Full text of DOI:10.1007/BF03345512

J. Endocrinol. Invest. 25: 779-784, 2002
Autoimmune thyroiditis in non-obese subjects with initial
diagnosis of Type 2 diabetes mellitus
M. Mateˇjková-Beˇhanová*, V. Zamrazil*, K. Vondra*, J. Vrbíková*, P. Kucˇera**, M. Hill*,
and M. Andeˇl***
*Institute of Endocrinology, **Department of Allergology and Immunology, and ***Diabetes Centre,
3rd Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague,
Czech Republic
ABSTRACT. Autoimmune thyroiditis is often as-
sociated with Type 1 diabetes mellitus (T1DM).
In non-obese adult-onset diabetes diagnosed
initially as Type 2 diabetes mellitus (T2DM),
there is a proportion of cases with so far undi-
agnosed T1DM. The objective of this study was
to estimate the frequency of autoimmune thy-
roiditis (AT) among non-obese (BMI <30.0
kg/m2) patients with T2DM and to compare the
frequency of AT in subgroups of patients ac-
cording to the presence of glutamic acid de-
carboxylase antibodies (GADA), insulin re-
quirement, and post-breakfast C-peptide lev-
els. The study included 118 adult patients (55
men and 63 women) with the initial diagnosis
of T2DM and age at the onset of diabetes >35
yr. Median of age was 66 yr (range 39-82), and
median duration of diabetes was 9 (range 1-
27) yr. AT was diagnosed using thyroid perox-
idase antibodies, TG-antibodies, US and TSH
levels. Nineteen per cent of the subjects were
found to have AT, and the frequency of AT did
not significantly differ between the groups of
GADA+ and GADA- subjects. There was no dif-
ference in the frequency of AT between the
group treated with hypoglycemic agents
and/or diet and the group requiring insulin. The
frequency of AT was higher in the group with
post-breakfast C-peptide levels ≤0.8 nmol/l
compared to the group with post-breakfast C-
peptide levels >0.8 nmol/l (37% vs 16%), how-
ever the group with post-breakfast C-peptide
levels ≤0.8 nmol/l had longer duration of dia-
betes.
(J. Endocrinol. Invest. 25: 779-784, 2002)
©2002, Editrice Kurtis
INTRODUCTION
(LADA) later (3). The typical patient with LADA is
25-yr old or older, non-obese and presents with
what clinically appears to be T2DM (4). Subse-
quent clinical course, characterized by a slowly
progressing development of insulin deficiency
and the presence of serological markers of au-
toimmunity (mainly the glutamic acid decarboxy-
lase antibodies – GADA), suggests that it is a form
of T1DM (5, 6).
AT is often associated with typical T1DM. This
has been reported in children (7-10) as well as in
younger adults (11-13). AT has been document-
ed using different diagnostic criteria that are a
combination of the presence of thyroid peroxi-
dase antibodies (TPOAb) or TG-antibodies
(TGAb), assessment of thyroid function, US imag-
ing of the thyroid and fine needle biopsy in some
studies.
Two major types of diabetes mellitus (DM) are
identified: Type 1 diabetes mellitus (T1DM), with
beta-cell destruction leading to absolute insulin
deficiency and Type 2 diabetes mellitus (T2DM),
with insulin resistance and usually relative (rather
than absolute) insulin deficiency (1). Regarding
adult-onset diabetes, a particular problem area
still remains in the classification of DM. Here, the
major problem is to distinguish the T2DM from a
slowly progressing form of the T1DM that was
first characterized in the early 1980’s (2) and
called latent autoimmune diabetes (AT) in adults
Key-words: Autoimmune thyroiditis, T2DM, glutamic acid decarboxy-
lase antibodies, thyroid peroxidase antibodies, TG-antibodies, C-pep-
tide.
Correspondence: Dr. Magdalena Mateˇjková-Beˇhanová, Institute of
Endocrinology, Národní 8, 116 94 Prague, Czech Republic.
Though the association of AT with T1DM is clear,
little is known about the risk of autoimmune thy-
roiditis in LADA. Here, the main problem still re-
E-mail: mbehanova@endo.cz
Accepted May 23, 2002.
779

Autoimmune thyroiditis in T2DM
C-peptide
mains of how to provide a clear definition of LADA,
the diagnosis of AT being far from easy as well. A
small number of studies investigated the preva-
lence of thyroid antibodies in adult patients who
were initially diagnosed as having T2DM. Gambe-
lunghe et al. (14) found a higher prevalence of
TPOAb in GADA+ subjects with initial diagnosis of
T2DM compared to GADA- subjects. In another
study, Groop et al. (15) examined a group of pa-
tients with T2DM who were controlled with diet or
oral hypoglycemic agents and a group of age-
matched T2DM patients who required insulin to
control their hyperglycemia. The frequency of
TPOAb was significantly higher in those diabetic
patients who required insulin than in those who
could be controlled without insulin (15).
C-peptide level was determined using IRMA (Immunotech,
Czech Republic) after overnight fast and 60 min after adminis-
tration of standardized breakfast consisting of 1650 kJ, and 46
g carbohydrate, 19 g fat and 13 g protein. The optimal cut-off
value for post-breakfast C-peptide was found using receiver op-
erating characteristic (ROC) at maximum likelihood ratio at the
value 0.80 nmol/l.
Antibody assays
TPOAb and TGAb were measured using ELISA (Milenia Biotec,
Germany; the cut-off limit for positivity was based on the upper
normal limit of the kit, which was 125 IU/ml for TPOAb and 250
IU/ml for TGAb). GADA were measured using 2 commercial
ELISA kits: ELIAS (Germany), with positive values >1500 mU/ml
and after ending of production with Diaplets Roche, with posi-
tive values >50 ng/ml. The sensitivity of ELIAS kit has been re-
ported to be equivalent to 26% and the specificity of 100% (17).
The sensitivity of Diaplets Roche kit has been reported of 69%
and the specificity of 98% (18). The results of Diaplets Roche
were compared with those obtained with ELIAS in 40 samples
using the Spearman’s correlation with respect to non-Gaussian
data distribution. The comparison found significant correlation
(r=0.581, p<0.001).
The objective aim of this study was to estimate the
frequency of AT in non-obese T2DM patients and
to compare the frequency of AT in subgroups of
patients divided according to the presence of GA-
DA, insulin requirement and post-breakfast C-pep-
tide levels.
Statistical analysis
MATERIALS AND METHODS
Study population
The results are presented as medians and 25-75 percentiles or
SE, or as percentages. Statistical analysis was performed using
the Statgraphics software, chi-square test, Fischer’s exact test, re-
spectively; Mann-Whitney test were carried out. P values less
than 0.05 were considered as significant.
The study population consisted of 118 adult patients (55 men
and 63 women) who were randomly selected from a population
of patients treated at an outpatient diabetes care unit in a dis-
trict of Prague (Prague 9). The selection criteria were as follows:
1. initial diagnosis of T2DM and treatment with hypoglycemic
agents and/or diet for at least 6 months after onset; 2. age at
onset of diabetes >35 yr and 3. BMI <30 kg/m2. The duration of
diabetes ranged from 1-27 yr, and none of the patients suffered
from a diabetic renal disease in the stage of chronic renal failure.
The study protocol was approved by the local Ethical Com-
mittee, and written informed consent was obtained from all
study participants.
RESULTS
AT was found in 23 subjects (19%), and the fre-
quency of AT appeared to be higher in women (16
cases, 25%) compared to men (7 cases, 13%),
p<0.10. TPOAb were found in 14 subjects (12%), the
frequency of TPOAb was significantly higher in wom-
en: 12 women (19%) vs 2 men (4%), p<0.05. The
median of positive TPOAb titres was 235 (range 155-
5050) IU/ml. TGAb were found in 8 subjects (7%),
the frequency of TGAb was similar in men and in
women: 6 women (9%) and 2 men (4%). The median
of positive TGAb titres was 1745 (range 365 - 3780)
IU/ml. New diagnosis of hypothyroidism was estab-
lished in 11 cases (9%), in 2 cases overt hypothy-
roidism and in 9 cases subclinical hypothyroidism.
We found GADA in 12.7% non-obese patients with
initial diagnosis of T2DM. GADA+ subjects were
found to have longer duration of diabetes than
those who were GADA-, with no difference in BMI
and age. The frequency of AT did not significantly
differ in GADA+ and GADA- subjects, the fre-
quency of TPOAb, however, tended to be higher
in GADA+ individuals (Table 1).
US procedures
Thyroid US was performed by 2 experienced investigators us-
ing the Toshiba SSA 270A and Hitachi equipment using a 7,5
MHz probe. AT was defined as the finding of diffuse or focal re-
duced echogenicity on US (16).
Thyroid function
Thyroid function was determined using TSH and free FT4 levels
measured with EIA (Roche Diagnostics, Analyser ES 300, nor-
mal range for TSH: 0.27 - 4.2 mIU/l, normal range for FT4: 12.0
– 22.0 pmol/l). The level of TSH >4.2 was consistent with hy-
pothyroidism.
Autoimmune thyroiditis
AT was defined as the presence of thyroid antibodies (TPOAb or
TGAb) together with typical finding on US of hypoechogenic
thyroid gland, or as hypothyroidism with US finding of hypoe-
chogenic thyroid gland.
Table 2 shows a comparison of the group of pa-
780

M. Mateˇjková-Beˇhanová, V. Zamrazil, K. Vondra, et al.
Table 1 - Autoimmune thyroiditis, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), C-peptide levels and
basic clinical characteristics in GADA- and GADA+ subjects. Data are presented as absolute numbers, ratios, percentages or as me-
dians (25-75 percentiles).
Total
GADA-
49:54
GADA+
6:9
Significance
NS
Male:female
55:63
BMI (kg/m2)
25.5 (23.7/27.3)
66 (58-70)
25.5 (23.8/27.3)
66 (58-70)
25.2 (21.2/27.4)
67 (58-70)
NS
Age (yr)
NS
Diabetes duration (yr)
Fasting C-peptide (nmol/l)
Post-breakfast C-peptide (nmol/l)
8.5 (4-15)
8.0 (4-15)
14.0 (5-19)
0.51(0.08-0.69)
0.96 (0.06-1.47)
p<0.03
p<0.02
p<0.02
p<0.06
0.74 (0.55-1.06)
1.44 (1.02-2.10)
0.77 (0.60-1.09)
1.47 (1.06-2.10)
TPOAb
Male:female
14 (11.9%)
2:12*
10 (9.7%)
2:8
4 (26.7%)
0:4
TGAb
8 (6.7%)
2:6
6 (5.8 %)
2:4
2 (13.3%)
0:2
NS
NS
Male:female
Autoimmune thyroiditis
Male:female
23 (19.5%)
7:16**
18 (17.4%)
7:11
5 (33.3%)
0:5
*p<0.05 for frequency of men compared to women; **p<0.10 for frequency of men compared to women.
tients treated with hypoglycemic agents and/or di-
et with the group of patients who required insulin to
reduce their hyperglycemia. The criterion used to
start insulin therapy was unsatisfactory compensa-
tion of diabetes with oral hypoglycemic agents re-
garding to glycosylated hemoglobin (HbA1c) and
post-prandial glycemia levels. However, in our
study there was not significant difference of HbA1c
in insulin requiring (median 9.8, SE=2.1%) and non-
insulin requiring subjects (median 8.6%, SE=2.5).
The subjects who required insulin had longer du-
ration of diabetes and higher frequencies of GA-
DA. They did not, however, differ from the non-in-
sulin requiring subjects in other characteristics (BMI,
age). The subjects who required insulin tended to
have a higher frequency of AT.
Table 3 shows the comparison of the subjects when
divided according to the post-breakfast C-peptide
levels. Both subgroups did not differ in age and
BMI, however the diabetes of the subjects with
post-breakfast C-peptide ≤0.8nmol/l lasted longer.
The frequencies of AT and TPOAb presence were
higher in the group with post-breakfast C-peptide
≤0.8nmol/l.
Table 2 - Autoimmune thyroiditis, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), glutamic acid decar-
boxylase antibodies (GADA), C-peptide levels and basic clinical characteristics in subjects who required treatment with insulin (insulin
requiring) and those who did not (non-insulin requiring). Data are presented as absolute numbers, ratios, percentages or as medians
(25-75 percentiles).
Non-insulin requiring
40:48
Insulin requiring
15:15
Significance
NS
Male:female
BMI (kg/m2)
25.3 (23.8-27.3)
66 (58-70)
25.7 (23.5-27.1)
66 (55-70)
NS
Age (yr)
NS
Diabetes duration (yr)
Fasting C-peptide (nmol/l)
Post-breakfast C-peptide (nmol/l)
GADA
7 (2-11)
16 (10-19)
p<0.001
p<0.001
p<0.001
p<0.05
NS
0.82 (0.64-1.15)
1.78 (1.24-2.23)
8 (9.1%)
0.39 (0.21-0.63)
0.76 (0.41-1.14)
7 (23.3%)
TPOAb
Male:female
8 (9.1%)
1:7**
6 (20.0%)
1:5°
TGAb
Male:female
6 (6.7%)
1:5
6.8%
1:1
NS
Autoimmune thyroiditis
Male:female
14 (15.9%)
3:11*
9 (30.0%)
4:5
p<0.10
*p<0.05 for frequency of men compared to women; **p<0.10 for frequency of men compared to women.
781

Autoimmune thyroiditis in T2DM
Table 3 - Autoimmune thyroiditis, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), glutamic acid decar-
boxylase antibodies (GADA) and basic clinical characteristics in the group with post-breakfast C-peptide >0.8 nmol/l compared to the
group with post-breakfast C-peptide ≤0.8nmol/l. Data are presented as absolute numbers, ratios, percentages or as medians (25-75
percentiles).
Post-breakfast
C-peptide >0.8 nmol/l
Post-breakfast
C-peptide >0.8 nmol/l
Significance
Male:female
BMI (kg/m2)
Age (yr)
45:52
25.6 (23.8-27.3)
66 (61-70)
8 (4-13)
10:9
25.0 (23.5-27.1)
63 (54-70)
17 (8-19)
NS
NS
NS
Diabetes duration (yr)
GADA
p<0.004
p<0.08
p<0.02
10 (10.3%)
5 (26.3%)
TPOAb
Male:female
8 (8.2%)
1:7*
6 (31.6%)
1:5*
TGAb
Male:female
6 (6.2%)
1:5
2 (10.5%)
1:1
NS
Autoimmune thyroiditis
Male:female
16 (15.5%)
5:11
7 (36.8%)
2:5
p<0.05
*p<0.05 for frequency of men compared to women.
DISCUSSION
cantly higher prevalence of TPOA in GADA+ sub-
jects was found. The population characteristics were
similar to the ones in our study, the only difference
being the subjects’ age (median 58; range 30-72 yr)
that was higher in our study. In the study of Gam-
belunghe et al., (14) 67 subjects were GADA+ and
174 subjects were GADA-, with prevalence of TPOA
23.9% and 5.2%, respectively (p<0.001). Compared
with these results, our study found the TPOAb to
be more frequent in GADA- subjects (9.7%).
Another study by Tuomi et al. (26), investigated 33
GADA+ and 69 GADA- subjects with characteristics
and median of age similar to our study. In this study,
the frequency of TPOAb in GADA- individuals was
19% and no statistically significant difference in
TPOA frequencies was found between GADA+ and
GADA- groups (26). It is not clear whether those
GADA- subjects have T2DM as the positivity of GA-
DA in the group of cases of non-obese T2DM may
not be the sole autoimmunity marker (6). Appro-
ximately 25% non-obese T2DM subjects may have
other markers of autoimmune diabetes than GADA
(3). The relatively high frequency of TPOAb in our
GADA- subjects could be attributed to the fact that
our population was older – the prevalence of AT has
been reported to increase in elderly subjects (27),
mainly in women (22).
In the present study, the frequency of AT in non-
obese patients with initial diagnosis of T2DM was
almost 20%. These results are consistent with the
frequency of AT in adult patients with T1DM that
has been reported from 20-40% (11-13, 19). The in-
cidence of autoimmune thyroiditis in the non-dia-
betic adult population varied from 5-10%, with sig-
nificantly higher incidence in women (20). On the
other hand, 2 studies of autopsy material reported
notably higher incidence of lymphocytic AT of
about 30% (21, 22). There is also a study in the pop-
ulation of blood donors that reported a very high
prevalence of TPOAb in female at age 55-64 about
30% (23). We have recent data obtained from a ran-
domly selected population from one region of the
Czech Republic. The incidence of TPOAb was 8.9%
in the whole adult population, whereas there were
21.1% TPOAb+ women in the age group of 50-65
yr (24). The incidence of AT in our population of
non-obese patients with initial diagnosis of T2DM
seems to be similar to that found in the general
population.
The comparison of our results with published data
on patients with an initial diagnosis of T2DM faces
difficulties due to the fact that different studies
used different selection criteria and suited differ-
ent populations. Furthermore, most of the studies
estimated only the frequency of thyroid peroxidase
antibodies and based their diagnosis of AT on in-
sufficient parameters. The use of US is associated
with higher sensitivity for the diagnosis of AT dis-
ease (25).
Groop et al. (15) studied 312 subjects with T2DM,
whose diabetes was diagnosed after the age of
35 yr and found significantly higher frequency of
TPOAb in subjects who required treatment with
insulin compared to those who did not require
such treatment (33.7 vs 19.8%, respectively). The
difference in the frequency of TPOAb between in-
In the study of Gambelunghe et al. (14), a signifi-
782

M. Mateˇjková-Beˇhanová, V. Zamrazil, K. Vondra, et al.
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