Current concepts: Diverse causes of hypoglycemia-associated autonomic failure in diabetes

The original concept of hypoglycemia-associated autonomic failure in type 1 diabetes and advanced type 2 diabetes posited that recent iatrogenic hypoglycemia causes both defective glucose counter-regulation (by reducing the epinephrine response in the absence of a glucagon response) and hypoglycemia unawareness (by reducing the sympatho-adrenal response and the resulting response of neurogenic symptoms), and thus, a vicious cycle of recurrent hypoglycemia. The clinical relevance of this phenomenon is now well established, but the mediators and mechanisms remain largely unknown. Recent data indicate that there are diverse causes of hypoglycemia-associated autonomic failure. In addition to hypoglycemia-induced autonomic failure, the disorder can be related to exercise or sleep. 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. Achievement of that goal will require plasma glucose-regulated insulin replacement or secretion. 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 prindples of aggressive glycemic therapy, and reducing the risk factors for hypoglycemia in people with diabetes.