OBJECTIVE: Insulin inhibition of insulin secretion has been described in normal lean subjects. In this study, we examined whether this phenomenon also occurs in the morbidly obese who often have severe peripheral insulin resistance. SUBJECTS: Twelve obese patients, normotolerant to glucose (8F/4M, body mass index (BMI) = 54.8 +/-2.5 kg/m(2), 39y) and 16 lean control subjects (10F/6M, BMI = 22.0 +/-0.5 kg/m(2), 31y). DESIGN AND MEASUREMENTS: An experimental study using various parameters, including an euglycemic hyperinsulinemic clamp (280pmol/min/m(2) of body surface), an oral glucose tolerance test (OGTT), electrical bioimpedance and indirect calorimetry. RESULTS: The obese subjects were insulin resistant (M = 19.8 +/-1.6 vs 48.7 +/-2.6 mu mol/min kg FFM, P < 0.0001) and hyperinsulinemic in the fasted state and after glucose ingestion. Fasting plasma C-peptide levels (obese 1425 +/- 131 pmol/l vs lean 550 +/- 63 pmol/l; P < 0.0001) decreased less during the clamp in the obese groups (-16.9 +/-6.9% vs -43.0 +/-5.6% relative to fasting values; P = 0.007). In the lean group, the C-peptide decrease during the clamp (percentage variation) was related to insulin sensitivity, M/FFM (r = 0.56, P = 0.03), even after adjustment for the clamp glucose variation. CONCLUSION: We conclude that, in lean subjects, insulin inhibits its own secretion, and this may be related to insulin sensibility. This response is blunted in morbidly obese patients and may have a role in the pathogenesis of fasting hyperinsulinemia in these patients.256798804