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DOI: 10.1111/j.1464-5491.2007.02376.x
Review Article
Blackwell Publishing Ltd
The mechanisms that underlie glucose sensing during
hypoglycaemia in diabetes
R. McCrimmon
Yale University School of Medicine, Department of Internal Medicine, New Haven, CT, USA
Accepted 10 October 2007
Abstract
Hypoglycaemia is a frequent and greatly feared side-effect of insulin therapy, and a major obstacle to achieving nearnormal glucose control. This review will focus on the more recent developments in our understanding of the mechanisms
that underlie the sensing of hypoglycaemia in both non-diabetic and diabetic individuals, and how this mechanism
becomes impaired over time. The research focus of my own laboratory and many others is directed by three principal
questions. Where does the body sense a falling glucose? How does the body detect a falling glucose? And why does this
mechanism fail in Type 1 diabetes? Hypoglycaemia is sensed by specialized neurons found in the brain and periphery, and
of these the ventromedial hypothalamus appears to play a major role. Neurons that react to fluctuations in glucose use
mechanisms very similar to those that operate in pancreatic B- and A-cells, in particular in their use of glucokinase and
the KATP channel as key steps through which the metabolic signal is translated into altered neuronal firing rates. During
hypoglycaemia, glucose-inhibited (GI) neurons may be regulated by the activity of AMP-activated protein kinase. This
sensing mechanism is disturbed by recurrent hypoglycaemia, such that counter-regulatory defence responses are triggered
at a lower glucose level. Why this should occur is not yet known, but it may involve increased metabolism or fuel delivery
to glucose-sensing neurons or alterations in the mechanisms that regulate the stress response.
Diabet. Med. 25, 513–522 (2008)
Keywords hypoglycaemia, glucose-excited neurons, glucose-inhibited neurons, ventromedial hypothalamus, AMPactivated protein kinase
ACTH, adrenocorticotrophic hormone; AgRP, agouti-related peptide; AMP, adenosine monophosphate;
AMPK, AMP-activated protein kinase; APF, action potential frequency; Arc, arcuate nucleus; ATP, adenosine
triphosphate; CRH, corticotrophin-releasing hormone; CSF, cerebrospinal fluid; DMH, dorsomedial hypothalamus; ECF,
extracellular fluid; GABA, gamma-aminobutyric acid; GE, glucose-excited neuron; GH, growth hormone; GI, glucoseinhibited neuron; GLUT, glucose transporter; GK, glucokinase; HAAF, hypoglycaemia-associated autonomic failure;
KATP, ATP-sensitive potassium channel; KO, knock out; MCT2, monocarboxylate transporter 2; MRNA, messanger
ribonucleic acid; NO, nitric oxide; NOS, nitric oxide synthase; POMC, pro-opiomelano cortin; PVN, paraventricular
nucleus; rt-PCR, reverse transcription polymerase chain reaction; T1DM, Type 1 diabetes mellitus; VDCC, voltagedependent calcium channel; VMH, ventromedial hypothalamus; VMN, ventromedial nucleus
Abbreviations
Introduction
Shortly after the introduction of insulin in the management of
T1DM, clinicians became aware of the potential for insulin
therapy to induce iatrogenic hypoglycaemia. Despite the
introduction of insulin analogues and improved delivery
systems, hypoglycaemia remains the major adverse effect of
Correspondence to: Rory J. McCrimmon, Yale University, Department of
Internal Medicine—Section of Endocrinology, PO Box 208020, New Haven,
CT 06520-8020, USA. E-mail: rory.mccrimmon@yale.edu
© 2008 The Author.
Journal compilation © 2008 Blackwell Publishing Ltd. Diabetic Medicine, 25, 513–522
insulin therapy and has emerged as a major limitation to
achieving near-normal glucose control, which is required to
reduce the risk of microvascular complications [1]. An increasing awareness of hypoglycaemia in clinical practice provided
the initial stimulus to a series of excellent and detailed human
physiological studies in the 1980s and 1990s, which greatly
increased our understanding of the counter-regulatory defence
systems that prevent and correct hypoglycaemia and, importantly, how these differed over time in individuals with T1DM
(for a detailed review of this area see [2]). However, in order
to understand the mechanisms that underlie glucose sensing, a
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Glucose sensing during hypoglycaemia • R. McCrimmon
FIGURE 1 Neuroendocrine and neuronal
pathways involved in generating the counterregulatory response to hypoglycaemia. Sensing
of hypoglycaemia by specialized neurons in the
hypothalamus leads to: (i) activation of both
branches of the autonomic nervous system,
culminating (amongst other actions) in the
secretion of epinephrine and noradrenaline
from the adrenal medulla and in the suppression
of insulin release and stimulation of glucagon
release from the pancreas, and (ii) stimulation to
release both anterior and posterior pituitary
hormones such as ACTH and GH.
prerequisite to understanding why this homeostatic system
becomes defective in T1DM, investigators have in recent years
increasingly used more basic in vitro techniques and animal
models. This is an area of research that is developing rapidly,
and focuses on three basic questions. Where does the body
detect hypoglycaemia? How does the body detect hypoglycaemia?
And why does this mechanism become defective over time in
T1DM? This review will focus on the more recent developments in this field, which are beginning to answer these three
important questions.
Where does the body sense a falling
glucose?
Glucose is an integral part of whole-body energy homeostasis
and is tightly regulated by numerous endocrine, neuronal and
behavioural systems, which ensure that glucose levels in the
blood are maintained within a narrow physiological range. It
is perhaps not surprising, given the fundamental importance of
glucose to the organism, that the capacity to sense glucose is
not limited to any single organ system. Apart from the classical
glucose sensor, the pancreatic B-cell, glucose-sensing neurons
in the periphery have, to date, been found in the intestine [3],
hepatoportal vein [4 –9] and carotid body [10]. Within the
brain, glucose-sensing neurons are found in areas such as the
septum [11], amygdala [12], striatum [13], motor cortex [14],
hindbrain [15–19] and hypothalamus [20–25] (Fig. 1). It is
anticipated, but has not as yet been convincingly shown, that
these central and peripheral glucose-sensing neurons form an
integrated neural network that monitors and responds to
changes in the glucose levels to which they are exposed.
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The reliance of the brain on glucose to meet its energy
demands suggests that, within the context of hypoglycaemia,
brain glucose sensing may predominate. Specialized neurons in
the hypothalamus and hindbrain [26] are recognized as playing
an important role in glucose sensing during hypoglycaemia.
Within the hypothalamus, we now recognize that glucosesensing neurons are found in certain distinct regions, namely
the VMH [27–30] (which includes the arcuate and ventromedial
nuclei), the PVN [31] and the DMH [32]. Perhaps the most
studied of these regions is the VMH. Chemical destruction of
the VMH in a rodent model with ibotenic acid was shown to
cause a ~75% reduction in the hormonal counter-regulatory
response to acute hypoglycaemia [29]. Later, it was shown in
awake rats that local perfusion of the VMH with 2-deoxyglucose
(a non-metabolizable form of glucose that effectively causes
‘local hypoglycaemia’) stimulated a classical systemic counterregulatory response [30], whereas local perfusion of the
VMH with glucose during systemic hypoglycaemia markedly
suppressed the hormonal counter-regulatory response [28].
Taken together, these three studies provided good evidence for
the VMH playing a key role in the sensing of hypoglycaemia.
The glucose-sensing neurons share certain common features.
Within the brain, they localize to regions adjacent to the third
or fourth ventricle or to the circumventricular organs (these
are regions of the brain where the blood–brain barrier is ‘leaky’
or absent). This potentially allows glucose-sensing neurons
direct sampling, and hence monitoring, of glucose levels in the
blood, brain and CSF. This is important because the presence
of the blood–brain barrier ensures that brain glucose levels are
only ~10–30% of the levels seen in the blood [33 –35]. Thus,
glucose-sensing neurons are able to integrate changes in
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glucose within each of these different regions. In addition,
glucose-sensing neurons are generally located in areas involved
in the control of the autonomic nervous system, neuroendocrine
function, nutrient metabolism and energy homeostasis. What
this effectively means is that brain glucose-sensing neurons are
able to receive inputs from blood nutrient levels and a variety of
endocrine hormones, as well as from numerous peripheral and
central sensory systems. This information can then be synthesized
and used to generate the appropriate physiological response,
the ultimate aim of which is to preserve glucose homeostasis.
How does the body detect a falling glucose?
In 1953, Jean Mayer proposed the ‘glucostatic hypothesis’
[36]. Hypothalamic ‘glucoreceptors’, it was proposed, could
sense fluctuations in glucose and translate that signal into a
change in neural activity [36]. The defining feature of these
neurons should be their use of glucose, not simply as a fuel, but
as a signalling molecule that regulates their activity. All neurons
use glucose as their major fuel source and all neurons will
ultimately alter their firing rates when glucose homeostasis is
significantly disrupted, but glucose-sensing neurons alter their
membrane potential, action potential frequency and/or rate of
neurotransmitter release over the more physiological ranges of
glucose to which they are exposed. Such specialized neurons
were first demonstrated by Oomura and colleagues in 1969
[22]. These neurons are ‘glucose’-sensing in so far as glucose is
the major metabolic substrate for the brain, but the fact that
these neurons can use other fuels, such as lactate produced
either by astrocytes [37–39], delivered locally [40,41] or
systemically [42–45] to alter their function, suggests that it is
more likely to be intracellular ATP that determines the activity
of these neurons. This is intriguing because neuronal levels of
ATP are generally thought to be well maintained, thus it is
also likely that subcellular compartmentalization of the glucosesensing apparatus must exist to provide sensing capability.
Such compartmentalization has been shown within pancreatic
β-cells [46].
GE neurons
There are thought to be two predominant subtypes of glucosesensing neurons, namely GE neurons (whose activity increases
as glucose levels rise) and GI neurons (whose activity decreases
as glucose levels rise) [47]. The mechanisms through which
these neurons sense alterations in glucose remain incompletely
understood. Classical glucose sensing in the pancreatic islet
served as a model for the initial research in this field [48]. In the
pancreatic β-cell, glucose is transported into the cell through a
high-capacity glucose transporter (GLUT) to allow rapid equilibration of extracellular and cytosolic glucose. The rate of glucose
metabolism, which is closely coupled to insulin secretion, is
determined by glucokinase (GK), the enzyme in the rate-limiting
step of glycolysis [49]. Metabolism of glucose leads to several
intracellular events, the culmination of which is an increase in
© 2008 The Author.
Journal compilation © 2008 Blackwell Publishing Ltd. Diabetic Medicine, 25, 513–522
DIABETICMedicine
cytosolic calcium. One of the key steps in this signalling pathway is the depolarization of the B-cell that follows closure of
ATP-sensitive potassium (KATP) channels in the plasma membrane [48]. The exciting discovery of glucokinase and KATP
channels in glucose-sensing regions in the brain lead to the
hypothesis that these enzymes might also serve key roles in
glucose sensing, particularly in GE neurons [48,50].
KATP channels have been demonstrated throughout the
brain, including hypothalamic regions thought to be involved
in glucose sensing [27,51–53]. Using single-cell rt-PCR to analyse
glucose-sensing neurons (identified electrophysiologically in
a hypothalamic slice preparation), investigators have shown
that they express mRNA for Kir6.2 and SUR1, the two subunits
that comprise the KATP channel in the pancreatic B-cell [54]. In
addition, electrophysiological studies of the rat [27,55–57]
and mouse [58] have demonstrated that sulphonylureas
(agents that block the KATP channel) can alter the response of
GE neurons to changes in ambient glucose, and Kir6.2 KO
mice show impaired glucose counter-regulation to systemic
hypoglycaemia [58]. Finally, in vivo perfusion of the VMH of
rodents with glibenclamide (a KATP channel blocker) suppresses
[59], whereas diazoxide (a KATP channel opener) amplifies
[60], hormonal counter-regulatory responses to acute hypoglycaemia. However, KATP channels are present on many different
neurons and so while they may be required for glucose sensing
they are unlikely to have a regulatory role.
In the pancreatic B-cell, GK is the critical regulator of
glycolytic production of ATP and KATP channel activity [49].
The pancreatic form of GK is also present in areas of the brain
involved in glucose sensing [61– 63]. GK mRNA is expressed
in ~70% of GE neurons [54], and glucokinase has also been
shown to play a regulatory role in GE neuron-sensing ability
[54,57,61,64]. In addition, the selective down-regulation of
GK in GE neurons in primary VMH neuronal cultures led to
the loss of all demonstrable GE and GI neurons [65]. However,
extracellular levels of glucose are only about 10 –30% of the
levels found in blood. Microdialysis studies in rats [33,34,66]
and human subjects [67] have shown that the ECF glucose
levels to which neurons are exposed are in the range of 1–
2 mM, and fall to a similar degree during acute hypoglycaemia
(~0.5 mM) [33]. Both euglycaemic and hypoglycaemia ECF
glucose levels are beneath the range of glucose levels in which
GK usually acts in a regulatory manner, thus for GK to
perform this role in glucose-sensing neurons it almost certainly
has to operate within a distinct subcellular compartment.
Glucose signalling in the pancreatic B-cell also requires the
GLUT Type 2 (GLUT-2). GLUT-2 mRNA has been found in
brain glucose-sensing regions [54,68]; in transgenic mice,
central GLUT-2 has been shown to be involved in the counterregulatory response to hypoglycaemia. Intriguingly, reintroducing GLUT-2 to glial cells, but not to neurons, restored the
defective counter-regulatory response to hypoglycaemia [69].
Taken together, these studies provide good evidence that the
glucose-sensing mechanism used by the GE neuron has many
similarities with the pancreatic β-cell. In particular, GK and
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Glucose sensing during hypoglycaemia • R. McCrimmon
FIGURE 2 Hypothetical sensing mechanism of
GE neurons. Glucose enters the GE neuron
through GLUT 2 or 3, and is phosphorylated by
GK, acting as the gatekeeper, and regulating the
production of cytosolic ATP in a subcellular
compartment. The ATP closes KATP channels in
the plasma membrane, causing depolarization.
In turn, this leads to Ca2+ influx through
VDCCs, stimulating neurotransmitter release
and/or increased APF. Lactate, produced locally
by astrocytes or arriving systemically, enters the
neuron via MCT2 and can then be metabolized
to form ATP.
FIGURE 3 Hypothetical sensing mechanism of
GI neurons. In GI neurons, GK may once again
act as the gatekeeper. A falling glucose results in
an increase in the AMP : ATP ratio, an effect
that can be mimicked pharmacologically by
AICAR. AMPK, once activated, stimulates the
formation of NOS, which may diffuse out to
adjacent neurons or glial cells. In addition,
AMPK may act on chloride channels leading to
neuronal depolarization and neurotransmitter
release and/or increased APF. This action of
AMPK can be blocked pharmacologically by
compound C.
the KATP channel appear to be key points through which an
increase in the ambient glucose leads to altered firing of GE
neurons (Fig. 2).
GI neurons
In contrast, GI neurons show a decrease in activity as glucose
levels rise [47]. It is perhaps easier to think of GI neurons as
those glucose-sensing neurons that become more active when
glucose levels fall, and as such they may use signalling mechanisms more relevant to the pancreatic A-cell. Unfortunately,
like the A-cell, the signalling pathways used by the GI neuron
are not well understood (Fig. 3). This may reflect the fact that
they are few in number, comprising only 3–14% of neurons in
the ventromedial hypothalamic nucleus [61,70]. However,
recent evidence suggests that GI neurons may be more prevalent:
when improved slice techniques are used in conjunction with
novel methods for identifying GI neurons (e.g. membrane
potential dyes), as many as ~30– 40% of all neurons in the
VMH are reported to be GI neurons [71]. GK mRNA is
expressed in around 40% of GI neurons, and may also serve a
regulatory role in these neurons. [65].
More recently, evidence has also emerged that AMP-activated
protein kinase (AMPK) plays a key role in the sensing pathway
used by GI neurons (Fig. 3). AMPK has been described as an
intracellular ‘fuel gauge’ in that it is activated in response to a
rise in the intracellular ratio of AMP to ATP and acts to switch
off energy-consuming anabolic processes and switch on energyproducing catabolic processes [72]. Within the brain, AMPK
516
expression is thought to be predominantly neuronal in distribution, with very little expression evident in astrocytes [73].
Canabal et al. [71] demonstrated that in VMN GI neurons
exposed to 2.5 mM glucose, AICAR (an activator of AMPK),
mimicked the excitatory effect of low glucose (0.5 mM) on
action potential frequency. Both low glucose and AICAR
were shown to mediate their effects, in part, through an increase
in nitric oxide (NO) production in GI neurons. Conversely,
increased NO production in response to a low glucose was
blocked by compound C, an inhibitor of AMPK [71]. In a
related series of studies, Mountjoy et al. [74] reported that
activation of AMPK with AICAR or inhibition with compound C altered neuronal activity in GI, but not GE, neurons
in an ex vivo hypothalamic cell culture system obtained from
the mediobasal (including VMN and Arc) hypothalamus. In
this study, AMPK had no effect on the KATP channel [74], but
others have suggested that AMPK may instead act on a chloride channel to depolarize the plasma membrane [75]. In
rodent studies, in vivo pharmacological activation of AMPK in
the VMH during acute hypoglycaemia amplifies the glucose
counter-regulatory response in normal Sprague-Dawley rats
[76], and restores the hormonal counter-regulatory response
to hypoglycaemia in rats with defective counter-regulation
[77]. Conversely, down-regulation of AMPK in the VMH using
specific RNA interference suppresses the counter-regulatory
response to acute hypoglycaemia [78]. In addition, mice that
selectively lack the alpha-catalytic subunit of AMPK in
POMC or AgRP neurons (both neuronal types are located in
the medio-basal hypothalamus and are involved in feeding
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behaviour and energy homeostasis) lose the responsiveness
of these neurons to changes in extracellular glucose [79].
What these studies all indicate is that the brain contains
specialized neurons that exist in distinct locations and are able
to monitor and react to alterations in the glucose concentration
to which they are exposed. These neurons, by virtue of specific
sensing systems, translate the rate or quantity of glucose
oxidation into a neural signal that alters neuronal firing rates
and, in the case of hypoglycaemia, leads to the stimulation of
a systemic glucose counter-regulatory defence response. The
glucose-sensing neurons seem to use signalling mechanisms
that are very similar to those used by pancreatic B- and A-cells.
The GE neuron, which seems to operate more under conditions
of eu- or hyperglycaemia, may use glucokinase as its key
regulatory step, and the KATP channel to then translate that
signal into altered neuronal firing rates. In contrast, while the
GI neuron (which operates more under hypoglycaemic
conditions) may still use glucokinase as a regulatory enzyme,
it appears more dependent on alterations in intracellular
AMPK activity that, in turn, may act via a chloride channel to
alter neuronal firing rates. It is highly likely that these two
neuronal populations communicate with each other, perhaps
via the inhibitory neurotransmitter GABA [80], to co-ordinate
their responses to a changing blood glucose. Potentially, the
counterbalance between GI and GE neuronal activity forms
the most sensitive means of regulating and maintaining blood
glucose within a narrow physiological range and ensuring an
adequate supply of glucose to the brain.
Counter-regulation in T1DM
In health, a fall in plasma glucose level is rapidly detected and
a sequence of counter-regulatory responses triggered, which
mainly involve: (1) suppression of insulin secretion; (2) counterregulatory hormone release, which rapidly promotes
endogenous glucose production and limits peripheral glucose
utilization; and (3) subjective awareness of hypoglycaemia. In
T1DM, these compensatory systems are disrupted at every
level. Firstly, for most individuals, insulin delivery from its
subcutaneous depot is unregulated and continues despite the
development of hypoglycaemia. Secondly, most individuals
with T1DM will over time develop defects in the hormonal
counter-regulatory defence against hypoglycaemia. Within
5 years of diagnosis of T1DM, hypoglycaemia fails to stimulate
the release of glucagon, the major counter-regulatory hormone
(Table 1) [81]. As a result, individuals with T1DM are
particularly dependent on the sympathoadrenal (primarily
adrenaline and noradrenaline) response to low blood glucose.
However, within 10 years of diagnosis, the majority of
patients develop additional impairments in sympathoadrenal
and other neurohormonal responses against hypoglycaemia
(Table 1) [81]. In addition, symptom awareness becomes
impaired in individuals with T1DM. The term hypoglycaemiaassociated autonomic failure (HAAF) was introduced by
Cryer to incorporate both defective glucose counter-regulation
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Table 1 Percentage of individuals with T1DM showing deficient
responses in each of the major hypoglycaemic counter-regulatory
hormones over time. From Mokan et al. [81]
Duration
of diabetes
Glucagon
(%)
Epinephrine
(%)
Cortisol
(%)
GH
(%)
< 1 year
1–5 years
5–10 years
> 10 years
27
75
100
92
9
25
44
66
0
0
11
25
0
0
11
25
and hypoglycaemia unawareness [1]. The presence of HAAF
greatly increases the risk of suffering severe hypoglycaemia in
patients with T1DM [82].
The major factor leading to the loss of glucagon secretion in
response to acute hypoglycaemia in T1DM appears to be the
loss of insulin secretion from the B-cell. This is because the
glucagon-secretory defect is selective (responses to other stimuli
such as arginine remain intact), and develops concomitantly
with progressive B-cell loss in T1DM [83]. Based on earlier rat
anatomical studies suggesting that blood flow in the islet was
predominantly from B- to A-cell, it was proposed that insulin
under ordinary conditions tonically inhibited glucagon secretion
by the pancreatic A-cell [84 –86]. Hence, the ‘switch-off’
hypothesis posited that during hypoglycaemia when insulin
secretion is suppressed, glucagon is released from the A-cell. In
T1DM, pancreatic B-cells are destroyed in the autoimmune
inflammatory process such that this ‘switch-off’ of insulin no
longer occurs. In fact, intra-islet insulin levels may actually
rise, leading to the suppression of glucagon secretion [84 – 86].
There is good evidence in support of this hypothesis, from both
in vitro [85–89] and in vivo [89] rodent studies. However, the
pancreatic α-cell has an extensive and complex autonomic
innervation (reviewed in detail in Taborsky et al. [90]) with
considerable redundancy, so while insulin may be the primary
factor responsible for this defect, an additional role for
alterations in the autonomic nervous system cannot be excluded.
The almost universal defect in glucagon secretion means that
individuals with T1DM are very reliant on the sympathoadrenal
response to hypoglycaemia to restore blood-glucose levels.
Unfortunately, this response also appears to become defective
over time in T1DM [81]. The major reason for the development
of this defect is thought to be the experience of hypoglycaemia
itself. In the Diabetes Control and Complications Trial, which
compared intensive with standard insulin therapy in T1DM,
the major single factor predicting severe hypoglycaemia in
the study cohort was reporting a previous episode of severe
hypoglycaemia [91]. Intensive insulin therapy, which is
associated with more frequent hypoglycaemia, was shown to
lower the glucose level at which hormonal counter-regulation
was initiated in T1DM [92]. Hypoglycaemia per se is the likely
cause of this and it has been shown in both humans [93 –95]
and rodents [77,96 –97] that single or multiple episodes of
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antecedent hypoglycaemia lead to suppressed adrenaline
responses to a subsequent episode of hypoglycaemia.
Data gleaned from studies in rodents suggest that this defect
arises through changes in key brain glucose-sensing regions
such as the VMH. Recurrent hypoglycaemia has been shown
to markedly suppress the counter-regulatory response to 2deoxyglucose (a non-metabolized form of glucose) perfused
into the VMH of rats [98]. It has also been shown that the
glucose level at which you first see activation of glucoseinhibited neurons in the VMH is lower in rats that have experienced prior recurrent hypoglycaemia [99]. Moreover, in vivo
activation of AMPK in the VMH of rats who have experienced
prior recurrent hypoglycaemia can restore hormonal counterregulatory responses to a subsequent hypoglycaemic challenge
[77]. Similarly, opening of KATP channels in the VMH of recurrently hypoglycaemic rats leads to the restoration of normal
counter-regulatory responses to subsequent hypoglycaemia. If
our model is correct, these studies suggest that the balance
between GE and GI neuronal activity is altered by recurrent
hypoglycaemia. We would anticipate that GE neurons (acting
to suppress counter-regulation) are more likely to be active
and/or that GI neurons (acting to amplify counter-regulation)
are less likely to be active following recurrent hypoglycaemia.
The net effect is that full glucose counter-regulation is initiated at a lower glucose level. This gives individuals less time to
react to, and seek treatment for, hypoglycaemia.
Why does this mechanism fail in Type 1
diabetes?
The question we then need to ask is: why does this happen?
The most obvious explanation is that following recurrent
hypoglycaemia, glucose-sensing neurons are ‘seeing’ higher
glucose and/or ATP levels during a subsequent hypoglycaemic
challenge. This change may arise through an increased supply
of fuel through altered glucose [100], or alternate fuel transport
[101]. However, while these changes suggest an increased
capacity to transport fuels across the blood−brain barrier and
into glucose-sensing neurons, the data from human studies have
been mixed, with some indicating increased whole-brain glucose
[102], or acetate [103], uptake after chronic hypoglycaemia
and others showing no change [104].
Another possibility is that the brain is able to obtain
additional metabolic substrates from more local sources.
Recently, it has emerged that brain glycogen may act as a fuel
reserve during acute hypoglycaemia [105]. Moreover, brain
glycogen levels may actually increase in response to an acute
episode of hypoglycaemia [105,106]. This ‘super-compensation’
of brain glycogen may then provide the additional fuel reserve
that leads to defective glucose sensing during a subsequent
episode of hypoglycaemia. This theory is attractive, but
against it is the fact that brain glycogen levels appear to be very
low and a fraction of the levels seen in other tissues such as
muscle and liver. Also, ‘super-compensation’ of glycogen may
actually have arisen because of the model employed in these
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Glucose sensing during hypoglycaemia • R. McCrimmon
studies where pre-study infusions of glucose and insulin, rather
than hypoglycaemia per se, may have led to the described
phenomenon. Further research is needed in this area.
It has also emerged that mechanisms for regulating the
magnitude of the neuroendocrine response to acute hypoglycaemia exist within the brain. The CRH family of ligands and
receptors form an ancient and highly conserved means of
regulating the neuroendocrine stress response. Within the
brain, at key sites involved with autonomic activation, CRH
acting through the CRH-R1 receptor appears to lead to an
amplification of the autonomic response to stress whereas
Urocortin (part of the CRH family of peptides), acting through
the CRH-R2 receptor, suppresses the autonomic response to
stress. We were recently able to show that such a mechanism
operated in the VMH, with urocortin locally delivered to the
VMH markedly suppressing the counter-regulatory response
to acute hypoglycaemia [107], whereas CRH amplified the
response [108]. Moreover, unpublished work from our
laboratory would suggest that this counterbalanced system
might change following recurrent hypoglycaemia, with an
upregulation of CRH-R2-mediated suppressive effects in the
VMH. The net effect would be to suppress the counterregulatory response to subsequent hypoglycaemia.
We should not be surprised that there is no single answer
to the phenomenon of HAAF. Hypoglycaemia represents a
profound physiological stress and is likely to activate numerous
physiological defence systems that affect both biological and
behavioural responses. Our understanding of these physiological
defences remains limited, but it is reasonable to conclude that
recurrent hypoglycaemia may lead to an increase in the capacity
of glucose-sensing regions of the brain to use glucose and/or
alternate fuels, as well as to a change in the mechanisms that
fine-tune the hypoglycaemic stress response. The net effect of
these changes is to suppress the glucose counter-regulatory
response to a subsequent episode of hypoglycaemia.
What relevance are studies in rodents to
human disease?
The ultimate aim of all basic research is its translation into the
human model. In hypoglycaemia research, electrophysiological
studies of hypothalamic slice preparations and rodent models
offer much, but one must always be wary of over-interpreting
data. The limitations of cell-based and rodent studies are well
recognized. However, this does not make the work irrelevant
to human disease. Glucose homeostasis, in particular, is
fundamental to the survival of a vast range of species from
single-cell organisms to humans. AMPK, for instance, is a
critical part of the process whereby the yeast cell responds to a
period of fuel deprivation, and likewise in rodents clearly plays
a major role in glucose sensing during hypoglycaemia. Thus, it
appears likely that such ancient and conserved systems may be
important in human disease. Another example is glucokinase,
which, as reviewed earlier, has been shown in rodents to play
a regulatory role in glucose sensing in hypothalamic neurons.
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This finding led to human studies where fructose, a modulator
of glucokinase activity, was delivered systemically during
hypoglycaemia and was shown to amplify the counter-regulatory
response in both non-diabetic [109] and T1DM [110] subjects.
Finally, the recognition that recurrent hypoglycaemia might
lead to adaptive changes that increase the ability of the brain
to use alternate fuels has prompted trials in T1DM subjects
using medium-chain fatty acids that may provide neuroprotection, particularly during the night, while not leading to a
deterioration in overall glucose control.
In summary, our understanding of where and how glucose
is sensed has increased significantly in the last 20 years. We
now recognize that a network of specialized neurons exist that
continually monitor the ambient glucose level and that these
neurons act in such a way as to try to maintain glucose homeostasis. These neurons appear to use sensing mechanisms very
similar to those used within the pancreatic islet, with GK, the
K ATP channel and AMPK all playing key roles in central
glucose sensing. While this information has come largely
from rodent studies using a combination of in vitro and in vivo
techniques, it is anticipated that newer imaging techniques
such as positron emission tomography and magnetic resonance
spectroscopy will allow the translation of these findings into
the human model and determine their relevance to human
disease. The development of novel therapies or treatment
strategies designed to minimize the risk of hypoglycaemia
in insulin-treated individuals with diabetes relies on the
information that these studies will provide.
Competing interests
None to declare.
Acknowledgements
The author acknowledges the post-doctoral fellows and technical
staff who contributed greatly to the research that underpins
this review. The research work of the author is supported by
a research grant from NIDDK (69831), and a Career Development Award from the Juvenile Diabetes Research Foundation.
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