EFFECTS OF PROLONGED HYPERINSULINEMIA ON SERUM LEPTIN IN NORMAL HUMAN-SUBJECTS

We have studied the effect of prolonged hyperinsulinemia and hyperglyc emia on serum leptin levels in young nonobese males during 72-h euglyc emic-hyperinsulinemic and hyperglycemic (similar to 8.5 and 12.6 mM) c lamps. Hyperinsulinemia increased serum leptin concentrations (by RIA) dose-dependently. An increase in serum insulin concentration of > 200 pM for > 24 h was needed to significantly increase serum leptin. An i ncrease of similar to 800 pM increased serum leptin by similar to 70% over 72 h. Changes in plasma glucose concentrations (from similar to 5 .0 to similar to 12.6 mM) or changes in plasma FFA concentrations (fro m < 100 to > 1,000 mu M) had no effect on serum leptin. Serum leptin c oncentrations changed with circadian rhythmicity. The cycle length was similar to 24 h, and the cycle amplitude (peak to trough) was similar to 50%. The circadian leptin cycles and the circadian cycles of total body insulin sensitivity (i.e., GIR, the glucose infusion rates neede d to maintain euglycemia during hyperinsulinemic clamping) changed in a mirror image fashion. Moreover, GIR decreased between Days 2 and 3 ( from 11.4+/-0.2 to 9.8+/-0.2 mg/kg min, P < 0.05) when mean 24-h lepti n levels reached a peak. In summary, we found (a) that 72 h of hyperin sulinemia increased serum leptin levels dose-dependently; (b) that hyp erglycemia or high plasma FFA levels did not affect leptin release; (c ) that leptin was released with circadian rhythmicity, and (d) that 24 -h leptin cycles correlated inversely with 24-h cycles of insulin sens itivity. We speculate that the close positive correlation between body fat and leptin is mediated, at least in part, by insulin.