To our knowledge, this study represents the first randomized controlled trial of a directly observed VA/D supplementation program in active pulmonary tuberculosis patients with diabetes that focused on the contribution of anti-TB and DM treatment effect and the possible mechanisms.
Tuberculosis and diabetes interact with each other, which might make clinical treatment become more difficult than the single disease of pulmonary tuberculosis or diabetes. As diabetes alters immunity to tuberculosis, longer times to culture conversion with treatment, and a higher rate of relapse might result. Treatment failure and death are more frequent in diabetic patients than patients with PTB alone. Alisjahbana reported that in patients with high adherence to treatment, 6-month sputum cultures were positive in 22.2% of patients with diabetes mellitus and in 6.9% of controls and these differences remained after adjustment for age, sex, body mass index, and other factors . In a case–control study  treatment failure or death was seen in 41% of the patients with tuberculosis and diabetes mellitus, but in only 13% of those with tuberculosis alone. A recent study by Wang and colleagues  discovered that 1-year all-cause mortality was 17.6% in diabetic PTB patients versus 7.7% in non-diabetic controls, and death specifically attributable to pulmonary tuberculosis was significantly more common in diabetic patients (12.2% vs 4.2%).
The most important effector cells for containment of tuberculosis are phagocytes, monocytes and lymphocytes. Diabetes is known to affect chemotaxis, phagocytosis, activation, and antigen presentation by phagocytes in response to M tuberculosis. Vitamin A is an essential micronutrient for a variety of physiological processes, such as tissue differentiation, immunity, and vision. Also, the impacts of VA and retinoids on energy metabolism in animals and humans have been demonstrated in some basic and clinical investigations . Also, it has been proposed recently that vitamin D play a critical role in immunity, respiratory health and insulin resistance. Vitamin A, its metabolites and vitamin D directly inhibit mycobacterial growth in culture .
A recent randomized trial of vitamin A and Zinc supplementation focused on the effect on treatment outcomes in TB patients and found that supplementation with vitamin A and zinc did not affect treatment outcomes in participants with pulmonary tuberculosis at 8 wk . An important difference between this trial and our study is that single dose of 200,000 IU retinyl palmitate was used in the reported trial, while daily supplementation of 2000 IU retinol is being supplemented in our study. Also, vitamin A and Zinc supplementation on serum fasting blood sugar, insulin, apoprotein B and A-1 in patients with type I diabetes has been carried out , and found that combined zinc and vitamin A supplementation can improve serum apoprotein A-I, apoprotein B and the apoprotein B/apoprotein A-I ratio in patients with type I diabetes.
Some randomized controlled studies have focused on effect of vitamin D on glucose indices and vascular markers in type 2 diabetes[22, 23], which found that Vitamin D supplementation attenuated the increase in glycemia, and increased insulin secretion, improved systolic blood pressure and B-type natriuretic peptide levels. Mitri et al.  implemented a 2-by-2 factorial-designed, double-masked, placebo-controlled trial and discovered that cholecalciferol (2000 IU once daily) supplementation for 16 wk can improved β cell function and had a marginal effect on attenuating the rise in Hb A(1c) in adults at risk of type 2 diabetes.
Vitamin D has been shown to be involved in the host immune response toward Mycobacterium tuberculosis. Recently several VD supplementation trials to active TB patients are available. Administration of four doses of 2.5 mg vitamin D3 significantly hasten sputum culture conversion in patients with the tt genotype of the TaqI vitamin D receptor polymorphism . However, C Wejse et al.  reported that supplementation of three doses of 2.5 mg 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. It is possible that the dose used was insufficient. In our trial, we are supplementing VD by daily dose of 2000 IU cholecalciferol, and we are measuring the effect of the supplementation on clinical treatment in active TB patients with diabetes. In addition, prior studies have found that supplementation of VA or VD is associated with improved β cell function or hasten sputum culture conversion, our trial will allow us to determine whether this association will remain true for VA and/or VD use in patients with both TB and DM who have more severe clinical symptom and poorer prognosis, and the underlying mechanism is being investigated.
Despite its strengths, trial limitations should be noted. In our trial, only some doses of VA and VD are observed. However, we designed these doses on the basis of acquiring important information including the VA nutrition status in China by national survey , the recommended VA and VD intake formulated by the Chinese nutrition society. Also, abundant literature researches concerning the VA, VD level in the supplementation trials have been implemented. In addition, different distribution of some aspects of the subject in the four arms such as severity of the disease, fundamental nutrition status, socioeconomics status etc. may interfere or reduce our measured effect size. To minimize the differential effect between the four arms, we balanced the four arms regarding age, sex and randomized the subjects to different groups. Furthermore, multivariate logistic regression will be used to identify the measured size to adjust the possible impact factors.
We expect that results of our VA and/or VD supplementation trial will advance our knowledge of the efficacy of directly observed therapy for active PTB and DM. If our results provide evidence that VA and/or VD supplementation is effective in PTB and DM, further research protocols can be developed to observe the efficacy of other kind of micronutrients related to glucose metabolism and/or anti-mycobacterium on the patient with both PTB and DM. Data from this study will also allow us to examine the optimal biomarkers associated with PTB and DM treatment influenced by micronutrients. Newer regimens for PTB and DM treatment will emerge which may improve outcomes of clinical therapy and/or shorten the treatment period.