Pulsatile glucagon delivery enhances glucose production by perifused rat hepatocytes

We have compared the effects of pulsatile and continuous glucagon administration on hepatocyte glucose production in order to clarify the physiological role of pulsatile hormone secretion. Two identical columns containing freshly isolated rat hepatocytes mixed with polyacrylamide gel beads were perifused with oxygenated tissue culture medium. A fixed total amount of glucagon was delivered to one column as a continuous 90-min infusion and to the other column as a series of six 3-min pulses. A 15-min interpulse interval was chosen in order to approximate the 10- to 12-min interval observed in primates while permitting the resolution of individual hepatocyte responses. With this protocol, the EC50 values for pulsatile and continuous glucagon administration were 186 +/- 41 and 884 +/- 190 (SD) pg/ml, respectively. For glucagon concentrations less than 1,000 pg/ml, pulsatile administration always led to greater hepatocyte glucose production than continuous administration (P = 0.008) and, in the dose range equivalent to concentrations in portal plasma, pulsed glucagon enhanced glucose production twofold. The data suggest that pulsatile secretion is the more efficient means for islet A cells to stimulate hepatic glucose production.