Can vitamin C help in managing tuberculosis associated with diabetes mellitus?

To the Editors: Informative reviews on vitamin C and immune function have alluded to the pro-oxidant and antioxidant roles of the vitamin in microbial killing and host protection against inflammatory damage.1, 2 In the light of accumulating experimental evidence, we hereby submit hypotheses regarding how these putative roles of vitamin C might help in the management of tuberculosis (TB) associated with diabetes mellitus, a major co-morbidity to the infectious diseases globally. Immune dysfunction inherent to diabetes mellitus plays an important role in the development of active TB, largely from reactivation of latent infection due to Mycobacterium tuberculosis (Mtb). Escalating evidence suggests that oxidative stress (or more broadly disturbance of redox homeostasis) may also contribute to the development of TB associated with type 2 diabetes mellitus, as well as impacting its outcome. A conceivable hypothesis centres on oxidative stress, inherent to diabetes, that induces formation of metabolically dormant and drug-tolerant Mtb persisters, thus increasing the risk of subsequent reactivation of latent TB infection to active TB disease or rendering active TB disease more difficult to treat, in the face of intrinsic immunological dysfunction.3 These putative immunopathological mechanisms correlate well with the clinically observed increase in the risk of active TB in patients with poorly controlled diabetes mellitus.4 Vitamin C possibly has both pro-oxidant and antioxidant activities regarding mycobacteria (Table 1).5-7 Biologically plausible hypotheses pertaining to the modulation of anti-TB drug efficacy by these activities are summarized as follows. The former activity might help in bacillary killing through the oxidative burst,1, 2, 5 and the latter activity possibly in limiting the size of Mtb persister population, through inhibition of mycobacterial dormancy-related pathways5-7 that likely include guanosine pentaphosphate ((p)ppGpp) signalling, as there is a structural analogy of vitamin C and guanosine diphosphate, the substrate for (p)ppGpp synthesis.6 Vitamin C levels in subjects with type 2 diabetes have been found to be low, with fasting glucose, body mass index, smoking history and dietary vitamin intake as significant independent predictors.11 In addition, diabetic subjects likely have increased requirement of vitamin C.2, 11 Several clinical studies have alluded to the improvement of glycaemic control in diabetics with vitamin C supplementation.12 Importantly, low levels of vitamin C were also observed in some TB patients,13 and in a sizable population-based cohort study, adequate dietary intake of vitamin C has been suggested to protect against developing active TB in current smokers.14 Thus, it appears rewarding to consider exploration of the potential benefit of supplementation of this micronutrient in preventing active TB in diabetic subjects. Furthermore, the adjunctive role of vitamin C in the targeted treatment of latent TB infection associated with diabetes mellitus might warrant exploration in macrophage and animal models.5