During mild or moderate nonexhausting exercise, glucose utilization increases sharply but is normally matched by increased glucose production such that hypoglycemia does not occur. To test the hypothesis that redundant glucoregulatory systems including sympathochromaffin activation and changes in pancreatic islet hormone secretion underlie this precise matching, eight young adults exercised at 55-60% of maximal oxygen consumption for 60 min on separate occasions under four conditions: (a) control study (saline infusion); (b) islet clamp study (insulin and glucagon held constant by somatostatin infusion with glucagon and insulin replacement at fixed rates before, during and after exercise with insulin doses determined individually and shown to produce normal and stable plasma glucose concentrations prior to each study); (c) adrenergic blockage study (infusions of the α- and β-adrenergic antagonist phentolamine and propranolol); (d) adrenergic blockade plus islet clamp study. Glucose production matched increased glucose utilization during exercise in the control study and plasma glucose did not fall (92 ± 1 mg/dl at base line, 90 ± 2 mg/dl at the end of exercise). Plasma glucose also did not fall during exercise when changes in insulin and glucagon were prevented in the islet clamp study. In the adrenergic blockade study, plasma glucose declined initially during exercise because of a greater initial increase in glucose utilization, then plateaued with an end-exercise value of 74 ± 3 mg/dl (P > 0.01 vs. control). In contrast, in the adrenergic blockade plus islet clamp study, exercise was associated with glucose production substantially lower than control and plasma glucose fell progressively to 58 ± 7 mg/dl (P < 0.001); end-exercise plasma glucose concentrations ranged from 34 to 72 mg/dl. Thus, we conclude that: (a) redundant glucoregulatory systems are involved in the precise matching of increased glucose utilization and glucose production that normally prevents hypoglycemia during moderate exercise in humans. (b) Sympathochromaffin activation, perhaps sympathetic neural norepinephrine release, plays a primary glucoregulatory role by limiting glucose utilization as well as stimulating glucose production. (c) Changes in pancreatic islet hormone secretion (decrements in insulin, increments in glucagon, or both) are not normally critical but become critical when catecholamine action is deficient. (d) Glucoregulation fails, and hypoglycemia can develop, both when catecholamine action is deficient and when changes in islet hormones do not occur during exercise in humans.