Diminished Systemic and Antigen-Specific Type 1, Type 17, and Other Proinflammatory Cytokines in Diabetic and Prediabetic Individuals With Latent Mycobacterium tuberculosis Infection

The long-held association between tuberculosis and diabetes mellitus type 2 (DM) [1] has been given additional credence by a recent meta-analysis in which DM was shown to have a 3-fold increased risk for the development of active pulmonary tuberculosis [2]. In addition, DM is also known to be associated with a greater severity of tuberculosis, with a greater odds of cavitation, increased bacillary loads, delayed sputum conversion, treatment failure, relapse, and death [1, 3]. Despite the clinical and public health significance posed by the dual burden of tuberculosis and DM, very little is known about the immunological and biochemical mechanisms underlying this susceptibility. Enhanced susceptibility to tuberculosis in patients with DM has been ascribed to several factors, including direct effects related to hyperglycemia and insulin resistance and indirect effects related to macrophage and lymphocyte function [1, 3, 4]. Pre-DM (ie, intermediate hyperglycemia) is a high-risk state for DM that is defined by levels of glycemic variables that are higher than normal but lower than thresholds for DM. Pre-DM is also associated with the presence of insulin resistance and B-cell dysfunction—abnormalities that start before changes in blood glucose levels become detectable [5]. While a number of studies have examined the interaction of DM with active tuberculosis [3, 4], very few studies have examined the interaction of DM (and its pre-DM precursor) with latent Mycobacterium tuberculosis infection (hereafter, “latent infection”). Whether diabetes hastens the progression to active tuberculosis by increasing the risk of latent infection in healthy individuals or by increasing the risk of progression to active tuberculosis in latently infected individuals is not known. Moreover, the impact of diabetes or pre-DM on the innate and adaptive immune responses to mycobacteria-derived antigens in latent infection is also not known. Since type 1 and type 17 cytokines and the interleukin 1 (IL-1) family of cytokines are known to influence susceptibility to tuberculosis in both humans and in animal models [6, 7], we postulated that diabetes and/or pre-DM could perturb the normal homeostatic levels of these cytokines in latent infection. To this end, we compared levels of a panel of type 1, type 17, IL-1–family, and other relevant proinflammatory cytokines in individuals with latent infection and coincident DM or pre-DM to levels in individuals with latent infection but without DM. We also examined the influence of DM or pre-DM on M. tuberculosis antigen–specific cytokine production. Our data show both DM and pre-DM alter the levels of many proinflammatory cytokines at homeostasis and in response to M. tuberculosis antigens in latent infection and provides evidence for the potential contribution of impaired glucose tolerance to the increased risk for progression to active tuberculosis. Finally, our data also show that, among individuals with DM or pre-DM, those with latent infection exhibit significantly higher circulating levels of most proinflammatory cytokines, compared with those without latent infection.