INT J TUBERC LUNG DIS 10(6):696–700

© 2006 The Union

Diabetes mellitus is strongly associated with tuberculosis

in Indonesia

B. Alisjahbana,* R. van Crevel,† E. Sahiratmadja,‡ M. den Heijer,§ A. Maya,* E. Istriana,¶

H. Danusantoso,¶ T. H. M. Ottenhoff,# R. H. H. Nelwan,** J. W. M. van der Meer†
* Department of Internal Medicine, Medical Faculty, Padjadjaran University, Bandung, Indonesia; † Department of
Internal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; ‡ Eijkman Institute of
Molecular Biology, Jakarta, Indonesia; § Department of Endocrinology, Epidemiology and Biostatistics, Radboud University
Nijmegen Medical Center, Nijmegen, The Netherlands; ¶ Indonesian Tuberculosis Control Association, Jakarta Branch,
Jakarta, Indonesia; # Department of Immunohematology and Bloodbank, Leiden University Medical Center, Leiden,
The Netherlands; ** Infectious Disease Working Group, Medical Faculty, University of Indonesia, Jakarta, Indonesia

SUMMARY

S E T T I N G : Diabetes mellitus is a known risk factor for
tuberculosis (TB), but no studies have been reported
from South-East Asia, which has a high burden of TB
and a rapidly growing prevalence of diabetes.
O B J E C T I V E : To examine if and to what extent diabetes
is associated with an increased risk of TB in an urban
setting in Indonesia.
D E S I G N : Case-control study comparing the prevalence
of diabetes mellitus (fasting blood glucose level 126
mg/dl) among newly diagnosed pulmonary TB patients
and matched neighbourhood controls.
R E S U L T S : Patients and control subjects had a similar age
(median 30 years) and sex distribution (52% male), but
malnutrition was more common among TB patients
(median body mass index 17.7 vs. 21.5 kg/m2). HIV in-
fection was uncommon (1.5% of patients). Diabetes mel-
litus was present in 60 of 454 TB patients (13.2%) and
18 of 556 (3.2%) control subjects (OR 4.7; 95%CI 2.7–
8.1). Adjustment for possible confounding factors did
not reduce the risk estimates. Following anti-tuberculosis
treatment, hyperglycaemia reverted in a minority (3.7%)
of TB patients.
C O N C L U S I O N : Diabetes mellitus is strongly associated
with TB in young and non-obese subjects in an urban
setting in Indonesia. This may have implications for TB
control and patient care in this region.
K E Y W O R D S : tuberculosis; pulmonary; diabetes melli-
tus type 2; relative odds; case-control study; Indonesia

THE PREVALENCE of diabetes mellitus is increas- METHODS

ing worldwide, especially in Asia,1 where tuberculo-
At Perkumpulan Pemberantasan Tuberculosis Indo-
sis (TB) is highly endemic.2 Most textbooks state
nesia, an out-patient TB clinic in central Jakarta, and
that diabetes is a risk factor for TB, but little is
Hasan Sadikin General Hospital, Bandung, consecu-
known about the nature and strength of this rela-
tive new PTB patients aged over 15 years of age were
tionship. Original studies on this subject were mostly
included in the study. Diagnosis was based on clinical
conducted more than 40 years ago, and primarily in
presentation and chest X-ray examination, confirmed
the United States and Europe.3–5 To our knowledge,
by microscopic detection of acid-fast bacilli. Treatment
only one published Asian report shows that diabetic
consisted of a standard regimen, 2HRZE/4H3R3,* ac-
patients have an increased risk of developing pulmo-
cording to the Indonesian National TB Programme.
nary tuberculosis (PTB).6 If diabetes is a risk factor
Social workers visited the patient’s community and
for TB in this part of the world, this will have impor-
tant consequences for TB control and patient care,
as diabetes co-morbidity is related to a higher TB
* H  isoniazid; R  rifampicin; Z  pyrazinamide; E  etham-
case fatality rate.7 We therefore examined to what butol. Numbers before the letters indicate the duration in months
extent diabetes is associated with an increased risk of of the phase of treatment; numbers in subscript indicate the num-
TB in Indonesia. ber of times the drug is taken each week.

Correspondence to: Reinout van Crevel, Department of Internal Medicine, Radboud University Nijmegen Medical Center,
PO Box 9101, 6500 HB Nijmegen, The Netherlands. Tel: (31) 243618819. Fax: (31) 243541734. e-mail: r.vancrevel@
aig.umcn.nl
Article submitted 11 November 2005. Final version accepted 15 January 2006.
 Diabetes as a risk factor for TB in Indonesia 697

randomly selected a control subject of the same sex
and age (10%) living within the same rukun te-
tangga, the smallest residential unit in Indonesia, which
consists of 15–30 households. First-degree relatives of
patients were excluded. Control subjects with signs
and symptoms suggesting active TB or a history of
prior anti-tuberculosis treatment were also excluded.
Written informed consent was obtained from all sub-
jects, and the study was approved by the ethics com-
mittee of the Faculty of Medicine, University of Indo-
nesia, Jakarta.
No anti-diabetic agents were taken within 48 h be-
fore blood sampling for measurement of fasting blood
glucose (FBG) concentrations. Diabetes mellitus was
diagnosed if FBG was 126 mg/dl, and FBG concen-
trations were considered impaired for 110 and 126
mg/dl, in accordance with World Health Organiza-
tion (WHO) criteria.8 In all patients, FBG concentra-
tions were measured before and after one month of
anti-tuberculosis treatment and thereafter in a subset
of 89 patients. For those patients with discordant clas-
sification before and during anti-tuberculosis treat-
ment, the classification of diabetes was applied to the
first FBG measurement only. Semi-quantitative mea-
surement of glycosuria was done using urine dipsticks
(Combur test, Roche, Jakarta, Indonesia). Urine glu-
cose concentrations 30 mg/dl were considered ab-
normal. Plasma creatinine was measured to identify
additional renal co-morbidity if considered abnormal
(normal value 90 mmol/l for females and 110
mmol/l for males). Human immunodeficiency virus
(HIV) testing was conducted using the dipstick test
(Determine, Abbott Diagnostics, Hoofddorp, The
Netherlands).
Crude and adjusted odds ratios (ORs) were calcu-
lated as estimates of the relative risks with corre-
sponding 95% confidence intervals (CI) and a logistic
regression model. Adjusted ORs reflect the risk of TB
for people with diabetes mellitus compared to normal
individuals after adjustment for variables including:
sex, age, body mass index (BMI, calculated as kg/m2),
presence of TB contact in the family or household, in-
come and number of individuals per household.
RESULTS
Between March 2001 and March 2005, 481 new PTB
patients were recruited, of whom 454 were included
for further analysis. Twenty-seven were excluded be-
cause of a past history of TB (n  6) and incomplete
data (n  21). Patients had a median age of 30.0 years
(range 15–75), and 238 (52.4%) were male (Table 1).
All were newly diagnosed with PTB confirmed by
sputum microscopy. Mycobacterium tuberculosis cul-
ture results were available in 373 patients, and were
positive in 328 (87.9%). Patients presented after a
median of 3 months (range 1 week to over 1 year)
with cough (98.9%), haemoptysis (42.5%), shortness
of breath (66.1%), fever (77.3%) and weight loss
(84.1%). Cases had a median BMI of 17.7 kg/m2 (range
11.2–31.4). Antibodies against HIV were present in 6
of 402 TB patients examined (1.5%) and none of the
40 controls tested. Mild elevation of plasma creatinine
was found in one of 234 cases examined.
Six hundred and twenty-two subjects were re-
cruited as matched controls. Sixty-six were excluded
for further analysis because of suspected TB (n  22),
history of TB treatment (n  7) or incomplete data
(n  37). The remaining 556 controls had a similar
sex distribution, age (median 30.0 years; range 15–
76) and socio-economic background as the patients
(Table 1). Control subjects had a higher body weight
than patients, while history of TB contact was less
common (Table 1).
Diabetes mellitus was more common in patients
with TB than in control subjects (Figure). Sixty TB
patients (13.2%) had diabetes compared with 18
(3.2%) controls (OR 4.7, 95%CI 2.7–8.1) (Table 2).
Impaired FBG was present in 15 TB patients (3.3%)
and five controls (0.9%, OR 4.2, 95%CI 1.5–11.7).

Table 1 Characteristics of TB patients and control subjects

TB patients Control subjects

(n  454) (n  556)
n (%) n (%) P value
Male sex 238 (52.4) 292 (52.5) 0.513
Age classification, years
19 35 (7.7) 51 (9.2) 0.506
20–29 187 (41.2) 215 (38.7)
30–39 99 (21.8) 138 (24.8)
40 133 (29.3) 152 (27.3)
Income (US $/capita/day) (n  438) (n  535)
1 137 (31.3) 165 (30.8) 0.823
1–2 173 (39.5) 204 (38.1)
2 128 (29.2) 166 (31.0)
Overcrowding (2 individuals per bedroom) 256 (56.4) 325 (58.4) 0.361
History of TB contact 239 (52.6) 166 (29.9) 0.001
Body mass index, kg/m2, median (range) 17.7 (11.2–31.4) 21.5 (13.4–40.1) 0.001
698 The International Journal of Tuberculosis and Lung Disease

Figure Fasting blood glucose concentrations according to body mass index among TB patients
(A) and control subjects (B).

Glycosuria was present in 43 of 415 TB cases (10.4%) DISCUSSION

and 16 of 413 controls (3.6%), corresponding to an
We have found a strong association of TB and diabe-
OR of 3.1 (95%CI 1.7–5.6) (Table 2).
tes in two urban clinics in Indonesia. We believe this is
The median age of TB patients with diabetes, im-
the first study to examine this association in Indone-
paired FBG and no diabetes was 45.0, 45.0 and 27.1
sia, where more than 10% of the world’s TB patients
years, respectively (P  0.001). The median BMI was
live,2 and one of the first in South-East Asia. Almost
21.2, 16.9 and 17.8 kg/m2, respectively (Figure, A). Di-
15% of relatively young, lean TB patients in our
abetes was newly diagnosed in 36/60 patients (60.0%)
clinic presented with diabetes. This rate was much
and 12/18 controls (66.7%) with diabetes. Among 24
lower in control subjects with a similar age and socio-
patients with a history of diabetes, only 19 (79.2%)
economic background. Adjustment for possible con-
were being treated, all with oral hypoglycaemic agents.
founding factors did not reduce the strength of the
Repeated measurement during TB treatment showed
association.
normalisation of FBG in 2/53 (3.7%) patients who
Diagnosis of diabetes by a single measurement of
initially had FBG 126 mg/dl, and conversion to di-
FBG in PTB patients can be confounded by disease
abetes in 6/295 (2.0%) patients with normal FBG
activity. Previous studies have shown that blood glu-
before TB treatment.
cose levels may normalise during treatment of TB,9,10
Possible confounding of the relationship between
but in our study this occurred in only a small minority
diabetes and TB was examined using logistic regres-
of patients.
sion. Sex, income and overcrowding did not alter the
It seems unlikely that the strong association be-
OR significantly. History of TB contact was signifi-
tween TB and diabetes can be attributed to other fac-
cantly more common among cases than controls
tors, as socio-economic factors, living conditions and
(Table 1); however, adjustment to this variable did
presence of co-morbidity were similar. Adjustment
not reduce the risk estimates. TB patients had a lower
for the higher frequency of TB contacts among the
BMI than controls, but adjustment for BMI increased
cases did not lower the risk estimates. This difference
the risk estimates, showing that the association be-
may have been due to recall bias. Both cases and
tween TB and diabetes is not explained by differences
controls had probably been exposed to TB as they
in BMI.
came from the same (mostly overcrowded) urban en-
vironment, with an estimated TB incidence of 128 per
100 000 population.2 We also investigated whether
Table 2 Tuberculosis risk in diabetes, impaired FBG a difference in BMI can explain the association be-
and glucosuria tween TB and diabetes. TB patients had a much lower
BMI at presentation than control subjects, as they
Cases Controls
n (%) n (%) OR (95%CI) lose, on average, 10–15% of their body weight dur-
ing their illness. Diabetes cases had a significantly
Total tested, n 454 556
Normal FBG (110 mg%) 379 (83) 533 (96) 1.0* higher BMI in both patients and controls and, as a
Impaired FBG result, adjustment for BMI actually increased the risk
(110, 126 mg%) 15 (3) 5 (1) 4.2 (1.5–11.7) estimates.
Diabetes (126 mg%) 60 (13) 18 (3) 4.7 (2.7–8.1)
As this was a case-control study, we can only hypoth-
Total tested, n 415 413
No glucosuria 372 (90) 398 (96) 1.0* esise about the cause-effect relationship between TB
Glucosuria 43 (10) 15 (4) 3.1 (1.7–5.6) and diabetes. On the one hand, TB may have triggered
* Reference category, odds ratio  1.
the development of diabetes, e.g., by inflammation-
FBG  fasting blood glucose; OR  odds ratio; CI  confidence interval. associated insulin resistance. Effective anti-tuberculosis

treatment only normalised hyperglycaemia in a small
proportion of the diabetes patients, which pleads
against this hypothesis. A second possibility is that di-
abetes was already present in these subjects, acting as
a risk factor for the development of TB. Forty per cent
of TB patients presenting with hyperglycaemia had a
history of diabetes. As the study subjects were very
poor, with limited access to regular health care, the
proportion with undiagnosed diabetes may in fact
have been higher. Immunological studies support the
hypothesis that diabetes is a risk factor for TB. Pro-
duction of interferon-gamma, which is crucial for
host defence against TB, has been found to be low in
diabetic mice infected with M. tuberculosis,11 and it
has been shown that alveolar macrophages in TB
patients with diabetes show less activation.12 Co-
hort studies performed in Europe and the United States
in the 1930s also support this hypothesis: diabetics
showed a three- to four-fold increased risk of devel-
oping TB.4
A recent case-control study of TB patients in Mex-
ico reported a higher risk estimate than ours: the
prevalence of diabetes was 29.6%, which was 6.8-
fold higher than the background prevalence of diabe-
tes in the study area.3 Previous studies from Korea,
Europe and the US in which diabetes patients were
prospectively followed, reported risk estimates simi-
lar to ours.3–6,14,15
Compared to Western standards, patients with di-
abetes in our study had a remarkable phenotype, as
they were relatively young and certainly not obese. It
should be noted that diabetics in Asia are generally
younger and leaner than diabetics in Europe.16 The
prevalence of diabetes in our control group was sim-
ilar to previous data from a survey among the general
population in Indonesia, and from other countries in
Asia.1
If diabetes, as our study suggests, is such a strong
risk factor for TB, this may have significant clinical
and epidemiological implications. In 2025, 75% of
diabetics will live in developing countries where more
than 90% of TB cases reside.1,2 An increasing preva-
lence of diabetes in these countries may thus threaten
the success of TB control. Because diabetes was un-
noticed and untreated in the majority of TB patients
in our setting, it seems wise to screen TB patients for
diabetes. Based on our study, we would recommend
screening all TB patients above 35 years of age at
least once, and looking for symptoms of diabetes in
younger patients. Screening and earlier manage-
ment of diabetes may reduce the risk of developing
active TB. Future studies are needed to confirm this
hypothesis.
Diabetes as a risk factor for TB in Indonesia 699
Acknowledgements
This study is an indirect result of the project ‘Immunogenetic basis
of susceptibility to and disease manifestations of mycobacterial
infections’, conducted within the ‘Scientific Programme Indonesia
Netherlands’ (SPIN) and supported by the Royal Academy of Arts
and Sciences (KNAW), the Netherlands. We thank Prof Sangkot
Marzuki, director of the Eijkman Institute of Molecular Biology,
Jakarta, for his kind support in this collaborative project and Cees
Tack for critically reviewing the manuscript.
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700 The International Journal of Tuberculosis and Lung Disease
CONTEXTE : Le diabète sucré est un facteur de risque
connu pour la tuberculose (TB), mais aucune étude n’a
été rapportée à ce sujet en Asie du Sud-Est, qui connaît
un fardeau élevé de TB et une prévalence rapidement
croissante du diabète.
O B J E C T I F : Examiner si et dans quelle mesure le diabète
est associé à un risque accru de TB dans un contexte
urbain en Indonésie.
S C H É M A : Etude cas-contrôle comparant la prévalence
du diabète sucré (taux de glucose sanguin à jeun 126
mg/dl) parmi les patients dont la TB pulmonaire a été
nouvellement diagnostiquée et parmi des contrôles de
voisinage appariés.
R É S U L T A T S : L’âge médian des patients et des sujets-
contrôle était similaire (30 ans), de même que la distri-
M A R C O D E R E F E R E N C I A : La diabetes representa un fac-
tor de riesgo reconocido de tuberculosis (TB), pero no se
ha publicado ningún estudio en pacientes del sureste
asiático, una región con alta carga de morbilidad por TB
y una prevalecía rápidamente creciente de diabetes.
O B J E T I V O : Evaluar si existe y cuantificar la posible cor-
relación entre la diabetes y un riesgo aumentado de TB,
en un medio urbano en Indonesia.
M É T O D O S : Fue este un estudio de casos y testigos que
comparó la prevalecía de diabetes (glucemia en ayunas
126 mg/dl) en pacientes con diagnóstico reciente de
TB pulmonar y en un grupo testigo constituido por una
muestra emparejada de personas del vecindario.
R E S U L T A D O S : La edad en el grupo estudiado y el grupo
testigo fue semejante (mediana 30 años), al igual que la
distribución por sexo (52% de hombres), pero la desnu-
RÉSUMÉ
bution par sexe (52% de sexe masculin), mais la malnu-
trition est plus fréquente chez les patients TB (index
masse corporelle médian 17,7 versus 21,5 kg/m2). L’in-
fection VIH est rare (1,5% des patients). Le diabète
sucré est présent chez 60 des 454 patients tuberculeux
(13,2%) et chez 18 des 556 sujets-contrôle (3,2%) (OR
4,7 ; IC 95% 2,7–8,1). L’ajustement pour des facteurs
confondants possibles n’a pas réduit le risque estimé. A la
suite du traitement de la TB, l’hyperglycémie a régressé
chez une minorité (3,7%) des patients tuberculeux.
C O N C L U S I O N : Il existe une association étroite entre le
diabète sucré et la TB chez des sujets jeunes non obèses
dans un contexte urbain en Indonésie. Ceci peut avoir
dans cette région des implications pour la lutte anti-
tuberculeuse et les soins aux patients.
RESUMEN
trición fue más frecuente en el grupo de pacientes con
TB (mediana del índice de masa corporal 17,7 kg/m2
comparada con 21,5 kg/m2). La observación de infec-
ción por el VIH (1,5% de los pacientes) fue poco fre-
cuente. Se encontró diabetes en 60 de 454 pacientes con
TB (13,2%) y en 18 de 556 testigos (3,2% ; OR 4,7 ; IC
95% : 2,7–8,1). El ajuste con respecto a los posibles fac-
tores de confusión no redujo la estimación del riesgo.
Después del tratamiento antituberculoso, la hipergluce-
mia regresó en una minoría de los pacientes con TB
(3,7%).
C O N C L U S I Ó N : Se observó una alta correlación entre la
diabetes y la TB en los individuos jóvenes no obesos en
un entorno urbano en Indonesia. Esta observación po-
dría tener implicaciones en la lucha contra la TB y el
tratamiento de los pacientes en esta región.