Gluconeogenesis from lactate was increased more than twofold in perfused livers and isolated hepatocytes from 10- and 15-day-old suckling rats compared with adult rats and was not increased by fasting. Glucagon (10(-19)-10(-7) M) induced minimal activation of gluconeogenesis in hepatocytes from such animals even though it promoted accumulation of cAMP. Suckling rats had low plasma insulin levels and high plasma glucagon levels. The presented very low insulin/glucagon ratios were associated with high liver cAMP levels. Contrary to the situation in adult rats, glucagon levels fell with fasting. Insulin levels fell proportionally further so that the insulin/glucagon ratios declined. On the basis of these findings, it is proposed that the high glucagon and low insulin levels in young suckling rats result in high liver cAMP levels with resultant maximal stimulation of hepatic gluconeogenesis so that it cannot be further increased by fasting or exogenous glucagon. It is also suggested that milk is an important stimulus to the hyperglucagonemia of suckling rats in view of its high protein and low carbohydrate content.