Adipose tissue insulin resistance, not muscle insulin resistance, is associated with impaired metabolic health in humans

AIM: Obesity is a major contributor to insulin resistance (IR) and cardiometabolic diseases, but IR can manifest in a tissue-specific manner, resulting in discordant IR phenotypes. This study characterized metabolic and clinical differences between individuals with adipose and muscle IR. METHOD: ) in the PERSON study were analyzed. Participants were categorized into four groups based on indices of muscle and adipose insulin sensitivity. Muscle IR was assessed with a 7-point oral glucose tolerance test, and adipose IR was determined from fasting plasma insulin and non-esterified fatty acids. Detailed phenotyping was performed under controlled conditions and daily life. RESULTS: 42% of participants displayed discordant IR patterns. Independent of muscle IR, adipose IR was associated with an adverse cardiometabolic profile, including abdominal fat accumulation, higher fasting insulin, HOMA-IR and triglycerides, greater glycemic variability, and more liver fat and hepatic IR. In contrast, individuals with isolated muscle IR maintained a relatively healthy cardiometabolic profile, though women exhibited higher muscle fat infiltration and hepatic IR. CONCLUSION: These findings demonstrate that adipose IR is more strongly and consistently linked to impaired metabolic health than muscle IR, highlighting the importance of phenotype-specific strategies for prevention and treatment.