Age-Related Change in Ketone Body Metabolism: Diminished Glucagon Effect on Ketogenesis in Adult Rats*

The age-related changes in plasma ketone body levels and related substances such as carnitine and FFA of normal and streptozotocin diabetic rats, as well as its effects on glucagon-induced ketogenesis in isolated perfused rat livers, were examined in this study. The degree of increase of acetoacetate (AcAc) in adult rats (50-week-old) after a 36-h fasting period in both normal and diabetic rats was significantly smaller than that of young rats (8-week-old). Plasma total carnitine tended to decrease with aging. On the other hand, the plasma levels of FFA and glucagon in fasted adult rats were significantly higher than those in young rats. In parallel with the in vivo observation, the basal output of AcAc, but not 3-hydroxybutyrate, from adult rat livers was significantly smaller than that of the young normal and diabetic rats. The level of glucagon-stimulated AcAc output from the young rat liver was significantly higher than that from the adult rat liver in both the normal and diabetic rats. This study demonstrates that the hepatic unresponsiveness to glucagon in terms of its ketone body production by aging may be one of the major causes of hyperosmolar nonketotic coma in elderly people.