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 Baseline data from 229 adults (40-75 years, BMI 25-40 kg/m2) 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.