The cause-effect relation of tuberculosis on incidence of diabetes mellitus

Abstract

Tuberculosis (TB) is one of the oldest human diseases and is one of the major causes of mortality and morbidity across the Globe. Mycobacterium tuberculosis (Mtb), the causal agent of TB is one of the most successful pathogens known to mankind. Malnutrition, smoking, co-infection with other pathogens like human immunodeficiency virus (HIV), or conditions like diabetes further aggravate the tuberculosis pathogenesis. The association between type 2 diabetes mellitus (DM) and tuberculosis is well known and the immune-metabolic changes during diabetes are known to cause increased susceptibility to tuberculosis. Many epidemiological studies suggest the occurrence of hyperglycemia during active TB leading to impaired glucose tolerance and insulin resistance. However, the mechanisms underlying these effects is not well understood. In this review, we have described possible causal factors like inflammation, host metabolic changes triggered by tuberculosis that could contribute to the development of insulin resistance and type 2 diabetes. We have also discussed therapeutic management of type 2 diabetes during TB, which may help in designing future strategies to cope with TB-DM cases.

Keywords: Mycobacterium tuberculosis; diabetes; inflammation; insulin resistance; therapeutic strategies.

Figure 1

Impact of Mycobacterium tuberculosis (Mtb) infection on the physiological functions of adipocyte. Mtb infection leads to hypertrophy and immune cell infiltration into adipose tissue. Hypertrophic adipose tissue decreases expression of adiponectin, but increases expression of leptin and resistin. Decreased adiponectin expression reduces insulin sensitivity and through simultaneous upregulation of leptin and resistin, there is induction of inflammation and insulin resistance. Again, through mTORC2/Akt activation in adipocytes, Mtb bacteria cause inflammation and induce TNF-α and monocyte chemoattractant factor-1 (MCP-1) and reduce adiponectin. MCP-1 recruits macrophages and other cell type into adipose tissue. The infiltrated immune cells in adipocyte further produce inflammatory cytokine like TNF-α and IL-6. TNF-α binds to TNF receptor on adipocyte and induce activation of protein kinase A which phosphorylates hormone sensitive lipase and causes lipolysis in adipocytes. The inflammation in adipose tissue increased lipolysis, i.e. degradation of tri-acylglycerol (TAG) to di-acyleglycerol (DAG), mono-acylglycerol (MAG) and finally glycerol and release of free fatty acids (FFA). FFA through circulation gets deposited in other sites like liver and muscle. In liver, fat deposition leads to increase gluconeogenesis, gluconeolysis and leads to liver steatosis which results in increased plasma glucose concentration and finally leads to insulin resistance. Free fatty acid deposition in muscle tissue also causes insulin resistance in muscles.

Figure 2

Mycobacterium tuberculosis infection alters host metabolic pathways. Mtb and ESAT-6 protein increase glucose uptake and up-regulate glycolytic genes and inhibit oxidative phosphorylation causing Warburg effect. This results in production of pyruvate which is converted to lactate and is secreted out, excess pyruvate is transported to mitochondria and form acetyl-CoA (Ac-CoA) and finally produce ketone bodies 3 hydroxybutyrate (3HB). 3HB binds to GPR109a and cause lipid body formation. Ac-CoA is converted to OAA and enters in the TCA (Tricarboxylic acid) cycle. The OXPHOS and TCA cycle enzymes are downregulated (that include ACO2, IDH2, ACOD2 and SDH) by Mtb. As a result, CIT is accumulated which stabilizes and increases expression of hypoxia inducible factor-α (HIF-α) and increases production of itaconate. HIF-α induce lipid body formation, upregulation of glycolysis genes and inflammatory mediator like IL-1β. Itaconate inhibits production of reactive oxygen species (ROS). Decreased OXPHOS also causes production of ROS and reactive nitrogen species (RNS). Excess CIT is converted into Ac-CoA which is utilized in the fatty acid synthesis pathway and causes formation of membrane phospholipids. Cytosolic phospholipase A2 (cPLA2) release Arachidonic acid into cytosol which gives rise to prostaglandin and leucotrienes which cause inflammation. Various toll like receptor (TLR) and pattern recognition receptor (PRR)-triggered signaling stimulation cause NF-κB activation and transcription of inflammatory mediators, as well as production of HIF-1α. M. tuberculosis in phagosome secrete various lipases which degrade host lipids that are responsible for generation of fatty acids. The TNF-α-mediated signaling is also involved in formation of lipid droplets. CAC, cis-aconitate; CIT, citrate; FUM, fumarate; α-KG, α-ketoglutarate; NOS2, nitric oxide synthase 2; NOX2, NADPH oxidase; OAA, oxaloacetate; PGE2, prostaglandin E2; SUCC, succinate; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; ACOD2, aconite dehydrogenase, ACO2, aconitase2, SDH succinate dehydrogenase, IDH2, isocitrate dehydrogenase 2, LD, lipid droplets, OXPHOS, oxidative phosphorylation, AA-CoA, acyl Co-A.