Hypoglycaemia: the limiting factor in the glycaemic management of Type I and Type II diabetes.

Hypoglycaemia is the limiting factor in the glycaemic management of diabetes. Iatrogenic hypoglycaemia is typically the result of the interplay of insulin excess and compromised glucose counterregulation in Type I (insulin-dependent) diabetes mellitus. Insulin concentrations do not decrease and glucagon and epinephrine concentrations do not increase normally as glucose concentrations decrease. The concept of hypoglycaemia-associated autonomic failure (HAAF) in Type I diabetes posits that recent antecedent iatrogenic hypoglycaemia causes both defective glucose counterregulation (by reducing the epinephrine response in the setting of an absent glucagon response) and hypoglycaemia unawareness (by reducing the autonomic and the resulting neurogenic symptom responses). Perhaps the most compelling support for HAAF is the finding that as little as 2 to 3 weeks of scrupulous avoidance of hypoglycaemia reverses hypoglycaemia unawareness and improves the reduced epinephrine component of defective glucose counterregulation in most affected patients. The mediator and mechanism of HAAF are not known but are under active investigation. The glucagon response to hypoglycaemia is also reduced in patients approaching the insulin deficient end of the spectrum of Type II (non-insulin-dependent) diabetes mellitus, and glycaemic thresholds for autonomic (including epinephrine) and symptomatic responses to hypoglycaemia are shifted to lower plasma glucose concentrations after hypoglycaemia in Type II diabetes. Thus, patients with advanced Type II diabetes are also at risk for HAAF. While it is possible to minimise the risk of hypoglycaemia by reducing risks -- including a 2 to 3 week period of scrupulous avoidance of hypoglycaemia in patients with hypoglycaemia unawareness -- methods that provide glucose-regulated insulin replacement or secretion are needed to eliminate hypoglycaemia and maintain euglycaemia over a lifetime of diabetes.