Hypoglycaemia: Its pathophysiology in insulin treated diabetes and hypoglycaemia unawareness

Abstract

The limitations of current subcutaneous insulin delivery mean that hypoglycaemia is an inevitable side-effect of treatment of insulin-treated diabetes. Early after diagnosis, severe episodes of hypoglycaemia are relatively rare as physiological responses to hypoglycaemia are intact, the most important of which is the release of glucagon. This response, together with the activation of the sympathoadrenal system, oppose the glucose lowering effect of insulin. Autonomic activation generates symptoms which alert patients when their blood glucose is low. As duration of diabetes increases, the glucagon response becomes impaired and this delays the recovery of blood glucose from hypoglycaemic to normal levels. Protection from hypoglycaemia then depends upon sympathoadrenal activation and the release of circulating adrenaline which itself diminishes as the duration of diabetes increases. Sympathoadrenal activation is also impaired by periods of tight glycaemic control due to repeated episodes of hypoglycaemia itself. These acquired pathophysiological changes lead to a high risk of severe hypoglycaemia, in part due to hypoglycaemia unawareness. Avoidance of hypoglycaemia can partly restore hypoglycaemic responses and some symptomatic awareness. Insulin analogues, pump therapy and high quality skills training in insulin self-management may also reduce hypoglycaemic risks. Rates of hypoglycaemia are generally lower in type 2 diabetes although patients become increasingly vulnerable as endogenous insulin secretion declines. Until insulin can be delivered more physiologically, a major challenge, hypoglycaemia will remain the chief barrier to achieving glycaemic targets in insulin-treated diabetes.