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Psychological Stress May Induce
Diabetes-Related Autoimmunity in
Infancy
ANNELI SEPA,
PHD
1
JEANETTE WAHLBERG,
MD
1
OUTI VAARALA,
MD, PHD
1
ANN FRODI,
P
H
D
2
JOHNNY LUDVIGSSON,
MD, PHD
1
OBJECTIVE — In retrospective studies, a number of disparate environmental factors (includ-
ing experiences of serious life events) have been proposed as trigger mechanisms for type 1
diabetes or the autoimmune process behind the disease. Psychosocial stress in families may affect
children negatively due to a link to hormonal levels and nervous signals that in turn influence
both insulin sensitivity/insulin need and the immune system. Our aim was to investigate whether
psychological stress, measured as psychosocial strain in families, is associated with diabetes-
related autoimmunity during infancy.
RESEARCH DESIGN AND METHODS — The first 4,400 consecutive 1-year-old chil-
dren from a large prospective population-based project participated in the study. Parents com-
pleted questionnaires at birth and at 1 year, including various measures of psychosocial stress
(e.g., parenting stress) and sociodemographic background. Blood samples drawn from the
children at 1 year were analyzed for type 1 diabetes–associated autoantibodies toward tyrosine
phosphatase and GAD. Antibodies toward tetanus toxoid were used as non–diabetes-related
control antibodies.
RESULTS — Psychosocial factors, i.e., high parenting stress (odds ratio 1.8 [95% CI 1.2–2.9],
P ⬍ 0.01), experiences of a serious life event (2.3 [1.3–4.0], P ⬍ 0.01), foreign origin of the
mother (2.1 [1.3–3.3], P ⬍ 0.001), and low paternal education (1.6 [1.1–2.3], P ⬍ 0.01) were
associated with diabetes-related autoimmunity in the child, independent of family history of
diabetes.
CONCLUSIONS — Psychological stress, measured as psychosocial strain in the family,
seems to be involved in the induction, or progression, of diabetes-related autoimmunity in the
child during the 1st year of life.
Diabetes Care 28:290–295, 2005
T
ype 1 diabetes is a multifactorial dis-
ease caused by an autoimmune de-
struction of insulin-producing
-cells, particularly in genetically predis-
posed individuals (1). At present, a com-
bination of high concentrations of
tyrosine phosphatase autoantibodies (IA-
2As) and GAD autoantibodies (GADAs) is
considered to be the best (2) (and high
concentrations of IA-2As alone the sec-
ond best [3]) marker of this autoimmune
process. Various environmental hypothe-
ses have been suggested concerning the
trigger mechanisms, e.g., viral infections
(1), the hygiene hypothesis (4), and the
accelerator hypothesis (5). The accelera-
tor hypothesis suggests that insulin resis-
tance, due to extensive weight gain, is an
accelerator of the -cell destruction that
leads to type 1 diabetes. However, psy-
chological stress is another important
source for insulin resistance. Moreover,
there are also some risk factors not ex-
plained by these etiological hypotheses,
e.g., low socioeconomic status (6) and pa-
rental age (7).
As early as in the middle of the 17th
century, T. Wills suggested that nervous
system juice and prolonged sorrow were
important etiological factors in diabetes.
More recently, events related to severe
psychological stress have been reported
as risk factors for type 1 diabetes in a na-
tionwide Swedish case-referent study (8).
Another retrospective study found that
experiences of negative life events (e.g.,
separation of the parents, serious illness,
or death in the family) during the first 2
years of life were more common in newly
diseased diabetic children than in a con-
trol group (9). Recently, we reported as-
sociations between high parenting stress,
lack of support/confidence, and some risk
factors for type 1 diabetes, such as low
socioeconomic status (10). We hypothe-
sized that psychological factors may not
only precipitate diabetes, but may also
trigger or promote the progress of diabe-
tes-related autoimmunity.
Previously, psychological stress has
been linked to a number of negative
health consequences, ranging from pain
and sleep deficiencies to negative effects
on cardiovascular, endocrine, and im-
mune systems (11,12). It is also well
known that psychological stress decreases
insulin sensitivity, which in turn increases
pressure on the -cells (-cell stress). Ac-
cording to the attachment theory, infants
need to remain in physical proximity to
their caregivers in order to survive, which
in turn requires that infants be very sen-
●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●
From the
1
Diabetes Research Centre, Division of Paediatrics, Department of Molecular and Clinical Medi-
cine, Faculty of Health Sciences, Linko¨ping University, Linko¨ping, Sweden; and the
2
Division of Psychology,
Department of Behavioural Sciences, Faculty of Arts and Sciences, Linko¨ping University, Linko¨ping, Sweden
Address correspondence and reprint requests to A. Sepa, Division of Paediatrics, Department of Molecular
and Clinical Medicine, Linko¨ping University, SE 581 85 Linko¨ping, Sweden. E-mail:
anneli.sepa@imk.liu.se.
Received for publication 30 June 2004 and accepted in revised form 4 October 2004.
Abbreviations: ABIS, All Babies In Southeast Sweden; GADA, GAD autoantibody; IA-2A, tyrosine phos-
phatase autoantibody; SPSQ, Swedish Parenthood Stress Questionnaire.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
factors for many substances.
© 2005 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby
marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Epidemiology/Health Services/Psychosocial Research
ORIGINAL ARTICLE
290 DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005
sitive to parental moods, signals, and be-
haviors (13). Hence, psychological stress
in children might be caused by negative
family circumstances, e.g., parenting
stress, experiences of serious life events,
unemployment, or low socioeconomic
status, since the infants sense the stress
experienced by the parents (14).
The aim of the current study was to
investigate whether psychological stress,
measured as psychosocial strain in fami-
lies, is associated with the induction or
progression of diabetes-related autoim-
munity during infancy in the general pop-
ulation, i.e., irrespective of genetic risk for
type 1 diabetes.
RESEARCH DESIGN AND
METHODS — From 1 October 1997
to 1 October 1999, all parents-to-be in
southeast Sweden were invited to partic-
ipate in the All Babies In Southeast Swe-
den (ABIS) project, and 78.6% agreed,
yielding a sample of 17,055 families at
birth. In the current study, parental ques-
tionnaire responses from birth and 1 year
as well as blood samples from 1 year were
examined in the first 4,400 consecutive
families for whom data were available for
statistical analyses, i.e., no specific selec-
tion was made. The study cohort was rep-
resentative of the full ABIS cohort at birth
concerning parental age, educational
level, and foreign origin. Compared with
Sweden as a whole and the province of
O
¨
stergo¨tland, there was a slight under-
representation of parents born abroad
and parents with low education in the
current sample (15).
Measures
The Swedish Parenthood Stress Ques-
tionnaire. The Swedish Parenthood
Stress Questionnaire (SPSQ) (16) was
used to measure parenting stress at 1 year.
The SPSQ consists of 34 items, e.g., “It is
more difficult than I expected to raise a
child,” “My life is more or less controlled
by the needs of my child,” and “Thanks to
my child I have made several new ac-
quaintances.” The SPSQ was used with
6-point Likert-type response scales (range
1–6), and the stress score for each indi-
vidual was calculated as a mean value of
all SPSQ questions answered. In the cur-
rent study, a relatively strict criterion
(⬎95th percentile) was used to define the
cutoff for high stress in order to compen-
sate for a slight floor effect in the sample
(M ⫽ 2.59 compared with a theoretical
mean of 3.5). The instrument has good
internal validity (Cronbach’s ␣ for all sub-
scales ⱖ0.65) and good test-retest reli-
ability over 30 days (16).
Experiences of serious life events. Ex-
periences of serious life events were as-
sessed with two dichotomous (yes/no)
questions, at birth: “Have you experi-
enced something that you would describe
as a serious life event (e.g., death of a close
relative or divorce) during pregnancy?”
and at 1 year: “Has your child experienced
a serious or traumatic event (e.g., death in
the family, divorce, new guardian, or the
like)?”
Social support and confidence/security.
Social support and confidence/security
were assessed with two dichotomous
(yes/no) questions at birth: “Do you expe-
rience enough support from your social
environment for yourself and your new-
born baby?” and “Do you feel that you
have enough confidence/security so that
you can give yourself and your newborn
child a good start?” These rather crude
measures were used to assure capturing of
the mothers who truly lacked social sup-
port or confidence/security.
Additional psychological stress mecha-
nisms. Additional psychological stress
mechanisms measured in the question-
naires were as follows: foreign origin of
the parent, defined as the mother or the
father not born in Sweden (specified ori-
gin or race was not assessed); single par-
enthood, which was compared with
cohabiting or married parents; low socio-
economic status, measured as low paren-
tal education, defined as only having
finished 9-year compulsory school; pa-
rental unemployment (not maternity
leave), registered during the child’s 1st
year of life; and need for neonatal inten-
sive care (yes/no), assessed in the at-birth
questionnaire.
Autoantibodies. IA-2As and GADAs
were assessed in whole blood drawn from
the child at 1 year of age. The blood sam-
ples were analyzed by an immunoprecipi-
tation method (2). Positivity for IA-2As
and GADAs was determined as antibody
levels above the 95th percentile for
1-year-old healthy infants, which corre-
sponds to 34.8 World Health Organiza-
tion (WHO) units for IA-2A and 97.9
WHO units for GADA. Cutoffs at the 95th
percentile yielded samples of 220 infants
positive for IA-2A and 221 for GADA.
Only 33 of these infants were double pos-
itive, i.e., positive for IA-2A as well as
GADA.
In the 2nd international workshop
(Diabetes Autoantibody Standardization
Program, 2002), the specificity was 100%
for the IA-2A and 96% for the GADA as-
say and the sensitivity was 54 and 81%,
respectively. The intra-assay coefficient of
variation (CV) was 5.2%, and the interas-
say CV was 13%.
Non–diabetes-related antibodies.
Non–diabetes-related antibodies against
tetanus toxoid were analyzed in a sub-
group (n ⫽ 721) of the study population.
The selection criteria were 1) lack of sup-
port, lack of confidence, and/or high par-
enting stress (i.e., above the 95th
percentile on SPSQ; n ⫽ 404) and 2) so-
cial support, confidence/security, and low
parenting stress (i.e., below the 5th per-
centile on SPSQ; n ⫽ 317).
Antibodies toward tetanus toxoid
were detected with enzyme-linked immu-
nosorbent assay. Tetanus toxoid (0.1 g)
in PBS was used for coating the plates,
0.05% Tween-PBS was used as washing
buffer, and 1% human serum albumin in
PBS was used as blocking agent. The
whole-blood samples were studied at a
dilution of 1/400 in 0.2% human serum
albumin–0.05% Tween-PBS. Alkaline
phoshatase–conjugated anti-human IgG
(Fc) (Jackson ImmunoResearch) was
used as a secondary antibody. The results
were expressed as optical density units. A
homemade standard was prepared from a
pool of serum samples with high levels of
antibodies to tetanus toxoid to control the
interassay variation, which was 14%. The
intra-assay variation was 9%.
Potential confounding factors. Poten-
tial confounding factors that might influ-
ence the occurrence of diabetes-related
autoantibodies (1,7,17) were assessed in
the questionnaires. Autoimmunity in the
family was defined as a mother, father, or
sibling suffering from hypo- or hyperthy-
roidism, pernicious anemia, SLE/LED/
Lupus erythematosus, Mb Addison,
Celiac disease, inflammatory bowl disease
(Mb Crohn or Colitis ulcerosa), or rheu-
matoid arthritis. Type 1 diabetes in the
family was defined as a mother, father, or
sibling suffering from type 1 diabetes. In-
creased maternal/paternal age was de-
fined as being ⬎30 years at the time of the
birth of the child. Early introduction of
food (especially gluten and cow’s milk)
was controlled for by assessing the length,
in months, of exclusive breast-feeding.
Sepa and Associates
DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005 291
Size for gestational age was calculated ac-
cording to the formula of the National
Swedish Board of Health and Welfare,
yielding the categories small, appropriate,
or large for gestational age. The BMI of the
child was calculated based on the height
and weight reported by the parents at 1
year. Two groups, above and below the
90th percentile, were formed. Three dif-
ferent measures of child infections were
assessed at 1 year. The number of gastro-
enteritis and infections treated with pen-
icillin during the 1st year of life was
dichotomized into three or more versus to
two or less. The number of upper respira-
tory infections was dichotomized into two
or more versus one or none. Delivery
mode was assessed at birth and coded as
normal delivery versus cesarean section
(all other types of problematic deliveries
were excluded).
Procedure
The first questionnaire was completed by
the parents during the child’s 1st week of
life. Capillary blood was drawn from the
child, and the second questionnaire was
given to the parents at the 1-year checkup
at the well child clinics. The capillary
tubes with whole blood were sent to and
analyzed at the Clinical Research Centre,
Faculty of Health Sciences, Linko¨ping,
Sweden.
Statistical analyses
SPSS 11.0 was used to calculate
2
values,
Mann-Whitney analyses, Spearman’s
rank correlation coefficients (), and lo-
gistic regression analyses. The initial uni-
variate analyses were not corrected for
multiple comparisons, despite repeated
2
analyses, since the risk of missing ac
-
tual differences was regarded as more
problematic than the risk of finding false
differences concerning the selection of
variables for inclusion in the multivariate
analyses. However, the statistical signifi-
cances found in the univariate analyses
were still evaluated regarding their indi-
vidual theoretical plausibility and con-
cerning the uniformity of the patterns of
results, since an expected pattern of re-
sults is more likely to indicate a true ef-
fect. Concerning the multivariate logistic
regression analyses, only odds ratios with
P values ⬍0.01 were regarded as statisti-
cally significant in order to correct for
multiple comparisons.
The findings were examined for a
number of potential confounding factors;
if these were nonrelated to IA-2A, GADA,
and double positivity, they could not ex-
plain our findings. The sample was also
stratified for diabetes heredity, and the bi-
variate relation between parenting stress
and autoimmunity was examined in the
absence of diabetes heredity. Intercorre-
lations between the psychosocial vari-
ables associated with IA-2A and GADA,
respectively, were investigated using
Spearman’s r (). Multiple logistic regres-
sion analyses (forward stepwise) were
conducted in order to differentiate among
the psychosocial variables associated with
IA-2A and GADA separately and, if
needed, to investigate whether any poten-
tial confounding factors would be in-
cluded in the regression models. Odds
ratios (ORs) with 95% CIs were used as
approximate measures of relative risk.
Ethical considerations
Participating parents gave their consent
after receiving oral and written informa-
tion, as well as having been offered to see
a video film about the project. The par-
ents were not automatically informed of
the autoantibody status of their child.
However, they were told that they could
receive this information upon active re-
quest, but ⬍1% of the parents have taken
advantage of this possibility.
The ABIS project and the current
study were approved by the Research Eth-
ics Committees of the Faculty of Health
Science at the University of Linko¨ping,
Linko¨ping, Sweden, and the Medical Fac-
ulty at the University of Lund, Lund,
Sweden.
RESULTS — A significant association
between high parenting stress and con-
centrations of IA-2A above the 95th per-
centile was found (Table 1): 8.4% of those
with high parenting stress were IA-2A
positive [
2
(1) ⫽ 11.133, P ⬍ 0.001].
This association remained significant,
even in the strata 1) without as well as
with autoimmunity in the family and 2)
without type 1 diabetes in the family. 1)In
the strata without autoimmunity in the
family (n ⫽ 3,915), 8.6% of those report-
ing high parenting stress were IA-2A pos-
itive [
2
(1) ⫽ 9.929, P ⬍ 0.01].
Concerning the strata with autoimmunity
in the family (n ⫽ 473), 9.8% of those
reporting high parenting stress were
IA-2A positive. This distribution was al-
most equal to the distribution of the full
sample and the strata without autoimmu-
nity in the family, but it did not reach
statistical significance. 2) Concerning the
strata without type 1 diabetes in the fam-
ily (n ⫽ 4,180), 8.8% of those reporting
high parenting stress were IA-2A positive
[
2
(1) ⫽ 11.331, P ⬍ 0.001]. However,
regarding type 1 diabetes in the family
(n ⫽ 109), there were not enough sub-
jects in the high stress group (n ⫽ 4) for
statistical analysis.
In addition, the experience of a seri-
ous life event during the child’s 1st year of
life and maternal unemployment (not ma-
ternity leave) during the child’s 1st year of
life were significantly associated with con-
centrations of IA-2A above the 95th per-
centile (Table 1). There were very low
correlations between the three psychoso-
cial factors (strongest correlation: ⫽
0.055, P ⬍ 0.01) associated with in-
creased concentrations of IA-2, and the
multivariate logistic regression model in-
cluded only parenting stress (OR 2.0
[95% CI 1.3–3.0], P ⬍ 0.001) as a predic-
tor. The P value for experience of a serious
life event during the child’s 1st year of life
(1.9 [1.1–3.3]) was 0.025; therefore it
was disregarded as a predictor in this re-
gression model due to the correction for
multiple analyses.
With regard to concentrations of
GADA above the 95th percentile, there
were significant associations with foreign
origin (i.e., not born in Sweden) of the
mother and low parental education (Ta-
ble 1). There was a weak correlation (⫽
0.239, P ⬍ 0.01) between low maternal
and low paternal education. The multi-
variate logistic regression model of the
three psychosocial factors associated with
increased concentrations of GADA in-
cluded foreign origin of the mother (OR
2.1 [95% CI 1.3–3.3], P ⬍ 0.001) and low
education of the father (1.6 [1.1–2.3],
P ⬍ 0.01) as predictors.
The only psychological stress mecha-
nism associated with double positivity
was need for neonatal intensive care
(Table 1).
The bivariate relations between dia-
betes-related autoantibodies on the one
hand and potential confounds, such as di-
abetes heredity, increased parental age,
early food introduction, size for gesta-
tional age, BMI at 1 year, child infections,
and delivery mode, on the other were
mainly nonsignificant (Table 1). How-
ever, more than two upper respiratory in-
fections in the child during the 1st year of
life was associated with high IA-2A con-
Stress and autoimmunity in infancy
292 DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005
Table 1—Bivariate
2
associations to concentrations above the 95th percentile of IA-2A, GADA, and double positivity (n ⴝ 4,400)
IA-2A GADA
Double positivity
(i.e., IA-2A ⫹ GADA)
⬍95th (n/n) ⬎95th (n/n)
2
P ⬍95th (n/n) ⬎95th (n/n)
2
P ⬍95th (n/n) ⬎95th (n/n)
2
P
Psychological stress mechanisms
High parenting stress 326/356 30/356 11.133 ⬍0.001 — — — NS — — F NS
Lack of social support — — — NS — — — NS — — F NS
Lack of confidence — — — NS — — — NS — — F NS
Experiences of serious life events during
1st year of life
157/172 15/172 5.988 ⬍0.05 — — — NS — — F NS
Born abroad (mother) — — — NS 227/250 23/250 9.616 ⬍0.01 — — F NS
Born abroad (father) — — — NS — — — NS — — F NS
Single parenthood — — — NS — — — NS — — F NS
Low education (mother) — — — NS 290/313 23/313 3.909 ⬍0.05 — — F NS
Low education (father) — — — NS 486/525 39/525 7.323 ⬍0.01 — — F NS
Unemployed (mother) 198/215 17/215 4.743 ⬍0.05 — — — NS — — F NS
Unemployed (father) — — — NS — — — NS — — F NS
Need for neonatal intensive care — — — NS — — — NS 436/443 7/443 F ⬍0.05
Potential confounding factors
Autoimmunity in the family — — — NS — — — NS — — F NS
Type 1 diabetes in the family — — — NS — — — NS — — F NS
Increased age (mother ⬎30 years) — — — NS — — — NS — — — NS
Increased age (father ⬎30 years) — — — NS — — — NS — — — NS
Exclusive breast-feeding (number of
months)
— — M-W NS — — M-W NS — — M-W NS
Size for gestational age* — — — NS — — — NS — — — —
BMI at 1 year of age (⬎90th percentile) — — — NS — — — NS — — F NS
Gastroenteritis (ⱖ3 times) in the child
during 1st year of life
——FNS——FNS——FNS
Infections treated with penicillin (ⱖ3 times)
in the child during 1st year of life
———NS———NS——FNS
Upper respiratory infection (ⱖ2 times) in
the child during 1st year of life
453/488 35/488 5.820 ⬍0.05 — — — NS 480/488 8/488 F ⬍0.05
Cesarean section — — — NS — — — NS — — F NS
*Calculation of
2
for double positivity was not possible because of the small number in ⬎25% of the cells. F, Fisher’s exact test; M-W, Mann-Whitney test.
Sepa and Associates
DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005 293
centrations. When this variable was in-
cluded in the logistic regression analyses,
the IA-2A model included experiences of
a serious life event (OR 2.3 [95% CI 1.3–
4.0], P ⬍ 0.01) and parenting stress (1.8
[1.2–2.9], P ⬍ 0.01). The P value for up-
per respiratory infections (1.6 [1.1–2.3])
was ⬍0.05; therefore it was disregarded
as a predictor due to the correction for
multiple analyses.
There were no significant associations
between psychosocial factors and en-
hanced immune responsiveness reflected
as IgG-class antibodies toward tetanus
toxoid. Furthermore, neither IA-2A (⫽
0.038, NS) nor GADA (⫽0.046, NS)
were correlated with antibodies toward
tetanus toxoid.
CONCLUSIONS — In our prospec-
tive, population-based sample, we found
high parenting stress, experiences of seri-
ous life events, foreign origin of the
mother, and low socioeconomic status to
be associated with -cell–related autoim-
munity in young children. These associa-
tions were found despite a slight under-
representation of foreign origin and low
education in the current sample. The
above-mentioned psychosocial factors are
well known in the literature as creating
stress and strain in families, which in turn
may stress the infants (14), probably be-
cause of their sensitivity to parental
moods, signals, and behaviors (13). For
example, parenting stress has been asso-
ciated with poor marital quality (18),
poor parental well being (18), and more
caretaking hassles (19), i.e., poor infant
sleep, feeding difficulties, excessive cry-
ing, colic, and childhood infections. Ex-
periences of serious life events (e.g.,
parental separation, serious illness, or
death in the family) has been suggested to
trigger type 1 diabetes (8) or the autoim-
mune process behind the disease (9). Fi-
nally, to give birth to a child outside one’s
own native country might be perceived as
extra-stressful, since becoming a parent is
a major life transition that normally awak-
ens thoughts about one’s own origin and
sometimes also a need for proximity to
one’s own parents.
The fact that need for neonatal inten-
sive care was associated with double pos-
itivity, whereas neither size for gestational
age nor BMI at 1 year were associated with
diabetes-related autoimmunity, is inter-
esting. Many infants who need intensive
care have a low birth weight or are small
for date, with expected rapid weight gain,
which according to the accelerator hy-
pothesis is a risk for type 1 diabetes (5).
However, treatment at a neonatal inten-
sive ward includes daily repeated stressful
and painful procedures, giving an exten-
sive cortisol production in many children
(20). Thus, treatment at a neonatal inten-
sive ward could be interpreted as severe
psychological stress, and one could spec-
ulate about the risk of insulin resistance
and -cell stress. It would indeed have
been interesting to investigate the effect of
early weight gain as well, but that could
unfortunately not be assessed in the cur-
rent study.
A number of potential confounding
factors were investigated, but only re-
peated upper respiratory infections were
significantly associated with diabetes-
related autoantibodies in the initial uni-
variate analyses. However, upper
respiratory infections were not included
among the predictors when included in
the multivariate analysis.
Our results support the view that psy-
chosocial stress in the family induces
stress in the child (14) that is severe
enough to trigger or promote the progres-
sion of  -cell–related autoimmunity in
infants. There are a number of ways in
which psychological stress may affect the
body, e.g., via increased cortisol as well as
catecholamine concentrations (11,21).
Recently, stress has been associated with
the development of allergies (22) and has
been shown to influence the functional
profile of T-cells (22–24). Furthermore,
stress has been shown to modify the out-
come of immunization in humans (25).
We could not find any association be-
tween antibody levels of tetanus toxoid
and stress factors. This may suggest that
stress, in our study, specifically affected
-cell autoimmunity. In the case of diabe-
tes-related autoimmunity, the link could
be an increased need for insulin due to
hyperglycemia or decreased insulin sensi-
tivity caused by an upregulation of corti-
sol and cathecolamine levels (14,21,26),
placing increased demands on the insu-
lin-producing -cells (-cell stress).
However, measurement of insulin levels
was not included in the ABIS protocol,
and since whole-blood samples (taken at
random and not after fasting) were col-
lected, we were not able to perform the
analyses. Thus, the mechanisms of how
stress may induce -cell autoimmunity
remain unsolved in this early report of
psychological impact on  -cell
autoimmunity.
In children with concentrations
IA-2A or GADA above the 95th percen-
tile, the occurrence of double positivity
was found in ⬃15%, which indicates that
these two autoantibodies are associated,
though weakly, in the general population.
It seems that IA-2A and GADA are in-
duced independently in most children,
and the trigger mechanisms of these two
 -cell autoantibodies may be at least
partly different. This view is also sup-
ported by studies showing genetic, age,
and sex-related differences in the occur-
rence of -cell autoantibodies (2). How-
ever, we considered serious life events,
parenting stress, foreign origin, low edu-
cation, and neonatal intensive care as
markers of stress because they affect the
family climate in a negative way, which in
turn might induce stress in the child.
Thus, the association found is between
stress and -cell autoimmunity (of which
IA-2A and GADA are markers). There-
fore, we have no explanation as to why
associations with different psychological
stress mechanisms were seen in relation
to IA-2A, GADA, and double positivity.
IA-2A is closely related to the risk of type
1 diabetes in children, whereas GADA is
predictive of autoimmune diabetes in ad-
olescents and adults. Insulin autoanti-
bodies often appear as the first sign of
-cell autoimmunity in children and are
associated with type 1 diabetes, especially
in young children. In the current study,
-cell autoantibodies were studied in
lysed capillary blood samples for which
the analyses of insulin autoantibodies is
not recommended due to high unspecific
binding (data not shown). Thus, our re-
sults are restricted to the emergence of
IA-2A and GADA.
High concentrations of IA-2A and
GADA are the best markers for the devel-
opment of type 1 diabetes (2). However,
the levels of these autoantibodies fluctu-
ate in early childhood (2). The occurrence
of -cell autoantibodies, either IA-2A or
GADA, at 1 year of age does not imply a
high risk of type 1 diabetes, and most of
these infants will probably never develop
the manifest disease. Thus, our results so
far only imply that psychosocial stress is
associated with the induction or progres-
sion of -cell autoimmunity during the
1st year of life. The final aim is to study the
importance of stress factors for the devel-
opment of type 1 diabetes or decreased
Stress and autoimmunity in infancy
294 DIABETES CARE, VOLUME 28, NUMBER 2, FEBRUARY 2005
glucose tolerance, but for this purpose a
longer follow-up time is needed when an
unselected population of children is stud-
ied prospectively.
In conclusion, we suggest that psy-
chological stress, measured as psychoso-
cial strain in families, might be involved
in the induction or progression of diabe-
tes-related autoimmunity in infants, pos-
sibly via -cell stress. The findings of the
current study give some support for a
-cell stress hypothesis as an extension of
the accelerator hypothesis (5), in so far
that a number of different factors, e.g.,
psychological stress, puberty, and rapid
growth could be involved in the develop-
ment of type 1 diabetes.
Acknowledgments— The current study, as
part of the ABIS project, was generously sup-
ported by the Juvenile Diabetes Research
Foundation-Wallenberg Foundation (K 98-
99D-12813-01A), the Swedish Research
Council (Vetenskapsrådet; K99-72X-11242-
05A), the Swedish Juvenile Diabetes Founda-
tion (Barndiabetesfonden), the Swedish
Diabetes Association, the So¨derberg Founda-
tion, and the Novo Nordisk Foundation. None
of the funding organizations have had any role
in the design or conduction of the study (nei-
ther concerning collection, analysis, or inter-
pretation of the data, nor preparation, review,
and approval of the manuscript).
We are very grateful to all families partici-
pating in the ABIS project and to all staff mem-
bers at Mother and Baby Health Centres,
where the questionnaires and blood samples
were collected. Many thanks also to A.-C. Gil-
more-Ellis for administrative assistance; I.
Franse´n and C. Larsson for coordinating the
practical aspects of the ABIS project; L. Berg-
lert, J. Fredriksson, and the staff at the Clinical
Research Centre in Linko¨ping for laboratory
assessments; and A. Suomela at the National
Public Health Institute in Helsinki, Finland,
for the determination of antibodies against tet-
anus toxoid.
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