Tuberculosis-diabetes comorbidities

One in every ten adults is a diabetic (DM) patient. Long-term hyperglycemia in DM patients leads to decreased immune cell numbers and function, increasing the incidence of tuberculosis (TB). Chronic hyperglycemia severely impairs the function of innate immune cells, affecting processes such as monocyte differentiation into macrophages and dendritic cells. This impairs the recruitment, recognition, phagocytosis, and antigen presentation functions of macrophages and reduces the frequency of dendritic cells and natural killer cells. Additionally, hyperglycemia increases the inflammatory response of neutrophils, which exacerbates bacterial load.[1]

Diabetes mellitus (DM) significantly increases the risk of severe tuberculosis (TB) forms, including active TB (~3-fold), latent TB infection (LTBI, ~2-fold), TB recurrence after preventive treatment, and worsened outcomes following therapeutic treatment. DM is associated with higher rates of treatment failure, relapse, reinfection, and mortality. Furthermore, DM may contribute to resistance against first-line anti-TB drugs (e.g., rifampin) and second-line drugs (e.g., linezolid).[2]

Patients with DM-TB co-infection exhibit reduced levels of TH1 cytokines, such as interleukin (IL)-1 and IL-6, compared to non-diabetic individuals. Impaired macrophage function in DM, driven by oxidative stress, reactive oxygen species (ROS), dysregulated phagocytosis, and altered chemotaxis, increases susceptibility to TB reactivation from LTBI and exogenous reinfection. Chronic inflammation in both DM and TB is linked to oxidative stress, exacerbated by intrinsic factors (e.g., age, family history) and extrinsic factors (e.g., smoking).[2]

Increased expression of efflux pumps in DM patients may also contribute to phenotypic tolerance of Mycobacterium tuberculosis (Mtb) persisters to drugs like rifampin, further complicating TB management in diabetic individuals.[2]

See also: https://tbreadingnotes.blogspot.com/2024/08/pulmonary-tb-and-delay-in-anti.html

Chronic hyperglycemia may delay the activation of adaptive immune cells, including CD4+ and CD8+ T cells. CD4+ T cells are crucial in anti-tuberculosis immunity, promoting the proliferation of T lymphocytes and macrophage activation via interferon-gamma (IFN-γ) secretion. However, high blood glucose levels can delay CD4+ T cell activation, reducing IFN-γ secretion. Pulmonary tuberculosis (PTB) accounts for nearly 90% of TB cases, and CD4+ T lymphocytes differentiate into Th1, Th2, Th17, and Treg cells, essential for host defense against TB.[1]

See also: https://tbreadingnotes.blogspot.com/2024/08/identifying-mdrtb-transmission-hotspots.html

CD8+ T lymphocytes, upon recognizing MTB antigen peptides presented by MHC class I molecules, differentiate into cytotoxic T lymphocytes (CTLs). CTLs kill target cells by secreting perforin and granzymes and release IFN-γ and TNF-α, which activate macrophages for MTB clearance. During MTB infection, monocytes migrate to the lungs, differentiate into macrophages and dendritic cells, and present antigens to activate other immune cells. However, high blood glucose levels impair monocyte differentiation into macrophages due to reduced vitamin D levels and increased chemokine receptor CCR2 on monocyte surfaces, hindering effective immune responses.[1]

See also: https://tbreadingnotes.blogspot.com/2024/08/the-risk-of-tuberculosis-disease-among.html

In some DM patients, cytokine production (e.g., IL-1β, IL-8) decreases, impairing the phagocytic function of monocytes. This reduced cytokine activity can diminish MTB control, while high blood glucose levels alter the complement pathway, affecting monocyte signaling and limiting immune functions. Under hyperglycemic conditions, alveolar macrophage recognition of MTB is compromised, impeding the innate immune response. In the pulmonary microenvironment, macrophages polarize to M2-type, reducing their phagocytic and antimicrobial functions. Medications like glimepiride can exacerbate M2 polarization, impairing macrophage bactericidal abilities and increasing TB susceptibility.[1]

Macrophage activation status changes in DM-TB patients, with decreased HLA-DR, CD80, and CD86 expression and increased PD-L1 expression, which inhibits T cell function. High blood glucose may also cause M1 macrophage polarization through advanced glycation end products (AGEs) via pathways such as HIF-1a, PDK, and MAPK, leading to a pro-inflammatory response that damages lung tissue. Dendritic cells (DCs) in DM-TB patients show delayed activation and decreased frequency, likely due to high blood glucose, and DC frequency tends to improve with controlled TB treatment, emphasizing the impact of hyperglycemia.[1]

High blood glucose levels can reduce IFN-γ production by CD4+ T cells due to decreased MHC-II expression on antigen-presenting cells, impairing the immune response. Elevated glucose also hinders monocyte differentiation into dendritic cells, increasing reactive oxygen species (ROS) production and activating pathways like Wnt/β-catenin, which limits dendritic cell differentiation and maturation. In DM-TB patients, neutrophils often exhibit an excessive inflammatory response, increasing bacterial burden and worsening symptoms. Hyperglycemia can prompt neutrophils to release extracellular traps (NETs), leading to chronic inflammation and tissue damage.[1]

NK cell numbers inversely correlate with fasting blood glucose (FBG) levels in DM-TB patients, indicating an inhibitory effect of hyperglycemia. Additionally, hyperglycemia reduces the expression of CD107a, a marker of NK cell cytotoxic activity. Pro-inflammatory cytokines like TNF-α and IL-17, secreted by NK cells, are significantly elevated, causing excessive inflammation and tissue damage.[1]

DM affects Th1 cell production, leading to reduced IFN-γ secretion, which is crucial for MTB resistance. Poor glycemic control in TB patients correlates with lower IFN-γ levels, while well-controlled blood glucose tends to restore IFN-γ secretion over time. High blood glucose increases Th2 differentiation, potentially suppressing anti-TB immunity and reducing bacterial clearance. Th1 and Th17 cytokine levels (IFN-γ, TNF-α, IL-17) are higher in DM-TB patients, indicating a stronger cytokine response than in non-diabetic TB patients. Elevated HbA1c levels correlate with increased pro-inflammatory cytokines and reduced IL-10, illustrating Th1/Th17 upregulation and Th2 downregulation.[1]

Studies in Asia often report reduced pro-inflammatory and increased anti-inflammatory cytokines in CD4+ T cells of DM-TB patients, while studies from other regions note an increase in pro-inflammatory and a decrease in anti-inflammatory cytokines, suggesting regional differences in immune responses.[1]

In DM-TB patients, the levels of pro-inflammatory cytokines secreted by CD8+ T cells, including IFN-γ, IL-17, and IL-2, were elevated, while the expression of cytotoxic markers such as perforin, granzyme B, and CD107a on CD8+ T cells was significantly reduced. This increase in pro-inflammatory cytokines, along with a decrease in the CD8+ T cells' ability to clear bacteria, lowers the body’s resistance and leads to exacerbated tissue damage.[1]

The frequency of central memory CD8+ T cells was significantly positively correlated with FBG and HbA1c levels, while the frequency of naïve CD8+ T cells showed a significant negative correlation with these markers. In patients with tuberculosis pneumonia complicated by DM, the counts of CD4+ and CD8+ cells were significantly increased, whereas, in non-tuberculosis pneumonia complicated by DM, the counts of CD4+ and CD8+ cells were significantly decreased.[1]

DM did not affect the memory B cell subset, but in early-stage DM combined with TB, there was an increase in classical memory B cells. In active or latent TB combined with DM, there was an increase in activated memory B cells and atypical memory B cells, with a decrease in naïve B cells. Hyperglycemia, through nonenzymatic glycation and covalent glycation of proteins, may impair the biological function of immunoglobulins, thus weakening humoral immunity. Elevated resistin levels in the serum of insulin-resistant patients impaired ROS production, reducing the bactericidal function of macrophages in DM-TB comorbidity.[1]

Resistin, a 12 kDa soluble serum protein, plays a critical role in macrophage bactericidal activity, with ROS serving as a key mechanism in this process. Increased resistin levels promote insulin resistance while inhibiting ROS production by immune cells. Studies have observed significantly elevated resistin levels in both DM and severe TB patients. DM patients with three or more complications are at more than twice the risk for TB. Factors such as smoking, vitamin D deficiency, and lipid abnormalities not only contribute to DM-related renal and vascular complications but may also be associated with the reactivation of latent TB infections (LTBI).[1]

Oxidative stress in diabetes is closely linked to the formation of advanced glycation end-products (AGEs), which result from protein-sugar reactions. Elevated reactive oxygen species (ROS) levels are positively associated with increased AGEs and hyperglycemia. Antioxidants like resveratrol, found in grapes and berries, can mitigate these effects. The antidiabetic drug metformin reduces AGE production by suppressing soluble RAGE via AMP-activated protein kinase (AMPK), a key metabolic regulator. Similarly, the PPARγ agonist rosiglitazone alleviates AGE-induced endothelial dysfunction and diabetes-related vascular complications by activating the PI3K-AKT-eNOS pathway.[2]

Glucagon-like peptide-1 (GLP-1) and its receptor agonists, such as exendin-4, show potential in treating diabetes and preventing diabetic cardiomyopathy. Dysregulation of autophagy or mutations in autophagy-related genes (ATGs) contribute to various diseases, including diabetes and tuberculosis (TB). Autophagy plays a critical role in TB defense by degrading intracellular mycobacteria and inhibiting their survival. Metformin can induce autophagy in macrophages, enhancing phagosome maturation and facilitating Mycobacterium tuberculosis (Mtb) eradication by modulating inflammation and boosting antimicrobial activity.[2]

Nutrient-sensing pathways, such as those downstream of Sirtuin 1 (SIRT1), regulate autophagy and represent therapeutic targets for type 1 and type 2 diabetes. Resveratrol, a natural SIRT1 activator, induces phagolysosome fusion, restricts Mtb growth, and promotes autophagy. SIRT1 also cooperates with AMPK to combat oxidative stress in diabetes. Both SIRT1 and AMPK target common downstream effectors, including forkhead transcription factors, PPARα, and PGC-1α, which help reduce oxidative stress when activated together.[2]

The presence of complications in DM patients increases the risk of developing TB, likely due to long-term complications weakening the immune response. The proportion of DM-TB cases among Asians was 55%, compared to 22% for Caucasians and 23% for Blacks, suggesting a racial specificity in the occurrence of these diseases, with Asians showing a higher incidence of DM and TB.[1]

The Tuberculin Skin Test (TST) involves injecting PPD of tuberculin into the skin to observe delayed hypersensitivity reactions. New TST methods, such as C-TB, Diaskintest, and EC skin tests, have emerged. However, TST has lower specificity and is susceptible to cross-reactions from BCG vaccination and non-tuberculous mycobacteria (NTM). In contrast, IGRA detects TB by measuring IFN-γ release after specific antigen stimulation, offering higher specificity and avoiding cross-reactions from BCG and NTM. Currently, there are several IGRA methods available, such as AdvanSure™ TB-IGRA ELISA, Wantai TB-IGRA, Standard E TB-Feron (TBF), QIAreach QFT, ichroma™ IGRA-TB, VIDAS TB-IGRA, and T-Track TB.[1]

Although both TST and IGRA rely on the body's immune response, their sensitivity may be reduced in patients with compromised immunity, such as those with DM. DM-TB patients are more likely to present with lower lung field lesions and cavitation compared to TB patients without DM. Despite the usefulness of TST and IGRA in indicating disease status, neither test can distinguish between LTBI and active TB, and DM may reduce the sensitivity of both tests.[1]

Metformin is the first-line antidiabetic drug for type 2 diabetes mellitus (T2DM) due to its ability to regulate hyperglycemia through multiple mechanisms. It is also a promising adjunct to anti-TB drugs like isoniazid, as it reduces mycobacterial growth by inducing mitochondrial ROS production and mitigates inflammation and lung tissue damage by inhibiting the nuclear factor κB pathway, regardless of diabetes status. These properties make metformin a potential candidate for host-directed therapy (HDT) in TB-DM patients.[2]

Rifampicin, a key anti-TB drug, induces the expression of CYP3A4 and CYP2C8/9, lowering plasma concentrations of their substrates, including many oral hypoglycemic agents. This interaction can lead to hyperglycemia, necessitating careful monitoring of blood glucose and adjustments to medications like sulfonylureas in TB-DM patients to prevent hypoglycemia.[2]

Unlike many antidiabetic drugs, metformin is minimally affected by CYP-mediated metabolism or P-glycoprotein transport. This makes it a suitable option for combination therapy with rifampicin, bedaquiline, or delamanid, as it has minimal pharmacokinetic drug-drug interactions. Rifampicin increases OCT1 mRNA expression, enhancing metformin uptake in the liver and improving glucose regulation in healthy individuals. However, in TB-DM patients, rifampicin alters metformin plasma levels without significantly affecting blood glucose, though there remains a risk of lactic acidosis, its primary side effect.[2]

References: 

[1] Ye, Z., Li, L., Yang, L., Zhuang, L., Aspatwar, A., Wang, L. and Gong, W., 2024. Impact of diabetes mellitus on tuberculosis prevention, diagnosis, and treatment from an immunologic perspective. In Exploration (p. 20230138).

[2]  Al-Bari MAA, Peake N, Eid N. Tuberculosis-diabetes comorbidities: Mechanistic insights for clinical considerations and treatment challenges. World J Diabetes 2024; 15(5): 853-866.