Insulin resistance and hyperinsulinaemia precede the onset of obesity-induced DM2. The early adaptation of the ?-cell during the initial phase of overfeeding and weight gain has only been partly elucidated. We studied the early changes in insulin clearance and ?-cell responsivity during a positive and negative energy balance in lean healthy men.We studied in nine healthy lean men [age, 37 (27-43)?years; BMI, 23?6 (20?6-25?6)?kg/m(2) ] insulin sensitivity, insulin clearance, insulin secretion and static and dynamic ?-cell responsivity at baseline and after the hypercaloric and subsequent hypocaloric diet.Participants gained 7 [5?1-7?6]% of their initial body weight on the hypercaloric diet. Compared to baseline, insulin sensitivity and insulin clearance decreased, while glucose-stimulated insulin secretion was higher. The GLP-1 response to oral glucose did not change. The dynamic ?-cell responsivity index increased but the basal and static responsivity indexes did not change. Total and static disposition indexes (DIs) in the hypercaloric state showed a trend towards a decrease. During the hypocaloric diet, insulin sensitivity, glucose-stimulated insulin secretion and insulin clearance returned to baseline. The responsivity and the DIs were not different in the hypocaloric phase compared to baseline.A positive energy balance resulting in weight gain in lean men induces hyperinsulinaemia, which is explained by a combined effect on insulin clearance and insulin secretion. Increased insulin secretion was related to insulin resistance-induced higher glucose concentrations but also to increased dynamic ?-cell responsivity. Glucose sensitivity of the ?-cell did not change. These early adaptations are completely reversible during a negative energy balance after loss of the gained weight.? 2012 Blackwell Publishing Ltd.