The pathophysiology of iatrogenic hypoglycemia in patients with insulin-dependent diabetes mellitus has been studied extensively during the past decade. It is now widely recognized that some patients with long-standing diabetes lose their ability to secrete the major counterregulatory hormones, glucagon and epinephrine, and fail to have hypoglycemia-related autonomic warning symptoms. Many investigators focused initially on the role of autonomic neuropathy, assuming that the latter might explain the diminished epinephrine response to hypoglycemia and the blunted adrenergic warning signs. Although these studies confirmed that patients with advanced diabetic autonomic neuropathy have attenuated counterregulatory hormonal responses to hypoglycemia, many patients with inadequate counterregulatory hormone secretion lack the typical signs, symptoms, or cardiovascular reflex abnormalities typical of diabetic autonomic neuropathy. These patients may have a new variant of diabetic autonomic failure that selectively affects the central and peripheral autonomic mechanisms, which initiate epinephrine secretion and the defense against hypoglycemia.
A potentially reversible cause for the failure of the counterregulatory hormone response to hypoglycemia has also been recently described.In this instance, the central nervous system fails to recognize hypoglycemia. The brain does not activate counter-regulation, and the patient develops no symptoms of hypoglycemia. Decreased central recognition of hypoglycemia results from either strict antecedent control or from a recent hypoglycemic event.
The pathophysiology of hypoglycemia in patients with insulin-dependent diabetes mellitus is currently of great clinical interest. The recently completed Diabetes Control and Complications Trial  has documented conclusively that the excellent glycemic control achieved through intensive insulin therapy prevents multiple diabetic complications but confers an enhanced risk for severe hypoglycemia. Ten years ago, we reported that some patients with type I diabetes mellitus fail to secrete epinephrine in response to hypoglycemia and, therefore, do not develop the typical adrenergic symptoms that warn them that their blood sugar levels have decreased [2, 3]. The epinephrine response to hypoglycemia is critical in patients with type I diabetes, because most lack the ability to secrete glucagon in response to hypoglycemia and are, therefore, dependent on adrenergic mechanisms for acute glucose counterregulation. Some patients who fail to secrete epinephrine in response to hypoglycemia have advanced autonomic neuropathy, as shown by orthostatic hypotension . However, we also observed patients who had no symptoms of autonomic neuropathy and who did well on autonomic function tests yet failed to secrete epinephrine in response to hypoglycemia . Although the failure of acute glucose counterregulation in patients with type I diabetes has been confirmed by many investigators, the pathophysiology of this phenomenon and its relation to autonomic neuropathy and hypoglycemia unawareness have been controversial. We review this area of research by attempting to answer the following series of questions.
Is the Failure of Acute Glucose Counterregulation the Result of Autonomic Neuropathy?
Autonomic neuropathy does not adequately explain the failure of acute glucose counter-regulation in patients with type I diabetes, because some patients with inadequate epinephrine responses to hypoglycemia have no signs, symptoms, or cardiovascular reflex abnormalities indicative of autonomic dysfunction [2, 4-9]. Failure of glucose counterregulation in some of these patients may be the result of tight antecedent control or a recent hypoglycemic event. Even healthy persons have a decreased symptomatic response as well as a decreased epinephrine response to hypoglycemia 16 hours after a standardized hypoglycemic stimulus Figure 1[10, 11]. This proves that glucose counterregulation can be affected independent of autonomic neuropathy. In addition, hyperinsulinemia itself has recently been shown to suppress the counterregulatory response to hypoglycemia . These observations indicate that the interpretation of counterregulatory response to hypoglycemia is more complex than previously realized. However, we disagree with the recent suggestion  that failure in glucose counterregulation in diabetes is solely the result of metabolic abnormalities associated with diabetes and that preexisting autonomic neuropathy has no effect on the adrenergic response to hypoglycemia. Polinsky and colleagues  first showed that patients with idiopathic autonomic neuropathy fail to secrete epinephrine in response to hypoglycemia; this was confirmed in patients with both pure autonomic failure and multiple system atrophy. Because these patients did not have diabetes and presumably never had a spontaneous hypoglycemic event or hyperinsulinemia, these studies prove that autonomic neuropathy can disrupt the adrenergic response to hypoglycemia.