European Journal of Neurology 2007, 14: 738–744 doi:10.1111/j.1468-1331.2007.01765.

Headache prevalence related to diabetes mellitus. The Head-HUNT Study

A. H. Aamodta,b, L. J. Stovnera,b, K. Midthjellc, K. Hagena,b and J.-A. Zwarta,b
a
Norwegian National Headache Centre, Trondheim University Hospital; bDepartment of Neuroscience, Faculty of medicine, Norwegian
University of Science and Technology (NTNU), Trondheim, Norway; and cHUNT Research Centre, NTNU, Verdal, Norway

Keywords:
diabetes mellitus,
epidemiology, headache,
Helse undersøkelsen i
Nord-Trøndelag, migraine
Received 20 December 2006
Accepted 28 February 2007
In patients with diabetes mellitus (DM), there are changes in vascular reactivity and
nerve conduction that may be relevant for migraine pathophysiology. However, pre-
vious studies on the relationship between headache and DM have shown conflicting
results. The aim of the present study was to investigate a possible association between
headache and DM in a large population-based cross-sectional study. Associations
were assessed in multivariate analyses, estimating prevalence odds ratios (ORs) with
95% confidence intervals (CIs). Prevalence OR of migraine was lower amongst per-
sons with DM compared with those without DM, the OR being 0.4 (95% CI: 0.2–0.9)
for type 1 and 0.7 (95% CI: 0.5–0.9) for type 2 DM. Furthermore, OR of headache
were lower amongst those with duration of DM ‡ 13 years compared with those who
had got DM the last 3 years, OR 0.6 (95% CI: 0.4–0.9). The analyses revealed no clear
associations between non-migrainous headache and DM. The reason for the inverse
relationship between migraine and DM is unknown, but might be related to patho-
physiological abnormalities in patients with DM that protect against migraine.

have shown both an improvement and a deterioration

Introduction
To study comorbidity between headache and other
disorders may be of interest, partly because it may
enable better handling of the disorders and partly
because it may give clues to the pathophysiology of the
headache. The relation between headache and diabetes
mellitus (DM) is particularly interesting because DM
affects vascular reactivity [1,2] induces diabetic neur-
opathy [3], and leads to life-style changes which all may
be relevant in migraine pathopysiology. The question
about a possible genetic link between the two diseases
has been actualized after the recent genetic studies on
this topic [4,5].
The previous studies on the relationship between
headache and DM have yielded conflicting results. In
clinic-based and population-based studies the pre-
valence of migraine in DM patients has been shown to be
lower [6–8], similar [9,10], and higher [10,11] compared
with controls without DM. Tension-type headache
(TTH) has also been found to be more prevalent in
persons with DM than in controls without DM [11].
Furthermore, DM was more common amongst
teenagers with migraine compared with those without
migraine [12] and amongst elderly with TTH and sec-
ondary headaches compared with those with migraine
or without headache [13]. Finally, clinic-based studies
Correspondence: Anne Hege Aamodt, Norwegian National Headache
Centre, Trondheim University Hospital, N-7006 Trondheim, Norway
(tel.: +47 72 57 60 06; fax: +47 72 57 57 73; e-mail: anne.hege.
aamodt@ntnu.no).
of headache problems after the onset or treatment of
DM [11,14], and that hypoglycemic episodes seem to be
a precipitator of headache in some patients with DM
[15,16]. The main purpose of the present study was
to investigate the relationship between headache
(migraine included) and DM in a large population-
based study.
Methods
Study population
In 1995–1997 all inhabitants aged ‡20 years in Nord-
Trøndelag county were invited to participate in the
adult part of the Nord-Trøndelag Health study
(HUNT, Helse undersøkelsen i Nord-Trøndelag). The
target population has been described previously inclu-
ding both participants and non-participants [17].
Briefly, two questionnaires, including more than 200
health-related questions, were administrated to the
participants. A diagram of the population and sub-
groups participating in the present study is shown in
Fig. 1. The first questionnaire (Q1) was enclosed with
the invitation and delivered when attending the health
examination during which non-fasting blood samples
were drawn. All participants received a second
questionnaire (Q2) that was returned by mail.
Of the 92 566 invited individuals, 64 403 (70%)
answered Q1 which included two questions about DM
[18]. The Q2 included 13 questions about headache [19]
which was answered by 51 383 subjects, who constituted

738  2007 EFNS

 Headache prevalence related to diabetes mellitus 739

The adult population of Nord-Trøndelag county classified into two groups of either migraine or non-
n = 92 566 migrainous headache. The diagnoses were mutually
exclusive. Persons were classified as migraineurs if they
Respondents to question about self reported reported having migraine or fulfilled the following three
DM in Q1
n = 64 403 criteria: (i) headache attacks lasting 4–72 h (<4 h was
No Yes
accepted for those who reported visual disturbances
n = 62 439 n = 1964 often before headache); (ii) headache with at least one
of the following three characteristics: (a) pulsating
quality, (b) unilateral location, and (c) aggravation by
Respondents to questions about headache in Q2 physical activity; and (iii) during headache, at least one
i.e. participants in the Head-HUNT Study of the following symptoms: (a) nausea, (b) photophobia
n = 51 383
and/or phonophobia. A diagnosis of migraine with
aura (MA) was accepted in subjects who reported fre-
quent visual disturbances prior to headache if they
No Self reported Missing
self reported DM n = 134 otherwise fulfilled the criteria for migraine, even if they
DM n = 1499
n = 49 750 had attacks that lasted <4 h. Headaches that did not
fulfill the criteria for migraine were classified as non-
migrainous headache. Headache frequency was divided
in three categories; <7 days/month, 7–14 days/month,
Data on fasting Missing data on
glucose, fasting glucose, and >14 days/month.
anti-GAD and anti-GAD and The questions about headache were mainly designed
C-peptide C-peptide
n = 1097 n = 402 to determine whether the person suffered from head-
ache or not, to determine frequency of headache, and to
diagnose migraine according to a modified version of
the migraine criteria of the Headache Classification
Committee of the International Headache Society
Type 1 DM Type 2 DM Other types Unclassified DM (1988) [20]. The classification of the subjects has been
n = 179 n = 870 n = 10 n = 440
described in detail previously, and has been validated
by interview diagnoses [21].
Figure 1 Diagram of the population and subgroups in the present
study.
Diabetes mellitus

the ÔHead-HUNT StudyÕ. Our sample comprised indi-
viduals aged ‡20 years with valid ratings of both DM
and headache. A total of 51 249 answered the questions
about both DM in Q1 and headache in Q2 (99.7% of
the Head-HUNT participants), whereof 1499 had self-
reported DM. Results from fasting blood samples with
serum glucose, C-peptide and anti-glutamic acid
decarboxylase (anti-GAD) was available in 1097 (73.2%)
of the 1499 with self-reported DM and was used for
classification of DM. Non-fasting serum glucose was
available in 39 168 (76.2%) of the individuals included in
the Head-HUNT Study. During the health examination
1459 (97.3%) of the 1499 participants with self-reported
DM included in the present study also had blood samples
drawn for glycosylated hemoglobin (HbA1c).
Headache diagnoses
Subjects who answered ÔyesÕ to the question ÔHave you
suffered from headache during the last 12 months?Õ
were classified as headache sufferers. Based on the data
from the subsequent 12 headache questions, they were
Patients with known DM were identified by a positive
answer to the question ÔDo you have or have you had
diabetesÕ in Q1. This question was validated in HUNT 1
and there was a high concordance between question-
naire-based information from the participants and the
medical files of the general practitioners in the munici-
pality investigated [22]. The prevalence of DM in
HUNT 2 was 3.22% [18], which is comparable with
other studies in Norway [23] and other Nordic countries
[24,25].
Non-fasting serum glucose was drawn from all the
participants who attended the clinical examination and
was analyzed by using an enzymatic hexokinase method
[26]. A total of 210 persons with no previously known
DM had non-fasting glucose of ‡11.1 mmol/l. Infor-
mation about the results was sent to both the partici-
pants and their general practitioners (GPs) for follow-
up. Although a considerable proportion of these
probably had DM (the diagnostic criteria of DM are
met with two measurements of non-fasting glucose of
‡11.1 mmol/l), only those with self-reported DM were
included in the HUNT study as persons with DM [26].

 2007 EFNS European Journal of Neurology 14, 738–744

740 A. H. Aamodt et al.
Further information about DM was based on Q3
(with questions on how their DM was detected, various
symptoms, insulin or other kinds of treatment, medical
follow-up, diet, psychological well-being, other kinds of
medication, eye complications, education programme,
national insurance benefit, and diabetic foot problems)
and blood samples [26]. Subjects who reported DM in
Q1 had a 5 ml ethylenediaminetetraacetic acid (EDTA)
sample analyzed for HbA1c and were given an
appointment for a fasting blood test to be analyzed for
glucose, C-peptide and anti-GAD. Anti-GAD was an-
alyzed by immunoprecipitation, using (3H)leucine
translation-labeled GAD65 as an indicator. Reagents
were supplied by NOVO Nordisk Pharma AS,
(Bagsvaerd, Denmark) [26].
The criteria for defining type 1 DM was treatment
with insulin within 6 months after the diagnosis and
anti-GAD ‡8.0 (reference value <0.08), or anti-GAD
<8.0 and C-peptide <150 pmol/l. The criteria for la-
tent autoimmune DM in adults (LADA) were anti-
GAD >8.0 and treatment with tablets/diet or insulin
treatment started more than 12 months after the diag-
nosis. In the analyses of the present study, LADA was
classified as type 1 DM according to the international
classification [27]. Type 2 DM was defined by concen-
tration of anti-GAD <0.8 and no insulin treatment
within 1 year of diagnosis. A total of 404 persons of
1499 (27%) with self-reported DM had incomplete in-
formation on insulin treatment and results of C-peptide
and anti-GAD. Accordingly, it was not possible to
subtype their DM. Only 10 persons fulfilled criteria for
other kinds of DM than type 1 or 2, (gestational DM
and maturity onset diabetes of the young), and these
were categorized together with those with unclassified
DM in the analyses of the present study.
Statistical analyses
In the multivariate analyses, using logistic regression, we
estimated the prevalence odds ratio (OR) with 95%
confidence interval (CI) for the association between
headache and DM. Potential confounders such as gen-
der, age (10 years categories), and duration of education
(<10, 10–12, and >12 years) were adjusted for. Other
variables like blood pressure (BP), weight, body mass
index (BMI), previous myocardial infarction, previous
or current angina pectoris, previous stroke, alcohol
consumption, smoking, physical activity, anxiety and
depression (assessed with the Hospital Anxiety and
Depression Scale) [28], and use of antihypertensives,
analgesics, or other medications were also evaluated as
potential confounders. Differences between means (age,
BP, and BMI) were tested with one-way ANOVA and
between categories with chi-squared test. Data analysis
was performed with the Statistical Package for the Social
Sciences, version 13.0 (SPSS, Chicago, IL, USA).
Ethics
The HUNT study was approved by the regional
committee for ethics in medical research, and by the
Norwegian Data inspectorate.
Results
More men than women had DM (P ¼ 0.006) (Table 1).
Educational level, alcohol consumption, and the pro-
portion of smokers was lower amongst DM patients
compared with those without DM, whereas age, BMI,
mean systolic BP and the prevalence of previous myo-
cardial infarction was higher, (P < 0.0001 for all
variables) (Table 1).
Prevalence OR of migraine was lower amongst per-
sons with DM, both type 1 and type 2 compared with
those without DM, also evident after adjusting for
potential confounding with factors like age, gender,
educational level, BP, weight, BMI, previous myo-
cardial infarction, previous or current angina pectoris,
previous stroke, alcohol consumption, smoking, phys-
ical activity, anxiety and depression, use of antihyper-
tensives, analgesics or other medications (Table 2).
Relatively few individuals had DM and MA (n ¼ 10)
and no clear association was found between MA and
DM (data not shown). As demonstrated in Fig. 2, the
unadjusted prevalences of headache were lower in those
with DM in all age groups except in the age group 30–
39. There were few persons <40 years of age with both
migraine and DM (n ¼ 17). Although there were no
significant interactions between DM and age regarding
migraine (P ¼ 0.23), the results of the multivariate
analyses were also performed after stratifying for age at
40 years (data not shown). The results in the older
group were mainly unchanged, whereas the associations
did not reach statistical significance in those <40 years.
There were no significant associations between non-
fasting serum glucose levels (available in 39 168 parti-
cipants) or fasting serum glucose levels (available in
1097 persons with DM) and headache prevalence
(Tables 2 and 3). However, there were significantly
lower ORs of migraine amongst persons with DM and
HbA1c levels >6.6% compared with those with lower
HbA1c levels, OR 0.5 (95% CI: 0.3–0.7) (Table 3).
Regarding duration of DM, there were lower preval-
ence ORs of all headache types amongst those with DM
‡13 years compared with those who had got DM within
the last 3 years (Table 3). There was no clear associ-
ation between headache frequency and DM (data not
shown).
 2007 EFNS European Journal of Neurology 14, 738–744
 Headache prevalence related to diabetes mellitus 741

Table 1 Background data on persons without and with diabetes mellitus (DM) (type 1, type 2, and other types/unclassified)

Variables No DM All DM types Type 1 DM Type 2 DM Other types/unclassified DM

n 49 750 1499 179 870 450

Gender, female (%) 54.0 50.4 43.0 49.1 56.0
Mean age (SD) 48.6 (13.4) 64.7 (14.2) 61.1 (12.0) 67.1 (10.9) 61.5 (19.2)
Years of education ‡13 (%) 21.3 9.7 15.5 8.5 13.8
Mean BMI (SD) 26.3 (4.0) 28.9 (4.8) 27.4 (4.7) 29.4 (4.8) 28.4 (4.8)
Current smoking (%) 27.0 15.1 16.8 13.1 18.4
Alcohol
Abstainers (%) 11.4 27.4 22.0 30.8 27.0
Mean consumption >7 units/week (%) 2.7 1.1 0.6 1.1 1.3
Previous myocardial infarction (%) 2.9 12.1 9.0 13.4 11.6
Mean systolic blood pressure (SD) 137 (22) 153 (26) 149 (24) 156 (24) 149 (29)

BMI, body mass index; SD, standard deviation.

Table 2 Prevalence OR of headache related to DM and non-fasting glucose levels

All headache types Migraine Non-migrainous headache

a a
Variables Total % OR (95% CI) % OR (95% CI) % ORa (95% CI)

Self-reported DM
No 49 750 39.0 1.0 (reference) 12.3 1.0 (reference) 26.7 1.0 (reference)
Yes 1499 27.6 1.0 (0.9–1.1) 5.7 0.7 (0.6–0.9) 21.8 1.1 (1.0–1.3)
Missing 134 33.6 1.4 (1.0–2.1) 3.0 0.4 (0.1–1.0) 30.6 1.9 (1.3–2.7)
No DM 49 750 39.0 1.0 (reference) 12.3 1.0 (reference) 26.7 1.0 (reference)
Type 1 DM 179 22.3 0.7 (0.5–0.9) 3.9 0.4 (0.2–0.9) 18.4 0.8 (0.6–1.2)
Type 2 DM 870 26.4 1.0 (0.9–1.2) 4.6 0.7 (0.5–0.9) 21.8 1.2 (1.0–1.4)
Other types/unclassified 450 31.8 1.1 (0.9–1.3) 8.9 1.0 (0.7–1.4) 22.9 1.1 (0.9–1.4)
Missing 134 33.6 1.4 (1.0–2.1) 3.0 0.3 (0.1–1.0) 30.6 1.9 (1.3–2.7)
Serum glucose quartiles
£4.8 mmol/l 10 325 40.7 1.0 (reference) 13.4 1.0 (reference) 27.3 1.0 (reference)
4.9–5.2 mmol/l 9417 37.9 1.0 (0.9–1.0) 11.3 0.9 (0.8–1.0) 26.6 1.0 (1.0–1.1)
5.3–5.9 mmol/l 10 473 34.9 1.0 (0.9–1.0) 10.7 1.0 (0.9–1.1) 24.1 1.0 (0.9–1.0)
‡6.0 mmol/l 8953 30.7 0.9 (0.9–1.0) 8.8 0.9 (0.8–1.0) 22.1 1.0 (0.9–1.1)
Missing 12 215 46.4 1.1 (1.1–1.2) 15.4 1.0 (0.9–1.1) 31.1 1.1 (1.0–1.2)
P-trend value 0.102 0.188 0.456
a
Adjusted for gender, age, and educational level (multiple logistic regression); CI, confidence interval; DM, diabetes mellitus; OR, odds ratio.

fasting glucose, anti-GAD, and C-peptide in addition to

Discussion
In this large-scale population-based cross-sectional
study, migraine was significantly less prevalent amongst
patients with DM type 1 or 2 compared with individ-
uals without DM. Furthermore, migraine prevalence
was lower amongst those with duration of DM
‡13 years or HbA1c levels >6.6%. There were no
associations between DM and non-migrainous head-
ache.
The strengths of this study were the large and unse-
lected population and the use of validated diagnoses of
both DM and headache. There is probably no interest
related selection bias as headache and DM conditions
were two out of many objectives of the study. Previ-
ously, there have been no population-based studies on
the relationship between migraine and DM in adults
with diagnosis of DM based on blood samples with
questionnaire-based data. Our findings of an inverse
relationship between the prevalence of migraine and
DM are in accordance with a previous case–control
study [6] and with two large-scale population based
studies [7,8]. In another prospective population-based
study of the association between DM and chronic daily
headache (CDH), DM was associated with a better
prognosis of CDH at follow-up 11 months later al-
though a weak association between DM and CDH was
found at baseline [29]. Several factors may explain the
varying results in other previous studies. Most of the
studies that demonstrated a positive association be-
tween headache and DM were hospital-based series and
case–control studies in which admission rate bias
(Berkson’s paradox) may be a problem. In two
other population-based studies which demonstrated a
positive association between DM and migraine in

 2007 EFNS European Journal of Neurology 14, 738–744

742 A. H. Aamodt et al.

35 those with self-reported DM included in the present

study could be classified as to subtype of DM (type 1, 2,
30 or other types) because of missing data on insulin
Self reported DM treatment (Q3), C-peptide and anti-GAD. The ques-
No DM tionnaire-based headache diagnoses were not optimal
Migraine prevalence (%)

25
compared with the interview diagnoses [21]. The head-
ache questions had to be adapted to the other questions
20
in HUNT, and the number of items was limited. Thus,
the intention was to clarify whether the participants
15
suffered from headache or not, to categorize headache
sufferers according to headache frequency, and finally,
10 to clarify whether this headache was migraine or not.
Because of the limited space, the questionnaire did not
5 allow a further differentiation of headache diagnoses, or
to diagnose more than one headache type in each pa-
0 tient. Problems of misclassification and non-partici-
20–29 30–39 40–49 50–59 60–69 ≥70 pants have been addressed previously [19,30]. We have
Age groups (years)
argued that these problems probably do not invalidate
Figure 2 Migraine prevalence (%) with 95% confidence interval the finding of associations.
related to age in those with and without self-reported diabetes The negative relationship between DM and migraine
mellitus. found in the present study raises the question whether
DM may in some ways protect against developing
adolescents [12] and between DM and both TTH and migraine, or vice versa. The causality issue cannot be
secondary headache in elderly persons [13], no adjust- properly addressed in a cross-sectional study, but there
ment for confounding factors such as chronic somatic are several pathophysiological changes in DM that may
or psychiatric diseases was performed in the analyses. be relevant in this respect. As the inverse relationship
Furthermore, the sample sizes were considerably smaller was mainly shown in middle-aged and elderly persons
than in the present study. and headache prevalence was reduced in those with the
There are limitations of the present study that must duration of DM ‡13 years, one may speculate that the
be taken into account. Although the validity of self- lower headache prevalence is related to diabetic neuro-
reported DM in HUNT 1 was good [22], only 73% of pathy. This is associated with numerous changes of

Table 3 Prevalence OR of headache related to levels of fasting serum glucose, HbA1c and duration of the disease in patients with DM

All headache types Migraine Non-migrainous headache

Variables Total % ORa (95% CI) % ORa (95% CI) % ORa (95% CI)

Fasting serum glucose quartiles

£4.8 mmol/l 283 32.9 1.0 (reference) 6.7 1.0 (reference) 26.1 1.0 (reference)
4.9–5.2 mmol/l 280 21.4 0.6 (0.4–0.9) 3.9 0.7 (0.3–1.5) 17.5 0.7 (0.4–1.0)
5.3–5.9 mmol/l 268 27.2 0.8 (0.6–1.2) 4.5 0.7 (0.4–1.7) 22.8 0.9 (0.6–1.3)
‡6.0 mmol/l 266 24.8 0.6 (0.4–1.0) 4.9 0.7 (0.3–1.6) 19.9 0.7 (0.4–1.0)
P-trend value 0.060 0.303 0.909
HbA1c quartiles
£6.6% 340 36.8 1.0 (reference) 10.0 1.0 (reference) 26.8 1.0 (reference)
6.7–7.7% 387 25.6 0.6 (0.5–0.9) 4.4 0.5 (0.3–0.9) 21.2 0.8 (0.6–1.1)
7.8–8.9% 343 24.2 0.6 (0.4–0.8) 3.5 0.4 (0.2–0.8) 20.7 0.8 (0.5–1.1)
‡9.0% 389 24.4 0.6 (0.5–0.9) 4.4 0.5 (0.3–1.0) 20.1 0.8 (0.5–1.1)
P-trend value 0.08 0.003 0.85
Duration of DM
0–2.9 years 228 32.0 1.0 (reference) 6.1 1.0 (reference) 25.9 1.0 (reference)
3.0–5.9 years 291 26.1 0.8 (0.5–1.1) 3.8 0.6 (0.3–1.4) 22.3 0.8 (0.6–1.3)
6.0–12.9 years 285 25.3 0.8 (0.5–1.1) 4.6 0.8 (0.3–1.7) 20.7 0.8 (0.5–1.2)
‡13.0 years 277 21.7 0.6 (0.4–0.9) 3.6 0.6 (0.3–1.4) 18.1 0.6 (0.4–1.0)
P-trend value 0.10 0.47 0.16
a
Adjusted for gender, age, and educational level (multiple logistic regression); CI, confidence interval; DM, diabetes mellitus; HbA1c, glycosylated
hemoglobin; OR, odds ratio.

 2007 EFNS European Journal of Neurology 14, 738–744


neurotransmitters that may be relevant in the patho-
physiology of migraine, such as the reduced levels of
nitric oxide [31] and noradrenaline and substance P in
peripheral nerves [32], and changes in the expression of
calcitonin-gene-related peptide and 5-hydroxytrypta-
mine in nerve fibers in gut [32]. Another possible link
might be the renin-angiotensin system that is sup-
pressed in patients with DM [32,33] and may have
relevance for the migraine pathophysiology [34]. The
results of the present study may also be accounted for
by a reduced cerebrovascular reactivity related to
diabetic neuropathy or to vessel wall thickening, two
factors which conceivably may protect against migraine
because they may lead to reduced vessel dilation [35].
However, investigations of vascular reactions in
migraine are ambiguous and often contradictory [36].
The findings of reduced migraine prevalence amongst
persons with DM could also be due to the highly
regulated lifestyle that they are recommended to have,
and which may protect against migraine. Or vice versa,
migraineurs may be compelled to a lifestyle protecting
against DM. However, adjusting the analyses for life-
style factors like physical activity, exercise, smoking,
and alcohol consumption did not change the results.
One might also speculate that there is a genetic link
between the disorders, and that the genes associated
with migraine are protective against DM. A recent
polymorphism study demonstrated an association be-
tween migraine and the insulin receptor gene [4], but no
mutations in the insulin receptor gene were found in a
chromosome 19p13 linked migraine pedigree [5].
Only persons with self-reported DM were included in
HUNT as having DM. However, evidence suggests that
between one-third and one-half of cases with type 2
DM are undiagnosed [37]. In the present study, 210
persons with previously unknown DM had non-fasting
glucose ‡11.1 mmol/l. As a considerable proportion of
these probably had DM, it was relevant to investigate
the relationship between headache and non-fasting
glucose levels. However, no relationship between glu-
cose levels and headache was found in the present
study.
In conclusion, migraine prevalence seemed to be
lower amongst subjects with DM type 1 or type 2 than
amongst those without DM. The reason for this inverse
relation is unknown, but it may be related to patho-
physiological changes in patients with DM protecting
against migraine.
Acknowledgements
The Nord-Trøndelag Health Study (The HUNT Study)
is a collaboration between HUNT Research Centre,
Faculty of Medicine, Norwegian University of Science
 2007 EFNS European Journal of Neurology 14, 738–744
Headache prevalence related to diabetes mellitus 743
and Technology (NTNU, Verdal), Norwegian Institute
of Public Health, and Nord-Trøndelag County Council.
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