Epinephrine secretion, hypoglycemia unawareness, and diabetic autonomic neuropathy

The failure of some type I diabetic patients to secrete epinephrine and glucagon in response to hypoglycemia has been documented by many investigators, and most studies have confirmed that an inability to secrete these counterregulatory hormones places patients at risk for developing clinical hypoglycemia. Inadequate acute glucose counterregulation can result from multiple mechanisms. Failure of central glucoreceptors to recognize hypoglycemia and to activate counterregulation may be the most common. Decreased central recognition of hypoglycemia results from either strict antecedent glucose control or from a recent hypoglycemic event. Controversy about the relation between autonomic neuropathy and counterregulatory hormone secretion has arisen because divergent criteria have been used in the published studies for the diagnosis of autonomic neuropathy. Advanced adrenergic neuropathy, as evidenced by orthostatic hypotension, generally leads to decreased epinephrine secretion after hypoglycemia. Subclinical neuropathy, however, as diagnosed from measurement of heart rate variability, may diminish the awareness of hypoglycemia but does not affect counterregulatory hormone secretion. Failure of counterregulatory hormone secretion in some patients with type I diabetes, however, may represent a selective autonomic neuropathy; the disease has limited the patient's ability to secrete epinephrine and pancreatic polypeptide in response to hypoglycemia even though it has spared the autonomic neurons responsible for cardiovascular reflexes. Finally, recent provocative reports indicate that decreased responsiveness to adrenergic stimuli may cause hypoglycemia unawareness in some patients. Further documentation of this mechanism is required, and its relative importance with respect to other mechanisms needs to be established. These questions are increasingly important clinically because the Diabetes Control and Complications Trial has confirmed that the prevalence of severe hypoglycemia remains a major obstacle to attempts to prevent diabetic complications with intensive insulin therapy. Until glucose counterregulation is more fully understood and methods for preventing hypoglycemia developed, patients with recurrent hypoglycemia unawareness or a history of hypoglycemia-related accidents should probably not be treated with intensive insulin therapy.