The role of JAK/STAT signaling and the associated inflammatory pathways in patients with diabetic retinopathy and diabetic nephropathy consuming olive oil

Background: Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder associated with progressive microvascular complications, including diabetic retinopathy (DR) and diabetic nephropathy (DN), which represent leading causes of acquired blindness and end-stage renal disease, respectively. Chronic low-grade inflammation and dysregulated cytokine signaling are recognized contributors to microvascular injury in T2DM; however, the specific role of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway in distinguishing DR from DN remains poorly characterized. Olive oil, a principal component of the Mediterranean dietary pattern, contains bioactive compounds — including oleocanthal, oleuropein, and oleic acid — with established anti-inflammatory and antioxidant properties that may modulate inflammatory signaling cascades relevant to diabetic complications. Objective: To compare circulating concentrations of selected JAK/STAT-related proteins and inflammatory mediators among healthy controls and patients with type 2 diabetes mellitus (T2DM), with or without isolated diabetic retinopathy (DR) or diabetic nephropathy (DN). Methods: This cross-sectional observational study included 120 participants divided into four equal groups (n = 30 per group): healthy controls, patients with T2DM without DR or DN, patients with T2DM and DR without DN, and patients with T2DM and DN without DR. All participants reported habitual olive oil consumption as part of their usual diet; olive oil intake was not evaluated as an intervention or quantitative exposure. Serum glucose, HbA1c, BUN, creatinine, cystatin C, GM-CSF, IFN-α, IFN-γ, JAK1, JAK2, STAT1, STAT2, STAT5A, and TYK2 were measured. Twenty-four-hour urine samples were obtained for albumin measurement. Results: Compared with healthy controls, the T2DM groups showed higher circulating concentrations of the measured inflammatory and JAK/STAT-related proteins. Compared with uncomplicated T2DM, patients with DR had higher GM-CSF (p = 0.003), IFN-γ (p < 0.001), JAK1 (p = 0.001), JAK2 (p = 0.012), STAT1 (p = 0.033), STAT2 (p= 0.022), STAT5A (p = 0.008), and TYK2 (p = 0.019), whereas IFN-α did not differ significantly (p = 0.170). Compared with uncomplicated T2DM, patients with DN had higher IFN-γ, whereas the other evaluated JAK/STAT-related proteins did not differ significantly. JAK2 was the only measured protein that differed significantly between the DR and DN groups (DR > DN; p = 0.048). Conclusion: These cross-sectional findings support an association between altered JAK/STAT-related inflammatory profiles and diabetic microvascular complications, particularly DR. Because pathway phosphorylation, tissue-specific signaling, and longitudinal outcomes were not assessed, the findings should not be interpreted as direct evidence of JAK/STAT pathway activation or causality. Novelty of the Study: This study is among the first to simultaneously profile a broad panel of circulating JAK/STAT-related protein — JAK1, JAK2, STAT1, STAT2, STAT5A, and TYK2 — together with key inflammatory mediators (GM-CSF, IFN-α, and IFN-γ) across four clinically distinct diabetic phenotypes within a single cross-sectional design. The identification of JAK2 as the only marker significantly differentiating diabetic retinopathy from diabetic nephropathy (p = 0.048), combined with the documentation of olive oil as a background dietary characteristic, positions this study at the intersection of JAK/STAT-related inflammatory research and Mediterranean dietary science — an area that has received limited systematic investigation. Keywords: Diabetes mellitus; diabetic retinopathy; diabetic nephropathy; JAK/STAT; inflammation; cytokines; olive oil.