Aims/hypothesis: We aimed to evaluate the relationship between childhood growth measures and risk of developing islet autoimmunity (IA) and type 1 diabetes in children with an affected first-degree relative and increased HLA-conferred risk. We hypothesised that being overweight or obese during childhood is associated with a greater risk of IA and type 1 diabetes. Methods: Participants in a randomised infant feeding trial (N = 2149) were measured at 12 month intervals for weight and length/height and followed for IA (at least one positive out of insulin autoantibodies, islet antigen-2 autoantibody, GAD autoantibody and zinc transporter 8 autoantibody) and development of type 1 diabetes from birth to 10–14 years. In this secondary analysis, Cox proportional hazard regression models were adjusted for birthweight and length z score, sex, HLA risk, maternal type 1 diabetes, mode of delivery and breastfeeding duration, and stratified by residence region (Australia, Canada, Northern Europe, Southern Europe, Central Europe and the USA). Longitudinal exposures were studied both by time-varying Cox proportional hazard regression and by joint modelling. Multiple testing was considered using family-wise error rate at 0.05. Results: In the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, 305 (14.2%) developed IA and 172 (8%) developed type 1 diabetes. The proportions of children overweight (including obese) and obese only were 28% and 9% at 10 years, respectively. Annual growth measures were not associated with IA, but being overweight at 2–10 years of life was associated with a twofold increase in the development of type 1 diabetes (HR 2.39; 95% CI 1.46, 3.92; p < 0.001 in time-varying Cox regression), and similarly with joint modelling. Conclusions/interpretation: In children at genetic risk of type 1 diabetes, being overweight at 2–10 years of age is associated with increased risk of progression from multiple IA to type 1 diabetes and with development of type 1 diabetes, but not with development of IA. Future studies should assess the impact of weight management strategies on these outcomes. Trial registration: ClinicalTrials.gov NCT00179777 Graphical abstract: [Figure not available: see fulltext.]
Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk / Nucci, A. M.; Virtanen, S. M.; Cuthbertson, D.; Ludvigsson, J.; Einberg, U.; Huot, C.; Castano, L.; Aschemeier, B.; Becker, D. J.; Knip, M.; Krischer, J. P.; Mandrup-Poulsen, T.; Arjas, E.; Laara, E.; Lernmark, A.; Schmidt, B.; Akerblom, H. K.; Hyytinen, M.; Koski, K.; Koski, M.; Pajakkala, E.; Salonen, M.; Shanker, L.; Bradley, B.; Dosch, H. -M.; Dupre, J.; Fraser, W.; Lawson, M.; Mahon, J. L.; Sermer, M.; Taback, S. P.; Becker, D.; Franciscus, M.; Nucci, A.; Palmer, J.; Catteau, J.; Howard, N.; Crock, P.; Craig, M.; Clarson, C. L.; Bere, L.; Thompson, D.; Metzger, D.; Marshall, C.; Kwan, J.; Stephure, D. K.; Pacaud, D.; Schwarz, W.; Girgis, R.; Thompson, M.; Catte, D.; Lawson, M. L.; Bradley, B.; Daneman, D.; Sermer, M.; Martin, M. -J.; Morin, V.; Frenette, L.; Ferland, S.; Sanderson, S.; Heath, K.; Huot, C.; Gonthier, M.; Thibeault, M.; Legault, L.; Laforte, D.; Cummings, E. A.; Scott, K.; Bridger, T.; Crummell, C.; Houlden, R.; Breen, A.; Carson, G.; Kelly, S.; Sankaran, K.; Penner, M.; White, R. A.; King, N.; Popkin, J.; Robson, L.; Al Taji, E.; Mendlova, P.; Romanova, M.; Vavrinec, J.; Vosahlo, J.; Brazdova, L.; Venhacova, J.; Venhacova, P.; Cipra, A.; Tomsikova, Z.; Paterova, P.; Gogelova, P.; Einberg, U.; Riikjarv, M. -A.; Ormisson, A.; Tillmann, V.; Johansson, S.; Kleemola, P.; Parkkola, A.; Jarvenpaa, A. -L.; Hamalainen, A. -M.; Kiiveri, S.; Salonen, M.; Tenhola, S.; Salonen, P.; Jason, E.; Selvenius, J.; Siljander, H.; Ylitalo, S.; Paajanen, I.; Talvitie, T.; Lindstrom, K.; Huopio, H.; Pesola, J.; Veijola, R.; Tapanainen, P.; Alar, A.; Popov, E.; Virransalo, R.; Nykanen, P.; Danne, T.; Kordonouri, O.; Krikovszky, D.; Madacsy, L.; Khazrai, Y. M.; Maddaloni, E.; Pozzilli, P.; Mannu, C.; Songini, M.; de Beaufort, C.; Schierloh, U.; Bruining, J.; Bisschoff, M.; Basiak, A.; Wasikowa, R.; Ciechanowska, M.; Deja, G.; Jarosz-Chobot, P.; Szadkowska, A.; Cypryk, K.; Zawodniak-Szalapska, M.; Frutos, T. G.; Oyarzabal, M.; Serrano-Rios, M.; Martinez-Larrad, M. T.; Hawkins, F. G.; Arnau, D. R.; Konefal, M. S.; Hanas, R.; Lindblad, B.; Nilsson, N. -O.; Fors, H.; Nordwall, M.; Lindh, A.; Edenwall, H.; Aman, J.; Johansson, C.; Gadient, M.; Konrad, D.; Schoenle, E.; Becker, D.; Daftary, A.; Klein, M. B.; Gilmour, C.; Palmer, J.; Malone, P.; Tanner-Blasiar, M.; White, N.; Devaskar, U.; Horowitz, H.; Rogers, L.; Colon, R.; Frazer, T.; Torres, J.; Goland, R.; Greenberg, E.; Schachner, H.; Softness, B.; Ilonen, J.; Trucco, M.; Nichol, L.; Savilahti, E.; Harkonen, T.; Vaarala, O.; Luopajarvi, K.; Dosch, H. -M.. - In: DIABETOLOGIA. - ISSN 0012-186X. - 64:4(2021), pp. 826-835. [10.1007/s00125-020-05358-3]
Growth and development of islet autoimmunity and type 1 diabetes in children genetically at risk
Maddaloni E.;Pozzilli P.;
2021
Abstract
Aims/hypothesis: We aimed to evaluate the relationship between childhood growth measures and risk of developing islet autoimmunity (IA) and type 1 diabetes in children with an affected first-degree relative and increased HLA-conferred risk. We hypothesised that being overweight or obese during childhood is associated with a greater risk of IA and type 1 diabetes. Methods: Participants in a randomised infant feeding trial (N = 2149) were measured at 12 month intervals for weight and length/height and followed for IA (at least one positive out of insulin autoantibodies, islet antigen-2 autoantibody, GAD autoantibody and zinc transporter 8 autoantibody) and development of type 1 diabetes from birth to 10–14 years. In this secondary analysis, Cox proportional hazard regression models were adjusted for birthweight and length z score, sex, HLA risk, maternal type 1 diabetes, mode of delivery and breastfeeding duration, and stratified by residence region (Australia, Canada, Northern Europe, Southern Europe, Central Europe and the USA). Longitudinal exposures were studied both by time-varying Cox proportional hazard regression and by joint modelling. Multiple testing was considered using family-wise error rate at 0.05. Results: In the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, 305 (14.2%) developed IA and 172 (8%) developed type 1 diabetes. The proportions of children overweight (including obese) and obese only were 28% and 9% at 10 years, respectively. Annual growth measures were not associated with IA, but being overweight at 2–10 years of life was associated with a twofold increase in the development of type 1 diabetes (HR 2.39; 95% CI 1.46, 3.92; p < 0.001 in time-varying Cox regression), and similarly with joint modelling. Conclusions/interpretation: In children at genetic risk of type 1 diabetes, being overweight at 2–10 years of age is associated with increased risk of progression from multiple IA to type 1 diabetes and with development of type 1 diabetes, but not with development of IA. Future studies should assess the impact of weight management strategies on these outcomes. Trial registration: ClinicalTrials.gov NCT00179777 Graphical abstract: [Figure not available: see fulltext.]I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
