Clinical, metabolic, and immune interaction between tuberculosis and diabetes mellitus: implications and opportunities for therapies

Abstract

Introduction: Tuberculosis (TB) remains a major infectious threat to global health, while type 2 diabetes mellitus (diabetes) has reached epidemic proportions in many regions of the world. In low- and middle-income countries (LMIC) and among indigenous and minority communities in high-income settings (HIC), these diseases also increasingly overlap, posing new clinical and therapeutic challenges.

Areas covered: We searched PubMed/CINAHL/Web of Science/Scopus, Google Scholar up to 30 November 2024. Meanwhile, the Immuno-metabolic parallels between TB and Diabetes are underappreciated. Improved understanding of mechanisms may pave the way for novel therapeutic strategies, for example, using antidiabetic medications as adjuvant host-directed therapies (HDT) in active TB. We review the epidemiology of TB, diabetes and their combined comorbidity, their immune and metabolic mechanisms and clinical relevance, as well as potential opportunities for general and targeted therapeutic intervention.

Expert opinion: Immunometabolic interaction between diabetes and tuberculosis is bidirectional. Underlying this interaction are shared inflammatory mechanisms. It follows that treatments for diabetes and its complication may be beneficial in tuberculosis and that the treatment of both active and latent tuberculosis may improve glycemic control. These interactions are amenable to investigation in experimental models, in human experimental medicine studies and in clinical trials.

Keywords: TB; diabetes mellitus; host-directed therapy; inflammation; insulin resistance.

Figure 1. An overview of the Innate and Adaptive Immune Responses to M.tb infection and the effect of diabetes therapies thereon.

Hyperglycaemia, a hallmark of type II diabetes, inhibits protective innate immune responses which can be improved with successful diabetes treatment. Diabetes therapies typically inhibit pro-inflammatory immune responses, favouring the upregulation of immunomodulatory responses. M.tb: Mycobacterium tuberculosis; IL: Interleukin; TNFα: Tumor necrosis factor alpha; AGEs: advanced glycation end-products; APC: antigen presenting cell; MHCI: major histocompatibility complex class 1; MHCII: major histocompatibility complex class 2; IFN: interferon; TCR: T cell receptor; NK: natural killer; IDO: Indoleamine 2,3-dioxygenase; TGF: transforming growth factor; Th1: helper T cell subset type 1; Th2: helper T cell subset type 2; Treg: regulatory T cell subset. Created in BioRender. Kotze, L. (2024) https://BioRender.com/l93g049.

Figure 2. An overview of the influence of metformin and statins on the systemic and immune effects of M.tb infection in animal models, primarily those in mice and Guinea pigs.

AMPK: adenosine monophosphate-activated protein kinase; mTORC1: mammalian target of rapamycin complex 1; TFEB: transcription factor EB; Th2: helper T cell subset type 2. Created in BioRender. Kotze, L. (2024) https://BioRender.com/l93g049.