Clues Emerge for Autonomic Glitch in Diabetes

The mechanisms of hypoglycemia-associated autonomic failure (HAAF) in diabetes remain unknown, but several recently uncovered clues suggest the condition can be prevented or its effects minimized, according to this review.

A half dozen or more drugs have the potential to raise glucose concentrations or reverse glucose counter-regulatory defects characteristic of HAAF. Preclinical and clinical studies have shown that lactate affects brain metabolism, suggesting a mechanistic explanation for HAAF and approaches to managing the condition.

Alterations in the cerebral network also may play a role in the pathogenesis of HAAF, Philip E. Cryer, MD, of Washington University in St. Louis, said in a "Perspective" article published online in the New England Journal of Medicine.

"Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes," Cryer wrote. "It causes recurrent illness in most people with type 1 diabetes mellitus and in many with advanced type 2 diabetes mellitus and is sometimes fatal. It generally precludes maintenance of euglycemia over a lifetime of diabetes and thus full realization of the benefits of glycemic control."

HAAF arises from compromised defenses against hypoglycemia. Treatment-induced insulin excess can initiate a hypoglycemic episode, which often occurs during periods of less marked therapeutic insulin excess or even relative therapeutic insulin excess in patients with compromised defense mechanisms against hypoglycemia.

Patients with type 1 diabetes or advanced type 2 diabetes have beta-cell failure or endogenous insulin deficiency. Within the context of compromised physiologic defenses against hypoglycemia, falling plasma glucose levels do not elicit a normal metabolic response. Instead, insulin levels fail to decline, glucagon secretion does not increase, and epinephrine secretion is attenuated.

"This combination of compromised physiologic defenses causes the clinical syndrome of defective glucose counter-regulation, which increases the risk of recurrent hypoglycemia by a factor of 25 or more," according to Cryer.

Hypoglycemia-associated autonomic failure (HAAF) refers to recent hypoglycemia associated with defective glucose counter-regulation (by attenuated epinephrine response) and hypoglycemia unawareness (by attenuated sympathetic neural response), leading to a vicious cycle of recurrent hypoglycemia. The mechanisms of hypoglycemia-associated autonomic failure in diabetes remain unknown, but several recently uncovered clues suggest the condition can be prevented or its effects minimized.

The discovery that hypoglycemia attenuates defenses against subsequent episodes of hypoglycemia gave rise to the concept of HAAF: Recent hypoglycemia causes defective glucose counter-regulation (by attenuated epinephrine response) and hypoglycemia unawareness (by attenuated sympathetic neural response), leads to a vicious cycle of recurrent hypoglycemia.