Meta-Inflammation in Type 2 Diabetes Mellitus: Unveiling the Role of Aberrant CD4+ T-Cells and Pro-Inflammatory Cytokine Networks

Shubham Kumar Shaw¹Soumya SenGupta¹Rohila Jha¹Chandrasekhar Pattanaik¹Harapriya Behera¹Prakash Barik¹Dayanidhi Meher^2*Rajlaxmi Sarangi^2*Satish Devadas^1*

• ¹Institute of Life Sciences (ILS), Bhubaneswar, India
• ²Kalinga Institute of Medical Sciences (KIMS), Bhubaneswar, Odisha, India

This study aimed to investigate the causal or casual relation between dysregulated glucose metabolism and meta-inflammation in Type 2 Diabetes Mellitus (T2DM), and more importantly the mediators and cellular sources for this meta-inflammation. We examined whether T2DM meta-inflammation is driven by aberrant, inflamed T helper cells and if there was a direct link to HbA1c levels. Flow cytometry data revealed TNF-a secreting effector CD4+ T cells as key contributors to inflammation, while memory T cells secreting GM-CSF and IL-17, escalated and maintained meta-inflammation. Crucially, these cytokines were present even in the "resting CD4+ T cells", reflecting an aberrant, low grade chronically activated and inflamed immune system. Significantly higher antibody isotypes levels further substantiated these findings as proof of concept for sustained and inflamed APC-T cell-B cell nexus. while reduced IL-10 levels reflected a shift towards pro-inflammatory bias. Functional assays, phospho protein expression, ex-vivo inhibitor studies and confocal microscopy confirmed that basal meta-inflammation in T2DM is exclusively mediated by multiple T helper cell phenotypes via TNF-a /STAT-3 signaling axis. Plasma cytokine and antibody isotyping was profiled using multiplex immunoassays from undiluted plasma. Taken together these findings suggests that unchecked cytokine secretion, inflamed T helper subsets, unwarranted antibody isotypes, etc. may contribute to organ damage by further amplifying innate and adaptive immune responses. Monitoring inflammatory cytokines, antibody isotypes, and T helper cell subsets could significantly mitigate organ damage in T2DM, offering a more comprehensive approach to disease management. Thus, this study highlights the importance of not only achieving metabolic control during T2DM treatment but also monitoring and regulating immune homeostasis.