Abstract

Background/Objectives: Adolescence is a critical developmental period during which dietary quality and physical activity (PA) may influence insulin sensitivity and pancreatic β-cell function. This observational cohort study investigated how adherence to the Mediterranean diet (MedDiet) and participation in structured physical activity (PA) relate to metabolic changes over six months in Spanish male adolescents. Methods: A total of 78 participants (median age 11 years; IQR 10–12) were followed in a school-based study (2020–2021) and categorized by MedDiet adherence using the KIDMED index into medium (M) and high (H) groups. Metabolic health was assessed at baseline (T1) and after six months (T2) using lipid profiles, glucose, insulin, and several indirect indices of insulin resistance and β-cell function, including HOMA-IR, QUICKI, and SPINA indices. Statistical analyses included correlations and adjusted linear models, with false discovery rate correction applied. Results: At baseline, higher MedDiet adherence was associated with lower fasting insulin and improved insulin resistance markers (p ≤ 0.002). Over six months, adolescents with high adherence showed more favorable changes in insulin sensitivity (fasting insulin, HOMA-IR, QUICKI) and β-cell function (SPINA indices), with results remaining significant after correction (all pFDR < 0.05). LDL cholesterol levels also improved more markedly in participants combining high MedDiet adherence with structured PA (pFDR < 0.001). In contrast, triglycerides and TG-related indices increased across all groups, without differences between them (pFDR < 0.001). Conclusions: High MedDiet adherence combined with structured PA was associated with more favorable trajectories in insulin sensitivity, attenuated β-cell secretory demand, and a more favorable LDL-c profile. These findings support integrated lifestyle approaches for early cardiometabolic prevention in male adolescence.