Distinct Cytokine Profiles in Plasma and Tears Highlight Ophthalmologic Inflammation in Type 2 Diabetes without Retinopathy

RAFAEL JIMÉNEZ-LÓPEZ^1,2,3LAURA MARTÍN-CHAVES^1,2,3ÁNGEL MANUEL GUTIÉRREZ-GARCÍA⁴Ada Del Mar Carmona Segovia^1,2,3BEGOÑA MORA-ORDOÑEZ^2,3Sánchez-García AM^2,3LOURDES FERNÁNDEZ-ROMERO²Mora Murri^2,3MARÍA JOSÉ SÁNCHEZ-QUINTERO^2,3GERMÁN BERTELI-GARCÍA^2,3MIGUEL ANGEL SÁNCHEZ- CHAPARRO^2,3VICENTE BODI^5,6Jorge Rodríguez Capitán^2,3,6MANUEL F. JIMÉNEZ-NAVARRO^1,2,3,6FRANCISCO JAVIER PAVON-MORON^2*JOSÉ LORENZO ROMERO-TREVEJO^2,3

• ¹Faculty of Medicine, University of Malaga, Málaga, Andalusia, Spain
• ²UGC Salud Mental-Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina (IBIMA Plataforma BIONAND), Málaga, MALAGA, Spain
• ³Hospital Clínico Universitario Virgen de la Victoria, Málaga, Andalusia, Spain
• ⁴Centro de Salud Rincón de la Victoria, Rincón de la Victoria, Spain
• ⁵Institute of Health Research (INCLIVA), Valencia, Spain
• ⁶Biomedical Network Research Center on Cardiovascular Diseases, Carlos III Health Institute (ISCIII), Madrid, Madrid, Spain

Introduction. Type 2 diabetes mellitus is associated with chronic inflammation and systemic complications, including ophthalmologic manifestations. While blood cytokines serve as inflammatory biomarkers, their expression in tears and correlation with systemic inflammation remain unclear. This study compared cytokine profiles in plasma and tears of well-controlled type 2 diabetes patients and controls, assessing their correlation and potential as biomarkers for disease monitoring. Materials and methods. This cross-sectional study included 81 participants [40 with type 2 diabetes without retinopathy (T2DM group) and 41 controls (control group)] from primary care centers. Plasma and tear samples were analyzed using a multiplex immunoassay for 27 cytokines. Data were analyzed using ANCOVA (adjusted for age, hypertension, and dyslipidemia), and correlation analyses. Results. Patients in the T2DM group exhibited distinct inflammatory profiles. Plasma levels of IL-2 (P<0.05), IL-7 (P<0.05), IL-9 (P=0.001), and CCL4 (P<0.01) were significantly lower, while tear levels of IL-6 (P<0.01), CXCL8 (P=0.001), IL-15 (P<0.05), CCL5 (P<0.001), and VEGF (P<0.01) were elevated compared to controls. No significant correlations were observed between plasma and tear cytokines, suggesting independent regulation of systemic and ophthalmologic inflammation. Tear cytokines exhibited stronger intra-fluid correlations than plasma (98.4% vs. 66.5%), with minimal plasma-tear correlations (3.6%). Age influenced most tear cytokines (24/27 analytes) but had a weaker effect on plasma cytokines. Conclusions. Despite glycemic control, patients with type 2 diabetes exhibited increased tear cytokines in the absence of diagnosed retinopathy, contrasting with reduced plasma cytokines. The lack of correlations suggests localized ophthalmologic inflammation independent of systemic inflammation, highlighting a persistent risk of retinal vascular damage in type 2 diabetes.