Hypoglycaemia unawareness and the brain

Abstract

The intention of this paper is to critically review the current state of knowledge of the role of the brain in the syndrome of hypoglycaemia unawareness.Both the role of the brain in the detection of hypoglycaemia and initiation of the counterregulatory responses and the function of the cerebral cortex during acute hypoglycaemia are considered. The evidence for and against the brain as the primary site of mammalian hypoglycaemia sensing and the mechanisms whereby such sensing may occur and change in hypoglycaemia unawareness are discussed.Current evidence supports a major role for the central nervous system in hypoglycaemia sensing and there is increasing understanding of the mechanisms of counterregulatory failure and cognitive dysfunction in hypoglycaemia unawareness. More needs to be done to expand this understanding and translate it into therapeutic strategies to defend against severe hypoglycaemia in diabetes therapy. [Diabetologia (2002) -002-0877-7 Hypoglycaemia unawareness and the brainDiabetologia (2002) 45:949-958 DOI 10.1007/s00125 D. Smith, S. A. AmielGuy's, King's and St Thomas' School of Medicine, London, UK subjects. As blood glucose decreases, pancreatic insulin secretion decreases and glucagon secretion increases, stimulating endogenous glucose production and slowing the blood glucose fall. Later, sympathetic activation and catecholamine secretion, with release of growth hormone and adrenocorticotrophin, driving release of adrenal cortical steroids, contribute by supporting endogenous glucose production and reducing consumption of glucose by peripheral tissues. An associated complex of symptoms, including hunger, encourages an eating response. The functional anatomy of these responses indicate a central coordinating structure involving the regions around the hypothalamus, hippocampus and caudate nuclei. Failure of some or all of these counterregulatory mechanisms allows a more severe decrease in plasma glucose concentrations, resulting in cortical dysfunction. Thus counterregulatory failure is associated with impaired awareness of hypoglycaemia and an increased risk of severe hypoglycaemia, in which cognitive function is so disturbed that the patient can become drowsy, unco-ordinated, confused or even comatose. This is a Iatrogenic hypoglycaemia was described in the very first days of insulin therapy and hypoglycaemia without subjective awareness was described shortly thereafter. The British pioneer of diabetes therapy, R.D. Lawrence, himself diabetic, gave a clear account of neuroglycopenic hypoglycaemia with reduced subjective awareness more than 60 years ago [1]. Over 20 years ago the site of coordination of glucoregulatory responses was located in the hypothalamus [2].Hypoglycaemia sufficient to cause clinically significant cortical dysfunction does not occur in healthy

Cerebral glutamate metabolism during hypoglycaemia in healthy and type 1 diabetic humans

“…In line with this concept cerebral glucose concentrations measured by magnetic resonance spectroscopy (MRS) were higher in type 1 diabetic patients with hypoglycaemia unawareness than in healthy subjects during hyperglycaemia [6]. In contrast, no global alteration of brain glucose transport in type 1 diabetic subjects was found when positron emission tomography was employed for direct quantification of brain glucose uptake [7,8].…”

Canine Responses to Hypoglycemia in Patients with Type 1 Diabetes

“…21 Despite the wide range of hypoglycemia-related signals, people with diabetes often experience poor awareness of their own symptoms, with accuracy of detection typically waning over time due to the effects of advancing age or complications of the condition, such as autonomic neuropathy. 22 Although numerous techniques (e.g., glucose sensors, skin conductors, heart-rate monitors) have been developed to facilitate early detection of hypoglycemia, 23,24 none of these, as yet, are considered reliable, practical, or suitable for use outside clinical settings.…”

Hypoglycemia-Dependent β₂-Adrenoceptor Downregulation: A Contributing Factor to Hypoglycemia Unawareness in Patients with Type-1 Diabetes?

“…However, a recent article showed that blood-to-brain glucose transport, cerebral glucose metabolism, and blood flow are not increased after hypoglycemia [5]. Therefore, the pathophysiology of hypoglycemia unawareness still remains incompletely understood [10]. …”