Hypoglycemia in diabetes: pathophysiological mechanisms and diurnal variation

Iatrogenic hypoglycemia, the limiting factor in the glycemic management of diabetes, causes recurrent morbidity (and sometimes death), precludes maintenance of euglycemia over a lifetime of diabetes and causes a vicious cycle of recurrent hypoglycemia. In insulin deficient - T1DM and advanced T2DM - diabetes hypoglycemia is the result of the interplay of therapeutic insulin excess and compromised physiological (defective glucose counterregulation) and behavioral (hypoglycemia unawareness) defenses against falling plasma glucose concentrations. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation (by reducing epinephrine responses in the setting of absent insulin and glucagon responses) and hypoglycemia unawareness (by reducing sympathoadrenal and the resulting neurogenic symptom responses) and thus a vicious cycle of recurrent hypoglycemia. The clinical impact of HAAF-including its reversal by avoidance of hypoglycemia-is well established, but its mechanisms are largely unknown. Loss of the glucagon response, a key feature of defective glucose counterregulation, is plausibly attributed to insulin deficiency, specifically loss of the decrement in intraislet insulin that normally signals glucagon secretion as glucose levels fall. Reduced neurogenic symptoms, a key feature of hypoglycemia unawareness, are largely the result of reduced sympathetic neural responses to falling glucose levels. The mechanism(s) by which hypoglycemia shifts the glycemic thresholds for sympathoadrenal activation to lower plasma glucose concentrations, the key feature of both components of HAAF, is not known. It does not appear to be the result of the release of a systemic mediator such as cortisol or epinephrine during antecedent hypoglycemia or of increased blood-to-brain glucose transport. It is likely the result of an as yet to be identified alteration of brain metabolism. While the research focus has been largely on the hypothalamus, hypoglycemia is known to activate widespread brain regions including the medial prefrontal cortex. The possibility of post-hypoglycemic brain glycogen supercompensation has also been raised. Finally, a unifying mechanism of HAAF would need to incorporate the effects of sleep and antecedent exercise which produce a phenomenon similar to hypoglycemia induced HAAF.