Hypoglycaemia unawareness and the brain

Diabetologia, Jun 2002

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.

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Hypoglycaemia unawareness and the brain

D. Smith 0 S. A. Amiel 0 0 Guy's, King's and St Thomas' School of Medicine , London, UK 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. - 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 considerable clinical problem in the pharmacological treatment of diabetes mellitus. This paper will review some of the current literature describing the brains involvement in the mechanisms of control of glucose homeostasis and what can go wrong in patients with diabetes treated pharmacologically. In particular, we will focus on the current state of knowledge of hypoglycaemia sensing and the initiation of the protective counterregulatory responses and the cognitive events of acute hypoglycaemia. The physiological defences against severe hypoglycaemia in diabetes The neuroendocrine responses to hypoglycaemia begin at an arterial plasma glucose concentration just under 4 mmol/l, with a reduction in insulin secretion and a stimulation of pancreatic glucagon. The reduction of insulin secretion may be a local response and there is good evidence to show that factors locally within the pancreas are also crucial to the glucagon response. How glucagon-secreting alpha cells detect and respond to alterations in circulating glucose concentration is not clear, but that their action is in some sense dependent upon the insulin secretory response of the local beta cells is made evident by the diminution of glucagon responses to acute hypoglycaemia in the presence of sulphonylureas [3, 4]. It is thought that the sulphonylureas, acting through their specific receptors on the beta cell, support the concentrations of insulin within the islet, the corollary being that glucagon secretion is, at least in part, secondary to a reduction in beta-cell insulin secretion. Certainly, although the data are incomplete, loss of glucagon responses to acute hypoglycaemia correlates well with loss of C-peptide secretion and is found in patients with advanced Type II (non-insulin-dependent) diabetes mellitus and Cpeptide negative Type I (insulin-dependent) diabetes mellitus within the first five years of the disease [5, 6, 7] and perhaps in late onset Type II diabetes [8], at the insulin requiring stage. Nevertheless, there is also evidence for central involvement in the glucagon response, via activation of the sympathetic and parasympathetic nervous systems [9]. Compared to the responses of the pancreatic hormones, sympathetic stimulation and adrenaline secretion start at slightly deeper degrees of hypoglycaemia and have peripheral as well as direct hepatic actions. Both are under neurological control, and they act to support circulating glucose concentrations by stimulation of glycogenolysis and gluconeogenesis both directly and indirectly. An important part of the actions of the sympathetic nervous system and adrenaline is the peripheral enhancement of lipolysis, releasing non-esterified fatty acids. These provide substrates for gluconeogenesis and also diminish insulin-stimulated peripheral glucose uptake [10]. Glutamine uptake is also enhanced, although proteolysis is not increased [11]. Cortisol and growth hormone responses, which are important in the long-term maintenance of blood glucose concentrations, occur after more prolonged or a severe decrease in circulating glucose concentrations, as their release is secondary to hypothalamic activation [12, 13, 14], and their action on peripheral (...truncated)


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D. Smith, S. Amiel. Hypoglycaemia unawareness and the brain, Diabetologia, 2002, pp. 949-958, Volume 45, Issue 7, DOI: 10.1007/s00125-002-0877-7