This study was designed to define the effects on glucose metabolism of small increases of plasma EPI, comparable to increases observed during physiological sympathoadrenal activation. This study was also designed to determine the effects of EPI on glucose metabolism in older adults, in whom changes in adrenergic responsiveness of several tissues were described. Tolbutamide-boosted IVGTTs were performed during intravenous infusions of saline (control) or EPI at 2.7, 5.5, and 10.9 mmol/min to achieve physiological levels of EPI in 7 young subjects (19-26 yr of age) and 7 old subjects (62-75 yr of age), all with a normal screening OGTT. IVGTT results were analyzed to determine the AIR and with the minimal model method of Bergman to determine SI and SG. A significant fall was observed in AIR, SI, and SG for all subjects, even with the lowest dose of EPI, which resulted in only a two- to threefold increase in plasma EPI. Older subjects had a delayed recovery from hyperglycemia during the EPI infusions, although we detected no significant differences between the young and old subjects in the ability of EPI to alter either acute phase insulin secretion or insulin action. In contrast, the impairment of SG by EPI appeared to be greater in the elderly. We conclude that small increases of plasma EPI can significantly affect determinants of glucose tolerance in both young and old people.