During constant infusion of exogenous human insulin and glucose to healthy volunteers, a rise in glycemia was still able to stimulate the B-cell as judged from the increase in C-peptide plasma concentration. Nevertheless, under euglycemic conditions, the C-peptide concentration fell well below its initial level. This coincided, however, with severe hypolipacidemia. When the latter phenomenon was corrected through the simultaneous administration of exogenous triglycerides and heparin, a reascension in C-peptide plasma concentration was observed despite persistent hyperinsulinemia. It is proposed, therefore, that the hyperinsulinemic-euglycemic clamp procedure does not represent a reliable approach to explore the possible feedback action of insulin upon its own secretion rate, because of the interference upon B-cell secretory activity of factors such as changes in lipacidemia.