Regulation of hepatic glucose output during exercise by circulating glucose and insulin in humans

We have tested the hypothesis that hepatic glucose output (R(a)) during exercise in humans is subject to feedback control by circulating glucose within a control range that is determined by the circulating insulin concentration. Three exercise protocols based on 60-min cycle ergometer exercise at 55% maximal O2 consumption were used: 1) control, 2) insulin infusion with a euglycemic clamp, and 3) insulin infusion with a fixed-rate glucose infusion. R(a) was measured using a constant infusion of [3H]glucose. During the glucose clamp there was no R(a) response to exercise. There were significant inverse relationships between R(a) and plasma glucose during control exercise (r = -0.73, P < 0.001) and exercise with fixed-rate glucose and insulin infusion (r = -0.96, P < 0.001). During the fixed-rate glucose and insulin infusion, plasma glucose fell from the commencement of exercise but stabilized at a lower level. These results are interpreted in terms of a simple difference controller where R(a) is proportional to the deviation of plasma glucose from a defined set point. Insulin affects R(a) and regulates the steady-state glucose level by altering the sensitivity of this control system.