Introduction

The worldwide co-epidemic of tuberculosis (TB) and diabetes mellitus (DM) is still a global health concern. Metformin (MTF) is an approved drug for the treatment of type 2 DM. Recent literature has shown the benefits of MTF in TB patients, as well as in its prevention. As our knowledge in this field keeps progressing, we here provide a comprehensive overview on the multiple effects this drug has on the host (at various levels), and in the mycobacteria.

Tuberculosis in the diabetic patient

TB continues to be one of the world’s most costly and deadly infectious diseases, with almost 25% of the human population currently infected with either latent or active TB [1]. Although the disease burden by TB has been declining, this has not occurred fast enough [2]. Type 2 DM is a complicated metabolic disorder characterized by hyperglycemia and glucose intolerance. There are many comorbidities associated with DM; one in particular is an increased risk for developing an active TB [3] and TB recurrence after preventive treatment [4]. With DM recognized as a worldwide epidemic, and TB affecting one-third of the world population, efforts in controlling both diseases appear as urgent global priorities.

Diabetic patients have a much more likelihood of developing more severe forms of TB and worsened TB outcomes after treatment [5]. TB also hinders proper glycemic control [6]. Atypical clinical presentations of TB in the diabetic patient [7, 8], along with impaired drug clearance [9], an increased risk of drug resistance, lower exposure to anti-tuberculosis drugs, treatment failure, and recurrent TB, make diagnosis and treatment challenging.

A recent cross-sectional study aimed to study the prevalence of latent TB in DM patients found that not only this was close to 30%, but that age > 60 years, any comorbidity and ischemic heart disease were associated with latent TB, while the use of MTF was inversely correlated with it [10].

Metformin in anti-tuberculous treatment

Derived from the legume Galega officinalis, MTF is an insulin sensitizer medication that is used predominantly in the treatment of type 2 DM [11]. MTF exerts its primary effect at the molecular level as a reversible inhibitor of nicotinamide dinucleotide (NADH) dehydrogenase activity of the respiratory chain, resulting in suppression of ATP production [12, 13]. AMP-activated protein kinase is one of the key molecules by which MTF exerts its pleiotropic effects [14].

MTF is the first drug of choice for lowering glucose in diabetic patients with tuberculosis. It lacks clinically meaningful interactions with rifampicin, does not have a risk of hypoglycemia, and provides important cardiovascular benefits [15].

Fairly recent epidemiological studies have shown that MTF decreases the risk of developing active TB. In a nationwide study from Taiwan, this decreased risk was directly proportional to the MTF dosages in a comparison group of low versus high users [16]. A large retrospective cohort, also from Taiwan, showed that MTF use was associated with a reduced risk of developing TB in a dose pattern in patients with type 2 DM [17]. A large 12-year longitudinal cohort study, also from Taiwan, found that MTF use was an independent factor for predicting a reduced risk of active TB, after adjusting for comorbidities, diabetes complications, oral anti-diabetic therapy type and statin use [18].

A few studies on the usefulness of MTF in anti-TB therapy have recently been published (Table 1). A case–control study from India found that poor glycemic control is a risk factor for TB occurrence, and MTF has a protective effect against TB in diabetic patients [19]. A retrospective study from China sought to investigate whether MTF exhibited more efficacy in combination with anti-TB regimens for DM-TB patients and found a higher proportion of treatment success in the MTF group, as well as lower relapse rates as compared to the non-metformin group [20]. Two studies from Indonesia have shown that adding MTF to the intensive phase of anti-TB therapy leads to sputum smear reversion [21, 22]. A smaller retrospective study from South Korea did not find an effect of MET on sputum culture conversion or recurrence after 1 year, but found improvement in the sputum conversion rate in patients with cavitary pulmonary TB [23]. Most importantly, MTF may reduce mortality in diabetic patients. A retrospective cohort study from Taiwan showed that DM poses an increased risk of adverse TB treatment outcomes and MTF can reverse mortality related with DM during TB therapy [24].

Table 1 Metformin in anti-tuberculous therapy
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Anti-TB drugs, however, can alter MTF levels. Rifampicin increases MTF systemic exposure, possibly by increased absorption [25], without affecting its glucose-lowering efficacy [26].

Metformin against drug-resistant Mtb

Despite global efforts to control TB, the World Health Organization has estimated that 4.1% of new and 19% of previously treated TB cases in the world have rifampicin or multidrug-resistant TB [27]. Studies in a mouse model of TB have shown that MTF decreases the bacillary load in vivo, reducing also lung tissue pathology [28]. It seems that MTF inhibits intracellular growth of mycobacteria by inducing mitochondrial reactive oxygen species (ROS) [28].

As mentioned above, MTF is an inhibitor of mitochondrial complex I [29]. This respiratory chain complex is similar to bacterial NADH dehydrogenase NDH-1 complex used by persister Mycobacterium tuberculosis (Mtb) phenotypes [30]. Bacterial persistence has been proposed as one of the mechanisms leading to antibiotic resistance [31] (Fig. 1). MTF could be potentially used as a combination drug with existing anti-tuberculous therapy [32]. Such adjunct therapy may even be utilized in non-diabetic individuals [33], targeting drug-tolerant Mtb [30, 34]. MTF increases reactive oxygen species and facilitates phago-lysosome fusion leading to control of growth rates of drug-resistant Mtb [28]. Inhibition of the latter is a main mechanism by which Mtb survives within macrophages [35].

Fig. 1
figure 1

Metformin effects in mitochondria and mycobacteria. a Electron transport chain in a eukaryotic cell mitochondria. Metformin exerts its primary effect at the molecular level as a reversible inhibitor of NADH dehydrogenase activity of the respiratory chain, resulting in the suppression of ATP production. I complex I (NADH dehydrogenase), II complex II (succinate dehydrogenase), Q ubiquinone, III complex III (cytochrome bc1 complex), Cyt C cytochrome c, IV complex IV (cytochrome c oxidase). Orange arrows indicate electron flow. bM. tuberculosis cell membrane, including the electron transport chain. NDH1 complex I (NADH dehydrogenase), NADH nicotinamide adenine dinucleotide (reduced), NDH1 NADH dehydrogenase 1, SDH succinate dehydrogenase, MK menaquinone, Cyt C cytochrome c. Orange arrows indicate electron flow

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Metformin in the immune response to Mtb

DM may increase the susceptibility for pulmonary TB via multiple mechanisms. Those directly related to hyperglycemia and cellular insulinopenia and the indirect effect on macrophages and lymphocytes function, lead to diminished ability to contain Mtb [36]. Monocytes and macrophages play an important role in TB immunopathogenesis [37]. DM is known to affect chemotaxis, phagocytosis, activation and antigen presentation by phagocytes in response to TB [38].

MTF increases human peripheral mononuclear cell PBMC phagocytosis of zymosan particles, with decreased cytokine production upon stimulation of Mtb lysates in vitro [39]. Despite lowering the production of inflammatory cytokines, TNF-α, IFN-γ, and IL-1β ex vivo, MTF enhances innate host defense pathways in human leukocytes, such as ROS generation [39]. AKT and mTOR are central metabolic regulators, known to influence cytokine production. MTF regulates the AKT–mTOR pathway in PBMCs in healthy volunteers [39]. In humans, MTF also downregulates type I IFN pathways [39], which are known to be associated with active TB [40]. Type I IFNs interfere with IFN-γ-mediated activation of macrophages [41, 42]. IFN-γ is in fact an indicator of successful anti-TB treatment. MTF administered along with insulin in DM patients with TB for 2 months increased their IFN-γ levels [21].

It was suggested that MTF has anti-inflammatory effects that are independent of its glucose-lowering effect [43]. Soluble(s) forms of CD14 and CD163 are inflammatory markers in monocytes [44, 45] and for macrophage polarization, and they show a positive relationship with HbA1c levels [46]. These two markers, along with inflammatory C-reactive protein, decrease in TB-DM patients with MTF-containing treatment regimens [46].

Matrix metalloproteinases (MMPs) are key mediators in the pathology of TB [47]. Systemic levels of MMP-1, -2, -3, -7, -10, and -12 are significantly higher in TB-DM patients compared to TB alone or healthy controls, with the levels of MMP-1, - 2, - 3 and - 8 showing a positive relationship with bacterial burden and HbA1c levels at baseline [48]. Standard anti-TB therapy is associated with a significant reduction in the levels of MMP-1, -2, -3, -8 and -13 post-treatment [48]. Patients known to be diabetic before incident TB on MTF treatment exhibited significantly lower levels of MMP-1, -2, -3, -7, - 9 and -12 at baseline and of MMP-7 post-treatment [48]. These results suggest a protective effect of metformin in TB-DM with possible implications for its use in TB without DBM.

Conclusions

For more than half a century, MTF has proven itself as the first defense against insulin-resistant morbidities. MTF can modify the function of different biological pathways, improving the outcome of anti-TB therapy in Mtb-infected DM patients. Increasing evidences suggest that MTF participates with beneficial effects on cellular metabolic mechanisms, immune functions that are part of the innate responses to M. tuberculosis and gene transcription in Mtb itself (Fig. 2). Further research is needed to have a more complete understanding of the role of MTF in patients with DM and active TB infection. Studies should also evaluate any beneficial effect of incorporating MTF as adjunct anti-TB therapy in non-diabetic individuals [33], as well as in targeting drug-tolerant Mtb infection [30, 34].

Fig. 2
figure 2

The multiple actions of metformin in tuberculosis. Diagram showing the effects of metformin on hyperglycemia, type I interferon (IFN) downregulation, Mtb phagosomal persistence, oxidative chains, inflammatory matrix metalloproteinases (MMPs), in phago-lysosome (PL) fusion

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