Early feeding and risk of type 1 diabetes: experiences from the Trial
to Reduce Insulin-dependent diabetes mellitus in the Genetically at
Mikael Knip, Suvi M Virtanen, Dorothy Becker, John Dupre ´, Jeffrey P Krischer, and Hans K A˚kerblom for the TRIGR
Short-term breastfeeding and early exposure to complex dietary pro-
teins, such as cow milk proteins and cereals, or to fruit, berries, and
roots have been implicated as risk factors for b cell autoimmunity,
clinical type 1 diabetes, or both. The Trial to Reduce Insulin-de-
pendent diabetes mellitus in the Genetically at Risk (TRIGR) is an
international, randomized, double-blind, controlled intervention tri-
al designed to answer the question of whether weaning to an exten-
sively hydrolyzed formula in infancy will decrease the risk of type 1
diabetes later in childhood. In our pilot study, weaning to a highly
hydrolyzed formula decreased by ’50% the cumulative incidence
of one or more diabetes-associated autoantibodies by a mean age of
4.7 y. This finding was confirmed in a recent follow-up analysis to
10 y of age. Currently, the full-scale TRIGR takes place in 77
centers in 15 countries. The TRIGR initially recruited 5606 new-
born infants with a family member affected by type 1 diabetes and
enrolled 2159 eligible subjects who carried a risk-conferring HLA
genotype. All recruited mothers were encouraged to breastfeed. The
intervention lasted for 6–8 mo with a minimum study formula ex-
posure time of 2 mo, and hydrolyzed casein and standard cow milk–
based weaning formulas were compared. Eighty percent of the par-
ticipants were exposed to the study formula. The overall retention
rate over the first 5 y was 87%, and protocol compliance was 94%.
The randomization code will be opened when the last recruited
child turns 10 y of age (ie, in 2017).
Am J Clin Nutr 2011;94
Type 1 diabetes is characterized by the selective loss of insulin-
producing b cells in the pancreatic islets in genetically susceptible
individuals. The clinical disease presentation is preceded by an
asymptomatic period of highly variable duration (1). During that
period diabetes-associated autoantibodies appear in the peripheral
circulation as markers of emerging b cell autoimmunity. Evidence
suggests that b cell autoimmunity may be induced early in life
(2, 3). In parallel, recent studies have shown that the incidence
of type 1 diabetes is increasing even faster than before among
children in developed countries, among those ,5 y of age in
particular (4, 5). This scenario implies that any measure aimed at
primary prevention of type 1 diabetes (ie, prevention of the ini-
tiation of the diabetic disease process) has to start in infancy.
Early feeding may modify the risk of type 1 diabetes later in life.
Short-term breastfeeding and early exposure to complex dietary
proteins, such as cow milk proteins and cereals, or to fruit, berries,
and vegetable roots have been implicated as risk factors for
advanced b cell autoimmunity or clinical type 1 diabetes (6, 7).
Early nutritional intervention could offer a safe, preventive
modality for type 1 diabetes without the risks of aggressive
immune interventions and has, in fact, been successful in rele-
vant animal models of autoimmune diabetes, although the data
are not uniform (8–11).
TRIGR stands for Trial to Reduce Insulin-dependent diabetes
mellitus in the Genetically at Risk. It is an international, ran-
1From the Hospital for Children and Adolescents, University of Helsinki,
Helsinki, Finland (MK and HKA˚); Helsinki University Central Hospital,
Helsinki, Finland (MK); Folkha ¨lsan Research Center, Helsinki, Finland
(MK); the Department of Pediatrics (MK) and Tampere University Hospital
Research Unit (SMV), Tampere University Hospital, Tampere, Finland; Nu-
trition Unit, National Institute for Health and Welfare, Helsinki, Finland
(SMV); Tampere School of Public Health, University of Tampere, Tampere,
Finland (SMV); the Division of Endocrinology, Children’s Hospital of Pitts-
burgh of University of Pittsburgh Medical Center, Pittsburgh, PA (DB);
Robarts Research Institute, University of Western Ontario, London, Canada
(JD); and the Pediatrics Epidemiology Center, University of South Florida,
Tampa, FL (JPK).
2Presented at the conference “The Power of Programming: Developmen-
tal Origins of Health and Disease,” held in Munich, Germany, 6–8 May
3Members of the TRIGR Study Group are listed in the Supplemental
material under “Supplemental data” in the online issue.
4The funding nongovernmental organizations had no role in the design,
implementation, or analysis and interpretation of the data.
5Supported by the National Institute of Child Health and Development and
the National Institute of Diabetes and Digestive and Kidney Diseases; the NIH
(grant numbers HD040364, HD042444, and HD051997); the Canadian Insti-
tutes of Health Research; the Juvenile Diabetes Research Foundation Interna-
tional; the Commission of the European Community (specific Research and
Technical Development programme “Quality of Life and management of Liv-
ing Resources,” contract no. QLK1-2002-00372 “Diabetes Prevention”); Eu-
ropean Foundation for the Study Of Diabetes/Juvenile Diabetes Research
Foundation/Novo Nordisk Focused Research Grant; the Academy of Finland;
the Dutch Diabetes Research Foundation; and the Finnish Diabetes Research
6Address reprint requests and correspondence to M Knip, Hospital for
Children and Adolescents, University of Helsinki, PO Box 22 (Stenba ¨ckin-
katu 11), FI.-00014 Helsinki, Finland. E-mail: email@example.com.
First published online June 8, 2011; doi: 10.3945/ajcn.110.000711.
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KNIP ET AL