Endocrine Abstracts

Hypoglycaemia (low blood glucose) is the most important acute side effect of insulin and insulin secretagogue therapies for diabetes mellitus. The initial response to a threat to the circulating glucose concentration is cessation of endogenous insulin and stimulation of pancreatic glucagon release – neither of which happen in insulin deficient diabetes. Patients with diabetes depend on other autonomic and most importantly symptomatic responses to defend against falls in blood glucose low enough seriously to impair cognitive function. Up to 40% of people with established type 1 diabetes and an as-yet undetermined proportion of people with type 2 develop defects in these further responses which means that cortical impairment is the first clinical correlate of a falling glucose. This state increases risk of severe hypoglycaemia six fold. The defects in glucose counterregulation and hypoglycaemia perception are induced by antecedent exposure to hypoglycaemia and may be associated with other elements of autonomic dysfunction specific to the state of unawareness (i.e. not necessarily to classical diabetic autonomic neuropathy). Hypoglycaemia also affects brain function in the medium term, in that memory formation and consolidation are both adversely affected by low glucose, although in adults there is no strong evidence for permanent brain dysfunction from hypoglycaemic episodes from which apparently full recovery is made at the time.

The regional brain responses to acute symptomatic hypoglycaemia include stimulation of glucose-responsive neurones in the hypothalamus and brain stem nuclei and activation of brain regions involved in stress (the HPA axis); and interoception (the anterior cingulate cortex), as well as changes in activation in reward and appetite control pathways. Many of these central responses are altered in hypoglycaemia unaware patients. The differences in cortical responses may underlie clinical observations of low concern about hypoglycaemia expressed by many diabetic patients with hypoglycaemia unawareness and of reduced compliance with regimen changes intended to prevent hypoglycaemia. On-going research is using education and technology to help prevent recurrent hypoglycaemia in these patients and restore their protection from severe hypoglycaemia.

Declaration of funding

The work to be presented is a review but the author’s own work has received grant funding from Diabetes UK, Juvenile Diabetes Research Foundation International, Wellcome Trust, Medtronic Inc, The King’s College Hospital Charity.