High Concentrations of Immunoglobulin G Against Cow Milk Proteins and Frequency of Cow Milk Consumption Are Associated With the Development of Islet Autoimmunity and Type 1 Diabetes-The Trial to Reduce Insulin-dependent Diabetes Mellitus (IDDM) In...

Overview

Journal J Nutr

Publisher Elsevier

Specialty Nutritional Sciences

Date 2024 Jun 21

PMID 38906178

Authors

Sari Niinisto

David Cuthbertson

Maija E Miettinen

Leena Hakola

Anita Nucci

Tuuli E Korhonen

Heikki Hyoty

Jeffrey P Krischer

Outi Vaarala

Mikael Knip

Erkki Savilahti

Suvi M Virtanen

Affiliations

Soon will be listed here.

Abstract

Background: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) (NCT00179777) found no difference type 1 diabetes risk between hydrolyzed and regular infant formula. However, cow milk consumption during childhood is consistently linked to type 1 diabetes risk in prospective cohort studies.

Objectives: Our primary aim was to study whether humoral immune responses to cow milk and cow milk consumption are associated with type 1 diabetes in TRIGR children.

Methods: TRIGR comprised 2159 children with genetic susceptibility to type 1 diabetes born between 2002 and 2007 in 15 countries. Children were randomly assigned into groups receiving extensively hydrolyzed casein or a regular cow milk formula and followed up until age 10 y. Type 1 diabetes-related autoantibodies and antibodies to cow milk proteins were analyzed. Infant formula intake was measured by structured dietary interviews and milk consumption with a food frequency questionnaire. Associations of milk antibodies and milk consumption with risk to develop type 1 diabetes were analyzed using Cox survival model.

Results: Cow milk antibody concentrations both in cord blood [hazards ratio (HR) for islet autoimmunity: 1.30; 95% CI: 1.05, 1.61; HR for type 1 diabetes: 1.32; 95% CI: 1.02, 1.71] and longitudinally from birth to 3 years (HR for islet autoimmunity: 1.39; 95% CI: 1.07, 1.81; HR for type 1 diabetes: 1.43; 95% CI: 1.04, 1.96) were associated with increased risk of developing type 1 diabetes. The amount of regular infant formula was associated with reduced islet autoimmunity risk in the regular infant formula group (HR: 0.92; 95% CI: 0.85, 0.99). Furthermore, frequent liquid milk consumption after infancy was associated with increased risk of islet autoimmunity or type 1 diabetes.

Conclusions: Elevated cow milk antibody concentrations and high consumption of liquid milk after infancy are related to type 1 diabetes development in children with an increased genetic susceptibility to type 1 diabetes. Enhanced antibody concentrations to cow milk may provide a biomarker of immune system prone to develop islet autoimmunity. This trial was registered at clinicaltrials.gov as NCT00179777.

References

Palmeira P, Quinello C, Silveira-Lessa A, Zago C, Carneiro-Sampaio M . IgG placental transfer in healthy and pathological pregnancies. Clin Dev Immunol. 2012; 2012:985646. PMC: 3251916. DOI: 10.1155/2012/985646. View

Knip M, Virtanen S, Seppa K, Ilonen J, Savilahti E, Vaarala O . Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med. 2010; 363(20):1900-8. PMC: 4242902. DOI: 10.1056/NEJMoa1004809. View

Savilahti E, Saukkonen T, Virtala E, Tuomilehto J, Akerblom H . Increased levels of cow's milk and beta-lactoglobulin antibodies in young children with newly diagnosed IDDM. The Childhood Diabetes in Finland Study Group. Diabetes Care. 1993; 16(7):984-9. DOI: 10.2337/diacare.16.7.984. View

Knip M . Cow's milk antibodies in patients with newly diagnosed type 1 diabetes: primary or secondary?. Pediatr Diabetes. 2004; 4(4):155-6. DOI: 10.1111/j.1399-543x.2003.00029.x. View

Hummel S, Beyerlein A, Tamura R, Uusitalo U, Andren Aronsson C, Yang J . First Infant Formula Type and Risk of Islet Autoimmunity in The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Diabetes Care. 2017; 40(3):398-404. PMC: 5319477. DOI: 10.2337/dc16-1624. View

Siljander H, Honkanen J, Knip M . Microbiome and type 1 diabetes. EBioMedicine. 2019; 46:512-521. PMC: 6710855. DOI: 10.1016/j.ebiom.2019.06.031. View

Casas R, Bjorksten B . Detection of Fel d 1-immunoglobulin G immune complexes in cord blood and sera from allergic and non-allergic mothers. Pediatr Allergy Immunol. 2001; 12(2):59-64. DOI: 10.1034/j.1399-3038.2001.012002059.x. View

Koivusaari K, Syrjala E, Niinisto S, Takkinen H, Ahonen S, Akerlund M . Consumption of differently processed milk products in infancy and early childhood and the risk of islet autoimmunity. Br J Nutr. 2020; 124(2):173-180. DOI: 10.1017/S0007114520000744. View

Knip M, Akerblom H, Al Taji E, Becker D, Bruining J, Castano L . Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial. JAMA. 2018; 319(1):38-48. PMC: 5833549. DOI: 10.1001/jama.2017.19826. View

10.

Virtanen S, Saukkonen T, Savilahti E, Ylonen K, Rasanen L, Aro A . Diet, cow's milk protein antibodies and the risk of IDDM in Finnish children. Childhood Diabetes in Finland Study Group. Diabetologia. 1994; 37(4):381-7. DOI: 10.1007/s001250050121. View

11.

Vaarala O, Knip M, Paronen J, Hamalainen A, Muona P, Vaatainen M . Cow's milk formula feeding induces primary immunization to insulin in infants at genetic risk for type 1 diabetes. Diabetes. 1999; 48(7):1389-94. DOI: 10.2337/diabetes.48.7.1389. View

12.

Uusitalo U, Lee H, Andren Aronsson C, Vehik K, Yang J, Hummel S . Early Infant Diet and Islet Autoimmunity in the TEDDY Study. Diabetes Care. 2018; 41(3):522-530. PMC: 5829968. DOI: 10.2337/dc17-1983. View

13.

Savilahti E, Akerblom H, Tainio V, Koskimies S . Children with newly diagnosed insulin dependent diabetes mellitus have increased levels of cow's milk antibodies. Diabetes Res. 1988; 7(3):137-40. View

14.

Couper J, Steele C, Beresford S, Powell T, McCaul K, Pollard A . Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity. Diabetes. 1999; 48(11):2145-9. DOI: 10.2337/diabetes.48.11.2145. View

15.

Virtanen S, Hypponen E, Laara E, Vahasalo P, Kulmala P, Savola K . Cow's milk consumption, disease-associated autoantibodies and type 1 diabetes mellitus: a follow-up study in siblings of diabetic children. Childhood Diabetes in Finland Study Group. Diabet Med. 1998; 15(9):730-8. DOI: 10.1002/(SICI)1096-9136(199809)15:9<730::AID-DIA646>3.0.CO;2-C. View

16.

Honkanen J, Vuorela A, Muthas D, Orivuori L, Luopajarvi K, Tejesvi M . Fungal Dysbiosis and Intestinal Inflammation in Children With Beta-Cell Autoimmunity. Front Immunol. 2020; 11:468. PMC: 7103650. DOI: 10.3389/fimmu.2020.00468. View

17.

Franciscus M, Nucci A, Bradley B, Suomalainen H, Greenberg E, Laforte D . Recruitment and retention of participants for an international type 1 diabetes prevention trial: a coordinators' perspective. Clin Trials. 2013; 11(2):150-8. PMC: 3972359. DOI: 10.1177/1740774513510070. View

18.

Lamb M, Miller M, Seifert J, Frederiksen B, Kroehl M, Rewers M . The effect of childhood cow's milk intake and HLA-DR genotype on risk of islet autoimmunity and type 1 diabetes: the Diabetes Autoimmunity Study in the Young. Pediatr Diabetes. 2014; 16(1):31-8. PMC: 4104257. DOI: 10.1111/pedi.12115. View

19.

Lemke H, Coutinho A, Lange H . Lamarckian inheritance by somatically acquired maternal IgG phenotypes. Trends Immunol. 2004; 25(4):180-6. DOI: 10.1016/j.it.2004.02.007. View

20.

Savilahti E, Saarinen K . Early infant feeding and type 1 diabetes. Eur J Nutr. 2009; 48(4):243-9. DOI: 10.1007/s00394-009-0008-z. View