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ORIGINAL ARTICLE
Fatty fish consumption and risk of latent autoimmune diabetes
in adults
JE Löfvenborg
1
, T Andersson
1,2
, P-O Carlsson
3
, M Dorkhan
4
, L Groop
4
, M Martinell
5
, T Tuomi
6
, A Wolk
1
and S Carlsson
1
OBJECTIVE: It has been suggested that intake of fatty fish may protect against both type 1 and type 2 diabetes. Hypotheses rest on
the high marine omega-3 fatty acid eicosapentaenoic acid+docosahexaenoic acid (EPA+DHA) and vitamin D contents, with
possible beneficial effects on immune function and glucose metabolism. Our aim was to investigate, for the first time, fatty fish
consumption in relation to the risk of latent autoimmune diabetes in adults (LADA).
METHODS: Analyses were based on data from a Swedish case–control study with incident cases of LADA (n= 89) and type 2
diabetes (n= 462) and randomly selected diabetes-free controls (n= 1007). Diabetes classification was based on the onset of age
(⩾35), glutamic acid decarboxylase autoantibodies, and C-peptide. A validated food frequency questionnaire was used to derive
information on previous intake of fish, polyunsaturated long-chain omega-3 fatty acids (n-3 PUFA) and supplementation of fish oil
and vitamin D. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression, adjusted for age,
gender, body mass index (BMI), family history of diabetes, physical activity, smoking, education, and consumption of alcohol, fruit,
vegetables and red meat.
RESULTS: Weekly fatty fish consumption (⩾1vso1 serving per week), was associated with a reduced risk of LADA but not type 2
diabetes (OR 0.51, 95% CI 0.30–0.87, and 1.01, 95% CI 0.74–1.39, respectively). Similar associations were seen for estimated intake of
n-3 PUFA (⩾0.3 g per day; LADA: OR 0.60, 95% CI 0.35–1.03, type 2 diabetes: OR 1.14, 95% CI 0.79–1.58) and fish oil supplementation
(LADA: OR 0.47, 95% CI 0.19–1.12, type 2 diabetes: OR 1.58, 95% CI 1.08–2.31).
CONCLUSIONS: Our findings suggest that fatty fish consumption may reduce the risk of LADA, possibly through effects of marine-
originated omega-3 fatty acids.
Nutrition & Diabetes (2014) 4, e139; doi:10.1038/nutd.2014.36; published online 20 October 2014
INTRODUCTION
Recent findings suggest that fatty fish consumption may be
protective against autoimmune diabetes in children;
1,2
a Norwe-
gian study found a reduced risk of type 1 diabetes in children who
were given dietary supplementation of cod liver oil during first
year of life.
1
Likewise, a US study showed that the intake of
omega-3 fatty acids, was inversely associated with islet auto-
immunity in genetically susceptible children.
2
Fish intake has also
been associated with a reduced risk of other autoimmune diseases
in adults such as rheumatoid arthritis
3
and multiple sclerosis.
4
An
inverse relationship between fatty fish consumption and type 2
diabetes has also been proposed
5
but as shown in two recent
reviews, findings for type 2 diabetes are inconclusive.
6,7
The hypothesized effect has primarily been attributed to the
polyunsaturated long-chain omega-3 fatty acids (n-3 PUFA) found
in fish and fish oil, especially eicosapentaenoic (EPA) and
docosahexaenoic (DHA) acids. EPA and DHA possess anti-
inflammatory, immunomodulatory and gene expression regula-
tory properties.
8
Owing to the highly unsaturated properties of
EPA and DHA, they are able to be rapidly incorporated in the
membranes of immune cells, thereby alter their function
8
and
thus may be beneficial with regard to autoimmune diseases. This
cell membrane incorporation happens partly on the expense of
the pro-inflammatory arachidonic acid.
8
The anti-inflammatory
property may be of importance for autoimmune diabetes but also
type 2 diabetes as both conditions have been associated with low-
grade inflammation,
9
further, these properties of EPA and DHA
have been suggested also to affect insulin signaling.
10
Fatty fish is
also an important dietary source of vitamin D, which in recent
years has attained much attention for its immunoregulatory
properties and inverse association with both type 1 and type 2
diabetes.
11
Latent autoimmune diabetes in adults (LADA) may be the
second most common form of diabetes,
12
accounting for 9% of all
diabetes in Europe according to a recent report. LADA has been
described as a hybrid between type 1 and type 2 diabetes;
13
Like
type 1 diabetes, it is an autoimmune form of diabetes, but with a
slower autoimmune process than in classic type 1 diabetes. In
addition, LADA patients tend to have features of type 2 diabetes
including overweight and insulin resistance.
14
Risk factors are
largely unexplored and as far as we know, the risk of LADA in
relation to intake of fatty fish has never been investigated before.
Our aim was to investigate the risk of LADA, and type 2 diabetes
in relation to consumption of fatty fish and dietary supplementa-
tion of fish oil and vitamin D using data from Epidemiologic study
of risk factors for LADA and type 2 diabetes (ESTRID)—a new
Swedish population-based study with incident cases.
1
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;
2
Center for Occupational and Environmental Medicine, Stockholm County Council, Stockholm,
Sweden;
3
Department of Medical Sciences, Uppsala University, Uppsala, Sweden;
4
Department of Clinical Sciences, Lund University, Malmö, Sweden;
5
Department of Public
Health and Caring Sciences, Uppsala University, Uppsala, Sweden and
6
Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital; Research Program
for Diabetes and Obesity, University of Helsinki and Folkhalsan Research Center, Helsinki, Finland. Correspondence: Dr S Carlsson, Institute of Environmental Medicine, Karolinska
Institutet, Box 210, Stockholm SE171 77, Sweden.
E-mail: sofia.carlsson@ki.se
Received 3 July 2014; revised 18 August 2014; accepted 2 September 2014
Citation: Nutrition & Diabetes (2014) 4, e139; doi:10.1038/nutd.2014.36
© 2014 Macmillan Publishers Limited All rights reserved 2044-4052/14
www.nature.com/nutd
MATERIALS AND METHODS
Study population and design
Results were based on data from ESTRID; (http://www.ki.se/imm/estrid),
initiated in 2010 (Figure 1). The ESTRID data collection has been described
in detail elsewhere.
15
In short, incident cases of diabetes were identified
continuously using two population-based diabetes registries in Sweden
(ANDIS; All New Diabetics in Scania http://andis.ludc.med.lu.se/, and
ANDiU; All New Diabetics in Uppsala http://www.andiu.se/), aimed at
characterizing all new diabetes cases with regard to clinical and genetic
factors. To ESTRID we invited all new cases of LADA identified in Skåne
(from 2010 onwards) and Uppsala (from 2012 onwards) together with a
random sample of patients with newly diagnosed type 2 diabetes (four per
LADA case). For each LADA case, six diabetes-free controls (⩾35 years)
were randomly selected from the population of Scania and Uppsala, using
the Swedish population registry. They were matched to the cases by time
and region (incidence density sampling).
16
Analyses in the present paper
were based on data collected in ESTRID between its initiation in September
2010 and July 2013, with a response rate of 80% (cases) and 67% (controls).
As the present investigation concerned dietary habits prior to diagnosis,
the analysis of this paper were based on all patients participating in ESTRID
within 6 months of diagnosis, including 89 cases of LADA, 462 cases of
type 2 diabetes, and 1007 controls. The study was approved by the
Regional Ethical Review Board at Karolinska Institutet, Sweden, and all
participants provided written informed consent.
Diabetes classification and clinical analysis
Cases were diagnosed within the health-care system and at diagnosis,
blood samples were collected and analysed at the central laboratories of
the university hospitals of each county. Glutamic acid decarboxylase
autoantibodies was analyzed with enzyme-linked immuno sorbent assay
and levels are reported as an index value in relation to standard serum. The
method gives a maximum value of 250 IUml
−1
. At a cutoff of 10.7 IU ml
−1
,
sensitivity was 84% and specificity 98%.
17
For the current investigation,
and to minimize false positive cases, levels 420 IU ml
−1
were regarded as
positive, in line with the diabetes classification used in the ANDIS registry.
C-peptide was measured by an IMMULITE 2000 (Siemens Healthcare
Diagnostics Product Ltd, Llanberis, UK) or by Cobas e 601 analyzer
(Roche Diagnostics, Mannheim, Germany).
18
LADA was diagnosed if age
⩾35 years, glutamic acid decarboxylase autoantibodies 420 U ml
−1
and
C-peptide ⩾0.2 nmol l
−1
(Immulite) or ⩾0.3 nmol l
−1
(Cobas). Type 2
diabetes criteria were age ⩾35 years, glutamic acid decarboxylase
autoantibodies o10 and C-peptide 40.6 nmol l
−1
(Immulite) or 40.72
nmol l
−1
(Cobas). This was in line with previously used criteria,
13
except for
C-peptide levels which replaced the commonly used insulin criteria to
distinguish LADA from classical type 1 diabetes with adult onset. This is a
more direct indicator of remaining insulin production and a slow ’latent
onset’than mode of treatment, which is open to subjective evaluation.
Insulin resistance (HOMA-IR) and β-cell function (HOMA-β) was assessed by
HOMA (homeostatic model assessment), based on the relationship
between fasting glucose and C-peptide levels.
19
Assessment of exposures and covariates
Exposure data was obtained from a comprehensive health and lifestyle
questionnaire including a 132-item food frequency questionnaire. This
food frequency questionnaire has been validated against diet diaries
20–23
and for some items including fish intake, against biological markers.
24
There were 11 seafood items, four regarded fatty fish (herring/Baltic
herring/mackerel, salmon, sardines, smoked fish), four asked about lean
fish (cod/pollock/plaice/blue hake, tuna, pike/pike perch/perch, fish
fingers) and the remainder about shell fish, roe and other fish types (than
those mentioned above). There were also nine questions asking about red
meat products, five about fresh fruit/berries, and 15 about vegetables. The
Spearman correlation coefficients between these items and four 1-week
weighted diet records ranged from 0.6 to 0.7 for fruits, from 0.4 to 0.6 for
vegetables (AW, unpublished data, 1992) and were 0.5 for fatty fish, 0.4 for
lean fish and 0.6 for other seafood.
23
Participants were asked how often, on
average during the past year, they had consumed each item, with eight
pre-defined response alternatives ranging from 0 times per month to
⩾3timesperday.Patientswerespecifically instructed to provide information
on dietary habits as they had been the year preceding their diagnosis.
Average daily consumption of fatty fish was estimated by converting the
responses for each item to average daily intake and then summing these
into one fatty fish variable. Average daily marine n-3 PUFA (EPA+DHA)
intake from diet was calculated by multiplying the intake frequency of
each type of fish or seafood product with nutrient data from the Swedish
National Food Agency database. The estimated n-3 PUFA intake based on
the questionnaire has been validated against fatty acid content in
subcutaneous adipose tissue, with a Pearson’s correlation of 0.41.
23
The
questionnaire also included information on intake of vitamins, minerals
and supplements, including fish oil supplements and vitamin D.
Participants were instructed to report if they have used any of the
Figure 1. Schematic of the ESTRID study design.
Fatty fish and LADA
JE Löfvenborg et al
2
Nutrition & Diabetes (2014) 1 –6 © 2014 Macmillan Publishers Limited
products on a regular basis for a minimum of 3 months and if so, to specify
the time period of use. Consumption of supplements was rare and
therefore, consumption of fish oil and vitamin D was categorized as never/
ever in the analysis.
We also collected information on potential confounders, including
height and weight used for calculation of BMI (kg m
−2
), education, smoking
status, physical activity, family history of diabetes, and consumption of
alcohol.
Statistical analysis
Odds ratios (OR) with 95% confidence intervals (CI) of LADA and type 2
diabetes were calculated in relation to fatty fish intake, fish oil
supplementation and vitamin D supplementation using conditional logistic
regression models (SAS 9.3; SAS Institute Inc.). If the CIs did not include 1.0,
the ORs were interpreted as significant (this corresponds to a double-sided
P-value o0.05). Models were run adjusted for age and gender (model 1),
age, gender, education level (⩾9, 10–12, 412 years in school), smoking
(never, ever), alcohol consumption (abstainer, former drinker, 0.1–4.8 g per
week, ⩾4.9 g per week), physical activity (sedentary, moderate, moderate
regular, regular), family history of diabetes, and BMI (kg m
−2
) (model 2). To
account for dietary habits, additional adjustment was made for intake of
red meat products, vegetables and fresh fruit/berries (model 3). Results
from model 3 are presented in the text unless otherwise stated. P-values
were calculated using χ
2
(proportions) and Wilcoxon–Mann–Whitney test
(means).
RESULTS
Mean age was 59.2 years in controls, 57.6 years in LADA patients
and 62.9 years in type 2 diabetes patients. Compared with type 2
diabetes patients, those with LADA were leaner, had lower levels
of C-peptide, HOMA-βand HOMA-IR (Table 1). Fatty fish intake
was lowest among LADA patients, 51.7% consumed less than one
serving per week compared with 37.4% of type 2 diabetes patients
and 38.5% of controls (P= 0.0150, LADA vs controls). Fish oil
supplementation tended to be less frequent among LADA
patients; 7.4% reported ever use compared with 16.1% of controls
(P= 0.0636). Among controls, 21.2% had ever used vitamin D and/
or fish oil supplementation compared with 12.4% of LADA
patients (P= 0.0487).
In the analysis adjusted for age and gender, we observed a
reduced risk of LADA associated with weekly consumption of fatty
fish (OR 0.56, 95% CI 0.36–0.88) (Table 2), whereas no association
was found for type 2 diabetes (OR 0.93, 95% CI 0.73–1.19)
(Table 3). The reduced risk of LADA remained virtually unaffected
by additional adjustment for BMI, education, physical activity,
smoking, alcohol consumption, family history of diabetes, red
meat, vegetables and fresh fruit/berries (OR 0.51, 95% CI 0.30–
0.87, whereas no association with type 2 diabetes could be
detected (OR 1.01, 95% CI 0.74–1.39). More frequent consumption
than 1–2 times per week did not further reduce the risk.
Consumption of lean fish was neither associated with LADA
(OR 0.99, 95% CI 0.56–1.72) nor type 2 diabetes (OR 0.87, 95%
CI 0.63–1.19).
There was also indication of an inverse association between
estimated dietary marine n-3 PUFA levels and LADA (Table 2); OR
was estimated at 0.60 (95% CI 0.35–1.03) for intakes of ⩾0.3 g
per day (approximately equivalent to ⩾1 serving of fatty fish per
week). No further risk reduction was seen for intakes of 40.6 g
per day and no association was seen between n-3 PUFA and type
2 diabetes (Table 3). Use of fish oil supplements showed a similar
tendency toward a reduced risk of LADA (OR 0.47, 95% CI 0.19–
1.12), but no indication of a reduced risk for type 2 diabetes (OR
1.58, 95% CI 1.08–2.31). Additional adjustment for fatty fish intake
did not change these risk estimates. There was a tendency toward
a reduced risk of both LADA and type 2 diabetes in consumers of
vitamin D supplements, but numbers were small.
DISCUSSION
Our findings indicate that intake of fatty fish may reduce the risk
of LADA. We are not aware of any previous studies on
autoimmune diabetes in adults in relation to fatty fish but these
results are in line with studies on type 1 diabetes in children
1,2
as
well as with other autoimmune diseases in adults, namely
rheumatoid arthritis and multiple sclerosis.
3,4
A proposed mechan-
ism underlying the association is beneficial effects of marine n-3
PUFAs including EPA and DHA on the immune system, including
improved membrane fluidity of immune cells and alterations in
gene expression.
8
Our findings were also compatible with a
protective effect of vitamin D, previously shown to be inversely
associated with type 1 diabetes.
25
Several different cell types of
the immune system display vitamin D receptors including T cells
and B cells and the active metabolite of vitamin D, 1,25(OH)
2
D, has
the ability to regulate proliferation and function of these immune
cells. One commonly suggested mechanism for the involvement
of vitamin D in incident type 1 diabetes includes modification of T
cell differentiation.
26
The reduced risk of LADA was seen at intakes
of ⩾1 serving per week, or marine n-3 PUFA intakes of ⩾0.3 g
per day, with no further risk reduction at higher levels, suggesting
a threshold effect of dietary marine n-3 PUFA. Similar findings
were seen in a study of rheumatoid arthritis where constant
Table 1. Characteristics of subjects included in the analyses
Characteristics Controls Type 2 diabetes LADA P-value
a
P-value
b
No. of individuals 1007 462 89
Age, mean, years (s.d.) 59.0 (13.3) 62.9 (10.4) 57.6 (13.1) 0.0002 0.3615
Men, % 47.3 59.3 48.3 0.0547 0.8498
BMI, mean, kg m
−2
(s.d.) 26.0 (4.1) 31.4 (5.8) 27.1 (4.5) o0.0001 0.0188
1st degree relatives with diabetes (%) 24.3% 45.0% 48.3% 0.5679 o0.0001
GADA, median, IU ml
−1
(interquartile range) ——250
c
(199) —
C-peptide, mean, nmol l
−1
(s.d.) —1.33 (0.62) 0.68 (0.46) o0.0001
HOMA-β, mean (s.d.) —4.75 (3.38) 2.04 (2.02) o0.0001
HOMA-IR, mean (s.d.) —0.67 (0.43) 0.39 (0.27) o0.0001
o1 serving of fatty fish per week, % 38.5 37.5 51.7 0.012 0.0150
Fish oil supplementation, ever, % 16.5 19.1 9.0 0.022 0.0636
Vitamin D supplementation, ever, % 8.2 4.8 4.50 0.91 0.2099
Fish oil or/and vitamin D, ever, % 21.2 22.3 12.4 0.0341 0.0487
Abbreviations: BMI, body mass index; GADA, glutamic acid decarboxylase autoantibodies; HOMA-β, homeostatic model assessment-β-cell function; HOMA-IR,
homeostatic model assessment-insulin resistance; LADA, latent autoimmune diabetes in adults.
a
P-value for difference between LADA and type 2 diabetes.
b
P-value for difference between LADA and controls.
c
GAD autoantibody levels were truncated at 250.
Fatty fish and LADA
JE Löfvenborg et al
3
© 2014 Macmillan Publishers Limited Nutrition & Diabetes (2014) 1 –6
Table 2. Odds ratios of LADA in relation to intake of fatty fish, EPA and DHA from seafood and fish oil and vitamin D supplementation
Model 1 Model 2 Model 3
Cases/controls OR 95% CI Cases/controls OR 95% CI Cases/controls OR 95% CI
Fatty fish
o1 serving per week 46/388 1.0 43/362 1.0 43/362
1–2 servings per week 28/365 0.62 0.37–1.02 24/342 0.53 0.30–0.94 24/342 0.53 0.29–0.95
42 servings per week 15/254 0.49 0.26–0.90 14/244 0.49 0.25–0.96 14/244 0.48 0.24–0.99
⩾1 serving per week 43/619 0.56 0.36–0.88 38/586 0.51 0.31–0.85 38/586 0.51 0.30–0.87
Total EPA+DHA from seafood
o0.3 g per day 33/303 1.0 33/281 1.0 33/281
0.3–0.6 g per day 31/368 0.74 0.44–1.26 25/345 0.57 0.32–1.03 25/345 0.60 0.33–1.09
40.6 g per day 25/336 0.66 0.38–1.15 23/322 0.58 0.31–1.07 23/322 0.59 0.30–1.16
⩾0.3 g per day 56/704 0.70 0.44–1.12 48/667 0.57 0.34–0.96 48/667 0.60 0.35–1.03
Fish oil supplementation
Never 81/841 1.0 75/795 1.0 75/795 1.0
Ever 8/166 0.52 0.24–1.09 6/153 0.48 0.20–1.15 6/153 0.47 0.19–1.12
Vitamin D supplementation
Never 85/924 1.0 77/875 1.0 77/875 1.0
Ever 4/83 0.50 0.17–1.45 4/73 0.54 0.18–1.65 4/73 0.58 0.19–1.77
Vitamin D or/and fish oil
Never 78/800 1.0 72/757 1.0 72/757 1.0
Ever 11/207 0.53 0.27–1.02 9/191 0.48 0.23–1.02 9/191 0.49 0.23–1.03
Abbreviations; CI, confidence intervals; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LADA latent autoimmune diabetes in adults; OR, Odds ratios.
Model 1. Adjusted for age and gender Model 2. Adjusted for age, gender, BMI, smoking, education, physical activity, family history of diabetes and
alcohol intake Model 3. Adjusted for age, gender, BMI, smoking, education, physical activity, family history of diabetes, and intake of alcohol, fruit and
vegetables and, red meat.
Table 3. Odds ratios of Type 2 diabetes in relation to intake of fatty fish, EPA and DHA and supplementation of vitamin D and fish oil
Model 1 Model 2 Model 3
Cases/controls OR 95% CI Cases/controls OR 95% CI Cases/controls OR 95% CI
Fatty fish
o1 serving per week 173/388 1 157/362 1 157/362
1–2 servings per week 168/365 0.95 0.72–1.24 157/342 1.10 0.78–1.54 157/342 1.04 0.73–1.46
42 servings per week 121/254 0.91 0.68–1.23 117/244 1.08 0.74–1.58 117/244 0.97 0.65–1.45
⩾1 serving per week 289/619 0.93 0.73–1.19 274/586 1.09 0.80–1.48 274/586 1.01 0.74–1.39
Total EPA+DHA from seafood
o0.3 g per day 130/303 1.0 116/281 116/281
0.3–0.6 g per day 176/368 1.08 0.81–1.44 166/345 1.22 0.85–1.77 166/345 1.17 0.81–1.71
40.6 g per day 156/336 0.98 0.73–1.32 149/322 1.16 0.79–1.70 149/322 1.03 0.68–1.55
⩾0.3 g per day 332/704 1.03 0.80–1.33 315/667 1.19 0.85–1.67 315/667 1.14 0.79–1.58
Fish oil supplementation
Never 374/841 1 347/795 1 347/795 1
Ever 88/166 1.28 0.94–1.73 84/153 1.63 1.12–2.39 84/153 1.58 1.08–2.31
Vitamin D supplementation
Never 440/924 1.0 410/875 1.0 410/875 1.0
Ever 22/83 0.79 0.44–1.43 21/73 0.79 0.41–1.50 21/73 0.75 0.39–1.43
Vitamin D or/and fish oil
Never 365/800 1 97/207 1 97/207 1
Ever 97/207 1.01 0.82–1.47 93/191 1.40 0.97–2.01 93/191 1.35 0.93–1.94
Abbreviations: CI, confidence intervals; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; LADA latent autoimmune diabetes in adults; OR, Odds ratios.
Model 1. Adjusted for age and gender Model 2. Adjusted for age, gender, BMI, smoking, education, physical activity, family history of diabetes and
alcohol intake Model 3. Adjusted for age, gender, BMI, smoking, education, physical activity, family history of diabetes, and intake of alcohol, fruit and
vegetables, and meat.
Fatty fish and LADA
JE Löfvenborg et al
4
Nutrition & Diabetes (2014) 1 –6 © 2014 Macmillan Publishers Limited
relative risks were observed for intakes of 40.35 g per day.
3
Furthermore, a threshold effect at 0.25 g per day was observed in
a pooled analysis of randomized trials and prospective studies
investigating the role of fish and fish oil intake on mortality from
coronary heart disease.
27
In confirmation of most previous European reports,
6
there was
no association between fatty fish consumption and type 2
diabetes. Furthermore, an increased risk of type 2 diabetes was
seen in users of fish oil supplementation. Our findings are
compatible with a reduced risk of type 2 diabetes in users of
vitamin D supplementation as shown previously,
11
although
number of users was small. Vitamin D has been proposed to
influence the pathophysiology of type 2 diabetes by means of
affecting βcell function and insulin action. The pancreatic βcells
may be affected though binding of 1,25(OH)
2
D to its vitamin D
receptors, or by activation of vitamin D within the βcells. Insulin
action may be influenced by stimulating the expression of insulin
receptors, leading to improved glucose transportation.
28
Dietary information was based on a validated food frequency
questionnaire, and the estimated marine n-3 PUFA levels from the
questionnaire show a fairly strong correlation with PUFA content
in fat tissue.
23
A limitation of the case–control study design is the
retrospective collection of potential exposure; that is, cases
respond to the questionnaire after diagnosis, but while only
information on habits prior to diagnosis is of relevance. Hence, if
patients increased their consumption of fatty fish after recom-
mendations from their physicians, and reported accordingly, this
would lead to overestimation of the fatty fish intake among cases.
To minimize this bias, we provided careful instructions that dietary
habits should be reported as they were the year preceding
diagnosis, and furthermore, we only included patients who
responded to the questionnaire within 6 months of diagnosis.
Importantly an increase in fish intake following diagnosis does not
explain why LADA patients consumed half as much fatty fish and
fish oil supplements as controls and patients with type 2 diabetes;
overestimation of fish intake in patients would lead to an
overestimation of the OR rather than the opposite. The association
could be due to underreporting of fish consumption among
patients, but this does not explain the different results seen for
LADA and type 2 diabetes. In this context it is noteworthy that
with regard to type 2 diabetes, our results were in line with
previous European reports based on prospective data with fish
intake measured several years prior to disease onset.
6
With regard to confounding, fatty fish could be an indicator of a
healthy lifestyle or diet associated with a low diabetes risk; for
example, fatty fish consumers may consume less red meat, known
to be associated with an increased risk of type 2 diabetes,
29
or
more fruit and vegetables, associated with a reduced risk of type 2
diabetes.
30
Notably, the ORs remained virtually unaffected by
adjustment for a number of potential confounders, including
education, lifestyle and dietary factors. Also, to explain an OR of
the magnitude reported in this study, the factor must be a strong
correlate of fatty fish intake as well as a strong risk factor of LADA,
but not type 2 diabetes. The sensitivity and specificity of the
glutamic acid decarboxylase autoantibodies to distinguish auto-
immune diabetes implies that we may have some false positive
cases among the LADA patients; that is, patients with type 2
diabetes and vise versa. This misclassifications is however
unlikely to explain the different results seen for the two diabetes
types. Non-response could introduce bias if participating
controls differ from the population that generated the cases with
regard to dietary habits.
16
For example, subjects with high
socioeconomic status, known to have healthier eating habits,
were overrepresented in the sample, which could lead to an
overestimation of the inverse association between fatty fish intake
and LADA. We have no reason to believe this is the case as the
educational level of controls in ESTRID were in line with those in
the general population of Scania, based on data from statistics
Sweden (www.scb.se).
In summary, our findings suggest that fatty fish consumption
may protect against LADA, possibly through effects of marine
n-3 PUFA on the immune system. No association was observed
between fatty fish and type 2 diabetes indicating that
the association with LADA is driven by other mechanisms than
those related to type 2 diabetes features. Numbers were small
and our findings may be due to chance. Still, the internal and
external
1–4
consistency of findings and the magnitude of the
potential effect implies that the issue of fatty fish and fish oil in
relation to autoimmune diabetes is an important topic to
elucidate further.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGEMENTS
The ESTRID study is supported by The Swedish Research Council, The Swedish
Research Council for Health, Working Life and Welfare, AFA Insurance, and The
Swedish Diabetes Association. The Swedish Research Council is also supporting
ANDIS (including ALF funding for clinical research in medicine) and ANDiU (including
EXODIAB—strategic governmental funding for excellence of diabetes research in
Sweden).
AUTHOR CONTRIBUTIONS
TA contributed to the statistical approaches and considerations, interpretations of
data, and reviewing of the manuscript. P-OC, MD, LG, and MM contributed to
collection and interpretation of data and reviewing of the manuscript. TT and
AW contributed with interpretation of data and reviewing of the manuscript.
SC contributed to the design and conduct of the study, interpretation of data and
writing of the manuscript. JEL contributed to the conception, design and conduct of
the study, interpretation of data, and writing of the manuscript. All authors approved
the final version of the manuscript. JEL is the guarantor, affirming the integrity of the
data and that this is a truthful report of the study.
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