Insulin regulates blood glucose levels through glucose and lipid metabolism in the body. Insulin resistance is clinically defined as a condition where known amount of exogenous or endogenous insulin fails to increase glucose uptake and utilization as much as in a normal population (Lebovitz, 2001). In other words, the body develops diminished response to the actions of insulin or impaired sensitivity to insulin resulting in higher blood glucose levels. Insulin resistance is one of the pre-diabetic conditions that can lead to diabetes and metabolic syndromes (Suzuki et al., 1996; Ormazabal et al., 2018). IR is often associated with tuberculosis and is suggested to be a risk factor as well as a potential marker for active tuberculosis (Mao et al., 2011, Yurt et al., 2013). A cross-section cohort study in South Africa showed correlation between TB and IR in newly diagnosed TB patients which gets reverted after successful treatment (Philips et al., 2017). The overall (both male and female) prevalence of IR in this study was 25.4% (Philips et al., 2017). It has been shown that Mtb-infected mice are more susceptible to develop hyperglycaemia and insulin resistance than uninfected mice and this susceptibility is further increased with high-fat diet and age (Oswal et al., 2022). Mtb infection causes dysregulation of lipid metabolism and elevates the levels of circulating free fatty acids which causes ectopic deposition of lipids in organs important for glucose homeostasis like liver and skeletal muscles leading to development of IR (Badin et al., 2011; Oswal et al., 2022). Multiple studies suggest that TB-DM/IR incidents occur with altered lipid metabolism that includes high LDL (low-density lipoprotein) cholesterol, low HDL (high-density lipoprotein) cholesterol, high levels of very low-density lipoprotein (VLDL) triglycerides, resulting in severe clinical manifestation and disease outcome (Vrieling et al., 2018; Shvets et al., 2021). IR was also observed during the early phase of anti-tuberculosis therapy which can be attributed to impaired liver function due to the toxic effect of first-line anti-tuberculosis drugs like isoniazid, rifampicin and pyrazinamide (Shvets et al., 2019). Insulin resistance results in abnormalities in PI3K/Akt pathway causing wasting in muscle tissue which is also observed in tuberculosis patients (Wang et al., 2006; Mupere et al., 2014).

Tuberculosis patients generally have temporal hyperglycaemic conditions. Among the patients that are hyperglycaemic during the start of TB treatment, a high proportion of patients receive a new diabetes diagnosis without prior DM history ( Magee et al., 2018). The incidence of hyperglycaemia in tuberculosis may be attributed to stress, prolonged inflammation, change in the glucose and lipid metabolism of TB patients and insulin resistance syndrome (Guptan and Shah, 2000; Magee et al., 2018; Menon et al., 2020). A clinical study in India suggests that 7% tuberculosis patients had DM and 4.5% patients have IGT or impaired blood glucose tolerance and about 65% of IGT patients could revert to normoglycemic conditions after completion of anti-TB therapy (Krishnappa et al., 2019). There is a study in Periurban South Africa that shows an association between transient hyperglycemia, and TB-DM/TB-IGR (impaired glucose regulation) in newly diagnosed DM patients as well as an association between persistent hyperglycemia and TB-DM in patients with HIV-1, despite TB therapy (Kubjane et al., 2020). A meta-analysis investigation showed that 27.3% TB patients had newly developed hyperglycaemic condition at baseline level and after a follow-up of 3 - 6 months, 50% of the hyperglycaemic conditions remained unresolved (Menon et al., 2020). In a follow-up study in Brazil with HIV-positive TB patients, Moreira et al. (2018) had indicated that hyperglycemia frequently occurs in HIV-infected patients who initiate TB treatment, and it increases the risks of adverse TB outcomes (Moreira et al., 2018). Another screening study for diabetes among TB patients in India showed the prevalence of newly diagnosed diabetes was approximately 10.8% where HbA1c ≥ 47.5 mmol/mol was used for diagnosis of diabetes (Kumpatla et al., 2013). Various studies reveal that the prevalence of hyperglycaemia in tuberculosis patients varies between 10% to 26% which depends on age, sex and fasting blood glucose level (Moreira et al., 2018; Menon et al., 2020; Ephraim et al., 2021). An interesting study indicated that hyperglycaemia is associated with increased risk of patient delay in pulmonary tuberculosis which is a serious concern in the context of diagnosis of TB, increased risk of transmission of TB infection in the community as well as clinical manifestation of TB (Wang et al., 2017). Liver toxicity during tuberculosis is often associated with the first line anti-TB drugs which increase hepatic enzyme levels and may be responsible for hyperglycemia in diabetic patients (Molla et al., 2021). TB-DM and TB patients have high levels of liver enzymes compared to normal (Sama et al., 2017). The hyperglycemic response against anti-TB drugs like rifampicin may enhance the requirement for insulin in type 1 diabetes patients (Atkin et al., 1993). Thus, rifampicin disturbs glycemic control in both type 1 and type 2 diabetes.

Inflammation is critical for controlling infection and a dysregulation inflammatory response is central to pathogenesis of several pathogens including tuberculosis. The ability of M. tuberculosis to modulate the fundamental inflammatory processes such as recruitment of immune cells to the site of infection, prodcution of pro-inflammatory cytokines, production of eicosanoids and lipid mediators associated with inflammation favors its survival inside the host (Kaufmann and Dorhoi, 2013). Inflammation during active tuberculosis results in an environment with higher pro-inflammatory cytokine production as a protective response in host against the bacilli. Inflammation is nonresolving in nature in both active and latent tuberculosis (Kaufmann and Dorhoi, 2013), characterized by elevated levels of pro-inflammatory cytokines (He et al., 2020) which often lead to metabolic dysregulation and eventually type 2 diabetes (Spranger et al., 2003; Das and Mukhopadhyay, 2011; Tsalamandris et al., 2019). On the other hand, the hyperglycaemic environment often results in dysfunction of the immune system like inhibition of leukocyte recruitment, damage to the neutrophil function, macrophage dysfunction, depression of the antioxidant system and humoral immunity as well as modulation of inflammatory signaling cascades causing the DM patients to be susceptible to various infections (Casqueiro et al., 2012; Berbudi et al., 2020).

Co-incidence of pulmonary TB with pre-diabetes causes elevated type-I, type-II, and Th17 cytokine responses with higher circulating levels of interferon-gamma (IFN-γ), IFN-β, tumor necrosis factor-alpha (TNF-α), interleukin (IL)-2, IL-5, IL-17A, IL-17F, IL-10, IL-1β, IFN-β, transforming growth factor-β (TGF-β) and Granulocyte-macrophage colony-stimulating factor (GM-CSF), however, no significant correlation was observed between Mtb bacterial burden and cytokine levels (Kumar et al., 2014).

Toll-like receptors (TLRs) are members of the innate immunity that works as pathogen-associated molecular pattern (PAMP) receptors and play a crucial role in eliciting innate immune response which dictate subsequent adaptive immune responses (Akira and Takeda, 2004). Activation of TLRs usually triggers a signaling cascade which results in the production of pro-inflammatory cytokines/chemokines through nuclear factor kappa B (NF-κB) (Udgata et al., 2019). Several mycobacterial components are recognized by TLR2 and TLR4 (Means et al., 1999; Heldwein and Fenton, 2002). Several lines of evidences point to a role of TLRs in the development of insulin resistance and diabetes. Among the TLRs, TLR2 and TLR4 expression have been shown to be increased in conventional insulin resistance target tissues like skeletal muscle and adipose tissue of type 2 diabetic subjects (Creely et al., 2007; Reyna et al., 2008). Song et al. (2006) showed that TLR4 triggering leads to NF-κB activation and expression of TNF-α, IL-6, and resistin which have been implicated for the development of insulin resistance in adipocytes. Type 2 diabetic subjects were found to have significantly increased TLR2, TLR4 mRNA, and protein in monocytes and increased TLR2 and TLR4 expression was correlated with BMI, homeostasis model assessment–insulin resistance (HOMA-IR), glucose, A1C, Nϵ-(carboxymethyl) lysine (CML), and free fatty acid (FFA) (Dasu et al., 2010). Nonetheless, the expression levels of TLR2 were found to be upregulated in obese individuals who are at higher risk of development of insulin resistance as obese type 2 diabetes patients had higher expressions of TLR2 in comparison to obese patients without type 2 diabetes (Ahmad et al., 2012).

Interestingly, signaling through TLR2 can elicit both pro- and anti-inflammatory response depending on the nature and site of interaction with its ligand on the leucine rich repeat (LRR) motif present on the ectodomain of TLR molecule (Udgata et al., 2019). It has been found that a member of the PPE family of Mycobacterium tuberculosis, PPE18 interact with LRR 11~15 on TLR2 ectodomain and induces IL-10 production from macrophages and elicits anti-inflammatory responses (Nair et al., 2009). In contrast, PPE17 protein of Mtb was found to specifically interact with TLR2 LRR 15~20 domain to activate NF-κB and induced pro-inflammatory-type signaling (Bhat et al., 2012). Also, it has been shown that the cellular localization of heat shock protein 60 of Mtb (Mtbhsp60) upon interaction with TLR4 can dictate the inflammatory responses in macrophages (Parveen et al., 2013). Thus, there is a possibility of induction of insulin resistance by Mtb using PPE17/Mtbhsp60 by targeting the TLR-NF-κB-triggered signaling cascades. Interestingly, it has been shown that Mycobacterium sp. utilizes TLR2 to promote inflammation (Kanagawa et al., 2015). Mycobacterial secretory protein MTP53 (Rv2878c), a disulphide bond-like forming protein also induces TGF-β-activated kinase 1-mediated pro-inflammatory cytokine response during Mtb infection (Wang et al., 2019; Pal et al., 2022). Some lipases of Mtb can also trigger inflammatory responses and modulate immune responses (Rameshwaram et al., 2018). For example, Rv0183 is involved in triggering MyD88-NF-κB signaling and induction of inflammatory molecules like IL-6, TLR2, TLR6 and TNF-α (Xu et al., 2010). Another lipase LipC can hydrolyze short-chain esters and elicits cytokines/chemokines induction (Shen et al., 2012). The lipases have an adverse effect on patients, as they cause the production of inflammatory cytokines as well as generates excess free fatty acids/lipid mediators. Excess free fatty acids get deposited in tissues important for glucose homeostasis like liver and muscle to cause systemic insulin resistance that may lead to insulin resistance (Martinez et al., 2019).

Inflammation also plays a key role in the development of insulin resistance and T2D during obesity as deletion of jun kinase 1 (JNK1, a key negative regulator of insulin sensitivity in the obese state) in the nonhematopoietic compartment protects mice against HFD-induced insulin resistance and T2D by inhibiting HFD-induced inflammation (Solinas et al, 2007; Das and Mukhopadhyay, 2011). Inflammation changes the expression of key genes of adipose tissue including SREBP-1, Resistin, RANTES, leptin, and adiponectin involved in glucose homeostasis. The sterol regulatory element binding protein-1 (SREBP-1) regulates genes that are involved in fatty acid synthesis and lipogenesis during inflammation. TNF-α completely blocks SREBP-1 expression and its activation (Sewter et al., 2002; Das and Mukhopadhyay, 2011). Resistin also links to inflammation and higher resistin levels were observed in tuberculosis and T2D patients (Youn et al., 2004; Gharibeh et al., 2010; Das and Mukhopadhyay, 2011; Moideen et al., 2018). Resistin activates pro-inflammatory cytokines like IL-12 and TNF-α through the NF-κB-dependent pathway in mouse and human macrophages and is directly correlated to glucose homeostasis (Asensio et al., 2004; Silswal et al., 2005). RANTES also known as CCL5 is an adipokine secreted by adipocytes and involved in the recruitment of macrophages, T cells, eosinophils, and basophils (Appay and Rowland-Jones, 2001; Keophiphath et al., 2010) and cause inflammation. RANTES also impaired glucose-induced insulin secretion in mice by reducing the glucose-dependent secretion of glucagon-like peptides (Pais et al., 2014). RANTES is also involved in insulin responsiveness through CCR5, which regulates insulin signaling in the hypothalamus and contributes to systemic insulin sensitivity and glucose metabolism (Chou et al., 2016).

Adipose tissue functions as an endocrine organ by regulating metabolism and inflammation through secretion of adipokines, cytokines, peptides, and release of free fatty acids. Reports indicate that adipose tissue inflammation is consistently associated with excess fat mass and insulin resistance and development of type 2 diabetes (Guilherme et al., 2008; Burhans et al., 2019). Mtb infection in adipose tissue causes adipocyte hypertrophy, lipolysis, alterations in metabolic processes, and infiltration of immune cells (Ayyappan et al., 2019). Hypertrophic or enlarged adipocytes are characterized by altered secretion patterns of adipokines, as well as secretion of higher levels of pro-inflammatory cytokine like TNF-α and MCP-1, which not only impair insulin signaling in the skeletal muscle and liver but also induce systemic insulin resistance (Guilherme et al., 2008). Adipose tissue produces chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) and leptin which are strongly associated with inflammation. The adipokine MCP-1 promotes inflammation and diabetic nephropathy (Tesch, 2008). MCP-1 production is higher in adipose tissue and CD14⁺ monocytes in TB patients. MCP-1 is a potent pro-inflammatory molecule that plays a critical role in inducing inflammatory response during TB by attracting monocytes and T lymphocyte (Lin et al., 1998; Martinez et al., 2019). MCP-1 overexpression causes insulin resistance in adipose tissue and steatosis in the liver during obesity. Mtb-infected visceral adipose tissue has increased MCP-1 expression which alters adipocyte function (Erol, 2008). It is suggested that MCP-1 probably induces adipocyte dedifferentiation and adds to pathologies associated with hyperinsulinemia, insulin resistance and obesity, including type 2 diabetes (Sartipy and Loskutoff, 2003; Erol, 2008; Panee, 2012). Interestingly, it has been noted that addition of MCP-1 to differentiated adipocytes in vitro results in downregulation of insulin-stimulated glucose uptake as well as expression of various genes like LpL, adipsin, GLUT-4, aP2, beta3-adrenergic receptor and peroxisome proliferator-activated receptor gamma (PPAR-γ) (Sartipy and Loskutoff, 2003).

Mtb-infected adipose tissue recruits myeloid and NK-cell lineage which produce higher levels of TNF-α, IL-12 and other inflammatory molecules (Erol, 2008; Beigier-Bompadre et al., 2017). TNF-α binds to TNFR on adipocytes and increase production of intracellular cAMP that activates protein kinase A-induced lipolysis and generates free fatty acids (Zhang et al., 2002; Song et al., 2006). The lipolytic activity of TNF-α is shown to be influenced by glucose in adipocytes (Green et al., 2004). The increased free fatty acids released by the adipocytes are ectopically deposited in various organs like liver, skeletal muscles, pancreas and gastrointestinal tract causing lipotoxicity (Sears and Perry, 2015). In liver, free fatty acid increases TAG formation/accumulation (liver steatosis), increase hepatic glucose production (increased gluconeogenesis and glucogenolysis) and insulin resistance leading to hyperglycemia (Boden, 2003; Sears and Perry, 2015). Free fatty acid accumulation in skeletal muscles inhibit glucose uptake, reduce fatty acid oxidation and reduce insulin sensitivity which, results in insulin resistance (Delarue and Magnan, 2007; Lyons et al., 2016). The physiological changes and modulation in the signaling cascades in the adipose tissue during Mtb infection that can lead to insulin resistance is described in Figure 1 .

Mycobacterium tuberculosis can activate macrophages through various mechanisms like binding of pathogen associated molecular patterns (PAMPs) to the Toll like receptors (TLRs) present on the macrophages to induce production of pro-inflammatory cytokines (Dolasia et al., 2018), production of reactive oxygen species (ROS) by NADPH oxidase complex and reactive nitrogen intermediates (RNI) (Nathan and Shiloh, 2000), modulation of signaling pathways such as MAPK, NF-κB pathway (Cambier et al., 2014; Mayer-Barber and Sher, 2015). These activated macrophages can secrete various pro-inflammatory cytokines like TNF-α, IL-6 (Lumeng and Saltiel, 2011) which can lead to extensive remodeling of the adipose tissue (Sun et al., 2011; Hotamisiligil, 2017). One mechanism by which macrophage activation may contribute to adipocyte hypertrophy is through the secretion of matrix metalloproteinases (MMPs) which degrade extracellular matrix components, allowing adipocytes to expand in size (Lijnen et al., 2002). Macrophages can secrete MMPs, particularly MM2 and MMP-9, in response to M. tuberculosis infection (Quiding-Järbrink et al., 2001). On the other hand, levels of adipokines like resistin were found to be increased in pulmonary TB patients (Chang et al., 2013). Resistin is known to increase lipolysis in the visceral adipose tissue (Chen et al., 2014) by increasing expression of hormone sensitive lipase (HSL) leading to increased levels of serum free fatty acids (Qatanani et al., 2009) which cause a positive feedback loop that may contributes to the development of adipocyte hypertrophy (Pérez-Torres et al., 2019).Leptin is another important adipose-derived hormone, which regulates food intake and body weight, and is expressed by adipocytes of white adipose tissue (Kelesidis et al., 2010). Lower body fat and wasting in TB patients is probably associated with lower serum leptin concentrations and a gradual increase in leptin levels is observed post-TB treatment (vanCrevel et al., 2002). Also prolonged inflammation during tuberculosis may be responsible for decreased leptin production (vanCrevel et al., 2002). Leptin deficiency is shown to cause severe insulin resistance and related endocrine disorders in uncontrolled insulin-deficient diabetes (German et al., 2010).

Lipids and their mediators are important components of innate immunity against M. tuberculosis (Chen et al., 2008). The modulation in lipid profile can cause atherosclerosis, insulin resistance (Laakso et al., 1990) and other cardiovascular diseases (Dong et al., 2021). Mtb persists inside adipose tissue and alters its metabolic properties to modulate fatty acid metabolism (Neyrolles et al., 2006; Erol, 2008). Lipolysis in adipose tissue is another effect of tuberculosis that causes generation of low HDL and higher levels of total cholesterol, LDL, very low-density lipoprotein and non-esterified serum free fatty acids (NEFA) (Vrieling et al., 2018; Ayyappan et al., 2019). High serum triglyceride levels and free fatty acids result in the deposition of lipid granules in various organs, that is known to inhibit insulin-associated signaling cascades resulting in insulin resistance (Boden and Shulman, 2002; Xin et al., 2019). Lipid profile abnormalities and an increased risk of diabetes were observed in multidrug-resistant (MDR) TB patients (Biranu et al., 2021). Lipid mediator, lipoxin and leukotriene derived from arachidonic acid is associated with Mtb susceptibility and disease pathogenicity (Mayer-Barber and Sher, 2015). Interestingly, it has been observed that leukotriene B4 plays a central role in systemic inflammation and establishment of insulin resistance in animal model of diabetes (Li et al., 2015). Secretory mycobacterial lipase Rv0183 is shown to be involved in degradation of lipid bodies present in adipocyte or foamy macrophages causing generation of free fatty acids which may be responsible for metabolic syndrome during tuberculosis (Erol, 2008; Dhouib et al., 2010; Dedieu et al., 2013).

Persistent chronic inflammation is considered one of the major risk factors for development of cardiovascular diseases (Ferrucci and Fabbri, 2018) and systemic inflammation levels have been associated with sputum bacterial load (Mesquita et al., 2016). Interestingly, tuberculosis and cardiovascular diseases were found to have a close epidemiological connection (Huaman et al., 2015). It has been found that granuloma formation during tuberculosis can cause coronary arteritis leading to myocardial infarction (Rodríguez et al., 2012). In addition, production of pro-inflammatory cytokines by activated macrophages and CD4⁺ T cells can also contribute to development of cardiovascular complications (Huaman et al., 2015). The hallmarks of atherosclerosis are LDL oxidation, foam cell formation and inflammation (Chistiakov et al., 2017). Tuberculosis patients have been shown to have higher susceptibility to LDL oxidation and lipid peroxidation (Nezami et al., 2011) leading to formation of foam cell macrophages (Agarwal et al., 2021) which have been implicated to play a role in the development of TB granulomas and persisting Mtb infection. Diabetes is also often associated with dyslipidemia characterized by increased VLDL, LDL-cholesterol (LDL-C) and decreased high-density lipoprotein cholesterol (HDL-C) (Schofield et al., 2016) and the levels of oxidized LDL (oxLDL) were found to be significantly higher in diabetic patients (Banerjee et al., 2019). Uptake of oxLDL mediated by scavenger receptor CD36 accounts for a large proportion of the formation of macrophage foam cells and formation of atherosclerotic plaques (Luo et al., 2017). Furthermore, patients with concurrent TB and diabetes have been shown to have pro-atherogenic plasma lipid profile with significantly elevated levels of sphingomyelins and remnant-like lipoprotein particles (Vrieling et al., 2018). Therefore, M. tuberculosis infection and diabetes can independently contribute to the development of atherosclerosis.

Mtb proteins can affect host glucose and lipid metabolism to create a favourable condition for the survival of the bacilli. It is reported that pre-diabetic condition is favourable for survival of Mtb bacilli (Sinha et al., 2021). Some Mtb proteins are shown to modulate host metabolism to induce a favourable niche. For example, ESAT-6 protein of Mtb induces GLUT-1-mediated glucose uptake in macrophages which perturbs glycolytic pathway and causes foamy macrophages formation (Singh et al., 2015). Interestingly, Mtb-infected macrophages have increased glucose uptake, upregulated expression of glycolytic enzymes and downregulated levels of enzymes of tricarboxylic cycle and oxidative phosphorylation which results in lactate production causing the Warburg effect. (Shi et al., 2015; Howard and Khader, 2020). This results in decreased rate of mitochondrial respiration which causes inflammation in macrophages and adipocytes which is likely to further contribute to subsequent systemic insulin resistance (Wang et al., 2020). Mtb can utilize lactate with L-lactate dehydrogenase gene, lldD2 (Rv1872c) and facilitate its intracellular survival. It has been shown that lldD2 knock-out Mtb fails to efficiently replicate in human macrophages (Billig et al., 2017). The tuberculosis necrotizing toxin (TNT) of Mtb hydrolyses NAD⁺ and causes generation of reactive oxygen species (ROS) which is a risk factor for type 2 DM (Pajuelo et al., 2020). In M1-polarized macrophages, the TLR/PRR-triggered signaling causes NF-κB-induced inflammation and production of hypoxia mediated factor-1α (HIF-1α) (Corcoran and O'Neill, 2016; Dorrington and Fraser, 2019). HIF-1α induces lipid body formation, upregulation of glycolytic genes and inflammatory mediator like IL-1β (Howard and Khader, 2020). Increased glycolysis causes pyruvate production which is transported into the mitochondria and forms 3 hydroxybutyrate and enters into tricarboxylic acid (TCA) cycle and causes accumulation of citrate which is transported to cytosol. Citrate stabilizes HIF-1α and is converted to Acetyl-CoA which fed into fatty acid biosynthesis. The acyl-CoA synthase long-chain family members, mainly ACSL1 and ACSL4 introduce long chain fatty acid especially arachidonic acid into membrane phospholipid (Shi et al., 2019). Cytosolic phospholipase A2 (cPLA2) release arachidonic acid from membrane phospholipids. Arachidonic acid gives rise to prostaglandin and leukotrienes which are responsible factors of inflammation. Mtb also secretes lipases that are involved in formation of lipid droplets which are risk factors for DM (Rameshwaram et al., 2018). For example, Rv2672c exhibits both lipase and proteinase activity (Singh et al., 2017). The other secretory mycobacterial Rv1083 protein is a monoacylglycerol lipase which is involved in metabolizing the host cell membrane lipids (Saravanan et al., 2012). Mtb Rv0183 produces glycerol and free fatty acids which further causes metabolic perturbations (Grininger et al., 2021). Rv1076 is another Mtb secretory esterase that hydrolyzes short carbon chain substrate (Kaur et al., 2017; Li et al., 2017). Other secretary enzymes like Rv1984c hydrolyzes medium chain carboxylic esters and monoacylglycerol whereas Rv3452 is a phospholipase A2 (Schué et al., 2010). Intracellular Mtb in macrophages can utilize host amino acids directly from cytosol for biosynthesis of its proteins (Borah et al., 2019). The metabolic reprogramming and wasting syndrome during tuberculosis follow conserved mechanism in human patients, mice and zebrafish. The concentration of circulating small amino acids is lower in human patients as well as mycobacterium-infected mice and zebrafish (Ding et al., 2020). Circulating amino acids like histidine, tryptophan, methionine, and glutamine are significantly decreased in TB patients but in case of TB-DM, other amino acids like choline, glycine, serine, threonine levels are also lower as compared to patients with TB alone (Weiner et al., 2012; Weiner et al., 2018; Vrieling et al., 2019). Histidine, glutamine (and the (E,E)-isomer of bilirubin) are shown to be negatively associated with development of type 2 diabetes and histidine-mediated suppression of hepatic glucose production is a potential target for the treatment of type 2 diabetes (Kimura et al., 2013; Peddinti et al., 2017). TNF-α secreted during Mtb infection also plays a major role to promote lipid droplet formation (Guerrini et al., 2018; Jung et al., 2020). The alteration of host metabolic processes during infection with Mtb is described in Figure 2 .

In conclusion, active TB itself can induce various immune-metabolic changes like increased inflammation, adipose tissue modulation, increased free fatty acid levels leading to development of insulin resistance in patients that can lead to development of type 2 diabetes if not managed clinically. Irregular lipolysis in adipose tissue, altered glucose and lipid metabolism in adipose tissue and other organs including lungs due to increased accumulation of intracellular lipids as well as inflammatory milieu around the adipose tissue are possible reasons for development of IR during tuberculosis (Oswal et al., 2022). However, further studies are needed to find out the exact molecular mechanism of development of IR in TB patients. Prolonged hyperglycaemia can be considered as a risk factor for DM and cardiovascular diseases. The host immune response to active TB disease results in a prolonged state of systemic inflammation characterized by activation of various immune cells by binding with PAMPs through the TLRs resulting in elevated levels of pro-inflammatory cytokines like IL-1β and IL-6 which are known to directly inhibit insulin-stimulated glucose uptake and thus implicated in the etiology of type 2 diabetes. Various proteins/lipases of Mtb are involved in the activation of immune cells and thus involved in triggering inflammatory responses in the host. Modulation of adipose tissue signaling during tuberculosis may be one of the reasons of metabolic disorder and pre-diabetic conditions during tuberculosis. Adipose tissue infection by Mtb causes tissue inflammation, immune cell infiltration and modulation of adipokine secretion which altogether may be involved in generation of pre-diabetic conditions. Loss of adipose tissue due to increased lipolysis during tuberculosis leads to release of free fatty acids which in turn disrupts insulin signaling pathway in skeletal muscles and can cause systemic insulin resistance. Various Mtb proteins are responsible for host metabolic perturbation and modulation of lipid metabolism. Again, reduction in circulating amino acid levels like histidine, tryptophan, methionine and glutamine may diminish host capacity to resists pre-diabetic changes. A detail study on the molecular mechanisms by which M. tuberculosis disrupts host glucose homeostasis and understanding the signaling cascades is important to develop appropriate therapeutics to tackle hyperglycemic condition during TB.