Abstract
BackgroundLigands 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.MethodsWe 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).ResultsSystemic 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.ConclusionsOur data demonstrate that RAGE ligand levels reflect disease severity and extent in TB-DM, distinguish KDM from NDM and are modulated by metformin therapy.
Highlights
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-diabetes mellitus (DM)) has not been investigated
Our current findings reveal that systemic RAGE ligands levels indicate baseline disease severity and extent in tuberculosis-diabetes comorbidity (TB-DM), discriminate Diabetic before incident TB (KDM) from newly diagnosed DM (NDM) and are altered by anti-TB treatment (ATT) and metformin therapy
Elevated levels of circulating RAGE ligands in TB-DM To elucidate the effect of TB and DM on systemic RAGE ligand expression, we estimated the plasma levels of AGE, soluble RAGE (sRAGE), S100A12 and high mobility group box 1 (HMGB-1) in TB-DM, TB, DM and healthy controls (HC) individuals (Fig. 1)
Summary
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. DM affects the immune system by worsening both innate and adaptive immune functions, RAGE is a multiligand receptor of the immunoglobulin superfamily involved in inflammation, DM and its associated complications [11, 12]. Of the defined pathways implicated in the pathogenesis of diabetic complications, RAGE receptor signalling has been the most widely studied in leukocytes, immune function, and response to infection. The RAGE receptor signals through binding of AGEs, as the name implies, and the A8, A9 and A12 members of S100 protein family, the cellular stress signalling protein, high mobility group box 1 (HMGB-1), and β-amyloid sheets [13].
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