In order to determine whether central serotonin (5-HT) activity is related to sensitivity of insulin receptors, 19 healthy volunteers with normal basal glycemia and HbAlc were studied. The relationship between prolactin response to D-fenfluramine (delta PRL) in a challenge test and metabolic clearance rates (MCR) of glucose during the hyperinsulinemic-euglycemic clamp technique was evaluated. delta PRL had been chosen as a correlate of central 5-HT activity. Two levels of insulin concentration of approximately 70 mU/l (MCRsubmax) and 2000 mU/l (MCRmax) were used in a clamp, each for a duration of 120 min. A negative correlation was found between delta PRL and MCRsubmax (r = -0.55, P < 0.02) and between delta PRL and MCRmax (r = -0.51, P < 0.03). We did not find any correlation between the prolactin response to D-fenfluramine and body weight, body mass index (BMI) or waist and hip circumference (WHR). The data support the hypothesis of a close connection between 5-HT activity in the brain and peripheral sensitivity to insulin. The possible physiological mechanisms of this connection are discussed.