Hypoglycemia Unawareness—A Review on Pathophysiology and Clinical Implications

Hypoglycemia is a particular problem in people with diabetes while it can also occur in other clinical circumstances. Hypoglycemia unawareness describes a condition in which autonomic and neuroglycopenic symptoms of hypoglycemia decrease and hence are hardly perceivable. A failure to recognize hypoglycemia in time can lead to unconsciousness, seizure, and even death. The risk factors include intensive glycemic control, prior episodes of severe hypoglycemia, long duration of diabetes, alcohol consumption, exercise, renal failure, and sepsis. The pathophysiological mechanisms are manifold, but mainly concern altered brain glucose sensing, cerebral adaptations, and an impaired hormonal counterregulation with an attenuated release of glucagon, epinephrine, growth hormone, and other hormones, as well as impaired autonomous and neuroglycopenic symptoms. Physiologically, this counterregulatory response causes blood glucose levels to rise. The impaired hormonal counterregulatory response to recurrent hypoglycemia can lead to a vicious cycle of frequent and poorly recognized hypoglycemic episodes. There is a shift in glycemic threshold to trigger hormonal counterregulation, resulting in hypoglycemia-associated autonomic failure and leading to the clinical syndrome of hypoglycemia unawareness. This clinical syndrome represents a particularly great challenge in diabetes treatment and, thus, prevention of hypoglycemia is crucial in diabetes management. This mini-review provides an overview of hypoglycemia and the associated severe complication of impaired hypoglycemia awareness and its symptoms, pathophysiology, risk factors, consequences, as well as therapeutic strategies.