Awakening from Sleep and Hypoglycemia in Type 1 Diabetes Mellitus

The Diabetes Control and Complications Trial in type 1 diabetes (T1DM) unequivocally showed the benefi ts of good glycemic control in preventing the complications of diabetes. Despite the treatment advances of the past decade, today iatrogenic hypoglycemia remains the major impediment to the appropriate control of blood glucose [1]. While imperfect insulin replacement places the patient at increased risk for frequent hypoglycemia, patients with T1DM also suffer from compromised counterregulatory responses to hypoglycemia [2]. The responses of all three main counterregulatory hormones normally responsible for rapid reversal of hypoglycemia are severely disrupted in T1DM. First, a decrease in plasma glucose cannot turn off endogenous insulin secretion (which is either insignifi cant or absent). Second, glucagon release during hypoglycemia is impaired soon after onset of diabetes. Third, epinephrine release during hypoglycemia becomes progressively defective in T1DM; its release is triggered only at lower plasma glucose levels, and the maximal concentration of epinephrine released is also signifi cantly reduced [3]. This decrease in epinephrine response during hypoglycemia is accompanied by an attenuated autonomic neural response, which results in the clinical syndrome of impaired awareness of hypoglycemia (i.e., lack of the warning symptoms of prevailing hypoglycemia). Because of the disappearance of autonomic symptoms in such patients, mild hypoglycemia may occur without warning and may proceed unnoticed to more advanced and dangerous phases. Patients suffering from impaired awareness of hypoglycemia in addition to defective counterregulation may be at the greatest risk for developing severe hypoglycemia [4]. Hypoglycemia-associated autonomic failure (HAAF) describes a clinical syndrome apparently resulting from antecedent episodes of mild hypoglycemia that further degrade the counterregulatory response. As shown experimentally in people without diabetes, recurrent and/or recent episodes of hypoglycemia are associated with reduced sympathoadrenal (epinephrine and norepinephrine), symptomatic, and cognitive responses to subsequent hypoglycemia, impairing all of the defense mechanisms required for prevention and reversal of hypoglycemia [5]. Since patients with T1DM have an already reduced counterregulatory response (as mentioned above), HAAF represents a vicious cycle of hypoglycemia begetting further—and more severe— hypoglycemia. The critical role played by even mild episodes of hypoglycemia is exemplifi ed by studies that show that avoidance of hypoglycemia can improve the epinephrine response and reverse impaired awareness of hypoglycemia [6]. Furthermore, recent studies have shown improvement in the counterregulatory response to hypoglycemia in T1DM using pharmacological interventions, suggesting that hypoglycemia sensing plays a role in HAAF [7–9]. A particularly important condition, observed mainly in T1DM, is …