Er 2018-00226

REVIEW
Central Mechanisms of Glucose Sensing and

Counterregulation in Defense of Hypoglycemia
Sarah Stanley,1 Amir Moheet,2 and Elizabeth R. Seaquist2
1
Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York
10029; and 2Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, University of
Downloaded from https://academic.oup.com/edrv/article/40/3/768/5297093 by guest on 03 July 2023

Minnesota, Minneapolis, Minnesota 55455
ORCiD numbers: 0000-0002-0253-2663 (S. Stanley); 0000-0001-9909-6724 (A. Moheet);
0000-0002-1945-1034 (E. R. Seaquist).
ABSTRACT: Glucose homeostasis requires an organism to rapidly respond to changes in plasma glucose concentrations. Iatrogenic
hypoglycemia as a result of treatment with insulin or sulfonylureas is the most common cause of hypoglycemia in humans and is generally
only seen in patients with diabetes who take these medications. The first response to a fall in glucose is the detection of impending
hypoglycemia by hypoglycemia-detecting sensors, including glucose-sensing neurons in the hypothalamus and other regions. This detection
is then linked to a series of neural and hormonal responses that serve to prevent the fall in blood glucose and restore euglycemia. In this
review, we discuss the current state of knowledge about central glucose sensing and how detection of a fall in glucose leads to the
stimulation of counterregulatory hormone and behavior responses. We also review how diabetes and recurrent hypoglycemia impact
glucose sensing and counterregulation, leading to development of impaired awareness of hypoglycemia in diabetes. (Endocrine Reviews 40:
768 – 788, 2019)
G lucose homeostasis requires an organism to

rapidly respond to changes in plasma glucose
concentrations. This is particularly true in the face
is also a costly complication. Between  and ,
emergency room visits for hypoglycemia are esti-
mated to have cost .$ million in the United
of a fall in plasma glucose, because the difference States alone ().
between normoglycemia and life-threatening hy- The first central response to a fall in glucose is the
poglycemia can be as small as  mg/dL (. mmol/ detection of impending hypoglycemia by glucose-
L). Iatrogenic hypoglycemia as a result of treatment sensing neurons in the hypothalamus and other re-
with insulin or sulfonylureas is the most common gions. This detection is then linked to a series of neural
cause of hypoglycemia in humans and is generally and hormonal responses that serve to prevent the fall
only seen in patients with diabetes who take these in blood glucose and restore euglycemia. In this re-
medications. Hypoglycemia is extremely common in view, we first discuss the current state of knowledge
the life of patients with diabetes. A recent global about central glucose sensing and how detection of a
study that included ., insulin-treated patients fall in glucose leads to the stimulation of counter-
found that .% of the patients with type  diabetes regulatory hormonal and behavioral responses. We
and nearly % of the patients with type  diabetes then review how diabetes and recurrent hypoglycemia
ISSN Print: 0163-769X experienced any hypoglycemia in a month of pro- impact glucose sensing and counterregulation. Finally,
ISSN Online: 1945-7189 spective monitoring (). In the same study, % of we consider the mechanisms that contribute to the
Printed: in USA patients with type  diabetes and % of patients with development of impaired awareness of hypoglycemia
Copyright © 2019
type  diabetes experienced severe hypoglycemia in diabetes, a situation that increases the risk of ex-
Endocrine Society
Received: 7 September 2018
during the same month, which by definition only periencing severe hypoglycemia by more than sixfold
Accepted: 17 January 2019 includes episodes associated with sufficient neuro- (). The purpose of this review is to provide scientists
First Published Online: glycopenia to require the assistance of another and clinicians with an understanding of the com-
22 January 2019 person to treat the low blood glucose. Hypoglycemia plexity of glucose counterregulation.
768 https://academic.oup.com/edrv doi: 10.1210/er.2018-00226

REVIEW
ESSENTIAL POINTS
· Glucose-sensing neurons have been identified in the hypothalamus, brain stem, dorsal motor nucleus of the vagus,
nucleus accumbens, amygdala, paraventricular thalamus, prefrontal cortex, and the hippocampus
· Mechanisms used by glucose-excited, glucose-sensing neurons to detect changes in glycemia include detection of changes
in the ATP/ADP ratio, mitochondrial function, sodium glucose cotransport, and sweet receptors
· Mechanisms used by glucose-inhibited, glucose-sensing neurons to detect changes in glycemia include detection of
changes in the ATP/ADP ratio, AMP kinase activity, and the opening of tandem-pore K1 channels
· Brain regions with glucose-sensing neurons are highly connected and project to downstream areas that regulate secretion
of insulin, catecholamines, glucagon, cortisol, and GH
· Recurrent episodes of hypoglycemia, particularly in patients with diabetes who are treated with insulin or insulin
secretagogues, lead to impaired awareness of hypoglycemia
· The mechanisms responsible for the development of impaired awareness of hypoglycemia remain uncertain, but
upregulation of brain glucose transport, use of alternative fuels, and altered hypothalamic signaling have been

hypothesized
Glucose-Sensing Neurons (AP), the extracellular glucose concentration is likely to

be closer to plasma glucose levels (). Glucose diffusion
All neurons use glucose as a source of energy and are from the cerebrospinal fluid into the brain is also
silenced at very low glucose concentrations, but spe- variable, leading to differences in extracellular glucose
cialized neural populations also use glucose as a signal concentrations across brain regions (). Microdialysis
(, ). These glucose-sensing neurons modulate their studies suggest that brain interstitial glucose levels may
firing rate in response to changes in extracellular also change with neural activity. For example, extra-
glucose concentrations (). Glucose-sensing neural cellular glucose in the hippocampus decreased during a
populations can be broadly divided into two groups: spatial memory task (). Additionally, there is evidence
glucose-excited (GE) and glucose-inhibited (GI) that glucose transport into the CNS is altered by re-
neurons (). As the name suggests, GE neurons in- current hypoglycemia, feeding, fasting, and high glucose
crease their firing rate in response to increasing ex- (–). Finally, CNS glucose levels vary between strains,
tracellular glucose, and their firing rate decreases as ages, and species (, ). Despite the variability de-
glucose concentrations fall. In contrast, the firing rate scribed above, neurons in most brain regions are un-
of GI neurons decreases as glucose levels rise and likely to be exposed to glucose concentrations . mM,
increases as glucose concentrations fall. Glucose- with the exception of cells close to circumventricular
sensing cells are found outside the central nervous organs where glucose levels may be higher.
system (CNS), particularly in the pancreas but also in
the mouth, gastrointestinal tract, portal vein, and Locations of and neurotransmitters released by
carotid body (). These peripheral sensors provide glucose-sensing neurons
signals via polysynaptic pathways involving sensory Populations of glucose-sensing neurons have been
and vagal afferents to multiple CNS regions, many of described in multiple areas of the brain [Table  (,
which also contain glucose-sensing neurons. Collec- –); Fig. ]. Evidence for the ability of these
tively, peripheral and central glucose sensors likely populations to sense glucose changes comes from
provide a distributed system to detect and respond to several sources, as discussed in subsequent paragraphs.
altered glucose levels. These include expression of early response genes such
Extracellular glucose concentrations in the CNS are as c-fos induced by systemic glucose, electrophysio-
much lower than those in the systemic circulation. From logical studies in vivo and in ex vivo slices demon-
microdialysis studies, it is known that interstitial CNS strating modulation in firing rates with changes in
glucose concentrations range from ~. mM in the fed glucose, and expression of putative glucose sensors
state to . mM in fasted animals (–). In human such as glucose transporters (GLUTs), specific ion
studies, brain glucose concentrations have been shown channels, and components of the glucose metabolic
by magnetic resonance spectroscopy to be ~% of pathway such as glucokinase. The preclinical studies
plasma glucose values under a range of plasma glucose used to investigate CNS glucose sensing and coun-
concentrations (). However, some CNS regions lie terregulation have evolved from electrical stimulation
outside the blood–brain barrier. For circumventricular and lesions of anatomical regions to targeted, re-
organs, such as the median eminence and area postrema versible modulation of genetically defined neural
doi: 10.1210/er.2018-00226 https://academic.oup.com/edrv 769

REVIEW
populations. However, many of the neural populations from brain slices show that subpopulations of neurons
are heterogeneous, comprised of glucose-sensing and in this region are glucose excited and increase their
nonsensing populations or a combination of GE and firing rate as glucose levels increase from . to  mM
GI neurons, so stimulating them may reveal a dom- (). It is possible that these GE neurons may express
inant phenotype but miss the distinct roles of specific the neuropeptide pro-opiomelanocortin (POMC), as
subpopulations. patch clamp recordings suggest that firing rates of these
The most extensively studied glucose-sensing neurons fell as glucose levels were reduced from  to
populations are in the hypothalamus, a region at  mM () or from  to  mM (). However, other
the base of the forebrain. From studies examining the reports show no effect of glucose levels , mM on
expression of early immediate genes, particularly c-fos, POMC activity (). In other studies, c-fos induced by
and ex vivo electrophysiological recordings, glucose- hypoglycemia has been shown to overlap with ex-
sensing neurons are known to present in many hy- pression of neuropeptide Y (NPY) (). Recordings
pothalamic nuclei. These include the arcuate nucleus from ARC NPY neurons demonstrate that ~% of
(ARC) (, ), paraventricular hypothalamic nu- these neurons increase their activity as glucose falls ( to

cleus (PVH) (), dorsomedial hypothalamic nucleus . mM), indicating that they are glucose inhibited in
(DMH) (), ventromedial hypothalamic nucleus type (). Additionally, electrophysiological recordings
(VMH) (), lateral hypothalamus (LH) (, ), su- from ARC neurons expressing GH-releasing hormone
praoptic nucleus (), and possibly the medial preoptic (GHRH) show that most of these cells are GI neurons.
area (MPOA) (). More than % of GHRH neurons are activated
There are several populations of glucose-sensing as glucose levels decrease from  to . mM ().
neurons in the ARC. Both intracarotid glucose ad- Taken together, this evidence suggests that the ARC
ministration () and insulin-induced hypoglycemia contains populations of GE neurons, possibly
() increase c-fos expression in the ARC, suggesting expressing POMC, and GI neurons expressing NPY
that this region contains neurons activated by both and GHRH.
high and low glucose. Several neural populations in the Similarly, the PVH also appears to have sub-
ARC express putative glucose sensors such as gluco- populations of GI and GE neurons because both
kinase (, ) and GLUT (), as well as components insulin-induced hypoglycemia () and intracarotid
of possible glucose-sensing mechanisms such as ATP- glucose administration () increase PVH expression
sensitive potassium (KATP) channels (, ). In of c-fos. The putative glucose sensors glucokinase ()
keeping with this, ex vivo electrophysiological recordings and GLUT () are expressed in the PVH, and
Table 1. Summary of the Proportion and Markers for Glucose-Sensing Neurons in Specific Brain Regions
Proportion of Proportion of
Area GE Neurons Ref. Marker Ref. GI Neurons Ref. Marker Ref.
PVH 57% (20) 42% (20)
Medial ARC 4% (21) 14% (21) NPY (40%) (22)
GHRH (80%) (23)
Lateral ARC 13% (21) POMC (51%) (24) 1% (21)
VMH 14% (7) Glucokinase (64%) (7) 3% (7) Glucokinase (43%) (7)
LH 38% (25) MCH (83%) (26) 19% (25) Orexin (95%) (26)
NPY (70%) (27)
DMH 11% (28) GABA (60%) (29) 15% (28) GABA (30%) (29)
AP 11% (30) 12% (30)
PBN CCK (35%) (31)
NTS 35% (32) GABA (40%) (33) 21% (32) GABA (33%) (33)
TH (34) GLUT2 (35)
DVC 22% (20) 18% (20)

The proportions of GE and GI neurons in defined brain regions and markers for specific populations are shown. The percentage of each population with glucose-sensing properties is
shown in parentheses.
Abbreviation: DVC, dorsal vagal complex.
770 Stanley et al Brain Glucose Sensing and Counterregulation Endocrine Reviews, June 2019, 40(3):768–788
REVIEW
Figure 1. Sites of glucose-sensing neurons in mouse brain. GE and GI neurons are found in many brain regions. In the hypothalamus,
these include the PVH, ARC, DMH, VMH, and LH. Outside the hypothalamus, glucose-sensing neurons have been reported in the NAc,
amygdala, LC, and PBN. In the brain stem, the AP, NTS, and DMV also have glucose-sensing neurons.

electrophysiological recordings support the presence also show that DMH neurons respond to glucose, with
of glucose-sensing neurons, particularly in the dorsal approximately a third altering their firing rate as
parvocellular PVH, where ~% of neurons responded glucose increased from . to  mM (), and most of
to changes in glucose. Overall, in vivo electrophysio- these neurons were excited. In keeping with these
logical recordings in rats report that % of PVH findings, the activity of g-aminobutyric acid (GABA)
neurons are activated and % are inhibited by ap- ergic DMH neurons was also modulated by glucose. In
plication of  mM glucose (). The molecular identify ex vivo slices, lowering glucose from . to . mM
of these populations is not clear, but hypoglycemia activated % and inhibited % of GABAergic DMH
induces c-fos and FosB in PVH neurons expressing neurons ().
CRH (, ). One of the most highly examined hypothalamic
The DMH also contains glucose-sensing neurons. regions is the VMH. Again, both peripheral glucose
C-fos expression in the DMH is induced by both administration and insulin-induced hypoglycemia
hypoglycemia () and by glucose administration (), increase expression of c-fos in the VMH (, ).
again suggesting a mixed population, and glucokinase VMH neurons express GLUT (), glucokinase (,
is expressed at high levels in the nucleus (). In vivo ), AMP-activated protein kinase (AMPK) (), and
recordings in rats showed that  of  DMH KATP channels (, ), which have all been proposed
neurons were responsive to IV glucose administration, to be components of glucose-sensing pathways.
and of the glucose-responsive neurons, % were Electrophysiological recordings confirm the presence
excited (GE neurons) and % were inhibited (GI of both GE and GI neurons in the VMH. In rats, %
neurons) (). Ex vivo electrophysiological recordings of neurons are glucose excited, with decreased activity

REVIEW
as glucose is reduced from . to . mM, and % are The brain stem also contains a number of glucose-
glucose inhibited and increase their firing rate as sensing populations in the nucleus of the solitary tract
glucose is decreased (. to . mM) (). Glucokinase (NTS), AP, and dorsal motor nucleus of the vagus
is found in % of GE neurons and % of GI neurons (DMV) as well as the parabrachial nucleus (PBN).
in this region (). However, specific markers for GE Duodenal administration of glucose in rats increased
populations or GI populations in the VMH are not c-fos expression in NTS neurons (). Glucoprivation
known. Interestingly, a recent study done in humans with DG also induces c-fos immunoreactivity in the
with positron emission tomography (PET) showed NTS (). The NTS also expresses glucokinase as well
there to be a significant relationship between the as KATP channels, and electrophysiological studies
binding of a highly selective norepinephrine trans- show that % of NTS neurons are activated by  mM
porter ligand in the hypothalamus and the epineph- glucose whereas glucose inhibits % of NTS neurons
rine response during hypoglycemia (), suggesting (). Studies suggest that glucose-sensing populations
that the glucose-sensing neurons in the hypothalamus in the NTS are marked by several neuropeptides
may be norepinephrinergic. and neurotransmitters. Electrophysiological recordings

Similar to other hypothalamic regions, the LH also from NTS GABAergic neurons show that % are
contains subpopulations of GE and GI neurons. Both glucose excited and % are glucose inhibited (. to
hypoglycemia and hyperglycemia increase expression  mM glucose) (). A population of NTS GLUT-
of c-fos (, ), and subpopulations of LH neurons expressing neurons is activated by hypoglycemia.
express glucokinase (). Extracellular recordings in Their firing rate increases as glucose falls from  to
freely moving rats demonstrated that central admin- . mM (). Catecholaminergic neurons in the NTS
istration of the nonmetabolizable glucose analog are also reported to be glucose sensing. Extracellular
-deoxy-D-glucose (DG), which mimics hypoglyce- recordings in rats found that a population of glucose-
mia, increased activity in % of LH neurons (GI sensing neurons was in the caudal tyrosine hydroxylase–
neurons) and inhibited % (GE neurons) (). Ex- positive region of the NTS (). Supporting these
tracellular recordings in rhesus monkeys indicated that findings are results from ex vivo slice recordings
similar proportions of LH neurons, ~%, were glu- performed in mice expressing GFP in tyrosine hy-
cose inhibited (). However, in the LH, the identity of droxylase (rate-limiting enzyme in catecholamine
several glucose-sensing populations is known. Ex- synthesis)–positive neurons. Recordings from GFP/
pression of the neuropeptide orexin marks a pop- tyrosine hydroxylase–positive neurons showed that
ulation of GI neurons () whose activity (in  of  their firing rate decreased as glucose levels fell from 
neurons) was suppressed as glucose increased from . to  mM, suggesting that they are GE neurons ().
to  mM. Additionally, a proportion (%) of LH GE neurons and GI neurons have been described in
neurons expressing NPY (but not orexin) also appear the rostral ventrolateral medulla (, ), and c-fos
to be GI neurons, as they are hyperpolarized and immunoreactivity increases in catecholaminergic
reduce their firing rate in response to rising glucose neurons in the locus coeruleus (LC) () after hy-
(). In contrast, neurons expressing melanin- poglycemia, suggesting that they may also be a
concentrating hormone (MCH) are depolarized by glucose-sensing population. Glucose-sensing neu-
increased glucose (. to  mM,  of  neurons), and rons have also been described in the AP () with 
although only a small proportion increase their firing of  neurons inhibited by glucose whereas  of
rate, they are more likely to fire with the addition of a  neurons were activated by glucose ().
depolarizing input (). Neurons in the DMV may also respond to changes
Glucose-sensing neurons have also been reported in glucose. Glucokinase is expressed in this region (),
in the supraoptic nucleus of the hypothalamus. These and glucose-sensing neurons have been identified by
neurons express glucokinase () and KATP channels electrophysiological studies (). Similarly, hypogly-
(), and glucose treatment (. to  mM) increased cemia induced c-fos immunoreactivity in the lateral
intracellular calcium levels, suggesting that they are GE PBN of the pons in a subpopulation of neurons
neurons. Glucose also increased vasopressin and expressing cholecystokinin (CCK). In keeping with
oxytocin release, suggesting that the supraoptic GE this, electrophysiological studies confirmed that a
neurons may express these neuropeptides (). Other subpopulation of CCK LPBN neurons ( of ) were
hypothalamic regions may also harbor glucose-sensing depolarized as glucose levels fell from  to . mM
neurons. For example, glucokinase is expressed in the ().
preoptic area (, ), and hyperglycemia induces c-fos Glucose-sensing populations have been described
immunoreactivity in the preoptic area in rats (). in areas beyond the hypothalamus and hindbrain,
Immortalized hypothalamic cell lines expressing particularly in regions implicated in reward such as the
GnRH, a neuropeptide abundantly expressed in the nucleus accumbens (NAc) (), amygdala (), par-
preoptic area, increased c-fos and GnRH expression in aventricular thalamus (), prefrontal cortex (), and
response to  mM glucose (), and GnRH neurons in hippocampus (). These areas contribute to dopa-
vivo have been shown to be glucose sensing (). minergic pathways involved in reward processing. In
REVIEW
the NAc, a fourth of neurons are glucose sensing (), their firing rate (). However, KATP channels are not
with GE neurons predominantly in the NAc core and the only mechanism involved in GE neurons. In-
GI populations in the shell. However, these studies tracellular ATP levels do not increase in hypotha-
used supraphysiological glucose concentrations lamic neurons as glucose rises from  to  mM (),
( mM glucose). Both GE and GI neurons are suggesting that KATP channels do not play a role in
present in the amygdala, with electrophysiological glucose sensing in arcuate neurons that are modu-
studies in rats (using glucose concentrations from . lated by glucose levels . mM (high GE and high
to .mM) showing that GE and GI neurons make up GI). In keeping with this, high GE neurons are still
% and .% of amygdala neurons, respectively (). found in KATP-deficient mice (). In these neurons,
Neurons in the hippocampus may also respond to it is likely that a pathway involving transient receptor
changes in glucose. These neurons express glucokinase potential canonical type  (TRPC) channels is involved
(), GLUT (), KATP channels (), and sweet taste in the glucose-sensing mechanism (). Glucose sensing
receptors TR/TR in the corni ammonis fields and in GE neurons in the PVH () and GnRH neurons
dentate gyrus (). () is also reported to be independent of KATP

Glucose-sensing properties have been reported in channels.
CNS populations other than neurons. Tanycytes, Mitochondrial function can also play a role in
which line the third ventricle, express proteins likely to glucose sensing in ARC and VMH GE neurons.
be involved in glucose sensing such as glucokinase, Glucose sensing in POMC neurons exposed to glucose
KATP channels, and GLUT. In vitro studies dem- concentrations ranging from . to . mM is dis-
onstrate that intracellular calcium in tanycytes in- rupted by alterations in the mitochondrial fission
creases as glucose rises from . to  mM (). regulator, dynamin-related protein  (DRP) (). In
Astrocyte populations may also sense glucose, as the VMH, mitochondrial function has also been
GLUT is expressed in astrocytes in the hypothalamus shown to be critical to glucose sensing in GE neurons.
() and brain stem (). Glucose taken up by as- Increasing glucose induces mitochondrial fission
trocytes largely enters the glycolytic pathway to pro- through phosphorylated DRP and uncoupling pro-
duce lactate that is released via monocarboxylate tein . When uncoupling protein  expression was
transporters into the extracellular space (, ) and increased, the number of VMH GE neurons also
may provide an alternative energy source for neurons increased (). “In many GE neurons, the
(, ). The glucose-sensing mechanisms described sensing mechanism is thought
Many other cell populations are modulated by above rely on glucose metabolism, but metabolism- to be similar to that seen in
changing glucose via synaptic inputs from glucose- independent pathways have also been reported. pancreatic b cells…”
sensing neurons. Song et al. () reported that in the Sodium-glucose cotransporters (SGLTs) link the in-
ventromedial hypothalamus ~% of cells are directly ward transport of glucose and sodium, and as glucose
modulated by changes in extracellular glucose whereas levels increase and are transported into the cell, the
a further % of neurons were presynaptically in- cotransport of sodium ions would lead to de-
hibited or activated by altered glucose. polarization. SGLT, SGLTa, and SGLTb are
expressed in subpopulations of GE neurons (, ).
Mechanisms responsible for glucose sensing in GE An alternative signaling mechanism is via sweet taste
and GI neurons receptors. These are heterodimers of TR and TR
Multiple mechanisms have been described to play a and are expressed in the CNS, particularly in the ARC
role in glucose sensing (Fig. ). In many GE neurons, as well as in the periphery. The receptors are activated
the sensing mechanism is thought to be similar to that by glucose and also by sweeteners such as sucralose,
seen in pancreatic b cells and dependent on glucose but signaling does not rely on glucose metabolism. A
metabolism. VMH and ARC GE neurons, similar to role for these receptors is supported by studies
the pancreatic b cells, express glucokinase to phos- showing that sucralose application activated a signif-
phorylate glucose to glucose--phosphate (, ). icant proportion of ARC GE neurons whereas the
Glucokinase has a low affinity for glucose and there is sweet taste receptor inhibitor gurmarin inhibited the
no end product inhibition (), so glucokinase glucose responses in .% of ARC GE neurons ().
activity is proportional to glucose concentrations. The glucose-sensing mechanisms in GI neurons
Supporting a role for glucokinase, mice and humans are less well understood. GI neurons in the ARC and
with reduced glucokinase activity show an exaggerated VMH also express glucokinase, and decreased glucose
hormonal response to hypoglycemia (). As glucose leads to a reduction in intracellular ATP/ADP ratios.
concentrations increase, so too does glucose meta- Electrophysiological studies and calcium imaging
bolism, leading to an increased intracellular ATP/ADP suggest that the activation in VMH GI neurons is
ratio () and, through interconversion of adenine mediated by inactivation of an ATP-dependent
nucleotides, to an increased ATP/AMP ratio. In many chloride current (). The cystic fibrosis trans-
GE neurons, increased ATP/ADP leads to closure of membrane conductance regulator is activated by ATP
KATP channels, depolarizing the neurons and increasing and expressed in the hypothalamus. As glucose levels

REVIEW
fall, decreased ATP reduces the chloride current through low glucose () and altered neuronal activity (). The
the cystic fibrosis transmembrane conductance regula- pathway linking low glucose and AMPK to increased cell
tor, leading to depolarization (). There is also evidence activity is also likely to involve nitric oxide (NO). Both
to support a role for AMPK in glucose sensing. AMPK is hypoglycemia and -Aminoimidazole--carboxamide
activated as the ratio of AMP to ATP rises and, in turn, ribonucleotide increase NO, and this increase is absent
decreases anabolic processes while increasing catabolic when AMPK activity is blocked by compound C ().
processes to conserve energy (). In GI neurons on Glucose metabolism–independent pathways are
the VMH, activating AMPK with -Aminoimidazole- also present in GI neurons. LH orexin neurons are
-carboxamide ribonucleotide mimicked the effects of inhibited by both glucose ( mM) and the non-
metabolizable glucose analog DG ( to  mM). The
mechanism linking glucose to ion channel activity in
these cells is unknown, but glucose and DG lead to
opening of tandem-pore K1 channels, resulting in
hyperpolarization and reduced neural activity (, ).
However, although the tandem-pore K1 channels,

TASK and TASK, are involved in regulating ex-
citability of orexin neurons, they are not essential for
glucose sensing in orexin neurons. Orexin neurons in
TASK knockout mice, TASK knockout mice, or
TASK/ double knockout mice still responded to
altered glucose (. to  mM) (, ).
Projections from glucose-sensing neurons

Although the specific circuitry of glucose-sensing neu-
rons is not fully defined, it is clear that regions with
glucose-sensing neurons are highly interconnected. This
provides an anatomical framework to suggest that there
may be an integrated network of glucose sensors that fine
tune the response to altered glucose concentrations (Fig.
). Glucose-sensing neurons are present in a number of
brain regions and exert their actions through projections
to downstream areas, particularly via sympathetic and
parasympathetic efferent pathways in the brain stem and
spinal cord to metabolically active organs. The cell bodies
of vagal preganglionic neurons innervating organs such
as the pancreas, liver, and visceral adipose tissue are
found in the DMV and express choline acetyltransferase.
The DMV receives input from the brain stem and
hypothalamic and forebrain regions. In the brain stem,
neurons in the NTS are known to project to the DMV.
These include GABAergic neurons, of which some are
glucose sensing (). Cells in the A/rostral ventrolateral
medulla also provide input into the DMV. In the hy-
pothalamus, cells in the PVH, DMH, LH, and ARC
project to the DMV, and in the forebrain, neurons in the
MPOA and bed nucleus of the stria terminalis (BNST)
also provide input into the DMV. Additional hypo-
thalamic nuclei then connect to these regions, particu-
Figure 2. Putative glucose-sensing mechanisms in glucose-sensing neurons. In GE cells (upper
panel), glucose can enter cells via GLUTs (usually GLUT2 or GLUT3) and is phosphorylated by larly the VMH (, ).
glucokinase to glucose-6-phosphate. This, in turn, regulates cytosolic ATP production. In GE Sympathetic pancreatic innervation originates in
neurons, increased ATP closes KATP channels, leading to depolarization and calcium influx through the cholinergic sympathetic preganglionic neurons in
voltage-activated calcium channels. Metabolism-independent pathways have also been described the intermediolateral column (IML) of the spinal cord,
using sweet taste receptors and downstream signaling, sodium/glucose cotransporter, or transient and this region also receives input from regions with
receptor potential canonical type 3 (TRPC3) channels. Both sodium/glucose cotransporter and
glucose-sensing neurons. The rostral ventrolateral
TRPC3 channels lead to influx of cations and depolarization. In GI cells (lower panel), as glucose
entry decreases, intracellular ATP falls. Low ATP leads to an increase in AMPK activity. This may
medulla (RVLM), LC, and several hypothalamic areas,
reduce activity of chloride channels, possibly via neuronal NO synthase, whereas low ATP decreases including the PVH and LH, provide direct input into
activity of Na/K ATPases. Both of these lead to cell depolarization with low glucose. Alternative the IML. Multiple additional regions provide indirect
pathways involving closure of potassium leak channels with low glucose have also been described. projections to the IML via either the PVH or LH,
REVIEW
Figure 3. Connections to sympathetic and parasympathetic efferent pathways in the mouse brain. The DMV is the parasympathetic
efferent pathway. The DMV receives input from the NTS and the RVLM as well as from the PVH, DMH, LH, and ARC. The VMH connects
indirectly via the PVH. The sympathetic efferent pathway is via the IML of the spinal cord. This receives input from the RVLM, LC, as well
as the PVH and LH. Multiple hypothalamic regions, including the ARC, VMH, DMH, project to either the PVH or LH.

REVIEW
including the ARC, VMH, DMH, MPOA, and BNST maintain this balance, and when blood glucose falls
(, ). either because of insufficient intake or increased use, a
The specific projections of glucose-sensing neurons number of counterregulatory measures act to restore
from across the brain are largely unknown, but studies blood glucose levels to normal. In healthy individuals,
that examine the projections of neurons expressing as glucose levels fall, a sequential set of responses
defined neuropeptides, a portion of which are known occurs. These responses are the result of coordinated
to be glucose sensing, provide some insights into the effects directly in peripheral organs but also via actions
density and expanse of these projections. In the ARC, a in multiple CNS regions that then influence peripheral
subpopulation of NPY neurons, which also express organs via their innervation and actions of circulating
agouti-related peptide (AgRP), are GI neurons. Within hormones.
the hypothalamus, ARC AgRP/NPY neurons project
to the PVH and LH (), which would provide in- Hypoglycemia-induced reduction in
direct pathways to both sympathetic and para- insulin secretion
sympathetic pathways. Similarly, ARC POMC neurons As glucose falls below the physiological range (~ mg/

have also been reported to be glucose sensing and dL or ~. mmol/L), the initial response is a decrease in
project to the LH and PVH in addition to other hy- insulin secretion. As insulin levels fall, glucose uptake
pothalamic regions such as the VMH and DMH, as into insulin-sensitive tissues, including liver, muscle,
well as sending dense projections to the BNST (). and adipose tissue, also falls and insulin’s inhibition of
VMH neurons expressing steroidogenic factor- glycogenolysis and gluconeogenesis is relieved ().
(SF), a subpopulation of which are glucose sensing, These effects combine to decrease glucose efflux, in-
project widely. SF neurons in the dorsomedial VMH crease glucose influx, and restore euglycemia.
project to other hypothalamic nuclei, including the The fall in insulin release in response to hypo-
PVH, to lateral regions such as the amygdala, rostral glycemia is partly a consequence of decreased glucose
areas such as the BNST, and caudal areas including the stimulation directly on b cells. However, there is also
RVLM and LC (). In the LH, GI orexin neurons evidence for neural regulation of insulin release. The
have multiple projection sites to innervate almost the pancreas is densely innervated by both parasympathetic
entire hypothalamus, BNST, and cortex with caudal and sympathetic fibers (). Parasympathetic cho-
projections to the LC and the NTS, RVLM, and DMV linergic inputs may play a role in regulation of insulin
(, ). Similarly, LH MCH neurons, which are and glucagon. In many animal studies across different
largely glucose excited, project to most hypothalamic species, activation of DMV neurons (), vagal
nuclei, to the amygdala and BNST, and rostral to the stimulation (), and acetylcholine administration
RVLM and AP (). Neurons in the PVH project to () all increase both insulin and glucagon secretion.
the median eminence to regulate pituitary function but Conversely, parasympathetic blockade by atropine
also connect to other brain regions. Dense connections inhibits insulin release () and blunts glucagon
are seen within the PVH and to other hypothalamic secretory responses to hypoglycemia (). In human
regions (DMH, LH, MPO), to rostral regions such as studies, the role of the parasympathetic nervous
the BNST () and caudally to the NTS, DMV and system is complex. Atropine prevents increased
IML (). glucose-stimulated insulin release that occurs with
Brain stem PBN neurons, which are glucose the atypical antipsychotic olanzapine (), but va-
inhibited, project to thalamic and hypothalamic nuclei gotomy increases the periodicity of insulin release
(LH, VMH, zona incerta) as well as to the NTS. The (), so species differences may exist. In contrast,
specific projections of glucose-sensing CCK neurons sympathetic activation suppressed insulin release
in the PBN have been traced using genetically encoded (), and norepinephrine and epinephrine admin-
tracers. These neurons project predominantly to the istration reproduce sympathetic excitation by sup-
ipsilateral hypothalamus, with a particularly dense pressing insulin and stimulating glucagon release
input onto the dorsomedial VMH (). in humans (, ).
Both the PVH and LH have direct projections to
sympathetic preganglionic neurons. Lesion of the
The Counterregulatory Response to PVH, which projects to sympathetic preganglionic
Hypoglycemia in Health and Diabetes neurons, produces hyperinsulinemia (). However,
the effects of modulating LH activity are contradictory.
Under normal circumstances, blood glucose is Several studies reported that electrical stimulation of
maintained in a narrow range from  to  mmol/L. the LH inhibited glucose-stimulated insulin release
There is a delicate balance between glucose influx from (, ). However, infusion of norepinephrine into
ingestion and endogenous glucose production and the LH rapidly increased insulin and this effect was
glucose efflux through utilization and uptake in reversed by vagal blockade with atropine ().
insulin-sensitive and insulin-insensitive organs. Hor- Other CNS regions regulate sympathetic activity
mones, neurotransmitters, and behavior all act to via indirect projections to the IML and have been
REVIEW
implicated in the control of insulin release. There is gluconeogenesis (), leading to increased blood
considerable evidence to support a role for the VMH, glucose (). Glucagon can also stimulate lipolysis
which contains both GI and GE neurons, in modu- and ketogenesis when insulin levels are low, for ex-
lating insulin secretion. VMH lesions result in insulin ample, following an extended fast ().
hypersecretion (, ) whereas electrical stimula- Several mechanisms contribute to glucagon release
tion of the VMH suppressed insulin secretion (). in hypoglycemia. Perhaps one of the most important is
These results suggest that VMH activity may have an the reduction in insulin secretion that occurs when
inhibitory effect on pancreatic insulin release. More glucose falls, which in turn removes the inhibition of
recent studies support these findings. Using magne- glucagon release (). In healthy subjects, this leads to
togenetic neuromodulatory tools, acute stimulation of an exuberant response that restores euglycemia.
VMH neurons expressing glucokinase decreased However, this mechanism is not operational in pa-
plasma insulin whereas silencing these neurons in- tients with type  and advanced type  diabetes be-
creased insulin (). Similarly, optogenetic activation cause they cannot reduce insulin secretion in the
of VMH SF neurons increased blood glucose without setting of a fall in blood sugar. Exogenous insulin

increasing plasma insulin (). These findings suggest cannot be dissipated, so the inhibitory effects of cir-
that VMH GI neurons, which would normally be culating insulin cannot be attenuated and the tonic
activated by a decrease in blood glucose, may play a inhibition of glucagon secretion cannot be released.
role in suppressing insulin release in hypoglycemia. As a result, these patients generally do not have a
ARC neural populations may also regulate insulin glucagon secretory response to a fall in glucose ()
release. Studies using targeted overexpression of glu- The sympathetic nervous system and catechol-
cokinase in the ARC to enhance glucose sensing amines also play a critical role in increasing glucagon
showed blunted glucose-stimulated insulin release release. Sympathetic nervous system activation releases
(). CNS administration of melanocortin agonists norepinephrine locally and increases circulating epi-
inhibits basal insulin release (). This suggests that nephrine, which together act on B adrenergic re-
the melanocortin system, AgRP and POMC neurons ceptors on the a cell to stimulate glucagon secretion.
of the ARC and melanocortin receptors, may play a Blocking the activation of the autonomic nervous
role in regulating insulin secretion. system has been reported to eliminate % to % of
“Both cortisol and GH release
Hindbrain regions are also likely to play a role in the glucagon response to hypoglycemia ().
occur with relatively severe
control of insulin. Glucose-sensing neurons expressing Multiple CNS regions have been shown to play a hypoglycemia and provide a
leptin receptor in the PBN regulate insulin release, as role in hypoglycemia-induced glucagon secretion. In more sustained effect to
chemogenetic activation of these neurons blunts rodents, vagal stimulation increases plasma glucagon, maintain blood glucose.”
glucose-stimulated insulin release, resulting in im- and recent studies showed that optogenetic activation
paired glucose tolerance (). Although neurons in of GLUT neurons in the DMV significantly increased
the RVLM are modulated by glucose and their acti- vagal activity and glucagon secretion compared with
vation increases blood glucose, the effects on insulin control animals (). Sympathetic activity also stim-
have not been reported. ulates glucagon release, and many CNS regions with
In patients with insulin-treated diabetes, a fall in direct and indirect projections to sympathetic outflow
glucose occurs when more exogenously administered regions are implicated in regulating glucagon release.
insulin is present than required for the metabolic In the brain stem, chemogenetic activation of leptin
condition. Insulin secretion from the b cell is pro- receptor–positive neurons () and CCK neurons
foundly deficient in such patients, and reductions in () in the PBN increased plasma glucagon. Because
serum glucose concentration or changes in neural both the LH and PVH project to sympathetic pre-
input to the islet have a minimal effect on reversing ganglionic neurons, they may also play a role in
hypoglycemia. These patients cannot link brain glu- sympathetic stimulation of glucagon release. In
cose sensing that occurs in the brain regions detailed in keeping with this, the glucagon response to hypo-
previous paragraphs to a reduction in insulin secretion glycemia is enhanced in mice lacking the leptin re-
and must rely on other counterregulatory mechanisms ceptor in the LH and premammillary nucleus ().
to restore euglycemia. However, PVH lesions did not alter glucagon re-
sponses to hypoglycemia ().
Hypoglycemia-induced glucagon release Although the VMH does not project directly to
The threshold to elicit the increase in glucagon is in the sympathetic outflow regions, most evidence supports
range of  to  mg/dL (. to . mmol/L) its role in the glucagon response to hypoglycemia.
(–). The major effects of glucagon to increase Electrical stimulation of the VMH increases plasma
blood glucose are in the liver, to rapidly increase glucagon () whereas VMH lesions blunt the glu-
glycogenolysis and stimulate gluconeogenesis. Glu- cagon rise following hypoglycemia (, ). VMH
cagon also inhibits hepatic glucose uptake. Collec- injection of DG to mimic glycopenia induces glu-
tively, these actions produce a transient increase in cagon secretion (), and VMH administration of
hepatic glycogenolysis and a sustained increase in glucose during systemic hypoglycemia blunts the

REVIEW
counterregulatory glucagon response (). More VMH injection of DG to induce glucoprivation
recently, chemogenetic activation of VMH SF neu- stimulated epinephrine release -fold and norepi-
rons () and magnetogenetic activation of VMH nephrine release more than threefold () whereas
glucokinase neurons () have been shown to in- local VMH glucose infusion blunted the catechol-
crease plasma glucagon. Silencing of these populations amine response to systemic hypoglycemia (). A
blunted the counterregulatory response to hypogly- number of signaling mechanisms in the VMH have
cemia. In mice without VMH glucokinase expression, also been implicated in the full catecholamine
the glucagon response to hypoglycemia was also counterregulatory response to hypoglycemia, in-
blunted (). Similarly, reduced AMPK activity by cluding NO (), AMPK (), CRF (), b ad-
expression of a dominant negative AMPK in the ARC/ renergic receptors (), and GABA ().
VMH of rats reduced the glucagon response to hy- Individuals with type  and advanced type  di-
poglycemia (). abetes must rely on hypoglycemia-induced catechol-
amine secretion to prevent them from experiencing
Hypoglycemia-induced catecholamine secretion neuroglycopenia. Unfortunately, each episode of hy-

As glucose levels fall further to a threshold of between poglycemia transiently reduces the glucose level
 and  mg/dL (. to . mmol/L), epinephrine necessary to elicit catecholamine release. When an
levels begin to increase (). Increased epinephrine individual experiences several episodes of hypogly-
and norepinephrine have several effects to raise glu- cemia in a short period of time, catecholamine release
cose. Catecholamines increase hepatic gluconeogen- may not occur before the onset of neuroglycopenia.
esis and glycogenolysis to increase glucose influx. This situation has been called hypoglycemia-associated
Additionally, catecholamines also decreases glucose autonomic failure (). It is closely associated clini-
uptake by directly inhibiting insulin secretion from b cally with low symptomatic awareness of hypoglycemia,
cells and inhibiting insulin-stimulated glucose uptake presumably because at least some of the symptoms of
(). Catecholamines also increase lipolysis, pro- hypoglycemia are generated by the physical counter-
viding free fatty acids as an alternative energy source regulatory responses.
for peripheral tissues (). Sympathetic activation
leading to catecholamine release results in tremor Hypoglycemia-induced increases in cortisol
(), sweating (), and headache (). and GH
Several CNS regions have been reported to play a Both cortisol and GH release occur with relatively
role in this response. Ablation of catecholaminergic severe hypoglycemia and provide a more sustained
neurons in the spinal cord diminishes the catechol- effect to maintain blood glucose. The effects of both
aminergic response to insulin-induced hypoglycemia cortisol and GH are slow onset (on the order of hours),
(). Similarly, neurotoxic destruction of RVLM and some studies suggest that they may not play a
neurons blunted the catecholaminergic response to significant role in the acute response to hypoglycemia
systemic hypoglycemia (). Chemogenetic activa- (). Cortisol activates hepatic gluconeogenesis to
tion of GI CCK neurons in the PBN significantly increase plasma glucose and ketogenesis to provide
increases serum epinephrine concentrations, and si- alternative energy source for tissues, reduces insulin-
lencing these neurons blunted the counterregulatory dependent glucose uptake (), and increases fatty
response to hypoglycemia (). acid oxidation. Cortisol also increases lipolysis in some
Several hypothalamic regions are also likely to fat depots (). Cortisol also alters insulin receptor
play a role in the catecholaminergic response to hy- binding and signaling () and directly inhibits
poglycemia. Both the PVH and LH have dense pro- pancreatic insulin secretion (). GH induces insulin
jections to the sympathetic preganglionic neurons and resistance through a postreceptor mechanism (),
play a role in hypoglycemia-induced catecholamine activates gluconeogenesis, and stimulates lipolysis to
release. Silencing PVH neurons with lidocaine almost increase free fatty acids ().
halved the peak epinephrine response to hypoglycemia Cortisol (or corticosterone in rodents) is secreted
(). Overexpression of a dominant negative form of from the adrenal cortex in response to ACTH pro-
AMPK to reduce glucose sensing in the PVH blunted duced by the pituitary gland. ACTH release is, in turn,
the catecholaminergic response to hypoglycemia (). modulated by CRH (also known as corticotropin-
Local injection of thioglucose into the perifornical releasing factor). CRH is produced by neuroendo-
hypothalamus to elicit glucoprivation rapidly stimu- crine cells in the PVH and released from terminals in
lated epinephrine release, whereas depleting serotonin the median eminence into the pituitary portal system
in the perifornical hypothalamus blunted the cate- to be delivered to the anterior pituitary and to
cholaminergic response to hypoglycemia (). stimulate ACTH release into the systemic circulation.
The VMH is also critical to hypoglycemia-induced Hypoglycemia increases both CRH () and ACTH
catecholamine release. VMH lesions blunted epi- (). CRH is produced by PVH neurons and,
nephrine and norepinephrine release during mild and as expected, this region has been shown to affect
severe hypoglycemia in rats by % to % (). Local the ACTH/corticosterone response to hypoglycemia.
REVIEW
Disruption of PVH glucose sensing by expressing a and symptom response to subsequent hypoglycemia
dominant negative AMPK significantly blunted the and leads to the development of impaired awareness of
corticosterone response to hypoglycemia (). How- hypoglycemia. The mechanisms underlying the devel-
ever, silencing PVH neurons with lidocaine suppressed opment of impaired awareness of hypoglycemia are not
hypoglycemia induced ACTH but not corticosterone clearly understood. Changes in both neurotransmission
secretion (). Other studies have shown that inputs and adaptations in energy metabolism have been
into the PVH are important to the corticosterone re- postulated as possible causes that may lead to altered
sponse to hypoglycemia. Chemical lesions of the sensing of glucose by the brain. Development of im-
hindbrain catecholaminergic neurons innervating the paired awareness of hypoglycemia could also be related
PVH blunted the feeding and corticosterone increase to defects in the coordination of the counterregulatory
with hypoglycemia (). Other hypothalamic regions response to hypoglycemia. In this section we review
also project to the PVH and can modulate the coun- some of the potential mechanisms (Fig. ) that may
terregulatory corticosterone release. Silencing DMH contribute to the development of impaired awareness of
neurons with lidocaine blunted ACTH release and hypoglycemia. These proposed mechanisms are not

delayed corticosterone release with hypoglycemia (). mutually exclusive, it is likely that multiple factors
Optogenetic activation of VMH SF neurons markedly contribute to development of this syndrome, and how
increased plasma corticosterone (). Interestingly, patients with diabetes respond to recurrent hypogly-
activating SF neurons projecting to the PVH produced cemia may be different than from individuals with
a small, nonsignificant increase in corticosterone normoglycemia.
whereas activation of SF projections to the BNST
significantly increased corticosterone (). It also Upregulation of glucose transport to the brain
appears that the BNST-projecting VMH neurons Increase glucose uptake across the blood–brain barrier
receive inputs from the PBN, and this region has also has been proposed as a potential cerebral adaptation to
been shown to play a role in regulating corticosterone recurrent hypoglycemia, which allows neurons to
release. Activation of PBN leptin receptor–positive maintain metabolism during the stress of hypogly-
neurons also stimulates plasma corticosterone to mimic cemia and may lead to development of impaired
the response to hypoglycemia (). Plasma cortico- awareness of hypoglycemia. Previous studies in ro- “Exposure to repeated episodes
sterone is also increased by chemogenetic stimulation of dents have shown that chronic hypoglycemia resulted of antecedent hypoglycemia
PBN CCK neurons (). in increased expression of GLUT transporters in the results in reduced
GH is also released in response to hypoglycemia. endothelial cells of the blood–brain barrier along with counterregulatory hormone
Pituitary GH secretion is stimulated by GHRH and upregulation of brain glucose transport (, ). In a and symptom response to
subsequent hypoglycemia…”
inhibited by somatostatin, both produced in the hy- rodent study that used an in vivo microdialysis
pothalamus. Previous studies have shown that arcuate technique to measure brain glucose concentrations
GHRH neurons are activated by hypoglycemia () and following administration of IP glucose, animals ex-
so may be directly stimulated by low glucose to release posed to recurrent hypoglycemia were found to have
GHRH and increase GH secretion. Somatostatin- glucose concentrations threefold to fourfold higher in
expressing neurons are found in the periventricular the hippocampal extracellular fluid as compared with
hypothalamus, and there is conflicting evidence as to controls (), whereas the plasma glucose concen-
whether they are glucose sensing. In mice, somatostatin tration did not differ between the two groups, sug-
neurons do not express c-fos in response to hypogly- gesting upregulated transport of glucose into the brain.
cemia (), but in insulin-induced hypoglycemia in- However, other studies, especially in humans, have
duces c-fos immunoreactivity in SST neurons in ewes reported conflicting data on whether cerebral glucose
(). Other factors also regulate GH release, including transport or metabolism are altered after exposure to
GH secretagogues such as ghrelin. Ghrelin knockout recurrent hypoglycemia. Using magnetic resonance
mice or mice lacking ghrelin O-acyltransferase, which is spectroscopy, Creigo et al. () found glucose steady-
required for active ghrelin, become profoundly hypo- state concentrations in the occipital cortex to be higher
glycemic with fasting owing to a failure to increase GH during a hyperglycemic clamp in subjects with type 
(, ). However, in humans, studies suggest that diabetes and impaired awareness of hypoglycemia
ghrelin is acutely suppressed by insulin (with or without compared with healthy controls. Additionally, brain
hypoglycemia) and does not influence the counter- glucose uptake (calculated based on cerebral blood
regulatory response to hypoglycemia (). flow and brain arteriovenous glucose difference) was
maintained during hypoglycemia in subjects with
tightly controlled type  diabetes (who were pre-
Impact of Recurrent Hypoglycemia sumably more likely to be exposed to recurrent hy-
on Counterregulation poglycemia) compared with controls and subjects with
poorly controlled type  diabetes (). These ob-
Exposure to repeated episodes of antecedent hypo- servations support the hypothesis that brain glucose
glycemia results in reduced counterregulatory hormone transport or metabolism are altered after recurrent

REVIEW
hypoglycemia. Despite this, measurement of global in subjects with type  diabetes and impaired
rates of blood-to-brain glucose transport by PET in awareness of hypoglycemia and remained stable in
humans has not shown evidence of upregulation of subjects with type  diabetes and normal awareness of
glucose uptake. Utilizing PET, glucose transport was hypoglycemia and in nondiabetic controls. This sug-
shown to be normal in healthy subjects exposed to gests that lactate was used during hypoglycemia as an
hypoglycemia () and similar in subjects with type  alternate fuel source and may contribute to the de-
diabetes and impaired awareness of hypoglycemia velopment of impaired awareness of hypoglycemia
compared with subjects with type  diabetes and (). Other investigators have examined the effects of
normal awareness (). A recent study examined physiologically raised plasma lactate concentrations on
glucose transport kinetics in the hypothalamus of brain lactate concentration during hypoglycemia in
healthy subjects who underwent a protocol of repeated patients with and without impaired awareness of
antecedent hypoglycemia to experimentally induce hypoglycemia and in healthy controls (). In this
impaired awareness of hypoglycemia (). In this study, plasma lactate was raised by a single bout of
study, the glucose transport kinetics in the hypo- high-intensity interval training. The investigators

thalamus of healthy humans with experimentally found that the brain lactate level was increased in all
induced impaired awareness of hypoglycemia were groups at the start of the hypoglycemia that was in-
not different from those measured in the absence of duced following high-intensity interval training, but
impaired awareness of hypoglycemia. More studies the increase was most pronounced in subjects with
are needed to examine whether there are regional diabetes and impaired awareness of hypoglycemia.
differences in cerebral adaptation to recurrent During hypoglycemia, lactate levels decreased below
hypoglycemia. baseline in the group with impaired awareness of
hypoglycemia and remained unchanged in the other
Utilization of alternate fuels groups. This finding also suggests that lactate transport
Brain utilization of nonglucose substrates, including and oxidation of lactate may be enhanced in, and
lactate and ketones, has been proposed as a potential contribute to, development of impaired awareness
mechanism that could maintain energy metabolism of hypoglycemia. Similar to lactate, infusion of
during hypoglycemia. Lactate infusion during hypo- b-hydroxybutyrate has also been shown to reduce the
glycemia has been shown to lower the glucose level, magnitude of counterregulatory hormone responses
which triggers the hypoglycemia counterregulatory and symptoms in healthy humans (, ).
response, reduces the magnitude of epinephrine and Acetate transport into the brain has also been
hypoglycemia symptom responses, as well as prevents shown to be upregulated in subjects with type  di-
cognitive function deterioration (). These findings abetes and a history of hypoglycemia unawareness
suggest that the brain utilizes lactate as a fuel source compared with healthy controls (). Acetate is
when glucose supply is low, leading to alterations in transported into the brain by monocarboxylic acid
the counterregulatory response to hypoglycemia transporters, which are also responsible for trans-
similar to those seen in people with impaired porting lactate and other ketone bodies. It has been
awareness of hypoglycemia (). Using in vivo hypothesized that upregulation of these transporters in
magnetic resonance spectroscopy, brain lactate has response to recurrent hypoglycemia can provide the
been shown to fall significantly during hypoglycemia brain with alternate fuel sources during subsequent
hypoglycemia, leading to the development of impaired
awareness of hypoglycemia. Another study has shown
that the increase in lactate levels alone may not be
sufficient to offset the energy deficit caused by hy-
poglycemia (). In a rodent model, Herzog et al. ()
demonstrated that recurrent hypoglycemia enhances
transport of lactate into the brain but the elevated
lactate itself was not sufficient to support metabolism
as nonglucose fuel source. Instead, increased lactate
acted as a ‘metabolic regulator’ to maintain neuronal
glucose metabolism during hypoglycemia.
Alterations in brain glutamate metabolism have
been reported in subjects with type  diabetes and
impaired awareness of hypoglycemia (, ). Brain
glutamate concentration decreases during hypogly-
cemia, and this reduction has been ascribed to oxi-
dation of glutamate in response to hypoglycemia (,
Figure 4. Potential mechanisms that may contribute to the development of impaired awareness of ). In human studies, reduction in glutamate during
hypoglycemia after exposure to recurrent hypoglycemia. hypoglycemia was seen in heathy controls and subjects
REVIEW
with type  diabetes without impaired awareness of of hypoglycemia-induced hormone secretion ().
hypoglycemia but not in subjects with type  diabetes Increased GABAergic tone within the VMH has been
and impaired awareness of hypoglycemia (). These implicated in the development of impaired awareness
data were interpreted to suggest that in subjects with of hypoglycemia (). Rodents exposed to recurrent
impaired awareness of hypoglycemia, enhanced glu- hypoglycemia have elevated hypothalamic GABA
cose and/or alternate fuel transport into the brain levels at baseline, and they also fail to decrease these
eliminated the need to oxidize glutamate. GABA levels in response to hypoglycemia (, ).
These animals show an attenuated counterregulatory
Increase glycogen storage hormone response to hypoglycemia, and this response
Brain glycogen stored primarily in astrocytes can be can be restored with local blockage of GABAA re-
metabolized to lactate and exported to neurons to be ceptors (). In a human study, pharmacologic ac-
used as an energy source during hypoglycemia tivation of GABAA receptors has also been shown to
(–). Following a single episode of acute hy- reduce the counterregulatory response to subsequent
poglycemia in rodents, after plasma and brain glucose hypoglycemia ().

concentrations are restored, glycogen concentration Hypothalamic AMPK has been shown to play a
has been shown to increase several fold above the role in glucose sensing and modulating the counter-
baseline condition. This rebound increase in glycogen regulatory response to hypoglycemia (). Exposure
level above the pre-hypoglycemia level has been to recurrent hypoglycemia leads to reduced AMPK
termed “supercompensation” (). As a result of this activity in the VMH and may contribute to devel-
observation, investigators have hypothesized that opment of a defective counterregulatory response to
supercompensation of glycogen after hypoglycemia hypoglycemia (, ). Pharmacological activation
can supply extra fuel during subsequent hypoglycemia of AMPK within the VMH amplifies the counter-
and contribute to development of impaired awareness regulatory response to acute hypoglycemia and im-
of hypoglycemia. Supercompensation of glycogen has proves the blunted counterregulatory hormone response
also been shown to occur in rodent brains after ex- in both diabetic and normal rats exposed to antecedent
posure to recurrent episodes of hypoglycemia (). recurrent hypoglycemia (, ).
However, this increase in glycogen above baseline after Other glucose-sensing mechanisms may also be
single and recurrent hypoglycemia was not seen in defective in recurrent hypoglycemia. KATP channels
other rodent studies (). Differences in study design, open in GE neurons in response to low glucose,
including severity of hypoglycemia, use of anesthetics, leading to hyperpolarization and reduced firing rate,
and methods for monitoring glycogen content and and hypothalamic KATP channels are needed for an
glucose level during recovery from hypoglycemia, have appropriate response to hypoglycemia. VMH injection
been noted as possible explanations for the differences of the KATP channel opener diazoxide augments the
in these results (). However, a recent rodent study response to hypoglycemia in rodents with recurrent
found that glycogen supercompensation was in- hypoglycemia (). However, chronic treatment with
dependent of blood glucose levels in the post- KATP channel openers resulted in channel adaptation
hypoglycemia period (). In vivo C magnetic and decreased ability to sense hypoglycemia in vitro
resonance spectroscopy in conjunction with IV in- and in vivo (, ).
fusions of -[C]-glucose has been used to measure
brain glycogen metabolism in humans. In heathy Increase cerebral oxidative stress
humans, increased glycogen levels were noted Acute hypoglycemia increases reactive oxygen species
following a single episode of acute hypoglycemia but (ROS) levels in the hypothalamus (). NO pro-
not after exposure to recurrent hypoglycemia (). duction by neuronal NO synthase and activation of the
Glycogen levels were also noted to be similar in NO receptor soluble guanylyl cyclase (sGC) are
subjects with type  diabetes and impaired awareness thought to be critical for activation of VMH GI
of hypoglycemia compared with healthy controls neurons during hypoglycemia and for the initiation
(). These data from human studies did not support of a counterregulatory response (). Elevated ROS
the hypothesis that supercompensation of glycogen level leads to nitrosylation of sGC, which desensitizes
contributes to development of impaired awareness of sGC to NO (). Hypoglycemia induced increases in
hypoglycemia. hypothalamic ROS, leading to impaired action of NO
on its receptor sGC (), has been implicated in
Altered hypothalamic neurosignaling defective counterregulatory responses to hypoglyce-
Studies in rodent models have suggested that hypo- mia. In nondiabetic rats, enhancing the glutathione
thalamic GABA signaling plays an important role in antioxidant defense system by pretreatment with N-
regulating the counterregulatory hormone response to acetyl-cysteine (NAC) prevented both hypoglycemia-
hypoglycemia (). A decrease in the local availability induced VMH ROS production and an impaired
of glucose within the VMH is thought to lower local counterregulatory hormone response to subsequent
GABA release, which in turn modulates the magnitude hypoglycemia (). These results suggest that

REVIEW
increasing glutathione with NAC could be a potential hypoglycemia (). IV administration of naloxone, an
treatment option for impaired awareness of hypo- opioid receptor antagonist, during hypoglycemia aug-
glycemia. However, in a recent study by the same ments the plasma epinephrine response to hypogly-
investigators, pretreatment with NAC did not preserve cemia in dogs () and humans (). When infused
activation of VMH GI neurons by low glucose in during antecedent hypoglycemia, naloxone has been
diabetic rats exposed to recurrent hypoglycemia (). shown to prevent the development of the defective
Hyperglycemia associated with diabetes has also been counterregulatory hormone response to subsequent
shown to increase ROS levels in the brain (). Zhou hypoglycemia in healthy humans () and in subjects
and Routh () hypothesize that the NAC-related with type  diabetes (). These studies suggest that
increase in glutathione maybe not be sufficient to opioid signaling may play a role in the development of
compensate for the combined oxidative stress resulting impaired awareness of hypoglycemia. The mechanisms
from both hypoglycemia and hyperglycemia in di- by which opioid receptor antagonists may prevent the
abetic rats. They observed that overexpression of development of impaired awareness of hypoglycemia
VMH thioredoxin (Trx)- preserved the counter- are not known. Opioid receptors are expressed in VMH

regulatory response and activation of VMH GI (), where they could potentially modulate glucose
neurons by low glucose in rats with streptozotocin- sensing during hypoglycemia (, ). Opioid re-
induced diabetes before but not after exposure to ceptor antagonists are being tested as potential phar-
recurrent hypoglycemia. The Trx system, which is maceutical therapy for prevention and treatment of
composed of the reduced form of NAD phosphate, impaired awareness of hypoglycemia ().
Trx reductase, and Trx, is a key antioxidant system in
defense against oxidative stress (). These in-
vestigators concluded that recruitment of both glu- Conclusion
tathione and Trx antioxidant systems in the VMH
may be needed to prevent impaired awareness of Glucose homeostasis requires an organism to rapidly
hypoglycemia in diabetes. respond to changes in plasma glucose concentrations.
In health, glucose-sensing neurons located in the brain
Role of adrenal NPY and other regions detect the fall in glucose and trigger
NPY is cosecreted with catecholamines from adrenal the hormonal and neural responses that restore
chromaffin cells and has been postulated to be a euglycemia through a complicated network of inter-
possible mediator in the development impaired connected defenses. In patients with diabetes who are
awareness of hypoglycemia. NPY is known to mod- treated with insulin and insulin secretagogues, these
ulate the release and synthesis of adrenal catechol- counterregulatory mechanisms are often insufficient to
amine through adrenal Y receptors (). In a recent overcome the glucose-lowering effects of their medi-
study, investigators demonstrated that recurrent hy- cation. As a result, hypoglycemia is a common oc-
poglycemia reduced the epinephrine secretory capacity currence in the lives of such patients. Recurrent
of mouse adrenal through a mechanism involving episodes of hypoglycemia also cause impaired aware-
NPY activation of the Y receptor (). ness of hypoglycemia where the glucose level that elicits
the response falls below the neuroglycopenic threshold.
Role of opioid signaling Better understanding of how glucose-sensing neurons
Endogenous opiates have been shown to modulate respond to a fall in glucose and communicate this event
hormonal responses during hypoglycemia (). to downstream effectors will significantly improve di-
Plasma b-endorphin levels increase in humans after abetes care.
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REVIEW
Financial Support: This work was supported by a by an unrestricted grant from Novo Nordisk. A.A.M. has inhibited; GLUT, glucose transporter; IML, intermediolateral
Pathway Award from the American Diabetes Association nothing to declare. column; KATP, ATP-sensitive potassium; LC, locus coeruleus;
(1-17-ACE 31) to S.S. and by National Institutes of Health LH, lateral hypothalamus; MCH, melanin-concentrating
Grant NS035192 to E.R.S. hormone; MPOA, medial preoptic area; NAc, nucleus
Correspondence and Reprint Requests: Elizabeth R. Abbreviations accumbens; NAC, N-acetyl-cysteine; NO, nitric oxide; NPY,
Seaquist, MD, 420 Delaware Street SE, MMC 101, Minne- 2DG, 2-deoxy-D-glucose; AgRP, agouti-related peptide; neuropeptide Y; NTS, nucleus of the solitary tract; PBN,
apolis, Minnesota 55455. E-mail: seaqu001@umn.edu. AMPK, AMP-activated protein kinase; AP, area postrema; parabrachial nucleus; PET, positron emission tomography;
Disclosure Summary: S.A.S. consults for Redpin Ther- ARC, arcuate nucleus; BNST, bed nucleus of the stria ter- POMC, pro-opiomelanocortin; PVH, paraventricular hypo-
apeutics. E.R.S. has previously consulted for Sanofi, Lilly, minalis; CCK, cholecystokinin; CNS, central nervous system; thalamic nucleus; ROS, reactive oxygen species; RVLM, rostral
Medscape, and Zucara, has received grant funding from Lilly DMH, dorsomedial hypothalamic nucleus; DMV, dorsal ventrolateral medulla; sGC, soluble guanylyl cyclase; SF1,
for research through her institution, and is a member of the motor nucleus of the vagus; GABA, g-aminobutyric acid; GE, steroidogenic factor-1; Trx, thioredoxin; VMH, ventromedial
International Hypoglycemia Study Group that is supported glucose-excited; GHRH, GH-releasing hormone; GI, glucose- hypothalamic nucleus.

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REVIEW

Central Mechanisms of Glucose Sensing and

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G lucose homeostasis requires an organism to

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Glucose-Sensing Neurons (AP), the extracellular glucose concentration is likely to

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PVH 57% (20) 42% (20)

Medial ARC 4% (21) 14% (21) NPY (40%) (22)

GHRH (80%) (23)

Lateral ARC 13% (21) POMC (51%) (24) 1% (21)

NPY (70%) (27)

AP 11% (30) 12% (30)

PBN CCK (35%) (31)

TH (34) GLUT2 (35)

DVC 22% (20) 18% (20)

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Projections from glucose-sensing neurons

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