Hypoglycaemia unawareness and the brain
D. Smith
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S. A. Amiel
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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.
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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)