Clinical Science (1991) 81, 1-9
1
Editorial Review
Physiological disturbances in hypoglycaemia:effect on
subjective awareness
S. R. HELLER AND I. A. MACDONALD*
Northern General Hospital, Sheffield,U.K., and *Department of Physiology and Pharmacology, University of Nottingham Medical
School, Nottingham, U.K.
INTRODUCTION
Activation of the sympathochromaffin system (the sympathetic nervous system, adrenal medulla and extra-adrenal
chromaffin tissue) during hypoglycaemia causes profound
physiological changes, many of which are important in
limiting and reversing the falling blood glucose level. The
metabolic actions of adrenaline (reviewed recently in [ l ,
21) produce an increase in hepatic glucose output and an
inhibition of peripheral glucose uptake. In normal man
these effects are not essential in the prevention of hypoglycaemia during fasting [3] and exercise [4] or to the
recovery from insulin-induced hypoglycaemia [ 5, 61.
Glucagon is the main counter-regulatory hormone, with
recovery from insulin-induced hypoglycaemia being
impaired by 40% if its secretion is prevented by somatostatin [7]. Adrenaline secretion becomes critical in the
absence of glucagon, since, if release of both hormones is
blocked, recovery of the blood glucose level from insulininduced hypoglycaemia is abolished. Cortisol and growth
hormone contribute to recovery from prolonged hypoglycaemia but are not important acutely. In insulin-treated
patients whose glucagon response to hypoglycaemia is
attenuated after 1-2 years of diabetes [8,9], the metabolic
actions of adrenaline are especially important. Some
diabetic patients fail to release adrenaline during hypoglycaemia and are then at risk of severe hypoglycaemic
attacks [lo, 111. However, the presence of sympathochromaffin-mediated peripheral physiological responses
during hypoglycaemia may be equally, if not more,
important than metabolic effects in diabetic patients
treated with insulin, as these responses may underlie the
symptoms of hypoglycaemia perceived by the patient.
The purpose of this review is to discuss the role of the
Correspondence: Dr I. A. Macdonald, Department of
Physiology and Pharmacology, University of Nottingham
Medical School, Queen’s Medical Centre, Clifton Boulevard,
Nottingham NG7 2UH, U.K.
sympathochromaffin system during hypoglycaemia,
especially in regard to hypoglycaemic warning symptoms.
Peripheral physiological responses to hypoglycaemia
Sweating. Morphological studies using histochemical
and electron-micrographic techniques have shown that
human sweat glands are innervated by both sympathetic
post-ganglionic cholinergic and adrenergic fibres [ 12, 131.
Local administration of adrenaline can stimulate
sweating, an effect prevented by a-adrenergic antagonists
[ 141. However, sweating during hypoglycaemia occurs in
patients after adrenalectomy [151 or splanchnicectomy
[16], and is prevented by prior administration of atropine
[ 171. Thus, hypoglycaemia-induced sweating is probably
mediated centrally through sympathetic cholinergic fibres
[IS].
Cardiovascular system. Cardiac output increases
during hypoglycaemia owing to an initial increase in heart
rate and then in stroke volume [19, 201. Moderate hypoglycaemia results in a fall in diastolic blood pressure and a
rise in systolic blood pressure [21], an effect abolished by
prior adrenalectomy [22], adrenal denervation [16] or
ganglion blockade [23]. The change in blood pressure is
probably due to circulating adrenaline, since its infusion
has a similar effect [24,25].
Changes in peripheral blood flow are complex and
even modern experimental methods are not sufficiently
sensitive to completely clarify regional alterations.
Forearm and calf blood flows increase during hypoglycaemia [21], partly due to stimulation by adrenaline of
p-adrenoceptor-mediated vasodilatation in muscle and
stimulation of cholinergic sympathetic vasodilator fibres
to skeletal muscle and cholinergic sudomotor nerves to
the skin. These effects generally override a-adrenoceptor-mediated vasoconstriction due to adrenaline
[26-281. Hand blood flow, measured by venous occlusion
plethysmography, increases in response to hypoglycaemia
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S. R. Heller and I. A. Macdonald
during most [26-291, but not all [21, 291, studies. This
increase in flow is opposite to the effects of adrenaline,
and is thought to be due to release of neurogenic vasoconstrictor tone [26].
It is now apparent that the original presumption that
hand blood flow reflects cutaneous blood flow is somewhat misleading. There is a substantial amount of muscle
and subcutaneous tissue in the hand, and the relative
contributions of these and the cutaneous tissues to total
hand blood flow have not been determined. Abdominal
subcutaneous blood flow falls during hypoglycaemia [30],
and recent studies of cutaneous blood flow velocity (using
laser Doppler flowmetry) in diabetic patients during
insulin-induced hypoglycaemia showed a fall in flow when
measured at the base of the fingers [31] or on the forearm
or forehead [32]. However, in non-diabetic subjects, both
increased [32] and decreased [33] cutaneous blood flow
velocities have been reported. In the latter study, 60 min
of stable insulin-induced hypoglycaemia (blood glucose
level, 2.5 mmol/l) was compared with a period of similar
insulinaemia with maintained euglycaemia in non-diabetic
subjects. A laser Doppler flowmeter was applied to the
pulp of the great toe (comprising predominantly arteriovenous anastomotic flow) and the dorsum of the foot
(mainly nutritional flow), and total blood flow in the
contralateral great toe was measured by venous occlusion
plethysmography. Within 10 min of achieving stable
hypoglycaemia there was an increase in sweat evaporation
from the abdomen. Ten minutes later there were significant falls in total toe blood flow and in cutaneous blood
velocity at both sites, even though forearm blood flow
increased (as previously reported [21]). Thus, there is
some disagreement over the effects of hypoglycaemia on
cutaneous flow. However, a reduction in skin blood flow
would be consistent with the clinical features of pallor that
characterize hypoglycaemia in diabetes, and also with the
effects of adrenaline infusion (producing plasma adrenaline levels identical with those found in hypoglycaemia)
on cutaneous flow velocity [34].
There are alterations in splanchnic and splenic blood
flow during experimental insulin-induced hypoglycaemia.
Bearn et al. [35] reported an increase in splanchnic blood
flow, beginning 10 min after the hypoglycaemic nadir and
lasting for approximately 45 min. This may explain why a
subsequent study reported no change in splanchnic flow,
as measurements were made at the hypoglycaemic nadir
and 60 min later [20]. Recently, Doppler-ultrasound has
been used to show a 40-50% increase in superior mesenteric artery blood flow for 60 min after the production of
hypoglycaemia [36]. This effect is not due to a vascular
action of insulin, as insulin infusion with maintained
euglycaemia is accompanied by a slight fall in superior
mesenteric artery blood flow [37]. It appears that splenic
blood flow falls during and after hypoglycaemia [38].
Early studies of cerebral blood flow during hypoglycaemia in humans were inconsistent, with reports of no
effect [39] or of an increase [40, 411. These studies were
performed by cannulation of the carotid artery and
jugular vein, using a nitrous oxide method to determine
flow. More recently, the '"Xe-washout technique was
used to show increases in cerebral blood flow of approximately 20% in both diaetic patients and non-diabetic
subjects at a blood glucose level of 2 mmol/l [41]. The
increased cerebral blood flow in the diabetic patients
persisted into the euglycaemic recovery period, but it is
not clear whether this is of any physiological importance.
It seems likely that the majority of the haemodynamic
changes in hypoglycaemia are mediated by the cardiovascular effects of adrenaline, although there may be
some involvement of the sympathetic nervous system
(either activation or inhibition). Thus, one might expect an
altered pattern of changes in diabetic patients with
abnormal sympathochromaffin responses to hypoglycaemia.
Body temperature. Hypoglycaemia induced by insulin
[42], or by alcohol in glycogen-depleted subjects [43], is
accompanied by a fall in core temperature. In a warm
environment this reduction in temperature occurs despite
a rise in metabolic heat production, and is due to
increased heat loss from peripheral vasodilatation and
sweating [42]. The fall in core temperature is not prevented by skin vasoconstriction, as there is simple
conduction of heat to the skin surface from the underlying
muscle (which undergoes vasodilatation) through the
subcutaneous and cutaneous tissues. If subjects are
exposed to a cold environment for a sufficiently long
period such that shivering occurs, insulin-induced hypoglycaemia rapidly abolishes shivering and subjects also
cease complaining of feeling cold [42]. The consequence
of this is that hypothermia rapidly develops as a result of
high rates of heat loss with reduced heat production.
Shivering is rapidly restored by intravenous administration of glucose, even in muscles which remain hypoglycaemic due to arterial occlusion [42]. Thus, the inhibition of
shivering is not due to a shortage of glucose in skeletal
muscle, but is almost certainly caused by cerebral (probably hypothalamic) neuroglycopenia.
Tremor. Physiological tremor increases during hypoglycaemia [44] to a similar extent to that seen after
infusion of adrenaline [45, 461. Intra-arterial infusion of
isoprenaline causes local tremor, and it seems likely that
the increased tremor of hypoglycaemia is caused by a
peripheral action of adrenaline mediated through Badrenoceptors. In a study where effects of different
p-blocking agents on physiological responses during
hypoglycaemia were compared, propranolol had the
greatest effect in suppressing tremor, although increases
were attenuated by both metoprolol and atenolol [47].
Since the latter are selective P,-antagonists, this suggests
that tremor is mediated predominantly through &adrenoceptors, although the reduced tremor seen with
both metoprolol and atenolol indicates that there may be
a P,-adrenoceptor component to the tremor response.
Sympathetic nervous system. It is generally believed
that hypoglycaemia is a potent stimulus for activating the
sympathetic nervous system. However, this does not fit
entirely with the cardiovascular changes seen during
hypoglycaemia, as skin neurogenic vasoconstrictor
activity is presumed to diminish [26] and muscle blood
vessels dilate. Furthermore, it is now apparent that the
Physiological disturbances in hypoglycaemia
sympathetic nervous system is a discrete regulatory
system which is normally selectively activated rather than
responding in an all-or-none fashion. Attempts to directly
measure sympathetic activity in man are restricted to
microneurographic recording of action potentials from
superficial nerves in the limbs, or from measurements of
the turnover rate of plasma noradrenaline (most of which
arises from spill-over from the sympathetic neuroeffector
junction). With the latter technique it has been shown that
the rate of appearance of noradrenaline in the circulation
increases during hypoglycaemia [48]. Unfortunately, it
cannot be established whether in this instance the noradrenaline arises from sympathetic post-ganglionic nerves
or from the adrenal medulla. Direct recording of action
potentials in the peroneal nerve during hypoglycaemia in
non-diabetic subjects revealed a substantial increase in
muscle sympathetic activity [49]. It is likely that this
represented increased activity in vasoconstrictor nerves.
However, the functional relevance of this is unclear, as
muscle normally exhibits vasodilatation during hypoglycaemia, presumably through the effects of circulating
adrenaline. Skin sympathetic activity also increases during
hypoglycaemia [SO]. Berne & Fagius [SO] suggested this
was due to increased sudomotor nerve activity, and interpreted the altered firing patterns that they recorded as
indicating a decrease in skin sympathetic vasoconstrictor
nerve activity. Such an occurrence would be interesting in
the light of our own demonstration of reduced toe and
foot skin blood flow during hypoglycaemia [33], and it is
obvious that further studies are needed to clarlfy this.
In summary, the physiological changes in hypoglycaemia are predominantly the result of sympathochromaffin activation, although increases in gastric acid
secretion (Hollander test), gastro-intestinal motility [S 11
and salivation [18] are likely to involve parasympathetic
stimulation. The next section of this review will consider
the factors that contribute to subjective awareness of
being hypoglycaemic, and the extent to which the effects
of sympathochromaffin activation are determinants of this
awareness.
HYPOGLYCAEMICWARNING SYMPTOMS
After the introduction of insulin to treat insulin-dependent diabetes mellitus, it was soon apparent that severe
hypoglycaemia caused profound neurological dysfunction
culminating in unconsciousness. However, it was realized
that physiological responses at an earlier stage of hypoglycaemia could be used to warn patients that their blood
glucose level was falling below normal [52]. Warning
symptoms were divided into two groups that were thought
to be associated with either activation of the sympathetic
nervous system or cerebral dysfunction [53], and were
later termed ‘adrenergic’ and ‘neuroglycopenic’ symptoms, respectively [54].
Common adrenergic symptoms were sweating, tremor,
palpitations and facial flushing, whereas early neuroglycopenic symptoms included loss of concentration,
tiredness and tingling of the extremities. Some symptoms,
such as feelings of hunger, do not fall easily into either
3
category and different authors have chosen to place them
in either group.
Early papers described patients who had lost many of
their ‘adrenergic’ symptoms, which was attributed to the
use of longer-acting insulins, although the only common
factor was a duration of diabetes of over 5 years [SS, 561.
Neuroglycopenic symptoms were still often present;
although some patients became adept at recognizing
these, other patients found them less dependable and they
were then at risk of sudden episodes of unconsciousness.
If diabetic patients could always recognize impending
hypoglycaemia, then defects in endocrine counter-regulation would be unimportant, since the blood glucose level
could always be raised by eating. Yet, since those patients
who develop hypoglycaemia unwareness note a decrease
in adrenergic symptoms, one might predict an association
between impaired adrenaline counter-regulation and
hypoglycaemia unwareness.
However, increases in circulating adrenaline are not the
sole caue of hypoglycaemia awareness. French &
Kilpatrick [ 161showed that patients who had undergone a
splanchnicectomy, and so could not release adrenaline,
had all the usual symptoms of hypoglycaemia except
palpitations. This might be expected, since sweating is
mediated by sympathetic cholinergic fibres [18] and facial
flushing (and warmth), a common symptom of hypoglycaemia, is probably caused by loss of vasoconstrictor
tone and is not mediated by adrenaline. Thus, although
circulating adrenaline causes increased pulse pressure
(which is likely to contribute to the perceived palpitations), other ‘adrenergic’symptoms may be due to activation of the sympathetic nervous system. This idea is
supported by studies where hypoglycaemia was induced
in tetraplegic patients, who presumably had no resulting
sympathoadrenal response. ‘Adrenergic’ symptoms did
not develop, although patients exhibited neuroglycopenic
symptoms, such as drowsiness [57, 581. The term
‘adrenergic’ should probably be replaced by ‘neurogenic’,
which would reflect the pathophysiology more accurately
[591.
EFFECT OF B-BLOCKADE ON HYPOGLYCAEMIC
RESPONSES
Traditionally, /?-adrenoceptor antagonists (especially the
non-selective type) are contra-indicated in diabetic
patients treated with insulin [60]. Non-selective /?-blockade does not inhibit recovery of the blood glucose level in
normal subjects if hypoglycaemia is mild [27, 611,
although recovery may be delayed if high doses of insulin
are given [62, 631. Studies in diabetic patients given
propranolol demonstrate an impaired rise in the blood
glucose level after insulin-induced hypoglycaemia [611, a
consequence of inhibition of hepatic glucose output in the
absence of glucagon secretion. However, recovery of the
blood glucose level after hypoglycaemia in the presence of
B1-selectiveblocking agents was normal in some [64,65],
but not all [66,67], studies. This suggests that increases in
hepatic glucose output are mediated through /?,-adrenoceptors. The contradictory results of some of these
4
S. R. Heller and I. A. Macdonald
studies are probably due to the loss of P,-selectivity in
those studies that used higher concentrations of P-blocking agents. However, another important effect of pblocking drugs may be to modify hypoglycaemic warning
symptoms by masking peripheral sympathetic changes,
and few studies have directly measured the effects of this
class of drugs on physiological responses to and symptoms of hypoglycaemia.
The effect of P-blockers on hypoglycaemia-induced
sweating is variable, with some studies showing no effect
[27] and others demonstrating an increase [68]. Interestingly, in the former study there was an increase in sweating on the forehead, but not over the remainder of the
body [27]. Systolic blood pressure and diastolic blood
pressure rise when hypoglycaemia is induced during nonselective ,&blockade [27, 691, a consequence of increased
a-mediated vasoconstriction, secondary to reduced catecholamine clearance. (During hypoglycaemia in the
presence of P-blockade, there are enhanced plasma
adrenaline levels due to reduced clearance.) This results
in a baroreflex-induced bradycardia, which, in the
absence of a widening of pulse pressure, prevents the
perception of palpitations. In addition, peripheral vasoconstriction will block the common hypoglycaemic
symptom of warmth. However, neither selective nor
non-selective P-blocking drugs reduce total hypoglycaemic symptom scores in non-diabetic subjects [47]. While
some physiological responses and symptoms (e.g. tremor)
were reduced by prior ,4-blockade, others (e.g. sweating)
were increased. Furthermore, in patients with insulindependent diabetes, @,-selective blockade is accompanied by increased subjective sensation of sweating, but no
direct measurements were made [70]. It is not clear why
sweating should be more prominent when hypoglycaemia
is induced in the presence of @-blockade. One possibility
is that peripheral vasoconstriction, induced by unrestrained a-adrenoceptor stimulation and elevated plasma
adrenaline levels, prevents evaporation of sweat. Thus,
sweating appears more prominent due to pooling on the
skin surface. However, Molnar & Read [68] showed that
subjects had an increased loss of weight when hypoglycaemia was induced during pblockade, suggesting that
the rate of sweating was increased, and our measurement
of sweat evaporation would confirm this [47]. It would
seem appropriate to see whether skin sympathetic nerve
activity increases in these circumstances or if the
increased sweat production is due to the elevated plasma
adrenaline levels giving rise to a-adrenoceptor-mediated
sweating.
A recent study [71] of the effects of propranolol during
hypoglycaemia in insulin-dependent diabetic patients also
found that overall symptoms were actually increased in
the presence of propranolol. However, it also showed that
the blood glucose threshold at which symptoms first
appeared was lowered slightly by propranolol, although
the clinical significance of this observation was not clear
[71]. Similar observations have not been made with PIselective drugs.
In summary, neither selective nor non-selective pblocking drugs reduce overall symptoms of hypo-
glycaemia, and it is unlikely that they cause unawareness of
hypoglycaemia. However, the impairment in recovery of
the blood glucose level caused by non-selective agents
suggests that @,-selective drugs should be used in insulintreated patients requiring anti-anginal or anti-hypertensive treatment.
AWARENESS OF HYPOGLYCAEMIA
The study of Sussman et al. [72] is one of the few to
examine hypoglycaemic warnings in detail. When the
blood glucose level was lowered to a median of 1 mmol/l,
only five out of 44 diabetic patients did not have a sympathetic response (manifest indirectly by a rise in non-esterified fatty acid concentration). Of the remaining 39, 16
showed typical sympathetic changes, but were so mentally
obtunded due to neuroglycopenia that they failed to
recognize them, while the rest were aware of their physiological responses. We have shown that, among normal subjects and diabetic patients whose blood glucose level was
lowered during a glucose clamp, those who recognized
hypoglycaemia were those with significant increases in
circulating adrenaline and symptoms and signs due to
activation of the sympathetic nervous system [44].
Eleven of the 15 patients studied were unaware of
being hypoglycaemic when their blood glucose level was
2.5 mmol/l. These 11 had significantly smaller rises in
plasma adrenaline level and no symptoms or signs compared with the four patients who were aware of this
degree of hypoglycaemia [44]. Five of these 11 patients
had a history of loss of hypoglycaemic warnings but the
other six did not. The only distinguishing feature between
the 11 patients who were unaware of being hypoglycaemic at a blood glucose level of 2.5 mmol/l and the
four who were aware, was that the former had better diabetic control (i.e. a lower concentration of haemoglobin A, ).
The observation that most patients with insulindependent diabetes d o display a sympathochromaffin
response during severe hypoglycaemia (but are unable to
act appropriately because of neuroglycopenia) suggests
that the reduced or absent responses seen in many
patients at more moderate levels of hypoglycaemia may
be due to an alteration in the blood glucose threshold for
producing such responses. Grimaldi et al. [73] reported a
blood glucose threshold for an adrenaline response to
hypoglycaemia of between 3.1 and 1.6 mmol/l in seven
insulin-dependent diabetic patients with hypoglycaemia
unawareness, compared with a threshold of between 4.6
and 3.2 mmol/l in seven diabetic patients whose awareness was retained. The glycaemic threshold for an adrenaline response to hypoglycaemia is reduced after
intensified treatment of insulin-dependent diabetes [74].
Furthermore, there are reduced adrenaline responses to a
fixed level of moderate hypoglycaemia in diabetic patients
with good glycaemic control (indicated by a low concentration of haemoglobin A, [44, 751. Boyle et al. [76] have
also shown that the glycaemic threshold for the onset of
hypoglycaemic symptoms is at a higher level in insulintreated patients with poor glycaemic control (i.e. a high
concentration of haemoglobin A,) when compared with
Physiological disturbances in hypoglycaemia
non-diabetic subjects. Thus, the evidence indicates that
glycaemic thresholds for the release of hormones and the
development of symptoms are not necessarily fixed and
may be affected by the recent degree of glycaemic control.
However, there is no evidence that well-controlled
patients are protected from the cerebral dysfunction seen
during mild to moderate hypoglycaemia in non-diabetic
subjects. Tests of cognitive function show similar
impairments in well-controlled and poorly controlled
diabetic patients, and non-diabetic subjects at blood
glucose levels of 2.5-3.2 mmol/l [44, 771. Furthermore,
the appearance of an abnormal EEG pattern occurs at the
same blood glucose level in well-controlled and poorly
controlled diabetic patients [78].
The results described above suggest that many patients
with hypoglycaemic unawareness are still capable of
mounting a sympathoadrenal response, but at a lower
glycaemic level. Impaired cerebral function during
profound hypoglycaemia then prevents them from recognizing peripheral physiological changes. Some patients
with diminished sympathoadrenal responses are able to
rely on neuroglycopenic symptoms, but, perhaps because
these are not as consistent as neurogenic symptoms and
tend to occur at lower glycaemic levels, recognition of
them is impaired by cerebral dysfunction. This hypothesis
is supported by the results of a recent study where sympathoadrenal responses occurred at a lower blood glucose
level in patients who were unaware of being hypoglycaemic compared with those who were aware of hypoglycaemia [79]. It seems likely that the more severe
hypoglycaemia produced sufficient cerebral dysfunction
to prevent the ‘unaware’ patients from recognizing the
neurogenic signs and symptoms.
There is indirect evidence that impaired cerebral
function may prevent the recognition of hypoglycaemia
from a study which measured the effects of alcohol and
hypoglycaemia on hypoglycaemic symptoms, sympathetic
responses and psychomotor function [SO]. At relatively
mild hypoglycaemia (blood glucose level 2.5 mmol/l),
both diabetic patients and normal subjects when sober
recognized that their blood glucose level was low and
showed an increase in symptom score. However, when the
blood glucose level was lowered after ingestion of alcohol
(blood alcohol level approximately 20 mmol/l), both
groups were unaware of hypoglycaemia despite increases
in sweating and changes in heart rate. Furthermore, when
the subjects were hypoglycaemic after alcohol intake, the
overall symptom score increased to the levels seen during
hypoglycaemia alone, yet they failed to recognize that
their blood glucose level was low. Measurements of
reaction time demonstrated that cerebral function was
more severely impaired by the combination of hypoglycaemia and alcohol than hypoglycaemia alone, suggesting that cognitive impairment might be the cause of the
failure to recognize hypoglycaemic symptoms. In
addition, the direct effects of alcohol to reduce tremor
might also diminish the awareness of hypoglycaemia.
Recent work has raised the possibility that cerebral
adaptation to prevailing hypoglycaemia may modify the
physiological response to and awareness of hypo-
5
glycaemia, both acutely and during a subsequent hypoglycaemic episode. When the blood glucose level was
clamped at hypoglycaemic levels for up to 90 min in both
non-diabetic subjects and diabetic patients, although catecholamine levels remained high and peripheral physiological responses such as sweating and tremor were
maintained, hypoglycaemic symptom scores diminished
and cerebral function (as judged by reaction time)
improved [Sl, 821. Two recent studies in non-diabetic
subjects have shown that hypoglycaemia in a single 2 h
period [83],o r two 1 h periods [84], resulted in reduced
neuroendocrine responses and symptoms when hypoglycaemia was induced on the next day. These observations
suggest that cerebral tissue may respond to different
levels of glycaemia by altering cerebral glucose transport.
This has been demonstrated in rats, who show a decrease
in glucose transport into the brain when chronically
hyperglycaemic [85] and an increase in brain glucose
extraction when chronically hypoglycaemic [86]. Such a
mechanism might also explain the influence of glycaemic
control on physiological and symptomatic responses to
hypoglycaemia. However, if the prevailing blood glucose
level can alter glucose transport into human cerebral
tissue, the mechanism seems more rapid than in the rat,
and also may have different short-term and longer-term
effects. Hypoglycaemia had to be maintained for 5 days in
rats before changes in glucose transport were seen,
whereas functional improvements have been observed in
humans within a few hours. The acute adaptation
observed during hypoglycaemia in diabetic patients and
non-diabetic subjects [Sl, 821 was associated with
reduced symptoms and improved cognitive function,
despite sustained levels of counter-regulatory hormones.
By contrast, the influence of antecedent hypoglycaemia
was to reduce counter-regulatory responses to a subsequent period of hypoglycaemia. Furthermore, the observation that glycaemic thresholds for deterioration in
cognitive function are not altered by good glycaemic
control suggests that there are regional differences within
the brain. Clearly, much experimental work needs to be
performed to clarify these apparently contradictory
observations.
The original reports of reduced catecholamine
responses and loss of warning during hypoglycaemia
involved patients with longstanding diabetes and complications, and this led to the suggestion that the abnormality
was a consequence of autonomic neuropathy [87].
However, since normal responses are found in some
patients with established neuropathy [SS] and impaired
responses are seen in those with a short diabetic history
and no evidence of autonomic neuropathy [44], it is clear
that other factors are important. A recent study by Ryder
et al. [89] attempted to discover whether patients with a
history of troublesome hypoglycaemia showed any evidence of autonomic dysfunction, and also whether
patients with autonomic neuropathy demonstrated
inadequate counter-regulation. However, in this study
there were no measurements of plasma adrenaline levels,
so it is not known whether the patients with autonomic
neuropathy had defective responses to the induced
6
S. R. Heller and I. A. Macdonald
hypoglycaemia. Furthermore, the presence of hypoglycaemic unawareness was based on the patients' history,
not on objective measurement during experimental
hypoglycaemia, and unfortunately some of the control
patients had a history of such unawareness. Hepburn et al.
[go] undertook a questionnaire-based assessment of the
relationship between hypoglycaemic unawareness and the
incidence of autonomic neuropathy. Those patients with a
history of a loss of awareness of hypoglycaemia had an
increased incidence of severe hypoglycaemia, but did not
invariably demonstrate abnormal cardiovascular autonomic function.
The possibility that insulin species affects responses to
hypoglycaemia has recently been suggested by a number
of clinical reports linking the introduction of human
insulin to a loss of hypoglycaemic warning symptoms [91,
921. In non-diabetic subjects, hypoglycaemia induced with
human insulin was accompanied by lower noradrenaline
responses in some [93], but not all [94,95],studies. It was
recently reported that hypoglycaemia induced with
human insulin produced less marked alterations in
auditory
responses (an index of cognitive function
based on recording event-related cortical potentials) and
reduced awareness than seen with porcine insulin [96].
However, we have failed to find differential effects of
human and porcine insulin in inducing cognitive dysfunction or on the thresholds for counter-regulatory hormone
responses [97]. The first objective comparison of human
insulin and porcine insulin in patients with insulindependent diabetes mellitus was performed by Fisher et
al. [98]. There were some differences in the adrenaline
responses to hypoglycaemia between the insulin species,
especially in the patients with a long duration of diabetes,
but overall there were no substantial differences in the
cardiovascular responses or subjective awareness.
However, the method of inducing hypoglycaemia used in
this study (an intravenous bolus injection of insulin)
produces rapid rates of fall of blood glucose which are
likely to mask any differences in the blood glucose
threshold at which a response might be produced. Such
rates of fall are also uncommon in the clinical situation,
when the descent into hypoglycaemia is usually a much
slower event. A recent study of the effect of mild hypoglycaemia (blood glucose level 2.8 mmol/l) in patients
with insulin-dependent diabetes mellitus revealed no
difference in the counter-regulatory hormone responses
or the rate of recovery of blood glucose level when using
human insulin and porcine insulin [99]. However, glucose
recovery under such conditions is mainly dependent on
the dissipation of insulin action, and as the plasma insulin
profiles were similar on the two occasions, one would
have expected similar rates of glucose recovery. A firmer
conclusion on the importance of insulin species in
determining the effects of and responses to hypoglycaemia will hopefully be obtained from the large-scale
prospective studies currently in progress.
SUMMARY
Deficiencies in the release of glucagon and adrenaline
during hypoglycaemia in diabetic patients are associated
with a high frequency of severe hypoglycaemic episodes.
These have been attributed to a resulting inability to
increase hepatic glucose output acutely. A more
important consequence may be reduced awareness of
impending hypoglycaemia. Such hypoglycaemia unawareness is related to, but not entirely explained by,
diminished sympathetic activity, perhaps due to failure to
activate the sympathoadrenal system until a lower blood
glucose level is achieved. The patient's subsequent failure
to act appropriately would then be due to impaired
cerebral function preventing the perception of sympathoadrenal activation during the more severe hypoglycaemia.
Unawareness of moderate hypoglycaemia is common in
diabetic patients. Autonomic neuropathy probably
accounts for only a few cases of hypoglycaemia unawareness and other factors which are potentially important
include duration of diabetes, glycaemic control, insulin
species, and the degree and frequency of hypoglycaemia.
Further research is required to discover both the pathophysiological mechanisms of, and the treatment needed to
reverse o r prevent, the abnormality.
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