Association of intermuscular and intramuscular fat with insulin resistance, type 2 diabetes, and metabolic syndrome: A systematic review

BACKGROUND AND AIMS: Intermuscular and intramuscular fat may exacerbate cardiometabolic risk through insulin resistance. This systematic review explores the association of intermuscular and intramuscular fat with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), type 2 diabetes (T2D), and metabolic syndrome (MetS). MATERIALS: Following the PRISMA 2020 guidelines, PubMed, Scopus, Web of Science, and Cochrane Library were searched from inception to March 2025 for studies reporting ORs for muscle fat (assessed via computed tomography (CT), magnetic resonance imaging (MRI), or peripheral quantitative CT (pQCT)) and metabolic outcomes in adults above 18 years. Quality was assessed using the Newcastle Ottawa Scale (NOS), with narrative synthesis due to high heterogeneity. RESULTS: Seventeen studies (n = 2945-8081; 61.7% men; age range of 34.3-74.6 years; majority of participants were community-dwelling) were included. Intermuscular fat showed significant associations with HOMA-IR (OR 2.72-2.67), T2D (OR 1.22-3.27, in multiple studies), and MetS (OR 1.2-2.3). Intramuscular fat was linked to higher HOMA-IR (OR 2.83) and MetS (OR 2.46), with mixed results related to T2D. Muscle attenuation was associated with T2D (OR 1.26-1.36) and MetS (OR 1.35-1.77) varied by sex. Quality of the studies ranged from moderate (NOS of 5 and 6, in the majority of studies) to high (NOS of 8). CONCLUSIONS: Muscle fat infiltration is consistently associated with cardiometabolic risk, demonstrating potential sex-specific differences. Longitudinal, sex- and disease-specific, and methodologically standardized studies are needed to confirm causality and guide targeted interventions. The protocol is registered in the Open Science Framework (https://doi.org/10.17605/OSF.IO/DK5VP).