Marija Troskot Cuculić, Dora Sergo, Inga Kavazović, Viktor Peršić, Felix M Wensveen, Tamara Turk Wensveen
This study suggests that mild and severe HIRI are associated with distinct splicing programs and that these changes are closely associated with immune microenvironment remodeling, supporting the hypothesis of an RBP-AS-immune regulatory network. These findings, in which the RBP expression changes were independently validated in an external cohort, provide a basis for generating hypotheses regarding post-transcriptional regulation in HIRI.
INTRODUCTION: Chronic low-grade meta-inflammation contributes to insulin resistance and metabolic dysfunction in type 2 diabetes (T2D). γδ T cells have emerged as important mediators of metabolic inflammation, yet their responsiveness to metabolic improvement in humans remains poorly understood. We investigated whether successful antidiabetic therapy is associated with alterations in γδ T cell-mediated inflammation in patients with T2D.
METHODS: Twenty-five patients with poorly controlled T2D initiating SGLT2i therapy (n=15) or SGLT2i plus GLP-1RA (n=10) were prospectively followed for 12 months. Age- and sex-matched non-diabetic controls (n=30) were included at baseline. Peripheral blood γδ T cell phenotype and cytokine production were assessed by multiparametric flow cytometry. Metabolic, hepatic, and renal parameters were evaluated longitudinally.
RESULTS: At baseline, patients with T2D exhibited increased interferon-γ (IFN-γ) production by both Vδ1+ and Vδ2+ γδ T-cell subsets compared with controls, while subset frequencies remained unchanged. During follow-up, successful antidiabetic therapy was associated with a progressive reduction in IFN-γ production, reaching approximately 40% after 12 months (p<0.01). This reduction did not correlate with changes in HbA1c and was not enhanced by the addition of GLP-1 receptor agonist therapy. In contrast, lower IFN-γ production was associated with improved insulin sensitivity, reduced fat mass, and markers of improved metabolic health. The largest reductions were observed in individuals with mild hepatic or renal impairment and correlated with indices of organ involvement.
DISCUSSION: This real-world study shows that γδ T cell-mediated meta-inflammation decreases during successful antidiabetic therapy independently of glycemic control. IFN-γ production by γδ T cells is closely associated with insulin resistance, adiposity, and metabolic organ dysfunction, supporting its potential utility as a biomarker of metabolic tissue stress and therapeutic response in T2D.