Hypoglycemia unawareness.

Iatrogenic hypoglycemia is the limiting factor in the glycemic control of diabetes. It causes recurrent symptomatic and sometimes, at least temporally, disabling episodes in most people with type 1 diabetes, as well as in many with advanced type 2 diabetes. Furthermore, iatrogenic hypoglycemia precludes maintenance of euglycemia during the lifetime of a person with diabetes and thus full realization of the well established benefits of glycemic control. In this article I discuss the clinical problem of hypoglycemia in diabetes from the perspective of pathophysiology. First, the syndromes of defective glucose counterregulation and hypoglycemia without warning symptoms (known as hypoglycemia unawareness) are described, followed by the unifying concept of Hypoglycemia-Associated Autonomie Failure (HAAF). The concept of hypoglycemia-associated autonomie failure in diabetes posits that recurrent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness and thus leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. The clinical relevance of this phenomenon is now well established, but the mechanisms and mediators remain largely unknown. The short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The ultimate goal of lifelong maintenance of euglycemia in patients with diabetes remains elusive because of the pharmacokinetic imperfections of all current glucose-lowering therapies and the resulting barrier of hypoglycemia. Nonetheless, it is now possible both to improve the control of glycemia and to reduce the frequency of hypoglycemia in many people with diabetes. These results can be accomplished by recognizing the problem of hypoglycemia applying the principles of aggressive glycemic therapy and reducing the risk factors of hypoglycemia in people with diabetes.