Complex Link Between Prediabetes and Tuberculosis Risk

Prediabetes is a condition where blood glucose levels are higher than normal but not yet high enough for a Type 2 Diabetes (T2D) diagnosis. It is identified by fasting blood glucose (FBG) levels of 100–125 mg/dL, a 2-hour oral glucose tolerance test (OGTT) result between 140–199 mg/dL, or hemoglobin A1C values of 5.7–6.4%. Although the link between T2D and tuberculosis (TB) is not fully understood, evidence suggests that progression from prediabetes to T2D may increase susceptibility to Mycobacterium tuberculosis infection. For instance, prediabetes was found in 27% of household contacts of active TB patients, and over half of newly diagnosed TB patients in western India had either T2D or prediabetes.[1] See also: https://tbreadingnotes.blogspot.com/2024/08/a-model-for-propagation-and-control-of.html

Prediabetes can disrupt immune responses essential for controlling M. tuberculosis. Studies show that prediabetic TB patients have increased levels of both pro-inflammatory cytokines, such as IFN-γ, TNF-α, IL-12, IL-17, IL-1β, and GM-CSF, and regulatory cytokines, including IL-5, IL-10, and TGF-β. This dysregulation may impair the immune system’s ability to contain TB infection effectively. Furthermore, as T2D progresses—particularly in obese individuals—the levels of C1qTNF3 (CTRP-3), a cytokine that reduces inflammation, decline. Lower concentrations of C1qTNF3 have been linked to an increased risk of progressing from latent TB to active disease.[1] See also: https://tbreadingnotes.blogspot.com/2024/08/prevalence-of-various-forms-of-active.html

Once T2D is established, additional metabolic disturbances occur, such as hyperglycemia, dyslipidemia, and hormonal imbalances, which may create a more favorable environment for TB infection and persistence. T2D is commonly associated with diabetic dyslipidemia, characterized by elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol, and increased low-density lipoprotein (LDL) cholesterol. In patients with TB-T2D comorbidity, lipid metabolism shows features of both diseases. These individuals often have reduced amino acid levels and demonstrate less severe dyslipidemia than typically observed in T2D alone—possibly due to the chronic nature of both conditions and their interaction.[1]

Triglycerides play a significant role in TB infection, as M. tuberculosis can utilize host triglycerides as an energy source, especially in hypoxic conditions. This adaptation allows the bacteria to survive within granulomas, as seen in animal and human studies. A meta-analysis confirmed a link between latent TB infection and T2D. In T2D, lipid accumulation in macrophages promotes the formation of foamy macrophages, which foster bacterial persistence and contribute to tissue damage during TB. Serum triglyceride levels in T2D patients have been correlated with this process, although more clinical studies are needed to clarify this connection. Additionally, both T2D and pulmonary TB are associated with reduced HDL-cholesterol, which has been linked to more severe lung lesions in TB-T2D patients.[1]

Elevated oxidized LDL (Ox-LDL) levels in T2D patients may also increase susceptibility to TB. Ox-LDL accumulates in the lungs during active TB and is taken up by macrophages in high-glucose environments, leading to higher bacterial loads in both animal models and human cell cultures. These findings suggest that diabetic dyslipidemia—including elevated triglycerides and Ox-LDL—may not only heighten the risk of TB infection but also promote its progression.[1]

Managing diabetic dyslipidemia may influence the host's ability to respond to TB infection. A retrospective study in Taiwan found that T2D patients treated with statins had a lower risk of developing active TB compared to those not using statins. However, combining statins or fibrates with antibiotics did not improve treatment outcomes for patients with active TB, suggesting that controlling dyslipidemia may have different effects depending on whether TB is latent or active. Furthermore, BCG vaccination appears to impact lipid metabolism. Studies in guinea pigs and hyperlipidemic mice revealed that BCG vaccination reduced Ox-LDL accumulation and non-HDL cholesterol levels, leading to fewer foamy macrophages at infection sites. These results imply that BCG vaccination may offer protection against TB not only through immune stimulation but also by modulating lipid metabolism.[1]

A review of literature up to March 31, 2024, examined the link between prediabetes and tuberculosis (TB) treatment outcomes. Eight cohort studies involving 3,001 TB patients—752 of whom had prediabetes at baseline—were analyzed. These studies, conducted across six countries, focused on patients treated with standard anti-TB therapy and followed them for six to 24 months. Pooled data showed that TB patients with prediabetes had a higher risk of unfavorable treatment outcomes, such as treatment failure, modification, recurrence, or death, compared to normoglycemic patients. However, prediabetes was not associated with an increased risk of all-cause mortality during TB treatment.[2]

Although the mechanisms remain unclear, chronic low-grade inflammation and immune dysfunction are suspected to contribute to poorer outcomes in TB patients with prediabetes. The studies included strictly adhered to criteria assessing prediabetes at baseline and excluded cross-sectional analyses and studies lacking outcome data. Risk ratios (RR) and hazard ratios (HR) were used to measure the association, with odds ratios (OR) converted to RR when necessary. These findings highlight the need for early identification and management of prediabetes in TB patients to potentially improve treatment outcomes.[2]

Numerous studies and systematic reviews have established diabetes mellitus (DM) as a significant risk factor for both active tuberculosis (TB) disease and latent TB infection. In Taiwan, where TB is a notifiable disease, all suspected cases must undergo sputum smear tests and cultures, with confirmed cases registered in the National Tuberculosis Registry and provided standardized, free treatment. A longitudinal study using data from this registry identified incident cases of active TB, defining them by smear-positive or culture-positive results. Interestingly, this study found that individuals with prediabetes had a 27% reduced risk of developing active TB compared to those with normal blood glucose levels. However, the biological mechanisms behind this inverse association remain unclear and warrant further investigation.[3]

This was the first longitudinal study to explore the relationship between prediabetes and TB risk, presenting novel findings with important implications for addressing the dual epidemics of diabetes and tuberculosis. The potential protective role of obesity and prediabetes against TB suggests that the ongoing global nutrition transition may have complex effects on TB control efforts. While improved nutrition may offer some protection, it could also contribute to the growing burden of metabolic diseases like diabetes. More research is needed to clarify the biological basis of these associations and to guide public health strategies in managing the intersecting challenges of TB and diabetes worldwide.[3]

References:

1. Segura-Cerda, C.A., López-Romero, W. and Flores-Valdez, M.A., 2019. Changes in host response to mycobacterium tuberculosis infection associated with type 2 diabetes: beyond hyperglycemia. Frontiers in cellular and infection microbiology, 9, p.342.

2. Liang, L. and Su, Q., 2024. Prediabetes and the treatment outcome of tuberculosis: A meta‐analysis. Tropical Medicine & International Health, 29(9), pp.757-767.

3. Ko, T.H., Chang, Y.C., Chang, C.H., Liao, K.C.W., Magee, M.J. and Lin, H.H., 2023. Prediabetes and risk of active tuberculosis: a cohort study from Northern Taiwan. International Journal of Epidemiology, 52(3), pp.932-941.