Tuberculosis-diabetes comorbidities: Mechanistic insights for clinical considerations and treatment challenges

Abstract

Tuberculosis (TB) remains a leading cause of death among infectious diseases, particularly in poor countries. Viral infections, multidrug-resistant and ex-tensively drug-resistant TB strains, as well as the coexistence of chronic illnesses such as diabetes mellitus (DM) greatly aggravate TB morbidity and mortality. DM [particularly type 2 DM (T2DM)] and TB have converged making their control even more challenging. Two contemporary global epidemics, TB-DM behaves like a syndemic, a synergistic confluence of two highly prevalent diseases. T2DM is a risk factor for developing more severe forms of multi-drug resistant-TB and TB recurrence after preventive treatment. Since a bidirectional relationship exists between TB and DM, it is necessary to concurrently treat both, and promote recommendations for the joint management of both diseases. There are also some drug-drug interactions resulting in adverse treatment outcomes in TB-DM patients including treatment failure, and reinfection. In addition, autophagy may play a role in these comorbidities. Therefore, the TB-DM comorbidities present several health challenges, requiring a focus on multidisciplinary collaboration and integrated strategies, to effectively deal with this double burden. To effectively manage the comorbidity, further screening in affected countries, more suitable drugs, and better treatment strategies are required.

Keywords: Autophagy; Coinfections; Comorbidity; Diabetes mellitus; Drug-drug interactions; Treatment challenges; Tuberculosis.

Figure 1

Pathophysiological relationships between tuberculosis and diabetes mellitus and impacts of exogenous and endogenous factors. Both tuberculosis and diabetes mellitus show a bidirectional relationship at various points as depicted, which are affected by exogenous and endogenous factors. GH: Growth hormone; HCV: Hepatitis C virus; ART: Antiretroviral therapy; CTLA-4: Cytotoxic T-lymphocyte associated protein 4; PD-1: Programmed cell death protein 1; PDL-1: Programmed cell death ligand 1; IR: Insulin resistance; TB: Tuberculosis; COVID-19: Coronavirus disease 2019; HIV: Human immunodeficiency virus; MDR: Multi-drug resistant; XDR: Extreme drug resistance; TDR: Total drug-resistance; IL: Interleukin; TNFα: Tumor necrosis factor alpha.

Figure 2

Mechanistic insights into the pathophysiologies of tuberculosis and diabetes mellitus interactions. Mtb: Mycobacterium tuberculosis; IFN: Interferon; HDT: Host-directed therapy; Eis: Enhanced intracellular survival; ESAT-6: Early secretory antigenic target; ESX-1: Secretion system-1; vitD3: Vitamin D3; ROS: Reactive oxygen species; LAP: Microtubule-associated protein light-chain 3-associated phagocytosis; VDR: Vitamin D receptor; CAMP: Cathelicidin antimicrobial peptide; iNOS: Inducible nitric oxide synthase; RAAS: Renin–angiotensin–aldosterone system; IR: Insulin resistance; PXR: Rifampicin activates pregnane X receptor; N-CoR: The nuclear receptor corepressor; PPAR: Peroxisome proliferator-activated receptor; RXR: Retinoic acid receptor; ORF: Open reading frame; OATP2: The sinusoidal transporters organic anion transporting protein 2; DDIs: Drug-drug interactions; RIF: Rifampin.