Defining a Research Agenda to Address the Converging Epidemics of Tuberculosis and Diabetes

Abstract

There is growing interest in the re-emerging interaction between type 2 diabetes (DM) and tuberculosis (TB), but the underlying biological mechanisms are poorly understood despite their possible implications in clinical management. Experts in epidemiological, public health, basic science and clinical studies recently convened and identified research priorities for elucidating the underlying mechanisms for the co-ocurrence of TB and DM. We identified gaps in current knowlege of altered immunity in DM patients during TB, where most studies suggest an under-performing innate immunity, but exaggerated adaptive immunity to Mycobacterium tuberculosis. Various molecular mechanisms and pathways that may underly these observations in the DM host. These include signaling induced by excess advanced glycation end products (AGE) and their receptor (RAGE), higher levels of reactive oxidative species and oxidative stress, epigenetic changes due to chronic hyperglycemia, altered nuclear receptors and/or differences in cell metabolism (immuno-metabolism). Studies in humans at different stages of DM (no DM, pre-DM and DM) or TB (latent or active TB) should be complemented with findings in animal models, which provide the unique opportunity to study early events in the host-pathogen interaction. Such studies could also help identify biomarkers that will complement clinical studies in order to tailor the prevention of TB-DM, or avoid the adverse TB treatment outcomes that are more likely in these patients. Such studies will also inform new approaches to host-directed therapies. M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT Summary box• Type 2 diabetes is a syndrome characterised by a range of metabolic (e.g. hyperglycemia, hyperlipidemia), inflammatory, vascular and other changes that may all contribute to increasing TB susceptibility and pathology.• Monocytes and macrophages from diabetic patients and mice have defects leading to altered interactions with M. tuberculosis and delayed adaptive immune responses.• Most human studies have been conducted in patients with active TB, where those with TB-DM comorbidity are characterised by increased secretion of Th1, Th17 and Th2 cytokines. However, the few studies in individuals at risk for TB (LTBI) suggest a different cytokine profile.• Molecular pathways that involve AGE/RAGE, ROS, nuclear receptors and cellular metabolism are potential targets for host-directed therapies to reduce TB susceptibility or pathology in DM patients.• Animal models for TB-DM can improve our understanding of underlying mechanisms and effective treatment approaches for the comorbidity of TB and DM. IntroductionType 2 diabetes mellitus (DM) increases the risk of many infectious diseases, including tuberculosis 1 (TB), and it is now recognized that the increasing DM prevalence in high TB incidence countries such as Sub-Saharan Africa (SSA) is a challenge to TB control. 2 The known association between a chronic syndome like DM and an infectious disease like TB requires the near term development...

Diabetes mellitus comorbidity in patients enrolled in tuberculosis drug efficacy trials around the world: A systematic review

“…Several underlying mechanisms to understand adverse treatment outcomes of TB due to hyperglycaemia have been suggested . One mechanism is related to an altered immunological response which is important, but difficult to account for in TB treatment decisions.…”

Tuberculosis and diabetes: bidirectional association in a UK primary care data set

“…Some recent animal models of Mycobacterium tuberculosis (Mtb) have seen unexpected development of DM (eg, among guinea pigs), particularly those treated with antiglycaemic therapy as host-directed therapy for TB 20. Studies have shown induced hyperglycaemia and/or impaired glucose tolerance occur during the early phases of active TB disease,21 22 and these metabolic states themselves are linked with progression to overt DM among 20%–50% of individuals after 3–5 years 23.…”

Prevalence of dysglycemia and clinical presentation of pulmonary tuberculosis in Western India

“…Individuals with TB and DM have altered inflammation, T-helper type-1 immune responses, as well as defective neutrophil and macrophage function. 24 In addition, TB-infected alveolar macrophages among DM patients may alter host cell recognition and delay innate immune responses. 25–27 Whether these immune changes result in more severe TB disease among DM patients should be explored further.…”