ADECREASE in the plasma glucose concentration normally evokes a characteristic hierarchy of responses to avoid development of hypoglycemia (1–3) (Fig.1). Initially at approximately 70 mg/dl (4 mm), there is an increase in the secretion of counterregulatory hormones [glucagon, epinephrine, GH, and cortisol (ACTH)] and a concommitant increase in the discharge of autonomic nervous system neurotransmitters (norepinephrine and acetylcholine). If these initial responses do not prevent a further decrease in the plasma glucose concentration, by the time the plasma glucose concentration reaches 60 mg/dl (3.4 mm), the magnitude of the released catecholamines and acetylcholine is such that autonomic symptoms (sweating, tremor, hunger, anxiety, and palpitations) occur (2, 3).

These symptoms can mainly but not exclusively be attributed to neuronally released transmitters rather than adrenomedullary catecholamines, because most symptoms are absent or markedly attenuated by ganglionic blockade, cervical cord section, and sympathectomy but not by adrenalectomy (4–10). In an individual who has previously experienced such symptoms, they usually act as a warning to undertake protective measures against impending hypoglycemia (e.g. intake of food). This activation of the autonomic nervous system has probably evolved primarily as an alarm, rather than a counterregulatory mechanism, because neither ganglionic blockade, sympathectomy, adrenergic antagonists, nor cervical cord section by themselves lead to greater hypoglycemia after insulin administration and do not attenuate restoration of euglycemia (4–11). However, the autonomic, specifically the adrenomedullary, response becomes important to prevention or correction of hypoglycemia when other counterregulatory factors (especially glucagon) are deficient as is the case in most patients with insulin-dependent diabetes mellitus (IDDM) (12).