<p>Diabetes is a metabolic and inflammatory disease that disproportionately affects African American populations, yet clinical diagnostics often rely on biomarkers discovered and validated predominantly in White cohorts. This study investigates race-specific lipid and inflammatory features of diabetes to uncover biologically distinct disease signatures that may contribute to disparities in diagnosis and management. We analyzed clinical parameters from a well-matched subset of the HANDLS cohort (<i>N</i> = 40) and conducted targeted plasma lipidomics and multiplex cytokine profiling across African American and White individuals from the HANDLS cohort with and without diabetes. Then we validated key findings using a large and diverse cohort of African American and White individuals with type 2 diabetes from the NIH AllofUs program (<i>N</i> = 17,339). Our results reveal racially divergent signatures of diabetes. White individuals with diabetes exhibited elevated Cholesterol:HDL ratios, triglycerides, and classical inflammatory markers such as hs-CRP. In contrast, African American individuals with diabetes displayed minimal lipid elevations but showed increased Th17-related cytokines1. These differences were independent of statin use, age, and body mass index. Additionally, correlations between lipid to cytokine ratios and the glycemic marker hemoglobin A1C differed sharply by race, suggesting that the pathophysiology of diabetes is not uniform across populations. Our findings challenge standard diabetes biomarkers and emphasize the need for more inclusive diagnostic frameworks. By identifying population-specific biological patterns of diabetes, this study provides important insight into the roots of persistent health disparities and underscores the value of precision approaches to equitable diabetes care.</p>