At any Level of Adiposity, Relatively Elevated Leptin Concentrations Are Associated With Decreased Insulin Sensitivity

CONTEXT: The impact of obesity on glucose homeostasis has high interindividual variability, which may be partially explained by different adipokine concentrations. Leptin regulates energy balance and metabolism, and although its plasma levels are proportional to fat mass, they vary significantly across individuals with the same level of adiposity. OBJECTIVE: We tested whether glucose homeostasis differs in subjects with similar degrees of adiposity but different leptin levels. METHODS: We analyzed 1290 healthy adults from the Relationship Between Insulin Sensitivity and Cardiovascular Disease study cohort (30-60 years; male/female, 577/713; body mass index [BMI], 25 ± 3 kg/m2) characterized for body composition and metabolic variables with a 75-g oral glucose tolerance test, euglycemic-hyperinsulinemic clamp, β-cell function, and lipidomics. RESULTS: Individuals were divided into relatively high and low leptin (RHL and RLL) if they were above or below the sex-specific leptin-fat mass (%) regression. Despite similar glucose tolerance, RHL showed markedly higher fasting and oral glucose tolerance test insulin concentration (+30% and +29%, respectively; P < .0001) and secretion (+17% and +11%, respectively; P < .0001). Regardless of BMI, RHL individuals had lower whole-body (-17-23%, P < .0001) and adipose tissue insulin sensitivity (-24%, P < .0001) compared with RLL. Notably, lean RHL individuals showed similar insulin sensitivity and β-cell function to RLL individuals with overweight/obesity. CONCLUSION: Subjects with leptin levels that are inappropriately elevated for their fat mass show whole-body/adipose tissue insulin resistance and hyperinsulinemia, regardless of BMI.