Remembrance of things past: The consequences of recurrent hypoglycaemia in diabetes

Aims: People with type 1 and type 2 diabetes still frequently experience hypoglycaemia, which can be severe, leading to loss of consciousness. This review will examine the cellular consequences of recurrent hypoglycaemia. Methods: This review, based on the Dorothy Hodgkin Lecture given at the Diabetes UK 2022 annual symposium by the author, will discuss our current understanding of the mechanisms by which hypoglycaemia is detected and the consequences of recurrent exposure to hypoglycaemia. Results: Glucose-responsive cells found in the periphery as well as multiple areas of the brain are organised in a classical sensori-motor integrative network encompassing peripheral, hindbrain and hypothalamic components. The mechanism used by glucose-responsive neurons to detect hypoglycaemia parallel those of the classical glucose sensor the pancreatic ß-cell, namely in their use of glucokinase, K _ATP channels and AMP-activated protein kinase. Recurrent exposure to hypoglycaemia results in a series of cellular adaptations that may be designed to increase the resilience of cells to future hypoglycaemia. This review also highlights how hypoglycaemia, as an oxidative stressor, may also exacerbate chronic hyperglycaemia-induced increases in oxidative stress and inflammation, leading to damage to vulnerable brain regions. Conclusions: Impaired awareness of hypoglycaemia follows the adaptation of central glucose-responsive neurons to repeated hypoglycaemia and may represent a form of memory called habituation. In diabetes, recurrent hypoglycaemia may have tissue consequences as a result of a profound disruption in the cellular response to a hypoglycaemic challenge that increases vulnerability to oxidative damage.