• glucose metabolism
• insulin sensitivity
• leptin
• obesity

Leptin acts centrally and peripherally to regulate energy balance and metabolism. Its plasma levels are proportional to fat mass but show a wide interindividual variability that is only partially explained by sex and adiposity. We tested whether different leptin levels, despite similar fat depots, can explain the variable impact of adiposity on glucose homeostasis.
We analyzed 1372 healthy adults from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study cohort (30-60 years, M/F 595/777, BMI 26±4 kg/m2), followed-up after 3.5-years and characterized for body composition and metabolic variables with a 75-g oral glucose tolerance test (OGTT), euglycemic-hyperinsulinemic clamp, intravenous glucose bolus, β-cell function, insulin clearance and hepatic and adipose insulin sensitivity. Ultrasound examination of extracranial carotid arteries was also performed at baseline and follow-up.
The participants were divided into 3 groups: Hyperleptinemic (HyperL), Normoleptinemic (NormoL) and Hypoleptinemic (HypoL) on the basis of the residuals’ tertiles of the gender-specific plasma leptin vs fat mass fit. Despite a glucose tolerance similar to HypoL, HyperL showed markedly higher fasting and OGTT insulin levels (+55% and +69% respectively, p<0.0001), along with a reduction in whole-body (-27%, p<0.0001), hepatic (-22%, p<0.05) and adipose (-63%, p<0.0001) insulin sensitivity. Both fasting and OGTT insulin clearance were lower in HypoL compared to HyperL (-13% and -22% respectively, p<0.0001), independently of insulin secretion and insulin sensitivity. Compared to HypoL, HyperL also showed higher β-cell function (glucose sensitivity:+14%; acute insulin response to iv glucose:+12%, p<0.05). Overall, the associations were stronger in men and in lean individuals. After 3.5 years, changes in weight, glucose tolerance, insulin sensitivity, blood pressure and vascular aging were similar in the three phenotypes.
Subjects with inappropriately elevated leptin levels for their fat mass show more severe adiposity-related metabolic complications including whole-body, adipose tissue and hepatic insulin resistance and marked hyperinsulinemia, sustained by increased β-cell function and reduced insulin clearance.