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Systemic RAGE ligands are upregulated in tuberculosis individuals with diabetes co-morbidity and modulated by anti-tuberculosis treatment and metformin therapy.

ABSTRACT: BACKGROUND:Ligands of the receptor for advanced glycation end products (RAGE) are key signalling molecules in the innate immune system but their role in tuberculosis-diabetes comorbidity (TB-DM) has not been investigated. METHODS:We examined the systemic levels of soluble RAGE (sRAGE), advanced glycation end products (AGE), S100A12 and high mobility group box 1 (HMGB1) in participants with either TB-DM, TB, DM or healthy controls (HC). RESULTS:Systemic levels of AGE, sRAGE and S100A12 were significantly elevated in TB-DM and DM in comparison to TB and HC. During follow up, AGE, sRAGE and S100A12 remained significantly elevated in TB-DM compared to TB at 2nd month and 6th month of anti-TB treatment (ATT). RAGE ligands were increased in TB-DM individuals with bilateral and cavitary disease. sRAGE and S100A12 correlated with glycated hemoglobin levels. Within the TB-DM group, those with known diabetes (KDM) revealed significantly increased levels of AGE and sRAGE compared to newly diagnosed DM (NDM). KDM participants on metformin treatment exhibited significantly diminished levels of AGE and sRAGE in comparison to those on non-metformin regimens. CONCLUSIONS:Our data demonstrate that RAGE ligand levels reflect disease severity and extent in TB-DM, distinguish KDM from NDM and are modulated by metformin therapy.

SUBMITTER: Kumar NP

PROVIDER: S-EPMC6902343 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Systemic RAGE ligands are upregulated in tuberculosis individuals with diabetes co-morbidity and modulated by anti-tuberculosis treatment and metformin therapy.

Kumar Nathella Pavan NP Moideen Kadar K Nancy Arul A Viswanathan Vijay V Shruthi Basavaradhya S BS Sivakumar Shanmugam S Hissar Syed S Kornfeld Hardy H Babu Subash S

BMC infectious diseases 20191209 1

<h4>Background</h4>Ligands of the receptor for advanced glycation end products (RAGE) are key signalling molecules in the innate immune system but their role in tuberculosis-diabetes comorbidity (TB-DM) has not been investigated.<h4>Methods</h4>We examined the systemic levels of soluble RAGE (sRAGE), advanced glycation end products (AGE), S100A12 and high mobility group box 1 (HMGB1) in participants with either TB-DM, TB, DM or healthy controls (HC).<h4>Results</h4>Systemic levels of AGE, sRAGE ...[more]

PMID: 31818258

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Project description:Peripheral nerve injury (PNI) results in a fundamental reorganization of the translational machinery in the injured peripheral nerve such that protein synthesis is increased in a manner linked to enhanced mTOR and ERK activity. We have shown that metformin treatment, which activates adenosine monophosphate-activated protein kinase (AMPK), reverses tactile allodynia and enhanced translation following PNI. To gain a better understanding of how PNI changes the proteome of the sciatic nerve and ascertain how metformin treatment may cause further change, we conducted a range of unbiased proteomic studies followed by biochemical experiments to confirm key results.We used multidimensional protein identification technology (MUDPIT) on sciatic nerve samples taken from rats with sham surgery, spinal nerve ligation (SNL) surgery or SNL + 200 mg/kg metformin treatment. MUDPIT analysis on these complex samples yielded a wide variety of proteins that were sorted according to their peptide counts in SNL and SNL + metformin compared to sham. These proteins were then submitted to functional annotation analysis to identify potential functional networks altered by SNL and SNL + metformin treatment. Additionally, we used click-chemistry-based labeling and purification of nascently synthesized proteins followed by MUDPIT to further identify peptides that were synthesized within the injured nerve. With these methods, we identified apolipoprotein E (ApoE) as a protein profoundly increased by PNI and further increased by PNI and metformin. This result was confirmed by Western Blot of samples from SNL rats and spared nerve injury (SNI) mice. Furthermore, we show that 7-day treatment with metformin in naïve mice leads to an increase in ApoE expression in the sciatic nerve.These proteomic findings support the hypothesis that PNI leads to a fundamental reorganization of gene expression within the injured nerve. Our data identify a key association of ApoE with PNI that is regulated by metformin treatment. We conclude from the known functions of ApoE in the nervous system that ApoE may be an intrinsic factor linked to nerve regeneration after PNI, an effect that is further enhanced by metformin treatment.

Project description:BackgroundThere are only limited data from resource-limited settings available on the prevalence of non-communicable diseases and associated risk factors of tuberculosis patients. This study investigated non-communicable disease co-morbidity in tuberculosis patients from Moyen Ogooué Province, Gabon.MethodsAll patients aged 18 years or older consulting for tuberculosis (TB) symptoms in Gabon's Moyen Ogooué province and neighbouring provinces from November 2018 to November 2020 were screened for diabetes mellitus, hypertension, and risk factors thereof (obesity, dyslipidaemia, smoking and alcohol consumption). Logistic regression was performed to identify factors associated with TB-diabetes and TB-hypertension co-morbidities.FindingsOf 583 patients included, 227 (39%) were diagnosed with tuberculosis. In tuberculosis-confirmed patients, the prevalences of hypertension and diabetes were 16·3% and 12·8%, respectively. The prevalence of diabetes was twice as high in tuberculosis patients compared to non-tuberculosis patients. Factors independently associated with hypertension-tuberculosis co-morbidity were age >55 years (aOR=8·5, 95% CI 2·43, 32·6), age 45-54 years (aOR=4.9, 95%CI 1.3-19.8), and moderate alcohol consumption (aOR=2·4; 95% CI 1·02- 5·9), respectively. For diabetes-tuberculosis co-morbidity, age >55 years was positively (aOR=9·13; 95% CI 2·4-39·15), and moderate alcohol consumption inversely associated (aOR=0·26, 95% CI 0·08- 0·73). One-hundred-and-four (46%) of the tuberculosis patients had at least either dyslipidaemia, hypertension, diabetes, or obesity with a majority of newly-diagnosed hypertension and diabetes.InterpretationIntegration of screening of non-communicable diseases and their risk factors during TB assessment for early diagnosis, treatment initiation and chronic care management for better health outcomes should be implemented in all tuberculosis healthcare facilities.FundingThis study was supported by WHO AFRO/TDR/EDCTP (2019/893,805) and Deutsches Zentrum für Infektiologie (DZIF/ TTU 02.812).

Dataset Information

Systemic RAGE ligands are upregulated in tuberculosis individuals with diabetes co-morbidity and modulated by anti-tuberculosis treatment and metformin therapy.

Publications

Systemic RAGE ligands are upregulated in tuberculosis individuals with diabetes co-morbidity and modulated by anti-tuberculosis treatment and metformin therapy.

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