2. Original article
Effect of vitamin D supplementation in type 2 diabetes patients with
pulmonary tuberculosis
Sunil Kumar Kota a,
*, Sruti Jammula b
, Siva Krishna Kota c
, Prabhas Ranjan Tripathy d
,
Sandip Panda e
, Kirtikumar D. Modi a
a
Department of Endocrinology, Medwin Hospitals, Hyderabad, Andhra Pradesh, India
b
Department of Pharmaceutics, Roland Institute of Pharmaceutical Sciences, Berhampur, Orissa, India
c
Department of Anaesthesia, Central Security Hospital, Riyadh, Saudi Arabia
d
Department of Anatomy, Kalinga Institute of Medical Sciences, Bhubaneswar, Orissa, India
e
Department of Cardiology, JIPMER, Puducherry, India
1. Introduction
Current estimates of diabetes suggest that 285 million of
world’s adult population (6.4%) are suffering from diabetes [1].
India has 50.8 million and China has 43.2 million diabetics [2]. The
largest age group involved is 40–59 years. By 2030 it is projected
that 438 million of world’s adult population (7.8%) will be diabetics
with major chunk from India and China [1,3]. The largest age group
will move to 60–79 years age group.
Non-communicable disease including diabetes mellitus ac-
count for 60% of all deaths [4]. World health organization
estimates that there were 9.4 million cases of tuberculosis (TB)
equivalent to 139 cases per 100,000 population and 1.8 million
deaths from the disease [5]. India (1.98 million) and China (1.3
million) constitute 35% of TB cases worldwide. Number of
infectious cases in India is 0.87 million catering to a fifth of the
global burden of TB [5].
Calcitriol, the active form of vitamin D induces antimycobac-
terial activity in vitro [6]. A recent systematic review and meta
analysis suggests that individuals with TB had a lower level of 25
(OH) D than non TB individuals [7]. In North India (278N), 96%
neonates, 91% of healthy school girls, 78% healthy hospital staff and
84% pregnant women were found to have hypovitaminosis D (25
OHD < 20 ng/ml). In south India (138N), hypovitaminosis D is
equally prevalent among different population groups [8].
Based on basic and animal studies, vitamin D and calcium have
also been suspected as modifiers of diabetes risk [9]. There is
accumulating evidence to suggest that altered vitamin D and
calcium homeostasis may also play a role in the development of
type 2 diabetes mellitus (T2DM). A systematic review and meta
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 5 (2011) 85–89
A R T I C L E I N F O
Keywords:
Vitamin D deficiency
Type 2 diabetes
Pulmonary tuberculosis
Sputum smear conversion
A B S T R A C T
Aim: Diabetes and vitamin D deficiency are widely prevalent in India. Studies have proven correlation
between low vitamin D levels and pulmonary tuberculosis (PTB) and low vitamin D levels and insulin
resistance. We evaluated the effects of vitamin D supplementation on type 2 diabetes mellitus patients
with pulmonary tuberculosis (PTB).
Methods: Forty-five subjects (M:F = 34:11) were screened. Inclusion criteria were age >15 years, newly
diagnosed PTB cases with uncontrolled diabetes, serum vitamin D < 20 ng/ml. The patients with vitamin
D level < 20 ng/ml were randomly assigned to 2 groups. Group 1 subjects received oral cholecalceferol
(60,000 units/week) and calcium carbonate (1 g/day) along with anti tubercular treatment (ATT), while
group 2 subjects did not. Sputum was checked at interval of 2 weeks for 12 weeks. Primary end point was
time to achieve sputum smear conversion.
Results: Fifteen patients having vitamin D > 20 ng/ml were excluded. Age of the patients was 42.9 Æ 13.2
years and serum vitamin D levels were 18.4 Æ 15.3 ng/ml. Sputum smear conversion was 6 weeks in group 1
versus 8 weeks in group 2 (p = 0.067). Glycated hemoglobin levels reduced from 11.1 Æ 1.3 to 7.7 Æ 0.9 in
group1 versus 10.3 Æ 1.2 to 7.8 Æ 1.1 (p > 0.1).
Conclusion: Vitamin D can serve as adjuvant treatment of tuberculosis in diabetics with vitamin D
deficiency. Further studies are required to validate this observation and define a cut off for vitamin D level
to prevent immunological alterations.
ß 2012 Diabetes India. Published by Elsevier Ltd. All rights reserved.
* Corresponding author at: Department of Endocrinology, Medwin Hospitals,
Chiragh Ali Lane, Nampally, Hyderabad 500001, Andhra Pradesh, India.
Tel.: +91 9959369777; fax: +91 40 66623441.
E-mail address: hidocsunil@ibibo.com (S.K. Kota).
Contents lists available at SciVerse ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research &
Reviews
journal homepage: www.elsevier.com/locate/dsx
1871-4021/$ – see front matter ß 2012 Diabetes India. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.dsx.2012.02.021
3. analysis suggests that deficiency of vitamin D and calcium
negatively influences glycemia in T2DM [9].
2. Methods
2.1. Study subjects
The study was done in Medwin hospital, Hyderabad. The study
protocol and procedures were approved by the hospital ethical
committee. All participants were provided with full information
about the study’s purpose and they gave informed consent to
participate in the study.
All the patients presenting to the department of general
medicine, endocrinology and diagnosed with pulmonary tubercu-
losis (PTB) prior to commencement of antitubercular therapy (ATT)
were screened to participate in the study. Patients included were
>15 years age, newly diagnosed PTB cases, poorly controlled type 2
diabetes mellitus (T2DM) with HbA1C > 7% and serum vitamin
25(OH) D < 20 ng/ml. Diagnosis of PTB was made when patients
met with one of the following criteria. (a) At least 2 positive report
from 3 sputum smears (spot, morning, spot), (b) one positive smear
and typical pictures of lung infiltration by TB on chest X-ray.
Patients were excluded when age < 15 years, patients already on
ATT, serum 25 (OH) D > 20 ng/ml, patients with diseases affecting
vitamin D metabolism such as malabsorption, renal failure,
patients with prolonged immobilization.
2.2. Data collection
Baseline detailed clinical evaluation included history, lifestyle,
physical activity, dietary habits, fracture and falls, with clinical
assessment including anthropometry, chest examination, chest
radiography, sputum examination (for microscopy), blood sample
(complete blood count, erythrocyte sedimentation rate, serum
calcium, phosphorous, albumin, 25 (OH) D, renal parameters,
glycemic profile). Then patients were reviewed monthly till the
end of 12 weeks. Sputum was checked at the interval of 2 weeks.
2.3. Procedures
All the patients received intensive phase antimicrobial treat-
ment comprising of isoniazid, rifampicin, pyrazinamide and
ethambutol. Along with ATT, patients were randomized to receive
oral cholecalciferol sachets (60,000 IU/week) and calcium carbon-
ate (1000 mg/day) or not. All the patients were adjusted for oral
hypoglycemic agents and insulin for glycemic control.
2.4. Statistical analysis
After meticulous examination of the original study forms, data
were collected into a database in the mean Æ standard deviation
format. Online Graphpad Quickcalc software (http://www.graph-
pad.com/quickcalcs/index.cfm) was used to perform statistical
analyses. Analysis of variance (ANOVA) and the unpaired t test were
used to calculate differences among groups. p value < 0.05 was
considered significant.
3. Results
Total of 45 patients of 45 patients of T2DM with newly detected
PTB (male:female = 34:11). Fifteen patients with serum 25 (OH)
D > 20 ng/ml were excluded. Remaining 30 patients were divided
into group-1, who received vitamin D and group-2, who did not
receive same. So the prevalence of vitamin D deficiency in T2DM
with PTB was 30/45 (66.66%), with 25/34 males (73.5%) and 5/11
females (45.5%) were deficient in vitamin D levels. Mean age of the
study patients was 39.5 Æ 18.9 years (range 22–63 years) with mean
fasting blood sugar 230.5 Æ 30.3 mg/dl, post lunch blood sugar
320.5 Æ 45.6 mg/dl, HbA1C 10.4 Æ 4.4% and 25 (OH) D 12.1 Æ 4.3 ng/
ml.
Baseline characteristics of the both groups are depicted in Table
1. Tables 2 and 3 depict the follow up data for patients under group
1 and 2. Table 4 depicts the comparative data of the patients under
both groups.
4. Discussion
In subjects receiving 60,000 IU cholecalciferol per week along
with ATT, duration of sputum conversion to 100% negative for AFB
was 6 weeks compared to 8 weeks in subjects not receiving
cholecalciferol. It was accompanied by significant increase in
serum 25 (OH) D concentration in patients under the intervention
group. Thought the difference in achievement of sputum smear
negativity between was not significant, it showed a trend towards
early improvement in patient receiving oral cholecalciferol.
A trial by Martineau et al. [10] demonstrated that administra-
tion of four doses of 2.5 mg vitamin D (100,000 IU, 1 mg = 40 IU)
did not affect time to sputum culture conversion in the whole
study group, but it significantly hastened sputum culture
conversion in patients with tt genotype of the Taq 1 vitamin D
receptor polymorphism. Human vitamin D receptor is polymor-
phic; carriage of the t allele of the TaqI vitamin D receptor
polymorphism is associated with an increase in calcitriol-induced
phagocytosis of Mycobacterium tuberculosis (Mtb) in vitro [11]
and more rapid sputum culture conversion in patients with
pulmonary tuberculosis [12]. By contrast, carriage of the f allele of
the FokI vitamin D receptor polymorphism is associated with a
reduction in transcriptional activity [13], reduction of calcitriol-
induced phagocytosis [11], and slower sputum culture conversion
in pulmonary tuberculosis [13]. Our study population may be a
mixture of both alleles reflecting insignificant difference.
Several case series have reported that daily doses of 625 mg
(25,000 IU) to 2.5 mg (100,000 IU) vitamin D improve patients’
Table 1
Baseline characteristics of the patients under both groups.
Parameters Group 1
(n = 15, M:F = 9:6)
Group 2
(n = 15, M:F = 11:4)
Age (years) 38.4 Æ 19.6 40.2 Æ 17.7
Weight (kg) 49.1 Æ 4.5 44.6 Æ 5.6
Hb (gm/dl) 10.9 Æ 1.2 10.5 Æ 1.6
ESR (mm/1st hour) 98.6 Æ 22.7 89.6 Æ 19.6
Duration of T2DM (in years) 10.1 Æ 2.3 12.1 Æ 2.9
FBS (mg/dl) 237.2 Æ 33.2 223.8 Æ 19.6
PLBS (mg/dl) 316.6 Æ 43.7 326.6 Æ 49.6
HbA1C (%) 11.1 Æ 1.3 10.3 Æ 1.2
25-(OH) D (ng/ml) 12.8 Æ 4.5 11.1 Æ 4.7
Group 1: patients receiving vitamin D supplementation in the form of oral calciferol
(60,000 U/week). Group2: patients not receiving vitamin D supplementation. Hb:
hemoglobin; ESR: erythrocyte sedimentation rate; T2DM: type 2 diabetes mellitus;
FBS: fasting blood sugar; PLBS: post lunch blood sugar; HbA1C: glycated
hemoglobin.
Table 2
Follow up data of patients under group 1.
4 weeks 8 weeks 12 weeks
Sputum smear conversion No Yes Yes
FBS (mg/dl) 160.3 Æ 30.2 150.5 Æ 25.3 143.2 Æ 22.3
PLBS (mg/dl) 240.7 Æ 39.9 210.9 Æ 33.5 199.8 Æ 32.1
HbA1C (%) – – 7.7 Æ 0.9
25 (OH) D (ng/ml) 20.3 Æ 4.3 22.3 Æ 5.9 25.4 Æ 6.9
ESR (mm/1st hour) 72.3 Æ 18.5 64.3 Æ 18.5 51.1 Æ 12.5
S.K. Kota et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 5 (2011) 85–8986
4. response to antimicrobial treatment for pulmonary tuberculosis
[14]. Randomised controlled trials investigating doses of up to
125 mg/day vitamin D or equivalent in active tuberculosis have
shown no clinical benefit [15,16], but a trial investigating a higher
dose regimen (250 mg/day, 10,000 IU/day) reported reduced time
to sputum smear conversion in the intervention group [17]. We
provided vitamin D at the dosage of 60,000 IU/week, and report a 2
weeks reduction in sputum smear conversion.
Calcitriol modulates the host response to mycobacterial
infection by induction of reactive nitrogen and oxygen inter-
mediates [18] suppression of matrix metalloproteinase enzymes
implicated in the pathogenesis of pulmonary cavitation [19], and
induction of the antimicrobial peptide cathelicidin [20,21] which
induces autophagy [22]. Calcitriol modulates immune responses
by binding vitamin D receptors expressed by antigen-presenting
cells and activated lymphocytes to regulate transcription of genes
responsive to vitamin D. Some studies have reported that vitamin
D supplementation leads to increase in lymphocyte to monocyte
ratio, a biomarker of disease resolution in animal models.
To maintain uniformity all sputum samples of the study
population was analysed in our hospital laboratory. One of the
largest of trials [16] reported that administration of three doses of
2.5 mg (100,000 IU) vitamin D3 at baseline, 5 months, and 8
months did not influence clinical severity score or time to sputum
smear conversion in 365 patients in Guinea Bissau; however,
patients’ mean baseline concentration of 25-hydroxyvitamin D
was more than 70 nmol/l (28 ng/ml, 1 nmol/l = 2.5 ng/ml), and the
dosing regimen used was too low to influence serum 25-
hydroxyvitamin D concentrations at follow-up. A trial in 67
patients in Indonesia [17] reported enhanced sputum smear
conversion at 42 days, but not at 56 days, after initiation of
antimicrobial treatment in patients receiving 250 mg (10,000 IU)
vitamin D3 daily. The vitamin D content of the study preparation
was not verified, and participants’ serum 25-hydroxyvitamin D
concentrations were not reported before or after supplementation.
After 6 weeks in group1 and 8 weeks in group 2, the subjects
maintained the sputum smear negativity through the study period
of 12 weeks. Strict compliance to ATT might be the positive factor
in our study subjects.
However sputum smear conversion has limited value as a
biomarker of treatment response in PTB because microscopy is less
sensitive and less specific than culture for detection of vital MTb
bacilli in sputum [23]. Multivariate analysis shows that sputum
culture conversion, but not sputum smear conversion is indepen-
dently related to long term risk of treatment failure or relapse [24].
A recent study [10] has utilized this parameter as the biochemical
marker of improvement. We also utilized smear negativity as the
biomarker for treatment response and ended up in having
insignificant difference between the 2 groups, though it was
earlier in patients receiving vitamin D supplementation. Defect in
both humoral immunity (low complement factor 4, decreased
cytokine response after stimulation) and cellular immunity
(chemotaxis, phagocytosis, killing) observed in patients with
diabetes might be an additional factor in delay in response to
treatment [25].
Though a greater decline in glycemic parameters was
observed in patients receiving vitamin D, it was not statistically
significant. Studies have shown inverse relation between serum
25 (OH) D and 1 h post prandial glucose [26]. Vitamin D affects
exclusively the insulin response to glucose stimulation, whereas
it does not influence basal insulinemia [27]. Pancreatic b cells
express Vitamin D receptor (VDR) and 1-a-hydroxylase enzyme
needed for activation of vitamin D [28]. 1,25 (OH)2 D promotes
transcriptional activation of human insulin gene. Insulin
secretion is a calcium-dependent process [29]; therefore,
alterations in calcium flux can have adverse effects on b cell
secretory function. It is speculated that inadequate calcium
intake or vitamin D insufficiency may alter the balance between
the extracellular and intracellular b cell calcium pools, which
may interfere with normal insulin release, especially in response
to a glucose load [9]. Vitamin D may have a beneficial effect on
insulin action either directly, by stimulating the expression of
insulin receptor and thereby enhancing insulin responsiveness
for glucose transport [30], or indirectly via its role in regulating
extracellular calcium and ensuring normal calcium influx
through cell membranes and adequate intracellular cytosolic
calcium pool.
VDR are present on skeletal muscle and vitamin D directly
activates peroxisome proliferator activator receptor d [31], a
transcription factor implicated in the regulation of fatty acid
metabolism in skeletal muscle and adipose tissue [32]. Calcium is
essential for insulin- mediated intracellular processes in insulin-
responsive tissues such as skeletal muscle and adipose tissue [33],
with a very narrow range of intracellular cytosolic calcium needed
for optimal insulin-mediated functions [34]. In people without
diabetes, hypocalcemia is associated with impairment of insulin
release. Insulin receptor phosphorylation leading to insulin signal
transduction and increased glucose transporter-4 activity are
calcium dependent processes. Changes in intracellular cytosolic
Table 4
Comparative data of patients under both groups. NS: not significant. p < 0.05-statistically significant.
Baseline 12 weeks
Group1 (vitamin
D supplemented)
Group 2 (vitamin D
not supplemented)
p Group1 (vitamin D
supplemented)
Group 2 (vitamin D
not supplemented)
p
Number of patients 15 15 – 15 15 –
Hb (10 g/dl) 10.9 Æ 1.2 10.5 Æ 1.6 0.6 13.5 Æ 1.3 11.3 Æ 0.8 0.004
25-(OH) D (ng/ml) 12.8 Æ 4.5 11.1 Æ 4.7 25.4 Æ 6.9 10.2 Æ 0.9 0.0001
Change in ESR from baseline
(mm/1st hour)
– – – 39.6 Æ 12.4 24.0 Æ 14.9 0.004
FBS (mg/dl) 237.2 Æ 33.2 223.8 Æ 19.6 0.6 143.2 Æ 22.3 146.5 Æ 21.4 NS
PLBS (mg/dl) 316.6 Æ 43.7 326.6 Æ 49.6 0.7 199.8 Æ 32.1 197.5 Æ 35.6 NS
HbA1C (%) 11.1 Æ 1.3 10.3 Æ 1.2 0.4 7.7 Æ 0.9 7.8 Æ 1.1 NS
Duration for sputum smear
negativity
0 0 – 6 weeks 8 weeks NS
Table 3
Follow up data of patients under group 2.
4 weeks 8 weeks 12 weeks
Sputum smear conversion No Yes Yes
FBS (mg/dl) 169.3 Æ 29.8 155.5 Æ 23.9 146.5 Æ 21.4
PLBS (mg/dl) 245.8 Æ 33.9 220.3 Æ 22.9 197.5 Æ 35.6
HbA1C (%) – – 7.8 Æ 1.1
25 (OH) D (ng/ml) 10.9 Æ 1.4 11.1 Æ 1.6 10.2 Æ 0.9
ESR (mm/1st hour) 75.6 Æ 19.1 66.4 Æ 19.5 55.5 Æ 13.6
S.K. Kota et al. / Diabetes & Metabolic Syndrome: Clinical Research & Reviews 5 (2011) 85–89 87
5. calcium in primary insulin target tissues may contribute to
peripheral insulin resistance [35] via impaired insulin signal
transduction [35,36], leading to decreased glucose transporter-4
activity [35,37]. Changes in intracellular cytosolic calcim modulate
adipocyte metabolism, which may promote triglyceride accumu-
lation via increased de novo lipogenesis and inability to suppress
insulin-mediated lipolysis leading to fat accumulation [38] Studies
have proven inverse relation between insulin resistance and serum
vitamin D levels.
Vitamin D also improves systemic inflammation by (1)
interacting with vitamin D response elements in the promoter
region of cytokine genes to interfere with nuclear transcription
factors implicated in cytokine generation and action [39], (2)
Down-regulating activation of nuclear factor-k B [40], which is an
important regulator of genes encoding proinflammatory cytokines
implicated in insulin resistance [40] (3) by upregulating expression
of calbindin [41], a cytosolic calcium-binding protein found in
many tissues including pancreatic bcells [42] it interferes with
cytokine generation. Calbindin has been shown to protect against
cytokine-induced apoptosis that may occur after a rise in cytosolic
free calcium [43]. Effects of calcium on cytokines changes in
intracellular cytosolic calcium may lead to cytokine-induced
apoptosis [44].
None of our patients had hypercalcemia or any other major
adverse events. Narang et al. [45], who reported hypercalcaemia in
19 of 30 patients with smearpositive pulmonary tuberculosis
taking a daily dose of 10–95 mg vitamin D. There was much less
hypercalcemia in study by Martineau et al. [10], they showed that
serum corrected calcium concentration declined in both interven-
tion and control arms after initiation of antimicrobial treatment.
Such a decline might have resulted from a reduction in
granulomatous burden in patients responding to treatment,
leading to a decrease in extrarenal 1-alpha hydroxylation of 25-
hydroxyvitamin D and a fall in serum 1,25-dihydroxyvitamin D
concentrations. In a study by Ho-Pham et al., vitamin D
insufficiency was found to be a risk factor for TB in men, but
not in women [46]. We did not see any preferential affection by PTB
in our patients.
The limitations of our study were (a) smaller number of
participants, (b) lack of follow up after the study period, use of
sputum smear conversion rather than sputum culture conversion
as a marker for cure, (c) no division as per vitamin D levels of
deficiency, insufficiency and sufficiency, (d) we did not measure
albumin and uncorrected for albumin calcium levels could be
driven by albumin levels which are known to be low in PTB
patients.
Never the less, we believe that our study points to the role of
vitamin D in the ever growing number of diabetes and PTB. It also
calls for the need to do multicentric studies involving larger
number of patients with a longer follow up.
5. Conclusion
Severe hypovitaminosis D is more prevalent in diabetic
patients with pulmonary tuberculosis. Better improvement in
such patients after vitamin D supplementation emphasizes the
utility of vitamin D as adjuvant treatment of tuberculosis in
selected diabetic patients with vitamin D deficiency. Vitamin D
may be the missing link between emerging epidemic of
tuberculosis and diabetes. Further studies are required to validate
this observation and define a cut off of vitamin D level to prevent
immunological alterations.
Conflict of interest
None declared.
Acknowledgements
All the authors would like to express their heartfelt thanks to Dr.
Jagadeesh Tangudu, M Tech, MS, PhD and Sowmya Jammula, M Tech
for their immense and selfless contribution towards manuscript
preparation, language editing and final approval of text.
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