Immune-endocrine network in diabetes-tuberculosis nexus

Patients with both tuberculosis (TB) and diabetes may experience more severe illness and have a higher risk of spreading infection. A study found a lower prevalence of latent TB infection (LTBI) in individuals with prediabetes (23%) and newly diagnosed diabetes (23%) compared to healthy controls (33%) and chronic diabetes patients (33%). The findings suggest that metabolic changes in prediabetes and early diabetes may influence susceptibility to LTBI.[1]

Prediabetes is associated with meta-inflammation, which leads to insulin resistance (IR) and increased insulin production by pancreatic beta cells. This stage is characterized by a unique immune response, marked by increased levels of innate immune markers such as interferon-β (IFN-β), pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and anti-inflammatory cytokines (IL-10, IL-1Ra, TGF-β). These cytokines activate macrophages, which play a critical role in restricting Mycobacterium tuberculosis (M. tb) growth. Additionally, newly identified cytokines, IL-27 and IL-38, show contrasting patterns—IL-27 is elevated, while IL-38 remains low. Among adaptive immune cytokines, IL-17 increases, while IL-9 decreases, influencing neutrophil activation and recruitment to the lungs for M. tb clearance.[1]

Macrophages are key players in the inverse relationship between insulin resistance and LTBI. During insulin resistance, adipocytes secrete pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), which polarize macrophages to a pro-inflammatory state. These macrophages can either restrict M. tb growth or exacerbate meta-inflammation, worsening IR. Meanwhile, alveolar macrophages infected with M. tb produce IL-10, which can reduce inflammation but also serve as a reservoir for LTBI. This dual role suggests that immune-metabolic interactions influence TB susceptibility in individuals with prediabetes and diabetes.[1]

As prediabetes progresses to diabetes, the immune response undergoes significant changes. Prediabetes is characterized by increased innate immune markers, while adaptive immune responses, such as IL-2, IL-4, and IFN-γ, begin to decline. A rise in defensins and a drop in adaptive immune cytokines distinguish prediabetes from diabetes. In chronic diabetes, glycemic control and treatment stabilize cytokine levels, with pro- and anti-inflammatory cytokines returning to normal. However, increased levels of TGF-β, IL-1Ra, IFN-β, and α-defensin-1, along with reduced IL-15, IL-27, and IL-38, highlight an altered immune environment.[1]

LTBI further modifies this immune landscape by downregulating key cytokines, including IL-12, IL-2, IL-4, IL-9, IL-15, and IFN-β, while upregulating IL-10, IL-27, IFN-γ, and IL-17. The suppression of IL-12 and increase in IFN-γ suggest alternative pathways for Th1 activation in LTBI-positive diabetic patients, while the reduction in IL-33 and IL-4 indicates a weakened Th2 response. Notably, the downregulation of IFN-β and α-defensin-1 signals impaired TB immunity in chronic diabetes, raising concerns about the accuracy of IGRA tests for LTBI detection in these patients.[1]

The role of other immune cells in this interplay is also significant. Dendritic cells contribute to both insulin resistance and anti-TB immunity, while B cells and neutrophils may exacerbate IR. The impact of humoral immunity on TB remains uncertain, with studies showing both beneficial and harmful effects of antibodies. Additionally, the relationship between BCG vaccination and diabetes risk is debated. Some research suggests that neonatal BCG vaccination may induce meta-inflammation and increase diabetes risk, while a Canadian study found a small protective effect of BCG against type 2 diabetes. Animal studies further suggest that BCG may improve glycemic control, potentially offering protection similar to LTBI.[1]

Reference:

1. Aravindhan, V. and Yuvaraj, S., 2024. Immune-endocrine network in diabetes-tuberculosis nexus: does latent tuberculosis infection confer protection against meta-inflammation and insulin resistance?. Frontiers in Endocrinology, 15, p.1303338.