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Journal Club

Journal Club. Look AHEAD Research Group, Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013 Jul 11;369(2):145-54. doi : 10.1056/NEJMoa1212914.

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Journal Club

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  1. Journal Club Look AHEAD Research Group, Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013 Jul 11;369(2):145-54. doi: 10.1056/NEJMoa1212914. RönnT, Volkov P, Davegårdh C, Dayeh T, Hall E, Olsson AH, Nilsson E, Tornberg A, Dekker Nitert M, Eriksson KF, Jones HA, Groop L, Ling C. A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue. PLoS Genet. 2013 Jun;9(6):e1003572. doi: 10.1371/journal.pgen.1003572. 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7月18日8:30-8:55 ８階　医局

  2. Look AHEAD: No CVD benefit with lifestyle intervention in diabetics June 24, 2013 Michael O‘Riordan– Hard outcomes will be a focus at the American Diabetes Association meeting here, particularly from the Look AHEAD trial's lifestyle intervention in type 2 diabetes. Heart Disease and Stroke The Look AHEAD trial was halted early at the end of last year when an analysis showed no difference in the rate of nonfatal MI, nonfatal stroke, death, or hospitalization for angina among patients randomized to the intensive lifestyle intervention group vs the control group of education alone. There were, however, significant reductions in weight and improvements in physical-fitness levels among those in the intensive group.

  3. Rena R. Wing, Ph.D., Weight Control and Diabetes Research Center, Warren Alpert Medical School of Brown University and Miriam Hospital, Providence, RI; Paula Bolin, R.N., M.C., National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; Frederick L. Brancati,* M.D., M.H.S., Johns Hopkins School of Medicine, Baltimore; George A. Bray, M.D., Pennington Biomedical Research Center, Baton Rouge, LA; Jeanne M. Clark, M.D., M.P.H., Johns Hopkins School of Medicine, Baltimore; Mace Coday, Ph.D., Department of Preventive Medicine, University of Tennessee Health Sciences Center, Memphis; Richard S. Crow,* M.D., Division of Epidemiology and Community Health, University of Minnesota, Minneapolis; Jeffrey M. Curtis, M.D., M.P.H., NIH/NIDDK Southwest American Indian Center, Phoenix, AZ; Caitlin M. Egan, M.S., Weight Control and Diabetes Research Center, Warren Alpert Medical School of Brown University and Miriam Hospital, Providence, RI; Mark A. Espeland, Ph.D., Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC; Mary Evans, Ph.D., NIH/NIDDK, Bethesda, MD; John P. Foreyt, Ph.D., Department of Medicine, Baylor College of Medicine, Houston; SiranGhazarian, M.D., Roybal Comprehensive Health Center, Los Angeles; Edward W. Gregg, Ph.D., Centers for Disease Control and Prevention, Atlanta; Barbara Harrison, M.S., NIH/NIDDK, Bethesda, MD; Helen P. Hazuda, Ph.D., Department of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, San Antonio; James O. Hill, Ph.D., Center for Human Nutrition, University of Colorado Health Sciences Center, Aurora; Edward S. Horton, M.D., Joslin Diabetes Center, Boston; Van S. Hubbard, M.D., Ph.D., NIH/NIDDK, Bethesda, MD; John M. Jakicic, Ph.D., Department of Health and Physical Activity, University of Pittsburgh, Pittsburgh; Robert W. Jeffery, Ph.D., Division of Epidemiology and Community Health, University of Minnesota, Minneapolis; Karen C. Johnson, M.D., M.P.H., Department of Preventive Medicine, University of Tennessee Health Sciences Center, Memphis; Steven E. Kahn, M.B., Ch.B., Department of Medicine, University of Washington, Seattle; Abbas E. Kitabchi, Ph.D., M.D., Department of Preventive Medicine, University of Tennessee Health Sciences Center, Memphis; William C. Knowler, M.D., Dr.P.H., NIH/NIDDK Southwest American Indian Center, Phoenix, AZ; Cora E. Lewis, M.D., M.S.P.H., Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham; Barbara J. Maschak-Carey, M.S.N., C.D.E., Weight and Eating Disorder Program, University of Pennsylvania, Philadelphia; Maria G. Montez, R.N., M.S.H.P., C.D.E., Department of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, San Antonio; Anne Murillo, B.S., Department of Medicine, University of Washington, Seattle; David M. Nathan, M.D., Diabetes Unit, Massachusetts General Hospital, Boston; Jennifer Patricio, M.S., Department of Medicine, St. Luke’s–Roosevelt Hospital, New York; Anne Peters, M.D., Roybal Comprehensive Health Center, Los Angeles; Xavier Pi-Sunyer, M.D., Department of Medicine, St. Luke’s–Roosevelt Hospital, New York; Henry Pownall, Ph.D., Department of Medicine, Baylor College of Medicine, Houston; David Reboussin, Ph.D., Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC; Judith G. Regensteiner, Ph.D., Center for Women’s Health Research, University of Colorado Health Sciences Center, Aurora; Amy D. Rickman, Ph.D., R.D., L.D.N., Department of Health and Physical Activity, University of Pittsburgh, Pittsburgh; Donna H. Ryan, M.D., Pennington Biomedical Research Center, Baton Rouge, LA; Monika Safford, M.D., Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham; Thomas A. Wadden, Ph.D., Weight and Eating Disorder Program, University of Pennsylvania, Philadelphia; Lynne E. Wagenknecht, Dr.P.H., Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC; Delia S. West, Ph.D., Department of Health Behavior and Health Education, College of Public Health, University of Arkansas for Medical Sciences, Little Rock; David F. Williamson, Ph.D., Centers for Disease Control and Prevention, Atlanta; and Susan Z. Yanovski, M.D., NIH/NIDDK, Bethesda, MD. N Engl J Med. 369:145-54, 2013.

  4. Background Weight loss is recommended for overweight or obese patients with type 2 diabetes on the basis of short-term studies, but long-term effects on cardiovascular disease remain unknown. We examined whether an intensive lifestyle intervention for weight loss would decrease cardiovascular morbidity and mortality among such patients.

  5. Methods In 16 study centers in the United States, we randomly assigned 5145 overweight or obese patients with type 2 diabetes to participate in an intensive lifestyle intervention that promoted weight loss through decreased caloric intake and increased physical activity (intervention group) or to receive diabetes support and education (control group). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina during a maximum follow-up of 13.5 years.

  6. Eligibility Criteria Gender Men and women are eligible. Look AHEAD will endeavor to recruit approximately equal numbers of men and women. Type 2 diabetes mellitus Diabetes mellitus will be determined by self-report with verification (medical records, current treatment, verification from personal health care provider, or test results meeting the 1997 American Diabetes Association criteria of fasting glucose > 126 mg/dl, symptoms of hyperglycemia with casual plasma glucose > 200 mg/dl or two-hour plasma glucose > 200 mg/dl after a 75 gram oral glucose load). In an effort to identify individuals with type 2 diabetes (the population that would be most responsive to weight loss), individuals who have a clinical history strongly suggestive of Type 1 diabetes will be excluded. Individuals taking oral hypoglycemic medication or insulin and those who are treated with diet and exercise are eligible. No more than 30% of the study population will be using insulin at entry into the study. Body mass index Overweight individuals, with body mass index of 25 kg/m2 or greater (27 kg/m2 if currently taking insulin) are eligible. Weight loss is recommended for overweight individuals with one or more cardiovascular risk factors, including diabetes mellitus. There is no upper eligibility criterion for body mass index, however an upper limit on weight has been set (Section 4.2.1). Age Individuals aged 45-75 years old are eligible. Individuals older than 75 years of age are excluded due to their increased risk of competing mortality and potential safety concerns related to weight loss. Ethnicity All ethnic groups are eligible for the study. Look AHEAD has the goal of recruiting 33% of the study cohort from ethnic minority groups including African Americans, Hispanic Americans, American Indians, and Asian Americans. Data from NHANES III indicate that April 16, 2001 18 approximately 23% of individuals meeting the eligibility criteria for Look AHEAD will be from ethnic minorities.89 Blood pressure Look AHEAD will enroll individuals whose blood pressure is under at least moderate control: treated or untreated resting systolic/diastolic blood pressure less than 160/100 mmHg. Individuals whose blood pressure exceeds these levels during screening will be told to seek treatment. Such individuals may be rescreened after three months to re-assess blood pressure eligibility. Glycemic control Look AHEAD will enroll individuals whose HbA1c is less than 11%. Individuals whose HbA1c exceeds this level may require more urgent care and will be told to seek treatment. Such individuals may be re-screened after three months to re-assess HbA1c eligibility. Lipid control Individuals with a fasting triglycerides concentration less than 600 mg/dl are eligible. Individuals whose fasting triglycerides concentration exceeds this level may be rescreened after three months to re-assess triglycerides eligibility. History of cardiovascular disease Look AHEAD will recruit individuals both with and without a history of cardiovascular disease. Data from NHANES III indicate that approximately 29% of individuals meeting the eligibility criteria defined by the trial will have a history of cardiovascular disease.85 Cardiovascular event rates in diabetic individuals with heart disease are expected to be approximately twice those of diabetic individuals without a history of heart disease.

  7. Figure 1. Changes in Weight, Physical Fitness, Waist Circumference, and Glycated Hemoglobin Levels during 10 Years of Follow-up. Shown are the changes from baseline in overweight or obese patients with type 2 diabetes who participated in an intensive lifestyle intervention (intervention group) or who received diabetes support and education (control group). The reported main effect is the average of all between-group differences after baseline. Means were estimated with the use of generalized linear models for continuous measures. MET denotes metabolic equivalents; asterisks indicate P<0.05 for the between-group comparison. Data from 107 visits during year 11 were not included in the analyses.

  8. Figure 2. Cumulative Hazard Curves for the Primary Composite End Point. Shown are Kaplan–Meier estimates of the cumulative proportion of patients with a primary event. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. The numbers below the graph are the numbers of patients at risk in each study group at years 2, 4, 6, and 8 and at 10.4 years, when the last observed event occurred. The inset shows the same data on an expanded y axis.

  9. One possibility is that the study lacked sufficient power. However, we do not believe that this explains the negative result; the 95% confidence interval for the primary outcome excluded the benefit of 18% or more targeted in the trial’s design. Another possibility is that a sustained weight loss of more than that achieved in the intervention group may be required to reduce the risk of cardiovascular disease. In this regard, it is noteworthy that the differential weight loss between the two trial groups averaged 4% over the course of the study but only 2.5% at the end. However, our trial was planned to test the effects of an intensive lifestyle intervention, and the weight loss achieved in the intervention group is representative of the best that has been achieved with current lifestyle approaches. Third, the provision of educational sessions and the increased use of statins in the control group, as compared with the intervention group, may have lessened the difference between the two groups. In addition, the intensification of medical management of cardiovascular risk factors in routine medical care in the two study groups may have made the relative benefit of the intensive lifestyle intervention more difficult to demonstrate. The intervention may also have had different effects in different subgroups. Although none of the interactions with subgroups were significant, our data suggest that the event rate for the primary outcome was nonsignificantly lower in the intervention group than in the control group among patients with no history of cardiovascular disease at baseline but that it was nonsignificantly higher in the intervention group than in the control group among those with cardiovascular disease at baseline.

  10. Results The trial was stopped early on the basis of a futility analysis when the median follow-up was 9.6 years. Weight loss was greater in the intervention group than in the control group throughout the study (8.6% vs. 0.7% at 1 year; 6.0% vs. 3.5% at study end). The intensive lifestyle intervention also produced greater reductions in glycated hemoglobin and greater initial improvements in fitness and all cardiovascular risk factors, except for low-density-lipoprotein cholesterol levels. The primary outcome occurred in 403 patients in the intervention group and in 418 in the control group (1.83 and 1.92 events per 100 person-years, respectively; hazard ratio in the intervention group, 0.95; 95% confidence interval, 0.83 to 1.09; P = 0.51).

  11. Conclusions An intensive lifestyle intervention focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults with type 2 diabetes. (Funded by the National Institutes of Health and others; Look AHEAD ClinicalTrials.gov number, NCT00017953.)

  12. Message 過体重または肥満の2型糖尿病（DM）患者5145人を対象に、減量のための生活習慣強化介入の効果を無作為化比較試験で検討（Look AHEAD試験）。主要転帰（心血管死、非致死性心筋梗塞、非致死性脳卒中、狭心症による入院）の発生率は、介入群100人年当たり1.83件、対照群で1.92件だった（ハザード比0.95、P＝0.51）。

  13. http://www.mindthesciencegap.org/2012/03/21/exercise-can-change-your-dna/http://www.mindthesciencegap.org/2012/03/21/exercise-can-change-your-dna/

  14. http://healthramblings.com/2012/03/

  15. ２型糖尿病の発症に関与する候補遺伝子（複数保有すると発症確率が増大）２型糖尿病の発症に関与する候補遺伝子（複数保有すると発症確率が増大） Nat Genet. 2012 Sep;44(9):981-90.

  16. PLOS Genetics | www.plosgenetics.org June 2013 | Volume 9 | Issue 6 | e1003572

  17. Background Epigenetic mechanisms are implicated in gene regulation and the development of different diseases. The epigenome differs between cell types and has until now only been characterized for a few human tissues. Environmental factors potentially alter the epigenome.

  18. Methods Here we describe the genome-wide pattern of DNA methylation in human adipose tissue from 23 healthy men, with a previous low level of physical activity, before and after a six months exercise intervention. We also investigate the differences in adipose tissue DNA methylation between 31 individuals with or without a family history of type 2 diabetes. DNA methylation was analyzed using Infinium HumanMethylation450 BeadChip, an array containing 485,577 probes covering 99% RefSeq genes.

  19. Epigenetic mechanisms such as DNA methylation are considered to be important in phenotype transmission and the development of different diseases [9]. The epigenetic pattern is mainly established early in life and thereafter maintained in differentiated cells, but age-dependent alterations still have the potential to modulate gene expression and translate environmental factors into phenotypic traits [10–13]. In differentiated mamma-liancells, DNA methylation usually occurs in the context of CG dinucleotides (CpGs) and is associated with gene repression [14]. Changes in epigenetic profiles are more common than genetic mutations and may occur in response to environmental, behavioural, psychological and pathological stimuli

  20. 1) explore genomewide levels of DNA methylation before and after a six months exercise intervention in adipose tissue from healthy, but previously sedentary men; 2) investigate the differences in adipose tissue DNA methylation between individuals with or without a family history of T2D; 3) relate changes in DNA methylation to adipose tissue mRNA expression and metabolic phenotypes in vitro.

  21. Baseline characteristics of individuals with (FH+) or without (FH-) a family history of type 2 diabetes A total of 31 men, 15 FH + and 16 FH-, had subcutaneous adipose tissue biopsies taken at baseline.

  22. False discovery rateand q-value q-valueを計算するq-valueを定義 任意の値以上の統計量に対応づけられた最小の FDR ある値に割り当てられたq-valueは，その値を significanceのいちきにしたときのFDRを表す先ほどの例だと，q-value=<0.05のところをとると，FDRが5%となる p-valueとq-valuep-value p<0.05ということは False positive rateが0.05未満になるということ False positive rate = FP/(TN+FP) q-value q<0.05ということは False discovery rateが0.05未満になるということ http://en.wikipedia.org/wiki/False_discovery_rate#q-value http://www.slideshare.net/yuifu/fdr-kashiwar-3

  23. Clinical outcome and global changes in adipose tissue DNA methylation in response to exercise Subcutaneous adipose tissue biopsies were taken from 23 men both before and after exercise

  24. DNA methylation of individual CpG sites in human adipose tissue is influenced by exercise

  25. Figure 2. Analysis flowchart.

  26. DNA methylation in vitro decreases reporter gene expression

  27. DNA methylation of obesity and type 2 diabetes candidate genes in human adipose tissue

  28. Silencing of Hdac4 and Ncor2 in 3T3-L1 adipocytes is associated with increased lipogenesis

  29. Results Global DNA methylation changed and 17,975 individual CpG sites in 7,663 unique genes showed altered levels of DNA methylation after the exercise intervention (q,0.05). Differential mRNA expression was present in 1/3 of gene regions with altered DNA methylation, including RALBP1, HDAC4 and NCOR2 (q,0.05). Using a luciferase assay, we could show that increased DNA methylation in vitro of the RALBP1 promoter suppressed the transcriptional activity (p = 0.03). Moreover, 18 obesity and 21 type 2 diabetes candidate genes had CpG sites with differences in adipose tissue DNA methylation in response to exercise (q,0.05), including TCF7L2 (6 CpG sites) and KCNQ1 (10 CpG sites). A simultaneous change in mRNA expression was seen for 6 of those genes. To understand if genes that exhibit differential DNA methylation and mRNA expression in human adipose tissue in vivo affect adipocyte metabolism, we silenced Hdac4 and Ncor2 respectively in 3T3-L1 adipocytes, which resulted in increased lipogenesis both in the basal and insulin stimulated state.

  30. Conclusion In conclusion, exercise induces genome-wide changes in DNA methylation in human adipose tissue, potentially affecting adipocyte metabolism.

  31. Message 運動すると遺伝子自体が変化するといわれているが、筋肉以外にも脂肪細胞についても調べ、２型糖尿病発症に関係する遺伝子もかなり影響されていることが分かったということになる。 同じ遺伝子でも、環境（運動）により影響をうけることになる。

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