To define glycemic thresholds for activation of counterregulatory hormone secretion, initiation of symptoms (autonomic and neuroglycopenic), and onset of deterioration of cognitive function, we measured indexes of these responses during glycemic plateaus of 90, 78, 66, 54, and 42 mg/dl in 10 normal volunteers, with the use of the hyperinsulinemic glucose clamp technique. Activation of glucagon, epinephrine, norepinephrine, and growth hormone secretion began at arterialized venous plasma glucose concentrations of 68 +/- 1, 68 +/- 1, 65 +/- 1, and 67 +/- 2 (SE) mg/dl, respectively. Autonomic symptoms (anxiety, palpitations, sweating, irritability, and tremor) began at 58 +/- 2 mg/dl, which was significantly (P = 0.0001) lower. Neuroglycopenic symptoms (hunger, dizziness, tingling, blurred vision, difficulty thinking, and faintness) and deterioration in cognitive function tests began at 51 +/- 3 and 49 +/- 2 mg/dl, respectively, values that were both significantly (P = 0.018 and 0.004, respectively) lower than that for initiation of autonomic symptoms. We therefore conclude that there is a distinct hierarchy of responses to decrements in plasma glucose, such that the threshold for activation of counterregulatory hormone secretion occurs at higher plasma glucose levels than that for initiation of autonomic warning symptoms, which in turn occurs at higher plasma glucose levels than that for onset of neuroglycopenic symptoms and deterioration in cerebral function. Such a hierarchy would maximize the opportunity to avoid incapacitating hypoglycemia.