A recent study by scientists from the University of Leicester has uncovered a critical link between tuberculosis (TB) and glucose metabolism, raising concerns that undiagnosed TB may increase the risk of developing metabolic diseases like diabetes. The findings, published in PLoS Pathogens, offer fresh insights into the complex relationship between TB and diabetes, showing how chronic TB infection can significantly affect metabolic health.
TB remains one of the deadliest infectious diseases worldwide, accounting for the death of over 4,000 individuals every day. Despite existing treatments, TB continues to pose a severe health threat, especially to vulnerable populations. This new research suggests that undiagnosed TB could be a hidden factor contributing to the development of metabolic disorders like diabetes, complicating efforts to manage both conditions on a global scale.
The connection between TB and diabetes is well-established, with diabetes-related immune and metabolic changes known to increase susceptibility to TB. Studies have shown that people with diabetes are more likely to develop TB, and in turn, active TB can lead to hyperglycemia, impaired glucose tolerance, and insulin resistance. However, the mechanisms behind these effects have remained unclear. The present study shifts the focus from how diabetes worsens TB to the possibility that delayed diagnosis of TB itself may disrupt metabolism, promoting insulin resistance and increasing the risk of diabetes.
The researchers used laboratory models to investigate how pulmonary TB affects the liver during early infection. The liver plays a critical role in regulating glucose metabolism, and the study found that TB infection in the liver triggered significant immune responses that disrupted normal metabolic functions. Specifically, the researchers observed that TB upregulated genes linked to immune signaling while downregulating genes responsible for key metabolic processes, such as gluconeogenesis, the production of glucose from non-carbohydrate sources.
In addition to their laboratory models, the researchers reanalyzed existing human metabolic data, finding similar disruptions in liver glucose metabolism when patients transitioned from latent to active TB infection. Latent TB occurs when the bacteria remain dormant in the body without causing symptoms, but this study suggests that even in its latent form, TB could silently affect metabolic health, potentially leading to long-term consequences such as insulin resistance.
One of the most striking discoveries from the research was the impact of TB-induced inflammation on liver function. The study identified a specific immune signaling pathway—interferon (IFN) signaling—that interfered with the liver’s ability to regulate glucose production. This disruption was seen through reduced phosphorylation of key enzymes and transcription factors involved in gluconeogenesis, including CREB, GSK3a, and AMPK. These molecular changes hindered the infected mice’s ability to convert pyruvate, a gluconeogenic substrate, into glucose, suggesting impaired glucose regulation.
Additionally, the study found that TB patients exhibited reduced insulin sensitivity, a key risk factor for developing diabetes. These metabolic disruptions appeared to correlate with the progression of TB and were shown to improve when patients received effective TB treatment. This underscores the importance of incorporating metabolic screening into TB patient care, particularly during drug or vaccine trials, to prevent complications such as diabetes.
Bisht et.al. showed that hyperglycemia during active TB can lead to impaired glucose tolerance and insulin resistance. Chronic inflammation, a hallmark of pulmonary TB, is thought to be a contributing factor, as it affects metabolic organs like the liver and promotes insulin resistance. This systemic inflammation, triggered by TB, can extend beyond the lungs and disrupt the function of multiple organs involved in metabolism.
Chronic inflammation is a known risk factor for metabolic diseases, and this research demonstrates that TB-induced inflammation could significantly increase the likelihood of developing insulin resistance and, ultimately, diabetes. The researchers plan to further explore the molecular pathways involved in this process to develop targeted interventions for TB patients at risk of metabolic disorders. This study represents a significant advancement in understanding the broader health impacts of TB. Highlighting the link between TB and glucose metabolism opens new pathways for targeted treatments and reinforces the importance of early TB diagnosis to prevent potential metabolic complications such as diabetes. Early detection and treatment of TB, combined with metabolic monitoring, could be crucial in reducing the burden of both TB and diabetes worldwide.
References
- Das MK, Savidge B, Pearl JE, Yates T, Miles G, Pareek M, et al. Altered hepatic metabolic landscape and insulin sensitivity in response to pulmonary tuberculosis. PLOS Pathogens. 2024 Sep 27;20(9):e1012565.
- Krishna S, Jacob JJ. Diabetes Mellitus and Tuberculosis. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000 [cited 2024 Oct 22]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK570126/
- Bisht MK, Dahiya P, Ghosh S, Mukhopadhyay S. The cause-effect relation of tuberculosis on incidence of diabetes mellitus. Frontiers in Cellular and Infection Microbiology. 2023 Jun 26;13:1134036.