At any level of adiposity, relatively elevated leptin concentrations are associated with decreased insulin sensitivity

CONTEXT: The impact of obesity on glucose homeostasis has a high interindividual variability, which may be partially explained by different adipokines 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 1,290 healthy adults from the RISC study cohort (30-60 years, M/F 577/713, BMI 25 ± 3 kg/m2) characterized for body composition and metabolic variables with a 75-g OGTT, 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 OGTT insulin concentration (+30% and +29% respectively, p < 0.0001) and secretion (+17% and +11% respectively, p < 0.0001). Regardless of BMI, RHL individuals had lower whole-body (-17-23%, p < 0.0001) and adipose tissue insulin sensitivity (-24%, p < 0.0001) compared to 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.