Implications of diabetes mellitus on pathophysiology of Tuberculosis: Role of AGE-RAGE Axis and Glycated Proteins
Chronic hyperglycemia in diabetes mellitus promotes the formation of advanced glycation end products (AGEs) via non-enzymatic glycation of plasma proteins. AGEs and their receptor RAGE are central to diabetic complications, as they activate inflammatory pathways and oxidative stress. We studied the AGE-RAGE axis in uncontrolled diabetic individuals having pulmonary TB (PTB+DM), uncontrolled diabetic individuals with no infection (DM), and pulmonary TB patients (PTB). Levels of AGEs and RAGE were measured across these groups and compared to controls. The results showed significantly higher AGEs and RAGE levels in the diabetic milieu, reflecting chronic hyperglycemia. These AGEs were shown to be associated with impaired macrophage function, evidenced by reduced phagocytic capacity. Increased AGEs correlated with disease severity in tuberculosis patients co-affected by diabetes, indicating compromised immune responses. RAGE expression also showed a higher trend in TB patients, although not statistically significant, potentially influencing infection outcomes. Glycated calmodulin was also elevated in diabetic and TB-diabetes comorbid patients and negatively correlated with nitric oxide (NO) levels, suggesting that calmodulin glycation hinders NO production in diabetic conditions. Molecular dynamic studies revealed that glycosylation disrupts calmodulins interaction with inducible nitric oxide synthase (iNOS), potentially explaining the decreased NO levels in TB-diabetes comorbid patients. These findings underscore the detrimental impact of AGEs and RAGE in diabetic immune dysregulation, highlighting the need for therapeutic strategies to mitigate their effects on macrophage function and restore immune responses. HighlightsO_LIWe conducted this study to examine how hyperglycemia-driven AGEs and RAGE contribute to immune dysfunction and disease severity in diabetic and TB-diabetes patients. C_LIO_LIHigh AGEs and RAGE impairs macrophage function, decreasing phagocytic capacity and worsening disease severity in TB-diabetes comorbidity. C_LIO_LIGlycosylation disrupts calmodulins interaction with iNOS, contributing to lower NO levels and weakened immune responses in TB-diabetes comorbidity. C_LIO_LIThe AGE-RAGE axis should be studied further for these comorbid conditions to assess and improve macrophage function and restore immune responses. C_LI