Infant Feeding Practices and Their Possible Relationship to the
Etiology of Diabetes Mellitus
Policy
Statement
Pediatrics Volume 94, Number
5 November 1994, p 752-754
Infant Feeding Practices and Their Possible Relationship to the
Etiology of Diabetes Mellitus (RE9430)
AMERICAN ACADEMY OF PEDIATRICS
Work Group on Cow's Milk Protein and Diabetes
Mellitus
ABBREVIATIONS. IDDM, insulin-dependent diabetes
mellitus; BB, biobreeding.
Insulin-dependent diabetes mellitus (IDDM) is a common serious
genetic disorder affecting a large number of children and adolescents
around the world. The annual incidence rate in the United States is
approximately 15 per 100 000 persons under 19 years of age, with a
prevalence of 2.6 per 1000 persons. Accurate statistics on the ultimate
development of IDDM in adults are limited but suggest that the annual
rate varies by geographic regions. An adolescent peak occurs in most
populations, but approximately equal numbers of individuals develop
IDDM before and after 19 years of age.[1-10]
The etiology of beta cell damage and destruction appears to involve
an interphase between genetic predisposition and environmental insult;
IDDM is not inherited. Genetic alterations involving specific HLA
antigens located on chromosome 6 (and other possible non-chromosome 6
alterations) result in an increased risk that beta cell damage will
occur. It appears, however, that less than 5% of individuals possessing
the currently identifiable "diabetic genes" will ever become overtly
diabetic.[11-15] The pathologic process that leads to beta cell
destruction is autoimmune, involving both T-cell and B-cell responses
with cytokine release and free radical accumulation. Nitric oxide seems
the likely candidate as the final toxic mediator.[16-19]
BACKGROUND
There is a long history of attempts to link the expression of
diabetes to a variety of environmental events. The assumed relationship
between mumps infection and later development of IDDM spans almost a
century.[20] The critical unresolved questions include: 1) What
triggers the autoimmune process? 2) Is there a single trigger or do
many environmental insults accumulate to finally destroy the beta cell
mass? 3) Is there a period of special susceptibility and is this
correlated with specific environmental agents? 4) What is the duration
of the biologic latency period between the triggering insult and the
clinical expression of diabetes?
The available evidence supports the contention that several
environmental factors may be critically involved in the initiation and
continuation of the destructive autoimmune process--viral infections,
several specific toxins, nutritional alterations, and emotional
stress.[21-24] Furthermore, while single episodes (such as a mumps
infection) may rarely lead to diabetes, in most cases multiple and
varied insults over time are probably necessary. A recent article has
discussed the possible relationship between early exposure to cow's
milk protein and the development of IDDM.[25] Although the report
provides a conceptual framework, new methodology, and impressive
statistics, it is only one of a number of studies over the past 10
years that have attempted to unravel the complexities of infant feeding
practices and later development of IDDM.
HUMAN STUDIES
In 1984 the initial observation published linking infant feeding
practices and the later development of IDDM involved an ecological
study of breast-feeding practices over several years in Scandinavia.
The study showed that children born during years when breast-feeding
was common were less likely to develop IDDM compared with those born
during years when breast-feeding was less popular. These findings
inferred that either the absence of breast-feeding or the early
introduction of cow's milk formula to the infant's diet were factors in
the development of IDDM in genetically susceptible individuals.[26]
Since then over 90 articles have been published, both defending the
original concept and presenting arguments against its validity.
Gerstein,[27] in a meta-analysis, reviewed all the publications and
carefully selected about 20 studies that met stringent scientific
criteria. This analysis concluded that there was a modest, but
statistically significant association (odds ratio >= 1.5) between
the early introduction of cow's milk (and/or early termination of
breast-feeding) and the development of IDDM in childhood. The timing,
dosage, and duration of the infant's exposure to cow's milk may be
important, with some studies suggesting earlier age of onset of IDDM in
those who were not breast-fed or had very limited exposure to human
milk.[28-45]
A commentary by Kostraba[46] accompanying the Gerstein meta-analysis
appropriately broadens the discussion to include other aspects of
infant feeding and suggests caution in moving from statistical
relationships to causation. If a causal link exists between the
ingestion of cow's milk and the onset of diabetes, it seems that milk
protein or some subfraction is an active precipitator of the autoimmune
process in genetically susceptible subjects, rather than human milk
providing a protective influence. There is no evidence that processed
milk, such as that found in commercial infant formulas, is in any way
more or less harmful than whole cow's milk.
It has been known for several years that children with IDDM have an
increased frequency of antibodies to a variety of cow's milk proteins,
which is particularly evident in those with early onset IDDM. The
recent article by Karjalainen et al[25] extends these observations and
may provide additional insight into the initiation of the autoimmune
process. These investigators identified antibodies to a 17-amino acid
fragment of bovine serum albumin in 100% of a large group of Finnish
children with newly diagnosed diabetes. Bovine serum albumin, which is
present in cow's milk, is immunologically distinct from human serum
albumin with little or no cross-reactivity. Antibodies to the 17-amino
acid bovine serum albumin peptide molecule were found in few healthy
controls or siblings of diabetic children. These exciting, provocative
results have not been fully duplicated in extended studies in the
initial laboratory and have yet to be confirmed by other
investigators.[47]
ANIMAL STUDIES
To our knowledge, the first documentation of a link between cow's
milk protein and diabetes in susceptible animal strains was reported in
1984, shortly after the Scandinavian observations of breast-feeding
practices and the development of IDDM.[26,48] The addition of cow's
milk protein to routine rat chow increased the frequency of diabetes in
genetically susceptible biobreeding (BB) rats up to nearly 100%.
Removing all whole protein and replacing it with a protein hydrolysate
reduced the expression of diabetes in these animals to nearly zero.
Numerous studies of feeding have since been carried out utilizing
primarily the genetically susceptible BB rat and nonobese diabetic
mouse strains. Although many studies have confirmed a provocative
effect of milk proteins and beef proteins on the frequency of
diabetes,[49-53] this finding has not been invariably true. Several
investigators have been unable to replicate the early findings
consistently and have in some cases identified evidence that a number
of plant proteins, most notably soy, may also trigger diabetes in
susceptible animal strains.[54-59]
CONCLUSION
1. Insulin-dependent diabetes mellitus develops within a group of
individuals who carry specific diabetes susceptibility traits. Because
all of the potential diabetes "susceptibility genes" are not known,
currently it is not possible to identify all individuals at risk. It
appears, however, that a small percentage of such individuals will ever
develop clinical diabetes mellitus.
2. The autoimmune destructive process may be triggered by a number
of environmental events.
3. Early exposure of infants to cow's milk protein may be an
important factor in the initiation of the beta cell destructive process
in some individuals. It is not known whether the cow's milk protein in
commercially available infant formulas is associated with this
process.
4. The avoidance of cow's milk protein for the first several months
of life may reduce the later development of IDDM or delay its onset in
susceptible individuals.
5. Research directed toward further defining the possible
relationship between infant feeding practices and the development of
IDDM is needed.
RECOMMENDATIONS
1. Breast-feeding is strongly endorsed as the primary source of
nutrition during the first year of life for all infants.
2. In families with a strong history of IDDM, particularly if a
sibling has diabetes, breast-feeding and avoidance of commercially
available cow's milk and products containing intact cow's milk protein
during the first year of life are strongly encouraged.
3. Since the antigenicity of infant formulas and cow's milk may be
different and there is no evidence against the use of formula for
infants whose mothers do not breast-feed, commercial infant formulas
utilizing cow's milk protein remain the approved alternate.
4. The substitution of soy-based formulas for milk-based formulas is
not advised for either general or high-risk infant feeding practices
because of animal studies linking the ingestion of soy protein intake
to the development of diabetes.
5. The substitution of elemental formulas for milk-based formulas
has intellectual appeal as potential antigenically harmful large
proteins have been replaced by dipeptides, tripeptides, and
oligopeptides. However, because no scientific studies in humans
confirming their benefit are yet available, this feeding option cannot
be endorsed.
6. A prospective randomized trial in which genetically susceptible
infants avoid the ingestion of cow's milk should be developed through
collaborative national and international arrangements.
WORK GROUP ON COW'S MILK PROTEIN AND DIABETES
MELLITUS
Allan L. Drash, MD, Chair
Michael S. Kramer, MD
Jack Swanson, MD
John N. Udall, Jr, MD, PhD
REFERENCES
1. LaPorte RE, Fishbein HA, Drash AL, et al. The Pittsburgh
insulin-dependent diabetes mellitus (IDDM) registry: the incidence of
insulin-dependent diabetes mellitus in Allegheny County, Pennsylvania
(1965-1976). Diabetes. 1981;30:279-284
2. LaPorte RE, Tajima N, Akerblom HK, et al. Geographic differences
in the risk of insulin dependent diabetes mellitus: the importance of
registries. Diabetes Care. 1985;8(suppl 1):101-107
3. Diabetes Epidemiology Research International. Geographic patterns
of childhood insulin-dependent diabetes mellitus. Diabetes.
1988;37:1113-1119
4. Rewers M, LaPorte RE, King H, Tuomilehto J. Trends in the
prevalence and incidence of diabetes: insulin-dependent diabetes
mellitus in childhood. World Health Stat Q. 1988;41:179-189
5. Stone RA. Secular trends in incidence of childhood IDDM in 10
countries. Diabetes Care. 1990;39:858-864
6. WHO DIAMOND Project Group. WHO multinational project for
childhood diabetes. Diabetes Care. 1990;13:1062-1068
7. Joner G, Sovik O. The incidence of type I (insulin-dependent)
diabetes mellitus 15-29 years in Norway 1978-1982.
Diabetologia. 1991;34:271-274
8. Schoenle EJ, Bagot M, Semadeni S, Wiesendanger M, Molinai L.
Epidemiology of insulin-dependent diabetes mellitus in Switzerland:
increasing incidence rate and rural-urban differences in Swiss men born
1948-1972. Diabetes Care. In press
9. Nystrom L, Dahlquist G, Rewers M, Wall S. The Swedish childhood
diabetes study. An analysis of the temporal variation in diabetes
incidence 1978-1987. Int J Epidemiol. 1990;19:141-146
10. Tuomilehto J, Rewers M, Reunanen A, et al. Increasing trend in
type I (insulin-dependent) diabetes mellitus in childhood in Finland.
Analysis of age, calendar time and birth cohort effects during 1965 to
1984. Diabetologia. 1991;34:282-287
11. Todd JA, Bell JI, McDevitt HO. HLA-DQ beta gene contributes to
susceptibility resistance to insulin-dependent diabetes mellitus.
Nature. 1987;329:599-604
12. Todd JA, Bell JI, McDevitt JA. A molecular basis for genetic
susceptibility in insulin dependent diabetes mellitus. Trends
Genet. 1988;4:129-134
13. Morel PA, Dorman JS, Todd JA, McDevitt HO, Trucco M. Aspartic
acid at position 57 of the HLA-DQ beta chain protects against type I
diabetes mellitus: a family study. Proc Natl Acad Sci USA.
1988;85:8111-8115
14. Trucco M. Immunogenetics in insulin-dependent diabetes mellitus:
the second-event hypothesis. In: Belfione F, Bergman RN, Molinatti GM,
eds. Current Topics in Diabetes Research. Vol 12. Basel:
Karger; 1993, pp 135-146
15. Trucco M. To be or not to be ASP 57, that is the question.
Diabetes Care. 1992;15:705-715
16. Bottazzo GF. Death of a beta cell: homicide or suicide?
Diabetic Med. 1986;3:119-130
17. Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune
disease. N Engl J Med. 1986;314:1360-1368
18. Drell DW, Notkins AL. Multiple immunological abnormalities in
patients with type I (insulin dependent) diabetes mellitus.
Diabetologia. 1987;30:132-143
19. Kolb H, Kolb-Bachofen V. Nitric oxide: a pathogenic factor in
autoimmunity. Immunol Today. 1992;13:157-160
20. Harris HF. A case of diabetes mellitus following mumps.
Boston Med Surg J. 1899;140:645-649
21. Orchard TJ, Dorman JS, LaPorte RE, Ferrell RE, Drash AL. Host
and environmental interactions in diabetes mellitus. J Chronic
Dis. 1986;39:979-999
22. Diabetes Epidemiology Research International. Preventing insulin
dependent diabetes mellitus: the environmental challenge. Br Med
J. 1987;295:479-481
23. Drash AL, Lipton RB, Dorman JS, et al. The interface between
epidemiology and molecular biology in the search for the causes of
insulin dependent diabetes mellitus. Ann Med.
1991;23:463-471
24. Laron Z, Karp M, eds. Genetic Environmental Risk Factors for
Type I Diabetes (IDDM) Including a Discussion on the Autoimmune Basis.
London, England: Freund Publishing House, Ltd; 1992
25. Karjalainen J, Martin JM, Knip M, et al. A bovine albumin
peptide as a possible trigger of insulin-dependent diabetes mellitus.
N Engl J Med. 1992;327:302-307
26. Borch-Johnsen K, Joner G, Mandrup-Poulsen T, et al. Relation
between breast-feeding and incidence rates of insulin-dependent
diabetes mellitus. A hypothesis. Lancet. 1984;2:1083-1086
27. Gerstein HC. Cow's milk exposure type I diabetes mellitus. A
critical overview of the clinical literature. Diabetes Care.
1994;17:13-19
28. Scott FW. Cow milk and insulin-dependent diabetes mellitus: is
there a relationship? Am J Clin Nutr. 1990;51:489-491
29. Dahl-Jorgensen K, Joner G, Hanssen KF. Relationship between
cows' milk consumption and incidence of IDDM in childhood. Diabetes
Care. 1991;14:1081-1083
30. Virtanen SM, Rasanen L, Aro A, et al. Infant feeding in Finnish
children less than 7 yr of age with newly diagnosed IDDM. Childhood
Diabetes in Finland Study Group. Diabetes Care.
1991;14:415-417
31. Virtanen SM, Rasanen L, Aro A, et al. Feeding in infancy and the
risk of type 1 diabetes mellitus in Finnish children. Childhood
Diabetes in Finland Study Group. Diabetic Med.
1992;9:815-819
32. Dahlquist G, Blom L, Lonnberg G. The Swedish childhood diabetes
study--a multivariate analysis of risk determinants for diabetes in
different age groups. Diabetologia. 1991;34:757-762
33. Blom L, Dahlquist G, Nystrom L, Sandstrom A, Wall S. The Swedish
childhood diabetes study--social and perinatal determinants for
diabetes in childhood. Diabetologia. 1989;32:7-13
34. Dahlquist G, Savilahti E, Landin-Olsson M. An increased level of
antibodies to beta-lactoglobulin is a risk determinant for early-onset
type 1 (insulin-dependent) diabetes mellitus independent of islet cell
antibodies and early introduction of cow's milk. Diabetologia.
1992;35:980-984
35. Glatthaar C, Whittall DE, Welborn TA, et al. Diabetes in Western
Australian children: descriptive epidemiology. Med J Aust.
1988;148:117-123
36. Kostraba JN, Dorman JS, LaPorte RE, et al. Early infant diet and
risk of IDDM in blacks and whites--a matched case-control study.
Diabetes Care. 1992;15:626-631
37. Siemiatycki J, Colle E, Campbell S, Dewar RA, Belmonte MM.
Case-control study of IDDM. Diabetes Care. 1989;12:209-216
38. Mayer EJ, Hamman RF, Gay EC, Lezotte DC, Savitz DA, Klingensmith
GJ. Reduced risk of IDDM among breast-fed children. The Colorado IDDM
Registry. Diabetes. 1988;37:1625-1632
39. Kostraba JN, Cruikshanks KJ, Lawler-Heavner J, et al. Early
exposure to cow's milk and solid foods in infancy, genetic
predisposition and risk of IDDM. Diabetes. 1993;42:288-295
40. Fort P, Lanes R, Dahlem S, et al. Breast feeding and
insulin-dependent diabetes mellitus in children. J Am Coll
Nutr. 1986;5:439-441
41. Kyvik KO, Green A, Svendsen A, Mortensen K. Breast feeding and
the development of type 1 diabetes mellitus. Diabetic Med.
1992;9:233-235
42. Metcalfe MA, Baum JD. Family characteristics and insulin
dependent diabetes. Arch Dis Child. 1992;67:731-736
43. Nigro G, Campea L, De Novellis A, Orsini M. Breast-feeding and
insulin-dependent diabetes mellitus. Lancet. 1985;1:467
44. Bognetti E, Meschi F, Malavasi C, et al. HLA antigens in Italian
type 1 diabetic patients: role of DR3/DR4 antigens and breast feeding
in the onset of the disease. Acta Diabetol. 1992;28:229-232
45. Virtanen SM, Rasanen L, Ylonen K, et al. Early introduction of
dairy products associated with increased risk of IDDM in Finnish
children. Childhood in Diabetes in Finland Study Group.
Diabetes. 1993;42:1786-1790
46. Kostraba JN. What can epidemiology tell us about the role of
infant diet in the etiology of IDDM? Diabetes Care.
1994;17:87-91
47. Atkinson MA, Bowman MA, Kao KJ, et al. Lack of immune
responsiveness to bovine serum albumin in insulin-dependent diabetes.
N Engl J Med. 1993;329:1853-1858
48. Elliot RB, Martin JM. Dietary protein: a trigger of insulin
dependent diabetes in the BB rat? Diabetologia.
1984;26:297-299
49. Daneman D, Fishman L, Clarson C, Martin J. Dietary triggers of
insulin-dependent diabetes in the BB rat. Diabetes Res Clin
Exp. 1987;5:93-97
50. Coleman DL, Kuzava JE, Leiter EH. Effect of diet on incidence of
diabetes in nonobese diabetic mice. Diabetes.
1990;39:432-436
51. Scott FW, Daneman D, Martin JM. Evidence for a critical role of
diet in the development of insulin-dependent diabetes mellitus.
Diabetes Res Clin Exp. 1988;7:153-157
52. Scott FW, Elliott RB, Kolb H. Diet and autoimmunity: prospects
of prevention of type I diabetes. Diabetes Nutr Metabol Clin
Exp. 1989;2:61-67
53. Leslie RDG, Elliot RB. Early environmental events as a cause of
IDDM: evidence and implications. Diabetes. 1994;43:843-850
54. Scott FW, Sarwar G, Cloutier HE. Diabetogenicity of various
protein sources in the diet of the diabetes-prone BB rat. In:
Camerini-Davalos RA, Cole HS, eds. Prediabetes. New York: Plenum
Publishing Corp; 1988:277-285
55. Scott FW, Cloutier HC, Souligny J, Riley WJ, Hoorfar J, Brogren
CH. Diet and antibody production in the diabetes-prone BB rat. In:
Larkins R, Zimmet P, Chisholm D, eds. Diabetes 1988. Proceedings of the
13th International Diabetes Federation. The Netherlands: Elsevier
Science Publishers BV; 1989:763-767
56. Scott FW, Marliss EB. Conference summary: diet as an
environmental factor in development of insulin-dependent diabetes
mellitus. Can J Physiol Pharmacol. 1991;69:311-319
57. Hoorfar J, Scott FW, Cloutier HE. Dietary plant materials and
development of diabetes in the BB rat. J Nutr.
1991;121:908-916
58. Scott FW. Food, diabetes immunology. In: Forse SA, Kabbash L,
Blackburn GL, Bell SJ, eds. Diet, Nutrition and Immunity. Boca Raton,
FL: CRC Press. In press.
59. Hoorfar J, Buschard K, Dagnaes-Hansen F. Prophylactic
nutritional modification of the incidence of diabetes in autoimmune
non-obese diabetic (NOD) mice. Br J Nutr. 1993;69:597-607
----------------
The recommendations in this statement do not indicate an exclusive
course of treatment or serve as a standard of medical care. Variations,
taking into account individual circumstances, may be appropriate.
PEDIATRICS (ISSN 0031 4005). Copyright (c) 1994 by the American
Academy of Pediatrics.
No part of this statement may be reproduced in any form or by any
means without prior written permission from the American Academy of
Pediatrics except for one copy for personal use.
|