901-DQB1*0303 (DR9) CaucasiansDRB1*0301-DQB1*0201 (DR3) DRB1*0401-DQB1*0302 (DR4) Very high risk genotype(Caucasians) DRB1*0301 /0401 (DR3/4) High risk genotypes for type 1 diabetes Very high risk genotype （ Japanese ） DRB1*0901 /0901 (DR9/9)

8. Association of INS-VNTR with type 1 diabetes -596 VNTR -23 HphI 4.1 kb region of IDDM2 Class IIIhaplotype Class III  protective Class Ihaplotype Class I ＋ susceptible TH INS IGF2 VNTR Type 1 diabetes susceptibility

9. Frequency of class I INS-VNTR tended to be higher in type 1 diabetes than in controls Controls CasesOdds ratio France 1 55%84%4.2 UK 2 59%76%2.2 Japan 3 94%99% 1 Lucassen et al.Nature Genet 4:305, 1993 2 Bennet et al.Nature Genet 9:284, 1995 3 Kawaguchi et al. BBRC 233:283, 1997

10. NATURE |VOL 423 | 29 MAY 2003 |www.nature.com/nature

11. Association of CTLA4 with autoimmune diseases (Caucasian populations) Odds ratio(95% CI) Graves’s disease1.51(1.31-1.75) Hashimoto thyroiditis1.45(1.17-1.80) Type 1 diabetes1.14(1.07-1.21) SNP: +6230G>A (rs3087243) Ueda H et al. Nature 2003

12. Arg620Trp (R620W) of PTPN22 was consistently reported to be associated with autoimmune diseases in Caucasian populations Odds ratio (95%CI) Type 1 diabetesN. American 1 1.83 (1.28-2.60) Italian 1 2.31 (0.93-5.82) UK 2 1.78 (1.54-2.06) Caucasian 3 (C/T)1.7(1.3-2.3) (T/T)3.4(1.3-8.9) Graves's disease 2 1.43 (1.17-1.76) RA 4 1.74 (1.27-2.38) SLE 5 (C/T)1.37 (1.07-1.75) (T/T)4.37 (1.98-9.65) 1 Nat Genet 36:337, 2004, 2 Diabetes 53:3020, 2004, 3 Diabetes 54:906, 2005 4 Am J Hum Genet 75:330, 2004, 5 Am J Hum Genet 75:504, 2004

13. estimated by EM algorithm （ Haploview v2.03 ） SUMO4 2176bp M55V MAP3K7IP2 Exon 7 Exon 6 438C>T -504A>GM55V438C>Tfrequency Haplotype AGAC49.6% Haplotype BAGT35.9% Haplotype CAAC14.4% -504A>G D’: 1.0 for single pair of SNPs SUMO4 SNPs identified by re-sequencing in Japanese

14. 0.50.71.01.21.52.03.0 95%CI （ Caucasian) 95%CI （ Asian) Total (n=28,151) Meta-analysis Asian, Guo et al. 2004* Korean, Park et al. 2005 Japanese, Noso et al. 2005 Korean, Noso et al. 2005 Asian (n=4720) Caucasian, Guo et al. 2004 UK, Smyth et al. 2005* Canadian, Paterson et al. 2005 Caucasian (n=23,431) Summary OR:1.29 [95%CI: 1.15- 1.44] p = 4.0 x 10 -7 Summary OR:1.02 (95%CI: 0.98- 1.07) p = 0.25 (NS) SUMO4 M55V is associated with type 1 diabetes in Asians, but not in Caucasians. Noso S et al. Poster #098 Diabetes ( in press)

15. Reasons for apparent differences in susceptibility alleles for type 1 diabetes between Japanese and Caucasian populations Association Reasons for apparent Caucasian Japanese difference HLAyesyes allele difference INSyesyes allele frequency CTLA4yesrestricted clinical subtype PTPN22yes unknown allele absent SUMO4? yes heterogeneity?

16. From the Indiana University School of Medicine, Indianapolis (M.D.P., H.R.); the Benaroya Research Institute, Seattle (C.J.G.); the George Washington University Biostatistics Center, Rockville, MD (H.K.-S., P.F.M., J.M.L.); the University of Pittsburgh, Pittsburgh (D.J.B.); the University of California, San Francisco, San Francisco (S.E.G.); Columbia University, New York (R.G.); University of Colorado Barbara Davis Center for Childhood Diabetes, Aurora (P.A.G.); the University of Miami Diabetes Research Institute, Miami ( J.B.M., J.S.S.); the University of Minnesota, Minneapolis (A.M.M.); the University of Texas Southwestern Medical School, Dallas (P.R.); the University of Florida, Gainesville (D.A.S.); Hospital for Sick Children, University of Toronto, Toronto (D.W.); and Stanford University, Stanford, CA (D.M.W.). N Engl J Med 2009;361:2143-52 2009 年 12 月 24 日

18. The immunopathogenesis of type 1 diabetes mellitus is associated with T- lymphocyte autoimmunity. However, there is growing evidence that B lymphocytes play a role in many T-lymphocyte–mediated diseases. It is possible to achieve selective depletion of B lymphocytes with rituximab, an anti-CD20 monoclonal antibody. This phase 2 study evaluated the role of B-lymphocyte depletion in patients with type 1 diabetes.

19. Linköping University, Linköping, Sweden (J.L., R.C.); Diamyd Medical, Pittsburgh (D.K.); University Medical Center– University Children’s Hospital, Faculty of Medicine, Ljubljana, Slovenia (T.B.); Hospital de Cruces– University of Basque Country, Barakaldo, Bizkaia, Spain (L.C.); the Department of Paediatrics, Leicester Royal Infirmary, Leicester, United Kingdom ( J.G.); the Diabetes Center for Children and Adolescents, Kinderkrankenhaus auf der Bult, Hannover, Germany (O.K.); Children’s Hospital, University of Helsinki, and Helsinki University Central Hospital, Helsinki (T.O.); University Campus Bio-Medico, Rome (P.P.); Hôpital Necker– Enfants Malades, Université René Descartes Paris 5, Paris ( J.-J.R); Stichting Diabeter, Rotterdam, the Netherlands (H.J.V.); and the Department of Medicine, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle ( J.P.). N Engl J Med 2012;366:433-42. 2012 年 2 月 1616 日

20. Figure 2. C-Peptide and GAD65 Autoantibody Levels, According to Study Group. Mean changes in stimulated C-peptide levels are shown in Panel A, and median GAD65 autoantibody levels are shown in Panel B. In Panel A, the I bars indicate standard deviations. In Panel B, the two-sided P value is shown for the four-dose regimen and the two-dose regimen combined as compared with placebo. To convert values for C peptide to nanograms per milliliter, divide by 0.333.

21. Conclusions Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period. (Funded by Diamyd Medical and the Swedish Child Diabetes Foundation; ClinicalTrials.gov number, NCT00723411.)

22. University of Minnesota, Minneapolis, MN, USA (Prof A Moran MD); University of South Florida, Tampa, FL, USA (B Bundy PhD, Prof J P Krischer PhD); University of Pittsburgh, Pittsburgh, PA, USA (Prof D J Becker MBBCh); Indiana University School of Medicine, Indianapolis, IN, USA (L A DiMeglio MD); University of California San Francisco, San Francisco, CA, USA (Prof S E Gitelman MD); Columbia University, New York, NY, USA (Prof R Goland MD); Benaroya Research Institute, Seattle, WA, USA (C J Greenbaum MD, S Sanda MD); Yale University, New Haven, CT, USA (Prof K C Herold MD); University of Miami Diabetes Research Institute, Miami, FL, USA (Prof J B Marks MD); University of Texas Southwestern Medical School, Dallas, TX, USA (Prof P Raskin MD); University of Florida, Gainesville, FL, USA (Prof D Schatz MD); Hospital for Sick Children, University of Toronto, Toronto, ON, Canada (D K Wherrett MD); Stanford University, Stanford, CA, USA (Prof D M Wilson MD); Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA (Prof J S Skyler MD); Steno Diabetes Center, Gentofte, Denmark (L Pickersgill MD); Leiden University Medical Center, Leiden, Netherlands (Prof E de Koning MD); Institute of Diabetes Research, Helmholtz Zentrum Munchen, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universitat, Munchen, Germany (Prof A-G Ziegler MD); Ulm University, Ulm, Germany (Prof B Boehm MD); University of Frankfurt-am-Main, Frankfurt, Germany (Prof K Badenhoop MD); German Diabetes Center, Dusseldorf, Germany (N Schloot MD); Hospitalsenheden Vest, Aarhus University Hospital, Aarhus, Denmark (J F Bak MD); Unit for Diabetes Prevention, University Campus Bio-Medico, Rome, Italy (Prof P Pozzilli MD); Hospital Arnau de Vilanova, Lleida, Spain (D Mauricio MD); University Hospital Basel, Basel, Switzerland (Prof M Y Donath MD); Hospital Universitario Cruces, Bilbao, Spain (Prof L Castano MD); Complejo Hospitalario Universitario Insular Materno- Infantil, Las Palmas de Gran Canaria, Spain (A Wagner MD); Aalborg Hospital, Aalborg, Denmark (H H Lervang MD); Bispebjerg Hospital, Copenhagen, Denmark (H Perrild MD); and Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark (Prof T Mandrup-Poulsen MD) http://dx.doi.org/10.1016/S0140-6736(13)60023-9

23. Background Innate immunity contributes to the pathogenesis of autoimmune diseases, such as type 1 diabetes, but until now no randomised, controlled trials of blockade of the key innate immune mediator interleukin- 1 have been done. We aimed to assess whether canakinumab, a human monoclonal anti-interleukin-1 antibody, or anakinra, a human interleukin-1 receptor antagonist, improved β-cell function in recent-onset type 1 diabetes.

24. Methods We did two randomised, placebo-controlled trials in two groups of patients with recent-onset type 1 diabetes and mixed-meal-tolerance- test-stimulated C peptide of at least 0 ・ 2 nM(0.72ng/ml). Patients in the canakinumab trial were aged 6–45 years and those in the anakinra trial were aged 18–35 years. Patients in the canakinumab trial were enrolled at 12 sites in the USA and Canada and those in the anakinra trial were enrolled at 14 sites across Europe. Participants were randomly assigned by computer-generated blocked randomisation to subcutaneous injection of either 2 mg/kg (maximum 300 mg) canakinumab or placebo monthly for 12 months or 100 mg anakinra or placebo daily for 9 months. Participants and carers were masked to treatment assignment. The primary endpoint was baseline-adjusted 2-h area under curve C-peptide response to the mixed meal tolerance test at 12 months (canakinumab trial) and 9 months (anakinra trial). Analyses were by intention to treat. These studies are registered with ClinicalTrials.gov, numbers NCT00947427 and NCT00711503, and EudraCT number 2007-007146-34. C-pep 3617 g/mol

26. Table 1: Baseline demographics and laboratory characteristics of participants in the canakinumab trial Data are number (%) or mean (SD), unless otherwise specified. Some percentages do not total 100 because of rounding. *Excludes two participants in the canakinumab group who did not report ethnic origin. †Recorded on case report form. ‡Excludes one participant in the placebo group who did not have a genetic test.

33. Findings Patients were enrolled in the canakinumab trial between Nov 12, 2010, and April 11, 2011, and in the anakinra trial between Jan 26, 2009, and May 25, 2011. 69 patients were randomly assigned to canakinumab (n=47) or placebo (n=22) monthly for 12 months and 69 were randomly assigned to anakinra (n=35) or placebo (n=34) daily for 9 months. No interim analyses were done. 45 canakinumab- treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0 ・ 01 nmol/L (95% CI –0 ・ 11 to 0 ・ 14; p=0 ・ 86), and between the anakinra and the placebo groups at 9 months was 0 ・ 02 nmol/L (–0 ・ 09 to 0 ・ 15; p=0 ・ 71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p=0 ・ 018), which was mainly because of a higher number of injection site reactions in the anakinra group.

34. Interpretation Canakinumab and anakinra were safe but were not effective as single immunomodulatory drugs in recent- onset type 1 diabetes. Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders. Funding National Institutes of Health and Juvenile Diabetes Research Foundation..

35. Message 1 型糖尿病（ DM ）患者 117 人を対象に、カ ナキヌマブと抗インターロイキン 1 （ IL- 1 ）薬 anakinra の免疫調節効果を 2 つのプ ラセボ対照試験で検証。混合食負荷試験で の C ペプチドの曲線下面積 2 時間値のプラセ ボ群との差は、カナキヌマブ群 12 カ月時で 0.01nmol/L （ P ＝ 0.86 ）、 anakinra 群 9 カ月時で 0.02nmol/L （ P ＝ 0.71 ）だっ た。

37. Melatonin Listeni/ ˌ m ɛ lə ˈ to ʊ n ɪ n/, also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes. In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions. Many biological effects of melatonin are produced through activation of melatonin receptors, while others are due to its role as a pervasive and powerful antioxidant, with a particular role in the protection of nuclear and mitochondrial DNA. Products containing melatonin have been available over-the-counter in the United States since the mid-1990s. In many other countries, the sale of this neurohormone is not permitted or requires a prescription. Melatonin http://en.wikipedia.org/wiki/Melatonin Ramelteon A new class of sleep agents that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus (SCN), instead of binding to GABA A receptors, such as with drugs like zolpidem, eszopiclone, and zaleplon.

38. http://www.channing.harvard.edu/nhs/ Nurses’ Health Study (original cohort) Nurses’ Health Study II Nurses’ Health Study III

39. Renal Division (Drs McMullan and Forman), Channing Division of Network Medicine (Drs McMullan, Schernhammer, Rimm, Hu, and Forman), Department of Nutrition, Harvard School of Public Health (Drs Rimm and Hu), and Department of Medicine, Brigham and Women’s Hospital (Drs McMullan, Schernhammer, Rimm, Hu, and Forman), Boston, Massachusetts. JAMA. 2013;309(13):1388-1396

40. Importance Loss-of-function mutations in the melatonin receptor are associated with insulin resistance and type 2 diabetes. Additionally, in a cross-sectional analysis of persons without diabetes, lower nocturnal melatonin secretion was associated with increased insulin resistance. Objective To study the association between melatonin secretion and the risk of developing type 2 diabetes.

41. Design, Setting, and Participants Case-control study nested within the Nurses’ Health Study cohort. Among participants without diabetes who provided urine and blood samples at baseline in 2000, we identified 370 women who developed type 2 diabetes from 2000-2012 and matched 370 controls using risk-set sampling. Main Outcome Measures Associations between melatonin secretion at baseline and incidence of type 2 diabetes were evaluated with multivariable conditional logistic regression controlling for demographic characteristics, lifestyle habits, measures of sleep quality, and biomarkers of inflammation and endothelial dysfunction.

47. Results The median urinary ratios of 6-sulfatoxymelatonin to creatinine were 28.2 ng/mg (5%-95% range, 5.5-84.2 ng/mg) among cases and 36.3 ng/mg (5%-95% range, 6.9- 110.8 ng/mg) among controls. Women with lower ratios of 6-sulfatoxymelatonin to creatinine had increased risk of diabetes (multivariable odds ratio, 1.48 [95% CI, 1.11-1.98] per unit decrease in the estimated log ratio of 6- sulfatoxymelatonin to creatinine). Compared with women in the highest ratio category of 6-sulfatoxymelatonin to creatinine, those in the lowest category had a multivariable odds ratio of 2.17 (95% CI, 1.18-3.98) of developing type 2 diabetes. Women in the highest category of melatonin secretion had an estimated diabetes incidence rate of 4.27 cases/ 1000 person-years compared with 9.27 cases/1000 person-years in the lowest category.

48. Conclusions and Relevance Lower melatonin secretion was independently associated with a higher risk of developing type 2 diabetes. Further research is warranted to assess if melatonin secretion is a modifiable risk factor for diabetes within the general population.

49. Message 看護師健康調査から 2 型糖尿病（ DM ）女性 370 人と対照 370 人を対象に、メラトニン 分泌と DM の関連を症例対照研究で検討。 ベースライン時の尿中 6- スルファトキシメ ラトニン／クレアチニン比低値で DM 発症 リスクが増加した。 1000 人年当たりの糖 尿病発症率は 、メラトニン分泌最大区分で 4.27 、最小区分で 9.27 と推定された。