Hypoglycemia remains a major barrier to the achievement of target levels of
glycemic control for most individuals with
insulin-dependent
type 1 diabetes (T1D). Both the loss of β cells and an accompanying defect in the α cell response to
hypoglycemia predispose patients with T1D to the development of low
blood glucose. Increased
glucose variability, exposure to
hypoglycemia, and impaired awareness of
hypoglycemia all contribute to increased risk of experiencing severe
hypoglycemia, which is explained by progressive impairment in
epinephrine secretion and autonomic symptom generation in response to
hypoglycemia leading to defective
glucose counterregulation and
hypoglycemia unawareness that characterize
hypoglycemia-associated autonomic failure (HAAF). Interruption of HAAF requires interfering with the mechanisms of brain adaptation to low
blood glucose that affect central
glucose sensing and the autonomic response to
hypoglycemia, or avoidance of
hypoglycemia that may allow for eventual recovery of counterregulatory and autonomic symptom responses. Strategies for
hypoglycemia avoidance that include continuous
glucose monitoring may reduce, but do not eliminate, clinically significant
hypoglycemia, with ongoing counterregulatory defects and impaired awareness of
hypoglycemia. Complete avoidance of
hypoglycemia can be achieved following pancreatic islet
transplantation and allows for the restoration of counterregulatory and autonomic symptom responses that evidences the potential for reversing HAAF in T1D.