Supraphysiological Hyperinsulinemia Increases Plasma Leptin Concentrations After 4 h in Normal Subjects

In rodents, food intake and insulin increase ob gene expression and circulating leptin concentrations, but it is unknown whether insulin regulates plasma leptin concentrations in humans. We measured plasma leptin concentrations in 27 normal subjects (16 men, 11 women; age, 24 +/- 1 years; BMI, 22.6 +/- 0.5 kg/m2; body fat, 18 +/- 1%) during a 6-h euglycemic hyperinsulinemic clamp (sequential insulin infusions of 1, 2, and 5 mU.kg-1.min-1 for 2 h each). During these insulin infusions, plasma leptin increased from a basal concentration of 7.4 +/- 1.6 ng/ml by -2 +/- 2, 17 +/- 4, and 50 +/- 6% to 7.2 +/- 1.5 (NS vs. basal), 8.5 +/- 1.7 (P < 0.001), and 10.4 +/- 2.0 ng/ml (P < 0.001), respectively. Of the subjects, eight also participated in a control study where saline was infused for 6 h. In these subjects, plasma leptin increased by 5 +/- 4, 26 +/- 10, and 62 +/- 10% during the insulin infusions, and decreased by 9 +/- 4 (P = 0.07 for change during saline vs. insulin), 13 +/- 4 (P < 0.01), and 17 +/- 4% (P < 0.001) after 2, 4, and 6 h of the saline infusion, respectively. Women had higher plasma leptin concentrations basally and during hyperinsulinemia (P < 0.001) than men, but this difference was entirely accounted for by greater adiposity in women (22 +/- 2 vs. 14 +/- 1%, P < 0.001). These data provide evidence for the insulin regulation of plasma leptin concentrations in humans. This effect requires hours of high insulin concentrations, implying that postprandial satiety is not regulated via changes in plasma leptin concentrations. Insulin may, however, be of importance in the long-term or diurnal regulation of plasma leptin concentrations.