Mechanisms underlying TB-DM comorbidity

Tuberculosis (TB) and diabetes mellitus (DM) frequently co-exist, particularly in low- and middle-income countries, where 95% of TB and 75% of DM cases occur. DM weakens the immune system, increasing susceptibility to active TB, while TB-induced stress hyperglycemia complicates DM management. Between 2016 and 2018, the prevalence of DM among TB patients ranged from 8.5% to 11%, reaching up to 45% in some cases. TB patients with DM experience prolonged smear and culture positivity, higher risks of complications, relapse, and mortality. Impaired immune responses, particularly dysfunctional T-cell activity and macrophage polarization, contribute to increased bacterial survival and dissemination. Hyperglycemia further disrupts immune defenses by promoting M2 macrophage polarization, reducing phagocytic activity, and impairing neutrophil migration due to glycated collagen buildup.[2] See also: https://lintblab.weebly.com/

The interplay between TB and DM extends beyond immune dysfunction to metabolic regulation. Chronic TB infections trigger prolonged inflammation and cortisol release, suppressing T-cell function and weakening infection control. Both diseases activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to elevated cortisol levels that exacerbate insulin resistance and worsen glycemic control. Furthermore, hyperglycemia generates Advanced Glycation End Products (AGEs), fueling chronic inflammation and further increasing TB susceptibility. Reduced production of key cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), compromises MTB containment, creating a cycle of immune impairment and increased disease severity.[2]

TB treatment also complicates DM management due to drug interactions. Isoniazid and rifampin, essential anti-TB drugs, influence the metabolism of several anti-diabetic agents, including sulfonylureas and HIV medications. Rifampin alters drug transport and metabolism via uridine diphosphate-glucuronosyltransferases, affecting glycemic control. However, metformin, with minimal impact on cytochrome P450 enzymes, has shown potential benefits in TB treatment by improving treatment success rates, reducing mortality, accelerating sputum culture conversion, and inhibiting latent TB reactivation. Moreover, metformin may help shorten TB treatment duration. Despite overlapping side effects of TB and DM medications—including neuropathy, hepatotoxicity, gastrointestinal issues, fluid retention, and hypoglycemia—metformin's promising anti-TB properties highlight its therapeutic potential in managing TB-DM comorbidity.[2]

The intricate cellular and molecular mechanisms underlying TB-DM comorbidity highlight a complex interplay that significantly impacts global health outcomes. Multi-omic approaches—including genomics, transcriptomics, proteomics, lipidomics, and metabolomics—offer crucial insights into immune dysfunction and inflammatory pathways in TB-DM patients. Cellular immunology studies reveal that DM impairs macrophage and neutrophil function, weakens cytokine signaling, and alters T-cell responses, increasing susceptibility to TB. Genetic variants, such as polymorphisms in IL-6 and IL-18, may predispose individuals to TB-DM, emphasizing the need for personalized medicine. Transcriptomic research indicates that TB-DM is characterized by chronic inflammation and dysregulated immune pathways, while proteomic studies suggest that changes in complement and coagulation cascades may be linked to lipid metabolism abnormalities. Lipidomic and metabolomic analyses further highlight disruptions in glycerophospholipids, bile acids, and carbohydrate metabolism, underscoring DM’s profound impact on TB pathophysiology.[1]

Beyond molecular mechanisms, epidemiological data underscore the significant prevalence of DM among TB patients, influenced by factors such as age, socio-economic status, lifestyle, family history, and hypertension. However, regional disparities in TB-DM comorbidity remain underexplored, necessitating investments in molecular epidemiology to tailor public health interventions. The bidirectional nature of TB-DM complicates clinical management, as DM correlates with higher mycobacterial loads and distinctive lung damage, accelerating disease progression. Integrated health strategies—including routine TB screening for DM patients, reciprocal screening, and expanded research into TB transmission dynamics—are essential. Investigating how DM-related multimorbidities shape inflammatory profiles could refine biomarker discovery and treatment approaches, improving patient outcomes.[1]

Advancements in single-cell analysis and multi-omic integration hold promise for transforming TB-DM management by offering deeper insights into immune dysfunction and potential therapeutic targets. Combining genetic, molecular, and clinical data could enable predictive models for disease progression and treatment response. Additionally, the potential development of TB vaccines tailored for immunocompromised populations may emerge from a refined understanding of TB-DM-specific immune alterations. Comprehensive risk scores incorporating socio-demographic, lifestyle, and clinical data could further optimize precision public health interventions. A multidisciplinary approach that integrates epidemiological, clinical, and multi-omic research is crucial to unravel the complexities of TB-DM, paving the way for more effective diagnostic tools, personalized treatments, and improved global health strategies.[1]

References: 

1. Araujo-Pereira, M., Vinhaes, C.L., Barreto-Duarte, B., Villalva-Serra, K., Queiroz, A.T.L., & Andrade, B.B. (2024). Intersecting epidemics: Deciphering the complexities of tuberculosis-diabetes comorbidity. Frontiers in Tuberculosis, 2, Article 1487793. 

2. Boadu, A.A., Yeboah-Manu, M., Osei-Wusu, S. and Yeboah-Manu, D., 2024. Tuberculosis and diabetes mellitus: The complexity of the comorbid interactions. International Journal of Infectious Diseases, p.107140.