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INT J TUBERC LUNG DIS 10(6):696–700

© 2006 The Union

Diabetes mellitus is strongly associated with tuberculosisin 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 ofInternal Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; ‡ Eijkman Institute ofMolecular Biology, Jakarta, Indonesia; § Department of Endocrinology, Epidemiology and Biostatistics, Radboud UniversityNijmegen Medical Center, Nijmegen, The Netherlands; ¶ Indonesian Tuberculosis Control Association, Jakarta Branch,Jakarta, Indonesia; # Department of Immunohematology and Bloodbank, Leiden University Medical Center, Leiden,

S U M M A R Y

The Netherlands; ** Infectious Disease Working Group, Medical Faculty, University of Indonesia, Jakarta, Indonesia

SETTING: 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.

OBJECTIVE: To examine if and to what extent diabetes

is associated with an increased risk of TB in an urban

setting in Indonesia.

DESIGN: 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.

RESULTS: 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.

CONCLUSION: 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.

KEY WORDS: tuberculosis; pulmonary; diabetes melli-

tus type 2; relative odds; case-control study; Indonesia

THE PREVALENCE of diabetes mellitus is increas-ing worldwide, especially in Asia,1 where tuberculo-sis (TB) is highly endemic.2 Most textbooks statethat diabetes is a risk factor for TB, but little isknown about the nature and strength of this rela-tionship. Original studies on this subject were mostlyconducted more than 40 years ago, and primarily inthe United States and Europe.3–5 To our knowledge,

only one published Asian report shows that diabeticpatients have an increased risk of developing pulmo-nary tuberculosis (PTB).6 If diabetes is a risk factorfor 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 TBcase fatality rate.7 We therefore examined to whatextent diabetes is associated with an increased risk of TB in Indonesia.

METHODS

At Perkumpulan Pemberantasan Tuberculosis Indo-nesia, an out-patient TB clinic in central Jakarta, andHasan Sadikin General Hospital, Bandung, consecu-tive new PTB patients aged over 15 years of age wereincluded in the study. Diagnosis was based on clinicalpresentation and chest X-ray examination, confirmedby microscopic detection of acid-fast bacilli. Treatment

consisted of a standard regimen, 2HRZE/4H3R3,* ac-cording to the Indonesian National TB Programme.Social workers visited the patient’s community and

* H isoniazid; R rifampicin; Z pyrazinamide; E etham-

butol. Numbers before the letters indicate the duration in months

of the phase of treatment; numbers in subscript indicate the num-

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: [email protected]

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 sexand age (10%) living within the same rukun te-tangga, the smallest residential unit in Indonesia, whichconsists 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 bloodglucose (FBG) concentrations. Diabetes mellitus wasdiagnosed if FBG was 126 mg/dl, and FBG concen-trations were considered impaired for110 and126mg/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 subsetof 89 patients. For those patients with discordant clas-sification before and during anti-tuberculosis treat-ment, the classification of diabetes was applied to thefirst 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 identifyadditional 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, TheNetherlands).

Crude and adjusted odds ratios (ORs) were calcu-lated as estimates of the relative risks with corre-sponding 95% confidence intervals (CI) and a logisticregression model. Adjusted ORs reflect the risk of TBfor people with diabetes mellitus compared to normalindividuals 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.

RESULTSBetween March 2001 and March 2005, 481 new PTBpatients were recruited, of whom 454 were includedfor further analysis. Twenty-seven were excluded be-cause of a past history of TB (n 6) and incompletedata (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 bysputum microscopy. Mycobacterium tuberculosis cul-ture results were available in 373 patients, and werepositive in 328 (87.9%). Patients presented after amedian of 3 months (range 1 week to over 1 year)

with cough (98.9%), haemoptysis (42.5%), shortnessof breath (66.1%), fever (77.3%) and weight loss(84.1%). Cases had a median BMI of 17.7 kg/m2 (range11.2–31.4). Antibodies against HIV were present in 6of 402 TB patients examined (1.5%) and none of the40 controls tested. Mild elevation of plasma creatininewas found in one of 234 cases examined.

Six hundred and twenty-two subjects were re-cruited as matched controls. Sixty-six were excludedfor 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 similarsex distribution, age (median 30.0 years; range 15–

76) and socio-economic background as the patients(Table 1). Control subjects had a higher body weightthan patients, while history of TB contact was lesscommon (Table 1).

Diabetes mellitus was more common in patientswith TB than in control subjects (Figure). Sixty TBpatients (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(n 454)n (%)

Control subjects(n 556)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) 0.361History 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

Glycosuria was present in 43 of 415 TB cases (10.4%)and 16 of 413 controls (3.6%), corresponding to an

OR of 3.1 (95%CI 1.7–5.6) (Table 2).The median age of TB patients with diabetes, im-

paired FBG and no diabetes was 45.0, 45.0 and 27.1years, respectively (P 0.001). The median BMI was21.2, 16.9 and 17.8 kg/m2, respectively (Figure, A). Di-abetes was newly diagnosed in 36/60 patients (60.0%)and 12/18 controls (66.7%) with diabetes. Among 24patients with a history of diabetes, only 19 (79.2%)were being treated, all with oral hypoglycaemic agents.Repeated measurement during TB treatment showednormalisation of FBG in 2/53 (3.7%) patients whoinitially had FBG 126 mg/dl, and conversion to di-

abetes in 6/295 (2.0%) patients with normal FBGbefore TB treatment.Possible confounding of the relationship between

diabetes and TB was examined using logistic regres-sion. Sex, income and overcrowding did not alter theOR significantly. History of TB contact was signifi-cantly more common among cases than controls(Table 1); however, adjustment to this variable didnot reduce the risk estimates. TB patients had a lowerBMI than controls, but adjustment for BMI increasedthe risk estimates, showing that the association be-tween TB and diabetes is not explained by differencesin BMI.

DISCUSSION

We have found a strong association of TB and diabe-tes in two urban clinics in Indonesia. We believe this isthe first study to examine this association in Indone-sia, where more than 10% of the world’s TB patientslive,2 and one of the first in South-East Asia. Almost15% of relatively young, lean TB patients in ourclinic presented with diabetes. This rate was muchlower in control subjects with a similar age and socio-economic background. Adjustment for possible con-founding factors did not reduce the strength of theassociation.

Diagnosis of diabetes by a single measurement of FBG in PTB patients can be confounded by disease

activity. Previous studies have shown that blood glu-cose levels may normalise during treatment of TB,9,10

but in our study this occurred in only a small minorityof patients.

It seems unlikely that the strong association be-tween TB and diabetes can be attributed to other fac-tors, as socio-economic factors, living conditions andpresence of co-morbidity were similar. Adjustmentfor the higher frequency of TB contacts among thecases did not lower the risk estimates. This differencemay have been due to recall bias. Both cases andcontrols had probably been exposed to TB as they

came from the same (mostly overcrowded) urban en-vironment, with an estimated TB incidence of 128 per100 000 population.2 We also investigated whethera difference in BMI can explain the association be-tween TB and diabetes. TB patients had a much lowerBMI at presentation than control subjects, as theylose, on average, 10–15% of their body weight dur-ing their illness. Diabetes cases had a significantlyhigher BMI in both patients and controls and, as aresult, adjustment for BMI actually increased the riskestimates.

As this was a case-control study, we can only hypoth-esise about the cause-effect relationship between TB

and diabetes. On the one hand, TB may have triggeredthe development of diabetes, e.g., by inflammation-associated insulin resistance. Effective anti-tuberculosis

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

Table 2 Tuberculosis risk in diabetes, impaired FBGand glucosuria

Casesn (%)

Controlsn (%) OR (95%CI)

Total tested, n 454 556Normal FBG (110 mg%) 379 (83) 533 (96) 1.0*Impaired FBG

(110, 126 mg%) 15 (3) 5 (1) 4.2 (1.5–11.7)Diabetes (126 mg%) 60 (13) 18 (3) 4.7 (2.7–8.1)

Total tested, n 415 413No glucosuria 372 (90) 398 (96) 1.0*Glucosuria 43 (10) 15 (4) 3.1 (1.7–5.6)

* Reference category, odds ratio 1.FBG fasting blood glucose; OR odds ratio; CI confidence interval.



Diabetes as a risk factor for TB in Indonesia 699

treatment only normalised hyperglycaemia in a smallproportion of the diabetes patients, which pleadsagainst this hypothesis. A second possibility is that di-abetes was already present in these subjects, acting asa risk factor for the development of TB. Forty per cent

of TB patients presenting with hyperglycaemia had ahistory of diabetes. As the study subjects were verypoor, with limited access to regular health care, theproportion with undiagnosed diabetes may in facthave been higher. Immunological studies support thehypothesis that diabetes is a risk factor for TB. Pro-duction of interferon-gamma, which is crucial forhost defence against TB, has been found to be low indiabetic mice infected with M. tuberculosis,11 and ithas been shown that alveolar macrophages in TBpatients with diabetes show less activation.12 Co-hort studies performed in Europe and the United States

in the 1930s also support this hypothesis: diabeticsshowed 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: theprevalence 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 wereprospectively 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. Itshould be noted that diabetics in Asia are generallyyounger and leaner than diabetics in Europe.16 Theprevalence of diabetes in our control group was sim-ilar to previous data from a survey among the generalpopulation in Indonesia, and from other countries inAsia.1

If diabetes, as our study suggests, is such a strongrisk factor for TB, this may have significant clinicaland epidemiological implications. In 2025, 75% of diabetics will live in developing countries where morethan 90% of TB cases reside.1,2 An increasing preva-

lence of diabetes in these countries may thus threatenthe success of TB control. Because diabetes was un-noticed and untreated in the majority of TB patientsin our setting, it seems wise to screen TB patients fordiabetes. Based on our study, we would recommendscreening all TB patients above 35 years of age atleast once, and looking for symptoms of diabetes inyounger patients. Screening and earlier manage-ment of diabetes may reduce the risk of developingactive TB. Future studies are needed to confirm thishypothesis.

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.

References

1 King H, Aubert R E, Herman W H. Global burden of diabetes,

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veilance, planning, financing. WHO report 2005. WHO/HTM/

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4 Root H F. The association of diabetes and tuberculosis. N Engl

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D S, Chaisson R E. Survival of patients with pulmonary tuber-

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tion of diabetes mellitus and its complications. Part 1: diagno-

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10 Basoglu O K, Bacakoglu F, Cok G, Sayiner A, Ates M. The oral

glucose tolerance test in patients with respiratory infections.

Monaldi Arch Chest Dis 1999; 54: 307–310.

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Th1-type cytokines and inducible nitric oxide in mice with

streptozotocin-induced diabetes mellitus and infection with

Mycobacterium tuberculosis. Clin Exp Imm 2004; 139: 57–64.

12 Wang C H, Yu C T, Lin H C, Liu C Y, Kuo H P. Hypodense alve-

olar macrophages in patients with diabetes mellitus and active

pulmonary tuberculosis. Tubercle Lung Dis 1999; 79: 235–242.

13 Ponce-De-Leon A, Garcia-Garcia Md Mde L, Garcia-SanchoM C, et al. Tuberculosis and diabetes in southern Mexico.

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view of the association of the two diseases. Am Rev Tuberc

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15 Mugusi F, Swai A B, Alberti K G, McLarty D G. Increased

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700 The International Journal of Tuberculosis and Lung Disease

R É S U M É

C O NTE XT E : 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 rapidementcroissante du diabète.

O B JEC 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 HÉMA : 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 UL T ATS : L’âge médian des patients et des sujets-

contrôle était similaire (30 ans), de même que la distri-

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 diabètesucré 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 NCL US IO 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.

R E S U M E N

MARCO DE REFERENCIA : 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 JET I VO : Evaluar si existe y cuantificar la posible cor-

relación entre la diabetes y un riesgo aumentado de TB,

en un medio urbano en Indonesia.

MÉ T ODO 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 UL T ADO 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-

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 NCL US IÓ 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.

case control dr bachti

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