Broad-Spectrum Effects of Carbohydrate Reduction on Inflammatory and Immune Mediators in Type 2 Diabetes

Abstract

Background: Chronic low-grade inflammation contributes to the development and complications of type 2 diabetes (T2D). Nutritional ketosis improves glycemic control and weight, but its broader immunomodulatory effects are less well defined. Methods: In this post-hoc analysis, adults with T2D (n = 195) or prediabetes (n = 89) in a two-year continuous care intervention (CCI) with individualized carbohydrate reduction emphasizing nutritional ketosis were compared with T2D participants receiving usual care (UC, n = 63). Serum was collected at baseline, 1, and 2 years for high-sensitivity CRP, 15 cytokines/adhesion molecules, and comprehensive blood count (CBC)-derived indices. Linear mixed-effects models evaluated longitudinal changes, while regression (including least absolute shrinkage and selection operator, LASSO) examined associations with mean β-hydroxybutyrate (BHB), weight change, HbA1c, and HOMA-IR. Results: Nineteen of 21 markers declined at 1 year in CCI, largely sustained at 2 years; UC showed no changes. Higher BHB predicted reductions in WBC, ICAM-1, VEGF-A, and systemic immune-inflammation index (SII), while weight loss correlated with IL-6, IL-18, IL-1β, and TNF-α. Conclusion: CCI induced broad, durable anti-inflammatory effects, supporting its role in lowering systemic inflammation and cardiometabolic risk.