We studied glucagon and insulin binding to isolated hepatocyte receptors in Wistar-Furth (WF) and Sprague-Dawley (SD) rats, using 125I-labeled hormones. Hepatocytes from WF rats bound more glucagon than hepatocytes from SD rats. There were no differences in insulin binding. These observations prompted us to investigate other strain differences. Fasting and nonfasting serum glucose, glucagon, insulin, and growth hormone were measured. WF animals had a lower fasting glucose and higher fasting glucagon than SD animals, while SD rats had higher nonfasting insulin levels and a higher hepatic glycogen content. Total hepatic glucose production in response to glucagon (10(-8) M) was greater in WF than in SD rats, while glucagon-stimulated gluconeogenesis from alanine was the same in the two groups of animals. We concluded that the decreased glucagon binding does not play a significant role in the maintenance of serum glucose or in the gluconeogenetic response glucagon, and that neither these responses nor the serum glucagon levels appears to be correlated with the number of glucagon receptors. We conclude further that different animal strains of the same species may differ in their biologic responses.