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 2010 年 11 月 18 日 8:30-8:55 ８階 医局 Knip M, Virtanen SM, Seppä K, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hämäläinen AM, Paronen J, Dosch HM, Hakulinen T, Akerblom HK; the Finnish TRIGR Study Group. Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity. N Engl J Med Nov 11;363(20): The NS, Suchindran C, North KE, Popkin BM, Gordon-Larsen P. Association of adolescent obesity with risk of severe obesity in adulthood. JAMA Nov 10;304(18):

the Hospital for Children and Adolescents (M.K., E.S., J.P., H.K.Å.) and Department of Obstetrics and Gynecology (K.T.), University of Helsinki and Helsinki University Central Hospital; the Nutrition Unit (S.M.V.), Immune Response Unit (O.V.), and Department of Health and Functional Capacity (A.R.), National Institute for Health and Welfare; and the Finnish Cancer Registry (K.S., T.H.) — all in Helsinki; the Department of Pediatrics (M.K.) and Research Unit (S.M.V.), Tampere University Hospital, and the Tampere School of Public Health, University of Tampere (S.M.V.), Tampere; the Immunogenetics Laboratory, University of Turku, Turku ( J.I.); the Department of Clinical Microbiology, University of Kuopio, Kuopio ( J.I.); the Department of Pediatrics, Jorvi Hospital, Espoo (A.-M.H.); and the Department of Pediatrics, University of Oulu, Oulu (A.-M.H.) — all in Finland; and the Hospital for Sick Children, Research Institute, University of Toronto, Toronto (H.-M.D.). N Engl J Med 2010;363:

Early exposure to complex dietary proteins may increase the risk of beta-cell autoimmunity and type 1 diabetes in children with genetic susceptibility. We tested the hypothesis that supplementing breast milk with highly hydrolyzed milk formula would decrease the cumulative incidence of diabetes-associated autoantibodies in such children. BACKGROUND

In this double-blind, randomized trial, we assigned 230 infants with HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes to receive either a casein hydrolysate formula or a conventional, cow’s-milk–based formula (control) whenever breast milk was not available during the first 6 to 8 months of life. Autoantibodies to insulin, glutamic acid decarboxylase (GAD), the insulinoma associated 2 molecule (IA-2), and zinc transporter 8 were analyzed with the use of radio binding assays, and islet-cell antibodies were analyzed with the use of immunofluorescence, during a median observation period of 10 years (mean, 7.5). The children were monitored for incident type 1 diabetes until they were 10 years of age. METHODS

The unadjusted hazard ratio for positivity for one or more autoantibodies in the casein hydrolysate group, as compared with the control group, was 0.54 (95% confidence interval [CI], 0.29 to 0.95), and the hazard ratio adjusted for an observed difference in the duration of exposure to the study formula was 0.51 (95% CI, 0.28 to 0.91). The unadjusted hazard ratio for positivity for two or more autoantibodies was 0.52 (95% CI, 0.21 to 1.17), and the adjusted hazard ratio was 0.47 (95% CI, 0.19 to 1.07). The rate of reported adverse events was similar in the two groups. RESULTS

CONCLUSIONS Dietary intervention during infancy appears to have a long-lasting effect on markers of beta-cell autoimmunity — markers that may reflect an autoimmune process leading to type 1 diabetes. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT )

Knip et al. conducted the study in Finland, where the prevalence of type 1 diabetes is among the highest in the world and continues to increase. In 2005, there were 64.2 cases of newly diagnosed type 1 diabetes per 100,000 Finnish children younger than 15 years of age.6 Knip et al. enrolled 230 breast-fed newborns born at term (≥36 weeks of gestation) who had a first-degree relative with type 1 diabetes (the mother in the case of 37% of the children, the father in 43%, a sibling in 15%, and more than one relative in 4%) and an HLA genotype associated with the risk of type 1 diabetes. The study’s principal finding was that at least one autoantibody developed in 17% of the babies fed the casein hydrolysate formula, as compared with 30% of the children fed the control formula (P = 0.02). Diabetes ultimately developed in similar numbers of children in each group — 7 of the 113 assigned to the casein hydrolysate formula (6%) and 9 of the 117 assigned to the cow’s-milk–based formula (8%) (a nonsignificant difference).

Although the group assignment was randomized, the infants assigned to receive the cow’s-milk–based formula were introduced to that formula at a median age of 1.1 months, whereas the children receiving the casein hydrolysate formula were first given the formula at a significantly later median age of 2.6 months (P = 0.03), raising the question of whether the results could be attributed to the timing of the introduction of the formula rather than to the content of the formula. Although statistical tools used to account for such differences suggest that the control formula resulted in more autoantibody seroconversions, the possibility that there were unmeasured confounders, such as the quantity of formula ingested, cannot be excluded. Increased attention has been focused on the roles of gut-associated microbiome and gut mucosal permeability on the host immune system.7 Still other research has suggested that oral administration of low-dose interferon- α preserves pancreatic insulin production in persons with recent-onset type 1 diabetes, despite the fact that such treatment did not alter circulating concentrations of interferon-α.8 it seems likely that dietary constituents, not too surprisingly, can influence the immune system and intermediary metabolism, our knowledge of the mechanisms at play are, at present, rudimentary.

Data from the ongoing multicenter Trial to Reduce IDDM in the Genetically at Risk (TRIGR; ClinicalTrials.gov number, NCT )9 should help clarify whether hydrolyzed casein formula exerts a protective effect against the risk of type 1 diabetes.

Message/Comments 10 年も観察！ １型糖尿病予防には赤 ちゃんのミルクの組成から介入！

JAMA. 2010;304(18): Carolina Population Center (Drs The, Suchindran, Popkin, and Gordon-Larsen) and Departments of Nutrition (Drs The, Popkin, and Gordon-Larsen), Biostatistics (Dr Suchindran), and Epidemiology (Dr North), Gillings School of Global Public Health, University of North Carolina, Chapel Hill.

Context Although the prevalence of obesity has increased in recent years, individuals who are obese early in life have not been studied over time to determine whether they develop severe obesity in adulthood, thus limiting effective interventions to reduce severe obesity incidence and its potentially life-threatening associated conditions. Objective To determine incidence and risk of severe obesity in adulthood by adolescent weight status.

Design, Setting, and Participants A cohort of 8834 individuals aged 12 to 21 years enrolled in 1996 in wave II of the US National Longitudinal Study of Adolescent Health, followed up into adulthood (ages years during wave III [ ] and ages years during wave IV [ ]). Height and weight were obtained via anthropometry and surveys administered in study participants’ homes using standardized procedures. Main Outcome Measures New cases of adult-onset severe obesity were calculated by sex, race/ethnicity, and adolescent weight status. Sex-stratified, discrete time hazard models estimated the net effect of adolescent obesity (aged <20 years; body mass index [BMI] ≥95th percentile of the sex-specific BMI- for-age growth chart or BMI ≥ 30.0) on risk of severe obesity incidence in adulthood (aged ≥ 20 years; BMI ≥ 40.0), adjusting for race/ethnicity and age and weighted for national representation.

Results In 1996, 79 (1.0%; 95% confidence interval [CI], 0.7%-1.4%) adolescents were severely obese; 60 (70.5%; 95% CI, 57.2%- 83.9%) remained severely obese in adulthood. By 2009, 703 (7.9%; 95% CI, 7.4%-8.5%) non– severely obese adolescents had become severely obese in adulthood, with the highest rates for non- Hispanic black women. Obese adolescents were significantly more likely to develop severe obesity in young adulthood than normal-weight or overweight adolescents (hazard ratio, 16.0; 95% CI, ).

Conclusion In this cohort, obesity in adolescence was significantly associated with increased risk of incident severe obesity in adulthood, with variations by sex and race/ ethnicity.

Message/Comments 思春期の肥満は、大人になってからとんで もない肥満になりやすい！ （まぁ 当たり前のようにも感じますが）