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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 (⩾1 vs <1 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.
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ORIGINAL ARTICLE
Fatty sh 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 sh 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 benecial effects on immune function and glucose metabolism. Our aim was to investigate, for the rst time, fatty sh
consumption in relation to the risk of latent autoimmune diabetes in adults (LADA).
METHODS: Analyses were based on data from a Swedish casecontrol study with incident cases of LADA (n= 89) and type 2
diabetes (n= 462) and randomly selected diabetes-free controls (n= 1007). Diabetes classication 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 sh, polyunsaturated long-chain omega-3 fatty acids (n-3 PUFA) and supplementation of sh oil
and vitamin D. Odds ratios (ORs) with 95% condence 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 sh consumption (1vso1 serving per week), was associated with a reduced risk of LADA but not type 2
diabetes (OR 0.51, 95% CI 0.300.87, and 1.01, 95% CI 0.741.39, respectively). Similar associations were seen for estimated intake of
n-3 PUFA (0.3 g per day; LADA: OR 0.60, 95% CI 0.351.03, type 2 diabetes: OR 1.14, 95% CI 0.791.58) and sh oil supplementation
(LADA: OR 0.47, 95% CI 0.191.12, type 2 diabetes: OR 1.58, 95% CI 1.082.31).
CONCLUSIONS: Our ndings suggest that fatty sh 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 ndings suggest that fatty sh 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 rst
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 sh consumption and type 2
diabetes has also been proposed
5
but as shown in two recent
reviews, ndings 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 sh and sh oil, especially eicosapentaenoic (EPA) and
docosahexaenoic (DHA) acids. EPA and DHA possess anti-
inammatory, 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 benecial with regard to autoimmune diseases. This
cell membrane incorporation happens partly on the expense of
the pro-inammatory arachidonic acid.
8
The anti-inammatory
property may be of importance for autoimmune diabetes but also
type 2 diabetes as both conditions have been associated with low-
grade inammation,
9
further, these properties of EPA and DHA
have been suggested also to affect insulin signaling.
10
Fatty sh 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 sh has never been investigated before.
Our aim was to investigate the risk of LADA, and type 2 diabetes
in relation to consumption of fatty sh and dietary supplementa-
tion of sh 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: soa.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 identied
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 identied 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 classication 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 specicity 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 classication 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
onsetthan 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
2023
and for some items including sh intake, against biological markers.
24
There were 11 seafood items, four regarded fatty sh (herring/Baltic
herring/mackerel, salmon, sardines, smoked sh), four asked about lean
sh (cod/pollock/plaice/blue hake, tuna, pike/pike perch/perch, sh
ngers) and the remainder about shell sh, roe and other sh types (than
those mentioned above). There were also nine questions asking about red
meat products, ve about fresh fruit/berries, and 15 about vegetables. The
Spearman correlation coefcients 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 sh, 0.4 for
lean sh 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-dened response alternatives ranging from 0 times per month to
3timesperday.Patientswerespecically instructed to provide information
on dietary habits as they had been the year preceding their diagnosis.
Average daily consumption of fatty sh was estimated by converting the
responses for each item to average daily intake and then summing these
into one fatty sh variable. Average daily marine n-3 PUFA (EPA+DHA)
intake from diet was calculated by multiplying the intake frequency of
each type of sh 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 Pearsons correlation of 0.41.
23
The
questionnaire also included information on intake of vitamins, minerals
and supplements, including sh 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 sh 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 sh 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% condence intervals (CI) of LADA and type 2
diabetes were calculated in relation to fatty sh intake, sh 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 signicant (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, 1012, 412 years in school), smoking
(never, ever), alcohol consumption (abstainer, former drinker, 0.14.8 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 WilcoxonMannWhitney 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 sh 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 sh 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
sh (OR 0.56, 95% CI 0.360.88) (Table 2), whereas no association
was found for type 2 diabetes (OR 0.93, 95% CI 0.731.19)
(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 0.741.39). More frequent consumption
than 12 times per week did not further reduce the risk.
Consumption of lean sh was neither associated with LADA
(OR 0.99, 95% CI 0.561.72) nor type 2 diabetes (OR 0.87, 95%
CI 0.631.19).
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 0.351.03) for intakes of 0.3 g
per day (approximately equivalent to 1 serving of fatty sh 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 sh 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 1.082.31). Additional adjustment for fatty sh 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 ndings indicate that intake of fatty sh may reduce the risk
of LADA. We are not aware of any previous studies on
autoimmune diabetes in adults in relation to fatty sh 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 benecial effects of marine n-3
PUFAs including EPA and DHA on the immune system, including
improved membrane uidity of immune cells and alterations in
gene expression.
8
Our ndings 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 modication 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 ndings
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 sh 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 sh 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 sh, EPA and DHA from seafood and sh 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 sh
o1 serving per week 46/388 1.0 43/362 1.0 43/362
12 servings per week 28/365 0.62 0.371.02 24/342 0.53 0.300.94 24/342 0.53 0.290.95
42 servings per week 15/254 0.49 0.260.90 14/244 0.49 0.250.96 14/244 0.48 0.240.99
1 serving per week 43/619 0.56 0.360.88 38/586 0.51 0.310.85 38/586 0.51 0.300.87
Total EPA+DHA from seafood
o0.3 g per day 33/303 1.0 33/281 1.0 33/281
0.30.6 g per day 31/368 0.74 0.441.26 25/345 0.57 0.321.03 25/345 0.60 0.331.09
40.6 g per day 25/336 0.66 0.381.15 23/322 0.58 0.311.07 23/322 0.59 0.301.16
0.3 g per day 56/704 0.70 0.441.12 48/667 0.57 0.340.96 48/667 0.60 0.351.03
Fish oil supplementation
Never 81/841 1.0 75/795 1.0 75/795 1.0
Ever 8/166 0.52 0.241.09 6/153 0.48 0.201.15 6/153 0.47 0.191.12
Vitamin D supplementation
Never 85/924 1.0 77/875 1.0 77/875 1.0
Ever 4/83 0.50 0.171.45 4/73 0.54 0.181.65 4/73 0.58 0.191.77
Vitamin D or/and sh oil
Never 78/800 1.0 72/757 1.0 72/757 1.0
Ever 11/207 0.53 0.271.02 9/191 0.48 0.231.02 9/191 0.49 0.231.03
Abbreviations; CI, condence 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 sh, EPA and DHA and supplementation of vitamin D and sh oil
Model 1 Model 2 Model 3
Cases/controls OR 95% CI Cases/controls OR 95% CI Cases/controls OR 95% CI
Fatty sh
o1 serving per week 173/388 1 157/362 1 157/362
12 servings per week 168/365 0.95 0.721.24 157/342 1.10 0.781.54 157/342 1.04 0.731.46
42 servings per week 121/254 0.91 0.681.23 117/244 1.08 0.741.58 117/244 0.97 0.651.45
1 serving per week 289/619 0.93 0.731.19 274/586 1.09 0.801.48 274/586 1.01 0.741.39
Total EPA+DHA from seafood
o0.3 g per day 130/303 1.0 116/281 116/281
0.30.6 g per day 176/368 1.08 0.811.44 166/345 1.22 0.851.77 166/345 1.17 0.811.71
40.6 g per day 156/336 0.98 0.731.32 149/322 1.16 0.791.70 149/322 1.03 0.681.55
0.3 g per day 332/704 1.03 0.801.33 315/667 1.19 0.851.67 315/667 1.14 0.791.58
Fish oil supplementation
Never 374/841 1 347/795 1 347/795 1
Ever 88/166 1.28 0.941.73 84/153 1.63 1.122.39 84/153 1.58 1.082.31
Vitamin D supplementation
Never 440/924 1.0 410/875 1.0 410/875 1.0
Ever 22/83 0.79 0.441.43 21/73 0.79 0.411.50 21/73 0.75 0.391.43
Vitamin D or/and sh oil
Never 365/800 1 97/207 1 97/207 1
Ever 97/207 1.01 0.821.47 93/191 1.40 0.972.01 93/191 1.35 0.931.94
Abbreviations: CI, condence 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 sh 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 sh and sh oil intake on mortality from
coronary heart disease.
27
In conrmation of most previous European reports,
6
there was
no association between fatty sh consumption and type 2
diabetes. Furthermore, an increased risk of type 2 diabetes was
seen in users of sh oil supplementation. Our ndings 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
inuence 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 inuenced 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 casecontrol 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 sh after recom-
mendations from their physicians, and reported accordingly, this
would lead to overestimation of the fatty sh 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 sh intake following diagnosis does not
explain why LADA patients consumed half as much fatty sh and
sh oil supplements as controls and patients with type 2 diabetes;
overestimation of sh intake in patients would lead to an
overestimation of the OR rather than the opposite. The association
could be due to underreporting of sh 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 sh
intake measured several years prior to disease onset.
6
With regard to confounding, fatty sh could be an indicator of a
healthy lifestyle or diet associated with a low diabetes risk; for
example, fatty sh 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 sh intake as well as a strong risk factor of LADA,
but not type 2 diabetes. The sensitivity and specicity 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 misclassications 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 sh 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 ndings suggest that fatty sh consumption
may protect against LADA, possibly through effects of marine
n-3 PUFA on the immune system. No association was observed
between fatty sh 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 ndings may be due to chance. Still, the internal and
external
14
consistency of ndings and the magnitude of the
potential effect implies that the issue of fatty sh and sh oil in
relation to autoimmune diabetes is an important topic to
elucidate further.
CONFLICT OF INTEREST
The authors declare no conict 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
EXODIABstrategic 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 nal version of the manuscript. JEL is the guarantor, afrming the integrity of the
data and that this is a truthful report of the study.
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the Creative Commons license, users will need to obtain permission from the license
holder to reproduce the material. To view a copy of this license, visit http://
creativecommons.org/licenses/by-nc-sa/4.0/
Fatty sh and LADA
JE Löfvenborg et al
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Nutrition & Diabetes (2014) 1 6 © 2014 Macmillan Publishers Limited
... There is some indication that diet may influence the risk of LADA, beyond any effects mediated through effects on BMI; Findings based on the ESTRID-study indicate an elevated risk of LADA in relation to high intake of sweetened beverages (45) and processed red meat (43), whereas a reduced risk is noted for high consumption of fatty fish (46). A shortage of data has made it difficult to confirm these findings in additional cohorts (the HUNT-study has limited information on diet, especially before 2006) and these findings should clearly be interpreted with caution. ...
... Lifestyle factors and LADA-findings from observational studies. Relative risk estimates extracted from references(28,36,(39)(40)(41)(42)(43)(44)(45)(46)(47). ...
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Background: LADA is a common form of diabetes described as a mix between type 1 and type 2 diabetes. Understanding of how genes and environmental factors interact in the development of LADA is central for future efforts to prevent the disease. This review aims to synthesize the literature on lifestyle factors linked to LADA risk and discuss their potential interaction with genetic susceptibility. Findings: Current knowledge on environmental risk factors for LADA is primarily based on observational data from Scandinavian populations. Increasing evidence suggest that lifestyle factors promoting type 2 diabetes such as obesity, sedentariness, low birth weight and smoking, is implicated in the risk of LADA. Data from mendelian randomization studies support that the link between LADA and obesity, low birth weight and smoking is causal. Limited evidence indicates that dietary factors including consumption of red meat, coffee and sweetened beverages may increase the risk while consumption of alcohol and omega-3 fatty acids may reduce the risk. Several lifestyle factors, including smoking and obesity, seem to interact with human leukocyte antigen genes associated with autoimmunity, conferring much stronger effects on disease risk among those exposed to both factors. Summary: Available studies suggest that lifestyle modification has the potential for prevention of LADA, particularly for individuals with high risk of disease such as those with genetic susceptibility. Research into risk factors of LADA is however limited, confirmations are warranted, many factors remain to be explored, and there is a need for intervention studies to assess causality.
... In a separate study of genetically susceptible children in a U.S. cohort, total estimated dietary n-3 PUFAs as well as n-3 PUFA concentration measured in erythrocyte membranes, were inversely associated with the development of islet autoimmunity and multiple autoantibodies and type 1 diabetes, with similar hazard ratios (HRs) observed in separate analyses focused on marine n-3 PUFAs (9). Studies in adults are scarce, but we previously reported a lower risk of latent autoimmune diabetes in adults (LADA) in those who regularly consume fatty fish (10). However, the results from other studies have not confirmed these findings, and others have reported the absence of an association between serum or erythrocyte n-3 PUFAs and childhood islet autoimmunity (11) or type 1 diabetes (12). ...
... This fits with previous observations in childhood type 1 diabetes in which incidence was inversely associated with fish oil supplementation in Norway (8) and fish consumption in the U.S. (9). High intake of fatty fish was associated with a lower risk of LADA in our previous study that was based on Swedish data (10). We are aware of only one previous study that specifically aimed to assess the impact of n-3 PUFAs on the progression from islet autoimmunity to clinical diabetes (12). ...
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Objective: Islet autoimmunity is associated with diabetes incidence. We investigated whether there was an interaction between dietary fish intake or plasma phospholipid n-3 polyunsaturated fatty acid (PUFA) concentration with the 65-kDa isoform of GAD (GAD65) antibody positivity on the risk of developing adult-onset diabetes. Research design and methods: We used prospective data on 11,247 incident cases of adult-onset diabetes and 14,288 noncases from the EPIC-InterAct case-cohort study conducted in eight European countries. Baseline plasma samples were analyzed for GAD65 antibodies and phospholipid n-3 PUFAs. Adjusted hazard ratios (HRs) for incident diabetes in relation to GAD65 antibody status and tertiles of plasma phospholipid n-3 PUFA or fish intake were estimated using Prentice-weighted Cox regression. Additive (proportion attributable to interaction [AP]) and multiplicative interactions between GAD65 antibody positivity (≥65 units/mL) and low fish/n-3 PUFA were assessed. Results: The hazard of diabetes in antibody-positive individuals with low intake of total and fatty fish, respectively, was significantly elevated (HR 2.52 [95% CI 1.76-3.63] and 2.48 [1.79-3.45]) compared with people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44 [95% CI 0.16-0.72] and 0.48 [0.24-0.72]) and multiplicative (P = 0.0465 and 0.0103) interactions. Individuals with high GAD65 antibody levels (≥167.5 units/mL) and low total plasma phospholipid n-3 PUFAs had a more than fourfold higher hazard of diabetes (HR 4.26 [2.70-6.72]) and an AP of 0.46 (0.12-0.80) compared with antibody-negative individuals with high n-3 PUFAs. Conclusions: High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity.
... A previous study by our group showed that 1,25-(OH) 2 D3 could regulate TLRs to downregulate NF-kB-p65 phosphorylation and significantly reduce IL-1b and TNF-a production (67). A Swedish-based case-control study found that taking vitamin D-rich fatty fish (≥1 time per week) may reduce the risk of LADA (153). Our prospective study demonstrated that 1a(OH)D3 combined with insulin therapy protected pancreatic b cell function in LADA patient, and no serious side effects were observed in the 1-a(OH)D3 therapy or insulin plus 1-a(OH)D3 therapy over a follow-up period of more than 1 year (154). ...
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Latent autoimmune diabetes in adults (LADA) is a type of diabetes characterized by slow autoimmune damage of pancreatic β cells without insulin treatment in the early clinical stage. There are differences between LADA and classical type 1 diabetes (T1D) and type 2 diabetes (T2D) in genetic background, autoimmune response, rate of islet function decline, clinical metabolic characteristics, and so on. The disease progression and drug response of patients with LADA are closely related to the level of islet autoimmunity, thus exploring the pathogenesis of LADA is of great significance for its prevention and treatment. Previous studies reported that adaptive immunity and innate immunity play a critical role in the etiology of LADA. Recent studies have shown that the intestinal microbiota which impacts host immunity hugely, participates in the pathogenesis of LADA. In addition, the progression of autoimmune pancreatic β cell destruction in LADA is slower than in classical T1D, providing a wider window of opportunities for intervention. Therefore, therapies including antidiabetic drugs with immune-regulation effects and immunomodulators could contribute to promising interventions for LADA. We also shed light on potential interventions targeting the gut microbiota and gut-associated immunity, which may be envisaged to halt or delay the process of autoimmunity in LADA.
... Increased supplementation of n-3 LC-PUFAs decreases mononuclear cell proliferation and interleukin 1b contents (45). High intake of fatty fish decreases the risk of diabetes conferred by GADA positivity (46), reduces the risk of LADA (47). Metabolomic profile study in patients with LADA did not find unique metabolite profile, LADA was therefore recognized metabolically an intermediate of t1dm and t2dm (48). ...
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... It has been shown in the various test contemplates. A few investigations uncovered the significance of unsaturated fats in the eating regimen and their application on the decrease of normal symptomatologies in immune system infections [10]. ...
... Indeed, infants supplemented with cod liver oil between seven and 12 months of age exhibited a significant lower risk of T1D compared to those receiving the supplementation from birth up to six months of age [171]. These findings could rely on the fact that the adaptive immune system is not fully mature during the first months of life [172], which might result in the lack of favorable immunomodulatory effects exerted by vitamin D. Interestingly, weekly fatty fish consumption (≥1 serving per week) has also been associated with a significant reduction in the risk of latent autoimmune diabetes in adults (LADA) [173]. ...
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To analyse the association between dietary long-chain n-3 polyunsaturated fatty acids (PUFAs) and incidence of rheumatoid arthritis (RA) in middle-aged and older women from the Swedish Mammography Cohort, a population-based prospective study. Data on diet were collected in 1987 and 1997 via a self-administered food-frequency questionnaire (FFQ). The risk of RA associated with dietary long-chain n-3 PUFAs and fish intake was estimated using Cox proportional hazard regression models, adjusted for age, cigarette smoking, alcohol intake, use of aspirin and energy intake. Among 32 232 women born 1914-1948, 205 RA cases were identified during a mean follow-up of 7.5 years (1 January 2003 to 31 December 2010; 2 41 120 person-years). An intake of dietary long-chain n-3 PUFAs (FFQ1997) of more than 0.21 g/day (lowest quintile) was associated with a 35% decreased risk of developing RA (multivariable adjusted relative risk (RR) 0.65; 95% CI 0.48 to 0.90) compared with a lower intake. Long-term intake consistently higher than 0.21 g/day (according to both FFQ1987 and FFQ1997) was associated with a 52% (95% CI 29% to 67%) decreased risk. Consistent long-term consumption (FFQ1987 and FFQ1997) of fish ≥1 serving per week compared with<1 was associated with a 29% decrease in risk (RR 0.71; 95% CI 0.48 to 1.04). This prospective study of women supports the hypothesis that dietary intake of long-chain n-3 PUFAs may play a role in aetiology of RA.
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To evaluate how long-term dietary intake of long-chain n-3 polyunsaturated fatty acids (LCn-3 PUFAs), estimated by repeated food frequency questionnaires (FFQs) over 15 years, is correlated with LCn-3 PUFAs in adipose tissue (AT). Subcutaneous adipose tissue was obtained in 2003-2004 (AT-03) from 239 randomly selected women, aged 55-75 years, after completion of a 96-item FFQ (FFQ-03). All participants had previously returned an identical FFQ in 1997 (FFQ-97) and a 67-item version in 1987-1990 (FFQ-87). Pearson product-moment correlations were used to evaluate associations between intake of total and individual LCn-3 PUFAs as estimated by the three FFQ assessments and AT-03 content (% of total fatty acids). FFQ-estimated mean relative intake of LCn-3 PUFAs (% of total fat intake) increased between all three assessments (FFQ-87, 0.55 ± 0.34; FFQ-97, 0.74 ± 0.64; FFQ-03, 0.88 ± 0.56). Validity, in terms of Pearson correlations between FFQ-03 estimates and AT-03 content, was 0.41 (95 % CI 0.30-0.51) for total LCn-3 PUFA and ranged from 0.29 to 0.48 for individual fatty acids; lower correlation was observed among participants with higher percentage body fat. With regard to long-term intake estimates, past dietary intake was also correlated with AT-03 content, with correlation coefficients in the range of 0.21-0.33 and 0.21-0.34 for FFQ-97 and FFQ-87, respectively. The correlations were improved by using average estimates from two or more FFQ assessments. Exclusion of fish oil supplement users (14 %) did not alter the correlations. These data indicate reasonable validity of FFQ-based estimates of long-term (up to 15 years) LCn-3 PUFA intake, justifying their use in studies of diet-disease associations.
Article
Importance: Red meat consumption has been consistently associated with an increased risk of type 2 diabetes mellitus (T2DM). However, whether changes in red meat intake are related to subsequent T2DM risk remains unknown. Objective: To evaluate the association between changes in red meat consumption during a 4-year period and subsequent 4-year risk of T2DM in US adults. Design and setting: Three prospective cohort studies in US men and women. Participants: We followed up 26,357 men in the Health Professionals Follow-up Study (1986-2006), 48,709 women in the Nurses' Health Study (1986-2006), and 74,077 women in the Nurses' Health Study II (1991-2007). Diet was assessed by validated food frequency questionnaires and updated every 4 years. Time-dependent Cox proportional hazards regression models were used to calculate hazard ratios with adjustment for age, family history, race, marital status, initial red meat consumption, smoking status, and initial and changes in other lifestyle factors (physical activity, alcohol intake, total energy intake, and diet quality). Results across cohorts were pooled by an inverse variance-weighted, fixed-effect meta-analysis. Main outcomes and measures: Incident T2DM cases validated by supplementary questionnaires. Results: During 1,965,824 person-years of follow-up, we documented 7540 incident T2DM cases. In the multivariate-adjusted models, increasing red meat intake during a 4-year interval was associated with an elevated risk of T2DM during the subsequent 4 years in each cohort (all P < .001 for trend). Compared with the reference group of no change in red meat intake, increasing red meat intake of more than 0.50 servings per day was associated with a 48% (pooled hazard ratio, 1.48; 95% CI, 1.37-1.59) elevated risk in the subsequent 4-year period, and the association was modestly attenuated after further adjustment for initial body mass index and concurrent weight gain (1.30; 95% CI, 1.21-1.41). Reducing red meat consumption by more than 0.50 servings per day from baseline to the first 4 years of follow-up was associated with a 14% (pooled hazard ratio, 0.86; 95% CI, 0.80-0.93) lower risk during the subsequent entire follow-up through 2006 or 2007. Conclusions and relevance: Increasing red meat consumption over time is associated with an elevated subsequent risk of T2DM, and the association is partly mediated by body weight. Our results add further evidence that limiting red meat consumption over time confers benefits for T2DM prevention.