Blood glucose concentration is normally maintained during starvation or increased insulin action by an asymptomatic parasympathetic response with bradycardia and mild hypotension, followed by a sympathetic response with glucagon and epinephrine secretion for short-term glucose counter regulation and growth hormone and cortisol in long-term regulation. Blood glucose concentration is normally maintained during starvation or increased insulin action by an asymptomatic parasympathetic response with bradycardia and mild hypotension, followed by a sympathetic response with glucagon and epinephrine secretion for short-term glucose counter regulation, and growth hormone and cortisol in long-term regulation. The release of catecholamine alerts the patient to take the required measures to prevent coma due to low blood glucose. The absence of warning signs of impending neuroglycopenia is known as "hypoglycemic unawareness". The failure of glucose counter regulation can be confirmed by the absence of glucagon and epinephrine responses to hypoglycemia induced by a standard, controlled dose of insulin (179).

In patients with type 1 diabetes mellitus, the glucagon response is impaired with diabetes duration of 1-5 years, and after 14-31 years of diabetes, the glucagon response is almost undetectable. It is not present in those with autonomic neuropathy. However, a syndrome of hypoglycemic autonomic failure occurs with intensification of diabetes control and repeated episodes of hypoglycemia. The exact mechanism is not understood, but it does represent a real barrier to physiologic glycemic control. In the absence of severe autonomic dysfunction, hypoglycemic awareness associated with hypoglycemia at least in part reversible.

Patients with hypoglycemia unawareness and unresponsiveness pose a significant management problem for the physician. Although autonomic neuropathy may improve with intensive therapy and normalization of blood glucose, there is a risk to the patient, who may become hypoglycemic without being aware of it and who cannot mount a counterregulatory response. It is our recommendation, that if a pump is used, boluses of smaller than calculated amounts should be used and, if intensive conventional therapy is used, long acting insulin with very small boluses should be given. In general, normal glucose and HbA1 levels should not be goals in these patients to avoid the possibility of hypoglycemia (180).

Further complicating management of some diabetic patients is the development of a functional autonomic insufficiency associated with intensive insulin treatment, which resembles autonomic neuropathy in all relevant aspects. In these instances, it is prudent to relax therapy, as for the patient with bona fide autonomic neuropathy. If hypoglycemia occurs in these patients at a certain glucose level, it will take a lower glucose level to trigger the same symptoms in the next 24-48 hours. Avoidance of hypoglycemia for a few days will result in recovery of the adrenergic response.