Metformin induced autophagy in diabetes mellitus – Tuberculosis co-infection patients: A case study

Novita, Bernadette Dian; Ali, Mulyohadi; Pranoto, Agung; Soediono, Endang Isbandiati; Mertaniasih, Ni Made

doi:10.1016/j.ijtb.2018.04.003

Cited by 20 publications

(33 citation statements)

References 31 publications

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“…Benefits of MET were observed by Srujitha et al (2017) who observed a protective role of MET against TB infection and showed that lack of glycemic control is a hazard for TB incidence. Additional benefits of MET such as reduced rates of TB infection (Lee et al, 2018) and increased sputum culture conversion in those with higher bacillary burden (Degner et al, 2018;Novita et al, 2019) have also been observed.…”

Section: Effect Of Metformin On Tuberculosis Outcomesmentioning

confidence: 99%

“…The ratio of monocytes, the precursor cells for macrophages, to lymphocytes was increased in peripheral blood (Lachmandas et al, 2019). MET was observed to modulate the host's innate immune response (Singhal et al, 2014;Lachmandas et al, 2019;Novita et al, 2019), including MET-induced increases in whole-blood reactive oxygen species FIGURE 2 | The effect of metformin on macrophage function and clinical outcomes. Studies labeled A, C, F, G, H, I, and J represent the effect of metformin on respective clinical outcomes.…”

Section: Metformin Effect On the Immune Response To M Tuberculosismentioning

confidence: 99%

“…Arai et al (2010) identified an underlying mechanism of MET inhibition of tumor necrosis factor (TNF) production and transcription factor expression by the ability of MET to inhibit TNF and tissue factor production with the addition of the stimulant lipopolysaccharide (LPS) or oxidized low-density lipoprotein (Lachmandas et al, 2019). Novita et al (2019) measured levels of microtubule-associated Protein 1 light chain 3B (MAP1LC3B), superoxide dismutase (SOD), and interferon in a small group of 22 patients with both TB and T2D. This group observed an increased MAP1LC3B, SOD, and interferon before and after MET treatment (Novita et al, 2019).…”

Section: Metformin Effect On the Immune Response To M Tuberculosismentioning

confidence: 99%

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Metformin as Host-Directed Therapy for TB Treatment: Scoping Review

2020

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Tuberculosis (TB) disease is an international health concern caused by the bacteria Mycobacterium tuberculosis (Mtb). Evolution of multi-drug-resistant strains may cause bacterial persistence, rendering existing antibiotics ineffective. Hence, development of new or repurposing of currently approved drugs to fight Mtb in combination with existing antibiotics is urgently needed to cure TB which is refractory to current therapy. The shortening of TB therapy and reduction in lung injury can be achieved using adjunctive host-directed therapies. There is a wide range of probable candidates which include numerous agents permitted for the treatment of other diseases. One potential candidate is metformin, a Food and Drug Administration (FDA)-approved drug used to treat type 2 diabetes mellitus (DM). However, there is a scarcity of evidence supporting the biological basis for the effect of metformin as a host-directed therapy for TB. This scoping review summarizes the current body of evidence and outlines scientific gaps that need to be addressed in determining the potential role of metformin as a host-directed therapy.

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Section: Effect Of Metformin On Tuberculosis Outcomesmentioning

confidence: 99%

Section: Metformin Effect On the Immune Response To M Tuberculosismentioning

confidence: 99%

Section: Metformin Effect On the Immune Response To M Tuberculosismentioning

confidence: 99%

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Metformin as Host-Directed Therapy for TB Treatment: Scoping Review

2020

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“…The proton pump inhibitor, pantoprazole, was tolerable when combined with doxorubicin in solid tumors (Brana et al, 2014) (Mandrioli et al, 2018) Pantoprazole Inhibition Inhibition of H+/K + ATPase proton pumps in membranes of intracellular endosomes and increase of endosomal pH, resulting in inhibition of autophagosome maturation. (Marino et al, 2010) Metformin Activation Activation of AMPK, a sensor of cellular energy levels (increased AMP/ATP ratio) in the cell (Novita et al, 2019) Ricolinostat (ACY-1215) Inhibition Selective inhibition of HDAC6, which mediates trafficking of ubiquitinated misfolded proteins to the aggresome/autophagy pathway. (Vogl et al, 2017) Vorinostat (suberoylanilide hydroxamic acid; SAHA) Activation Pan-HDAC inhibitor; inhibition of mTOR, which results in the dephosphorylation, and thus activation, of the autophagic protein kinase ULK1 and increases LC3 expression.…”

Section: Cancermentioning

confidence: 99%

“…The mycobacterium tuberculosis virulence is associated with perturbations in the autophagy process and AMPK signaling. Novita et al showed that metformin enhances the bactericidal effect of anti-tuberculosis treatment via autophagy in patients with tuberculosis and diabetes (Novita et al, 2019). Another study was designed to assess the effect of metformin by means of a detailed autophagy biomarker panel in tuberculosis (Padmapriyadarsini et al, 2019).…”

Section: Infectious Diseasesmentioning

confidence: 99%

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

2020

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Autophagy is a highly conserved multistep process and functions as passage for degrading and recycling protein aggregates and defective organelles in eukaryotic cells. Based on the nature of these materials, their size and degradation rate, four types of autophagy have been described, i.e. chaperone mediated autophagy, microautophagy, macroautophagy, and selective autophagy. One of the major regulators of this process is mTOR, which inhibits the downstream pathway of autophagy following the activation of its complex 1 (mTORC1). Alkylphosphocholine (APC) derivatives represent a novel class of antineoplastic agents that inhibit the serine-threonine kinase Akt (i.e. protein kinase B), which mediates cell survival and cause cell cycle arrest. They induce autophagy through inhibition of the Akt/mTOR cascade. They interfere with phospholipid turnover and thus modify signaling chains, which start from the cell membrane and modulate PI3K/Akt/ mTOR, Ras-Raf-MAPK/ERK and SAPK/JNK pathways. APCs include miltefosine, perifosine, and erufosine, which represent the first-, second-and third generation of this class, respectively. In a high fraction of human cancers, constitutively active oncoprotein Akt1 suppresses autophagy in vitro and in vivo. mTOR is a downstream target for Akt, the activation of which suppresses autophagy. However, treatment with APC derivatives will lead to dephosphorylation (hence deactivation) of mTOR and thus induces autophagy. Autophagy is a double-edged sword and may result in chemotherapeutic resistance as well as cancer cell death when apoptotic pathways are inactive. APCs display differential autophagy induction capabilities in different cancer cell types. Therefore, autophagy-dependent cellular responses need to be well understood in order to improve the chemotherapeutic outcome.

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Metformin promotes smear conversion in tuberculosis‐diabetes comorbidity and construction of prediction models

Wang

Zhou

Chen

et al. 2022

Clinical Laboratory Analysis

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Background The comorbidity of tuberculosis (TB) and diabetes mellitus (DM) is a global health concern. Metformin is commonly used in DM but the potential effectiveness in comorbid patients is uncertain. This retrospective study aims to investigate the effect of metformin on TB‐DM comorbidity and construct prediction models. Methods Patients diagnosed with TB‐DM in West China Hospital were retrospectively enrolled from Nov 2013 to Sep 2019. Electronic health records of patients were extracted. Two‐month smear conversion (2SC) was considered an outcome indicator of TB. Univariate and multivariate logistic regression (LR) were used to assess the role of metformin and other independent predictors. Meanwhile, prediction models were built by LR, elastic net regression, support vector machine, k‐nearest neighbors, and random forest. Results A total of 927 individuals were recruited, among which 408 (44.01%) were metformin‐exposed patients. A higher 2SC rate was observed in the metformin users. Other impact factors such as smoking, glucose, and creatinine levels were also identified. Multivariable models were then constructed using filtered variables. The support vector machine model yields the highest AUC (0.808, 95% CI: 0.767–0.849) and specificity (83.24%). LR model outperformed others in terms of sensitivity (69.71%). Conclusion This retrospective study of a large population from southwestern China provides strong clinical evidence for the positive effects of metformin in TB‐DM. Metformin is associated with a better therapeutic outcome and promising for the adjuvant therapy of TB‐DM. Furthermore, a combination of support vector machine and LR models is recommended to discriminate the patients with poor treatment outcomes.

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Metformin induced autophagy in diabetes mellitus – Tuberculosis co-infection patients: A case study

Cited by 20 publications

References 31 publications

Metformin as Host-Directed Therapy for TB Treatment: Scoping Review

Metformin as Host-Directed Therapy for TB Treatment: Scoping Review

Multiple Facets of Autophagy and the Emerging Role of Alkylphosphocholines as Autophagy Modulators

Metformin promotes smear conversion in tuberculosis‐diabetes comorbidity and construction of prediction models

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