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Cell. Mol. Life Sci. (2016) 73:705–722
DOI 10.1007/s00018-015-2079-8 Cellular and Molecular Life Sciences
REVIEW
Brain glucose metabolism during hypoglycemia in type 1 diabetes:

insights from functional and metabolic neuroimaging studies
Hanne M. M. Rooijackers1 • Evita C. Wiegers2 • Cees J. Tack1 • Marinette van der Graaf2,3 •
Bastiaan E. de Galan1
Received: 8 May 2015 / Revised: 16 October 2015 / Accepted: 20 October 2015 / Published online: 31 October 2015
The Author(s) 2015. This article is published with open access at Springerlink.com
Abstract Hypoglycemia is the most frequent complica- Abbreviations

tion of insulin therapy in patients with type 1 diabetes. ASL Arterial spin labeling
Since the brain is reliant on circulating glucose as its main ANLS Astrocyte-neuron lactate shuttle
source of energy, hypoglycemia poses a threat for normal BOLD Blood oxygenation level dependent
brain function. Paradoxically, although hypoglycemia CBF Cerebral blood flow
commonly induces immediate decline in cognitive func- CMRglc Cerebral metabolic rate of glucose
tion, long-lasting changes in brain structure and cognitive CMRO2 Cerebral oxygen metabolic rate
function are uncommon in patients with type 1 diabetes. In ECF Extracellular fluid
18
fact, recurrent hypoglycemia initiates a process of habitu- FDG F-Fluoro-2-deoxy-D-glucose
ation that suppresses hormonal responses to and impairs fMRI Functional magnetic resonance imaging
awareness of subsequent hypoglycemia, which has been GABA Gamma-aminobutyric acid
attributed to adaptations in the brain. These observations Glc-6-P Glucose-6-phosphate
sparked great scientific interest into the brain’s handling of GLUT Glucose transporter protein
glucose during (recurrent) hypoglycemia. Various neu- GPR81 G-protein-coupled receptor 81
roimaging techniques have been employed to study brain HAAF Hypoglycemia-associated autonomic failure
(glucose) metabolism, including PET, fMRI, MRS and HbA1c Glycosylated hemoglobin
ASL. This review discusses what is currently known about MCA Monocarboxylic acid
cerebral metabolism during hypoglycemia, and how find- MCTs Monocarboxylic acid transporters
ings obtained by functional and metabolic neuroimaging MRS Magnetic resonance spectroscopy
techniques contributed to this knowledge. NALS Neuron-astrocyte lactate shuttle
PET Positron emission tomography
Keywords Brain metabolism Hypoglycemia RF Radiofrequency
Type 1 diabetes mellitus Impaired SNR Signal to noise ratio
awareness of hypoglycemia Neuroimaging TCA Tricarboxylic acid
Cerebral blood flow VMH Ventromedial hypothalamus
3-OMG 11C-3-O-methyl-D-glucose
13
& Hanne M. M. Rooijackers C Carbon-13
Hanne.Rooijackers@radboudumc.nl 31
P Phosphorus-31
1
Department of Internal Medicine 463, Radboud University
Medical Center, PO Box 9101, 6500 HB Nijmegen,
The Netherlands Introduction
2
Department of Radiology and Nuclear Medicine, Radboud
University Medical Center, Nijmegen, The Netherlands The brain is one of the most metabolically active organs in
3
Department of Pediatrics, Radboud University Medical the body and it consumes energy disproportionate to its
Center, Nijmegen, The Netherlands size. In humans, the brain represents only about 2 % of
123
706 H. M. M. Rooijackers et al.
total body weight, yet it accounts for approximately 20 % almost always be prevented. When insulin is given to
of the body’s oxygen use and 25 % of the body’s use of experimentally induce hypoglycemia in people without
glucose. Glucose is the primary fuel for the adult brain. In diabetes, glucose levels at or below *3.8 mmol/L will
young adults, the ‘resting’ brain consumes approximately induce a glucagon response, the secretion of which by
110 g of glucose per day, i.e. 5.5 mg glucose per 100 g of pancreatic alpha-cells is probably controlled by the
brain tissue per minute [1]. Since the brain’s energy stores neighboring beta-cells [10, 11]. Such a glucose level also
are small, normal brain function depends on a continuous stimulates the secretion of adrenaline, whereas slightly
supply of glucose from the bloodstream. Under normal lower levels are needed to elicit autonomic warning
conditions, the human body takes great effort and is very symptoms, such as sweating, palpitations, trembling and
efficient in avoiding hypoglycemia in almost all circum- feeling hungry [10, 11]. These symptoms are aimed at
stances to maintain sufficient glucose delivery to the brain. initiating a behavioral response (i.e. ingesting carbohy-
Type 1 diabetes mellitus is an autoimmune-mediated drates). Further falls in plasma glucose values result in
disease, characterized by destruction of most, if not all, of neuroglycopenic symptoms, which range from mild cog-
the insulin-producing capacity of pancreatic beta-cells. As nitive impairment, such as difficulty in concentrating, to
a consequence, supplemental insulin treatment is required overt confusion and even coma or seizures in its most
to maintain glucose control and decrease the risk of com- severe form [10, 11].
plications resulting from hyperglycemia [2]. Unfortunately, In patients with type 1 diabetes, hypoglycemia typically
therapeutic insulin is still poor at mimicking the pharma- results from the interplay between therapeutic peripheral
cology of endogenous insulin. As a consequence, people hyperinsulinemia and impaired defenses against falling
with type 1 diabetes—in particular those aiming for strict plasma glucose levels [10]. These impairments first include
glycemic control—are at continuous risk of hypoglycemia, the inability to decrease insulin and to increase glucagon in
the average frequency of which has been estimated at two response to hypoglycemia. The latter is not a structural
non-severe, symptomatic episodes per week [3–5] and one defect, but specific for hypoglycemia and probably sec-
severe, potentially hazardous event, per year [4, 6, 7]. ondary to loss of control by non-functioning beta-cells
Although there is substantial variation in both the rate and [12]. In patients with longer diabetes duration and more
the severity of hypoglycemia, both between and within frequent exposure to hypoglycemia, adrenaline responses
persons [4, 8], this estimation means that the brains of to hypoglycemia become attenuated, in part due to a shift
people with type 1 diabetes are exposed to many thousands of these responses to lower glucose values [13]. The
of hypoglycemic episodes over a lifetime of diabetes. defective adrenaline responses are associated with,
Studying brain metabolism during hypoglycemia may although not necessarily the cause of, similar defects in the
reveal the potential harmful effects of (recurrent) hypo- emergence of autonomic symptom responses [14, 15].
glycemia on the brain and may increase our understanding Disappearance of these symptoms interferes with the
of metabolic adaptations that might underlie impairments ability to timely and accurately perceive, interpret and
in the defenses against hypoglycemia [9]. Modern neu- respond to falling plasma glucose levels. This inability is
roimaging techniques have enabled the study of cerebral known as the clinical syndrome of impaired awareness of
metabolism in vivo in a relatively non-invasive manner. hypoglycemia and increases the risk of particularly severe
This review will focus on the effect of hypoglycemia on hypoglycemia, defined as those events requiring assistance
brain (glucose) metabolism, with a particular emphasis on from another person [16], by a factor of six or more [17,
recent findings from functional and metabolic neuroimag- 18]. Both the attenuated adrenaline response and impaired
ing studies. Basic mechanisms of brain energy metabolism awareness of hypoglycemia are usually the result of (re-
and neuroimaging techniques will be discussed briefly. current) antecedent hypoglycemia rather than of autonomic
neuropathy, for which the term ‘hypoglycemia-associated
autonomic failure’ (HAAF) has been introduced [19].
Glucose counterregulation HAAF can be effectively treated by several weeks to
months of scrupulous avoidance of hypoglycemia [15, 20,
In healthy, non-diabetic humans, hypoglycemia is unlikely 21], although it appears that the symptomatic component
to ever occur due to a hierarchically coordinated system responds earlier and better than the hormonal component
that integrates insulin secretion and counterregulatory [15]. The underlying mechanism(s) explaining the attenu-
hormone and symptom responses [10, 11]. When glucose ating effect of prior hypoglycemia on responses to
levels in the low-physiological range (e.g. late post-ab- subsequent events have not been fully elucidated. How-
sorptive or fasting state) tend to fall, insulin secretion is ever, there is agreement that alterations in the brain play a
suppressed to such an extent that true hypoglycemia can pivotal role.
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Brain glucose metabolism during hypoglycemia in type 1 diabetes: insights from… 707
Morbidity associated with hypoglycemia hypoglycemic events of moderate severity were less likely
to develop neuronal damage or cognitive impairments or
The glucose level at which cognitive function declines is die during subsequent severe hypoglycemia than age-
subject to substantial variation; in some people cognitive matched littermates who were not pre-exposed to hypo-
dysfunction already occurs at plasma glucose levels glycemia [45, 46]. These data may help to explain recent
between 3.0 and 4.0 mmol/L, whereas others continue to observations that patients with type 1 diabetes and
function well at levels below 2.5 mmol/L [8, 22]. Almost impaired awareness of hypoglycemia, as a reflection of
all domains of cognitive function are potentially at risk recurrent hypoglycemia, appeared not at greater risk of
during acute hypoglycemia, with complex tasks (e.g. car dying than patients with intact awareness [47].
driving) being affected earlier than simple tasks [23, 24].
Prolonged and/or profoundly severe hypoglycemia may
eventually cause neuronal death [25, 26]. The cerebral The role of the brain in glucose counterregulation
cortex and hippocampus are the most vulnerable regions in
the brain to be injured by severe hypoglycemia, while the The brain is not just at the receiving end of hypoglycemia,
brain stem and cerebellum are most resistant [27]. How- but it plays an important role in both the detection of
ever, although persistent vegetative states or brain death hypoglycemia and in the subsequent initiation and coor-
resulting from hypoglycemia have been described [28–30], dination of counterregulatory responses to restore
most patients with type 1 diabetes recover uneventfully euglycemia, as described above. This system maintains
from even severe hypoglycemia complicated by seizures or glucose homeostasis through a classic sensory-motor inte-
coma, especially when they are young and in good clinical grative pathway in which a decrease in plasma glucose
condition. In addition, evidence for an association between levels is detected by an extended network of glucose
multiple episodes of severe hypoglycemia and long-term sensing neurons located within the brain and the periphery
cognitive decline in people with type 1 diabetes is lacking [48]. Specialized glucose-sensing cells are located in the
[31, 32]. Finally, although 4–10 % of all deaths in patients hepatic portal/mesenteric vein, gut, carotid body and oral
with type 1 diabetes have been attributed to hypoglycemia, cavity. In the brain, glucose-sensing neurons are found at a
most of these deaths are thought to be either accidental number of locations, but particularly in the ventromedial
(e.g. in traffic) or cardiovascular (e.g. arrhythmia) rather nucleus of the hypothalamus (VMH) and areas that origi-
than the direct consequence of brain death [33, 34]. nate from the hindbrain. Integrative networks receive
It should be noted that both the developing brain of projections from these sensing neurons and subsequently
young children with type 1 diabetes [35, 36] and the brain assimilate their input with signals from other brain regions,
of the elderly, in particular in patients with type 2 dia- such as information about circadian rhythm and arousal
betes [37, 38], seem more susceptible to harm from state. This information is relayed to motor neurons, which
hypoglycemia. Children with type 1 diabetes performed generate an output that drives the counterregulatory
worse on cognitive tests when they had a history of response and subsequently restores plasma glucose levels.
severe hypoglycemia below the age of 5 years, compared Conversely, glucose sensing may influence other neural
to patients without such a history and non-diabetic con- processes that have no role in glucose counterregulatory
trols [35]. In prospective cohorts of people with type 2 function [49].
diabetes, a history of severe hypoglycemia has been Although the VMH is only one of a number of regions
associated with cognitive decline and frank dementia [38], involved in the detection of hypoglycemia, it is thought to
as well as with greater risks of cardiovascular events and be the most important. The VMH serves as the central relay
death [39, 40]. On the cellular level, there are now station for signals from many other regions and plays a
indications that glucose deprivation may accelerate crucial role in the coordination of the counterregulatory
apoptosis of neurons, which could underlie neuronal cell responses to falling glucose levels. Animal studies have
death and predispose for cognitive decline [41]. It has shown that both destruction of the VMH and local perfu-
also been speculated that the acute, physiological changes sion of the VMH with glucose, disrupt counterregulatory
in hematological and hemodynamic parameters induced hormone responses to systemic hypoglycemia [50, 51].
by hypoglycemia may be particularly damaging when the Conversely, local glucopenia in the VMH stimulates these
vasculature has already been injured [42, 43], possibly responses in the absence of hypoglycemia [52]. In analogy,
explaining the discrepancy between type 1 and type 2 glucose counterregulation was also found defective in a
diabetes [31, 44]. Another factor explaining this discrep- patient with lesions from sarcoidosis in the hypothalamus,
ancy may lie in the concept of hypoglycemic presumably due to destruction of the glucose-sensing
preconditioning. Rodents exposed to recurrent neurons in the VMH [53].
123
The mechanism of glucose sensing by the brain, in between specific metabolic steps and ignores the potential
particular in the VMH, has not been fully clarified. Two contribution of other metabolites. Moreover, the highly
main types of glucose-sensing neurons have been identi- invasive nature of the Kety–Schmidt technique is a con-
fied: glucose-excited neurons, whose activity increases as siderable limitation for research in humans.
glucose levels rise, and glucose-inhibited neurons, which The past 40 years have shown rapid advances in modern
become more active as glucose levels fall and less active metabolic and functional neuroimaging techniques to study
when they rise [54]. These neurons ‘sense’ a fall in glucose brain (glucose) metabolism vis-à-vis CBF during hypo-
probably as a result of alterations in ATP/ADP and AMP/ glycemia, including positron emission tomography (PET),
ATP ratios, respectively, following a reduction in glucose functional magnetic resonance imaging (fMRI) and mag-
metabolism. This could explain why fuelling the VMH netic resonance spectroscopy (MRS). It is important to note
with an alternative source of energy, such as lactate, sup- that the distribution of CBF and the cerebral metabolic rate
presses glucose counterregulation [55, 56]. The subsequent of glucose (CMRglc) are closely linked to local brain activ-
intracellular actions that may ultimately lead to a coun- ity. Brain activation causes proportionate increases in both
terregulatory response probably involve activation of local CBF and CMRglc. These processes are being referred
AMP-activated protein kinase, formation of nitric oxide to as neurovascular coupling or neurometabolic coupling,
and release of glutamate in glucose-inhibited neurons. respectively, and hypothesized to be mediated by neuro-
Other potential mediators involved in these responses transmitter release and vasoactive metabolic products [67].
include (a decrease in) gamma-aminobutyric acid (GABA) Many functional neuroimaging techniques, including fMRI,
release from glucose-excited neurons, noradrenaline, rely on neurovascular coupling. The principles of the various
serotonin and corticotrophin-releasing hormone [57]. For imaging techniques will be briefly discussed (Fig. 1).
further reading on this subject, we refer to recent reviews
by McCrimmon [54] and Chan and Sherwin [57]. PET
Positron emission tomography can be used to measure

Cerebral glucose delivery, uptake and metabolism emissions from a variety of radioactively labeled tracers in
the brain to quantify CBF, glucose uptake and phospho-
Glucose is transported across the blood–brain barrier into rylation, oxygen consumption and brain receptors for major
extracellular fluid (ECF) by facilitated diffusion, mediated neurotransmitters, depending on the type of radiotracer
via glucose transporter protein 1 (GLUT1) [58]. The pre- used [68]. 15O-labeled water PET, for example, has been
dominant transporters involved in subsequent glucose uptake commonly applied to quantify regional CBF [69, 70]. For
from the ECF in neurons and in astrocytes are GLUT3 and the study of brain glucose metabolism, [18F]fluoro-2-
GLUT1, respectively [59], both insulin-independent glucose deoxy-D-glucose (FDG) is the most widely used tracer.
transporters. Once intracellular, glucose is phosphorylated by FDG is taken up by the brain in a similar manner as glu-
hexokinase as the initial step of glucose metabolism. The cose, but unlike native glucose, once phosphorylated
glucose-6-phosphate (Glc-6-P) thus produced can enter (FDG-6-P), it cannot be metabolized further, resulting in
several metabolic pathways in the brain [60]. accumulation of the tracer in the cell. Under steadystate
In 1945, Kety and Schmidt developed the first method to conditions, in which total influx of metabolites into a
quantitatively assess brain glucose uptake in humans in vivo pathway equals the outflow, the rate of tracer accumulation
and to derive data on its subsequent metabolism [61]. This in the brain can be used to estimate global and regional
highly invasive technique required the use of arterial and rates of glucose transport and metabolism [58]. PET has
internal jugular vein catheterizations to determine arteri- been particularly valuable in studying the effect of hypo-
ovenous concentration differences for glucose, which glycemia on CBF, brain glucose uptake and cerebral
together with measurement of global cerebral blood flow metabolic rate in humans with and without type 1 diabetes
(CBF) were then used to calculate the global cerebral [71–74]. However, this technique cannot be used to study
metabolic rate of glucose [61–64]. In humans, the Kety– glucose metabolism downstream of its conversion to glu-
Schmidt method was used to show that brain glucose uptake cose-6-phosphate [75]. Also, animal studies suggest that
falls during hypoglycemia and that this coincides with the the lumped constant, a correction factor that relates the
appearance of counterregulatory hormone responses and metabolic rate of FDG to that of native glucose [76], may
autonomic warning symptoms [65, 66]. However, whether increase during hypoglycemia [77, 78]. The tracer [11C]3-
these data can be used to reliably assess brain glucose O-methyl-D-glucose (3-OMG) may provide more robust
metabolism is a matter of debate. Indeed, the calculations information about cerebral glucose uptake at varying glu-
rely solely on the disappearance rate of glucose from the cose concentrations, as it is not phosphorylated [79], but its
circulation. Therefore, this technique cannot discriminate relative short half-life time (*20 min) and complex
123
between deoxygenated and oxygenated hemoglobin [82].

Regional brain activation increases local oxygen demands,
but because the consequent increase in CBF exceeds these
demands, the balance between deoxygenated and oxy-
genated hemoglobin changes towards the latter. This
change in hemoglobin oxygenation can be probed and
detected, so that a brain map of regions with increased or
decreased activation can be constructed [81]. fMRI has
been especially useful in detecting brain activation patterns
in response to specific cognitive tasks or visual stimulation.
Hypoglycemia has been reported to reduce regional BOLD
activation in response to these tasks, but less so in patients
with type 1 diabetes [83] than in non-diabetic subjects [84,
85]. These reductions in BOLD responses are commonly
attributed to decreased neuronal activity, yet the potential
impact of hypoglycemia on (global or regional) CBF,
neurovascular coupling or oxidative metabolism, remains
to be determined.
ASL
Fig. 1 A simplified illustration of the multiple metabolic pathways of Arterial spin labeling (ASL) is an MRI method that pro-
glucose in the brain and the metabolic signals used in different vides non-invasive quantification of global and regional
neuroimaging techniques. The initial step of glucose metabolism is CBF. ASL does not require an exogenous contrast agent,
phosphorylation of glucose to glucose-6-phosphate (Glc-6-P) by
but uses magnetically labeled arterial blood water as a
hexokinase. Glc-6-P can enter several metabolic pathways in the
brain. It can be metabolized to produce energy via glycolysis or the diffusible tracer. Arterial blood water is first labeled
TCA cycle. Glycolytic and TCA cycle intermediates are also used for magnetically using radiofrequency (RF) pulses. Subse-
the synthesis of amino acids and neurotransmitters. In addition, Glc-6- quently, this labeled arterial blood flows into the brain
P is a precursor for glycogen. Lastly, metabolism of Glc-6-P via the
where it exchanges with tissue water, after which an image
pentose phosphate pathway (PPP) provides pentose for nucleotide
synthesis and NADPH, required for reductive reactions, such as lipid is taken. The experiment is then repeated without labeling
synthesis and for protection against oxidative stress. Arteriovenous the arterial blood to create a control image. The signal
concentration differences (AV dif) can be used to estimate global difference between control and labeled images reflects
cerebral metabolic rate from the disappearance of metabolites from
local CBF [86, 87]. While the signal-to-noise (SNR) ratio
the circulation. PET (depicted in orange) uses radiolabeled glucose
analogues (such as FDG), which are trapped early in metabolism (for in BOLD fMRI is higher, ASL measures brain perfusion
example fluorodeoxyglucose-6-phosphate/FDG-6-P), to estimate rates more directly, enables quantification of CBF, and is suit-
of glucose uptake and metabolism. 31P MRS (depicted in blue) able for studying variations in CBF over a longer period of
provides information about ATP production and thus brain energy
time due to stable noise characteristics [88]. ASL thus
metabolism. 13C-MRS (depicted in green) is useful for estimating
TCA cycle fluxes and CMRglc, derived from 13C label incorporation allows the detection of changes in CBF during hypo-
into specific metabolites (Glu, Gln). Both ASL and BOLD fMRI glycemia and is, in contrast to fMRI, less dependent on
provide estimates of CBF other metabolic parameters, such as oxygenation or glucose
concentrations that might change during hypoglycemia. A
preparation limits the use of this compound in a clinical high magnetic field (e.g. 3 T) is usually recommended to
setting [80]. improve SNR when performing ASL.
fMRI MRS
Functional magnetic resonance imaging is primarily used Magnetic resonance spectroscopy is a non-invasive tech-
to study regional neuronal activation (patterns) by the nique, closely related to MRI. Both techniques make use of
detection of changes in oxygen demand by the brain [81], the spin properties of certain nuclei when brought into a
based on the concept of neurovascular coupling described magnetic field. For MRI, the proton nucleus is used to
above. Blood oxygenation level dependent (BOLD) con- construct a highly detailed anatomical image based on the
trast is one of the primary contrast mechanisms for fMRI, different water concentrations in various tissues. For MRS,
which exploits the differences in magnetic properties these spin properties are used to determine the
123
concentration of specific metabolites in the tissue exam-

ined. These concentrations are derived from the peaks in a
spectrum [89]. MRS is feasible on any nucleus possessing a
magnetic moment, but is most frequently performed on the
high natural abundant and MR sensitive proton nucleus
(1H), providing steady-state information on concentrations
of proton-containing brain metabolites at a single time
point [90]. However, because water contains most of the
proton nuclei, the water signal needs to be suppressed to
allow reliable measurements of metabolite concentrations.
As a consequence, the sensitivity of MRS is manifold
lower than that of MRI, even at high magnetic fields.
Nevertheless, since nearly all metabolites contain protons,
1
H-MRS is a powerful technique to identify and quantify a
large number of metabolites relevant for glucose metabo-
lism (e.g. lactate, glutamate, glutamine) at in vivo
concentrations typically above 0.5 mM.
The use of carbon-13 (13C) in MRS is specifically rel-
evant for the study of brain glucose metabolism. Carbon
exists in the human body in two isotopes, of which carbon-
12 (12C) is dominant with a natural abundance of 98.9 %.
12
C does not possess a net nuclear spin and consequently
cannot be detected by MRS. In contrast, 13C does possess a Fig. 2 Time series of 13C-MR spectra, acquired from a *125 mL
magnetic moment, but has a very low natural abundance of voxel, placed in the occipital cortex. Spectra are averaged over
1.1 %. However, the intravenous infusion of 13C-enriched 20 min, after administration of [1-13C]glucose during a hypoglycemic
clamp in one healthy subject. Once the infused [1-13C]glucose is
substrates, such as [1-13C]glucose, [3-13C]lactate or [3-13-
taken up by the brain and incorporated into various glucose
C]acetate, offers the possibility to study fluxes of these metabolites, an increase in signal over time is observed. Numbers
substrates in the brain through important metabolic path- indicate the position of the 13C label, as explained in more detail in
ways (Fig. 2). Fig. 3. Asp aspartate, Gln glutamine, Glu glutamate, Lac lactate (from
Ref. [143], with permission from Elsevier)
For the study of brain glucose metabolism, it is impor-
tant to note that [1-13C]glucose is taken up and metabolized
by the brain similar to native (i.e. unlabeled) glucose.
13
Following transport across the blood–brain barrier and C-MRS has been proven to be a valuable imaging
phosphorylation by hexokinase, glucose is the main sub- technique to study brain (glucose) metabolism via specific
strate for the production of energy (by formation of ATP) pathways in humans in vivo, under various conditions,
via glycolysis and the tricarboxylic acid (TCA) cycle [82]. including hyperglycemia [93] and hypoglycemia [94]. In
As such, 13C-MRS allows the fate of the 13C-labeled glu- addition, 13C labeled compounds other than glucose, such
cose to be followed as it flows into glycolysis. The 13C- as 13C-acetate and 13C-lactate, can be used to provide a
label is transferred from glucose on the C-1 position to more complete picture of the very complex metabolic
pyruvate on the C-3 position during glycolysis and, sub- processes in the brain. Indeed, 13C-acetate, which is
sequently, passes through all metabolites of the TCA cycle. metabolized almost exclusively in astroglia [95], has been
In this process, the 13C-label is incorporated into the MRS- used to distinguish astroglial and neuronal metabolism
detectable metabolites glutamate, glutamine and aspartate, more directly, and to study transport and metabolism of
all at specific carbon positions. Because these positions non-glucose fuels during hypoglycemia [96, 97].
change during the second time the isotope flows in the Phosphorus-31 (31P) is another naturally abundant
TCA cycle (Fig. 3), the time-course of 13C-label incorpo- nucleus with a relatively high sensitivity for MRS. 31P-
ration into these metabolites can be used as input for a MRS of the brain can be used to detect metabolites that
metabolic model to calculate the TCA cycle flux and play a key role in brain energy metabolism and provides
CMRglc [91]. However, although the fates of individual information on flux through the creatine kinase reaction
carbon atoms can be tracked in the TCA cycle, cerebral (e.g. ATP, phosphocreatine, inorganic phosphate), intra-
13
C-MRS provides no information about the loss of label in cellular pH and magnesium concentrations [98]. Thus far,
diffusible metabolites, such as glutamine and lactate which this technique has been seldom used to study brain meta-
may exchange between brain and blood plasma [82, 92]. bolism during hypoglycemia [99].
123
Fig. 4 Linear relationship between plasma and brain glucose levels

Fig. 3 One-compartment metabolic model describing the incorpora- under normo- and hypoglycemic conditions in healthy subjects (open
tion of 13C label from (infused) [1-13C]glucose into the TCA cycle squares) and patients with type 1 diabetes (closed circles). Brain
and its metabolites. When taken up by the brain, the 13C-label is first glucose levels were measured with 13C-MRS. The plasma versus
incorporated into the C3 position of pyruvate and subsequently into brain glucose relation was fitted with linear regression analysis to
the C3 position of lactate. Once the 13C-label continues through the determine reversible Michaelis–Menten kinetics to show the best fit
TCA cycle, it is incorporated into the C4 position of aKG, glutamate of the data with 95 % confidence intervals. R2 = 0.59, P \ 0.001.
and glutamine. In the second turn of the cycle, the label is equally Assuming continuation of this linear relationship between plasma and
distributed over the C2 and C3 positions of these metabolites. The brain glucose levels, brain glucose approaches zero at a plasma
TCA cycle flux can be estimated using a metabolic model where the glucose level of approximately 1.2 mmol/L (from Ref. [104], with
time courses of the uptake of the 13C-label in glutamate and glutamine permission from the American Diabetes Association)
in the different carbon positions, measured with 13C-MRS, are used as
input. Filled circles represent the carbon position that is labeled with
13
C, white circles represent unlabeled carbons. aKG a-ketoglutarate, on the vascular endothelium at the blood–brain barrier
BBB blood–brain-barrier, Glc glucose, Gln glutamine, Glu glutamate,
Lac lactate, LDH lactate dehydrogenase, Pyr pyruvate, Vgln exchange
[107, 108]. In accordance, Boyle and co-workers applied
rate between glutamate and glutamine, VTCA TCA cycle rate, Vx the Kety and Schmidt technique to show preservation of
exchange rate between a-ketoglutarate and glutamate brain glucose transport rather than a fall during hypo-
glycemia in healthy volunteers after prior exposure to
hypoglycemia, whereas it fell when such exposure had not
Cerebral nutrient transport capacity taken place [65]. The investigators went on to report sim-
and hypoglycemia ilar findings of preserved glucose transport in patients with
type 1 diabetes and near-normal glycosylated hemoglobin
Glucose uptake (HbA1c), possibly reflecting high hypoglycemic burden, as
they also had reduced awareness of hypoglycemia [66].
As mentioned above, glucose uptake into the brain occurs In mice and in rats, very low plasma glucose values,
through facilitated transport independent of insulin. As a typically well below 2.0 mmol/L, have been found to
consequence, there is a linear relationship between plasma proportionally increase brain glucose uptake as a function
glucose concentrations and brain glucose content over a of increased cerebral perfusion [102, 109]. Various neu-
range of plasma glucose values up to *30 mmol/L [100– roimaging studies investigating glucose transport over the
103]. This linear relationship also extends well into the blood–brain barrier in humans have produced conflicting
hypoglycemic range, although data below plasma levels of results. A 1H-MRS study performed under hyperglycemic
*2.5 mmol/L are missing in humans (Fig. 4) [104]. To conditions showed greater brain glucose concentrations in
explain HAAF, it has been hypothesized that chronic or patients with type 1 diabetes and impaired awareness of
repeated hypoglycemia increases glucose transport capac- hypoglycemia than in people without diabetes [110].
ity over the blood–brain barrier to compensate for the fall However, a similar study found no evidence of altered
in glucose availability to the brain during subsequent brain glucose transport in healthy volunteers subjected to
hypoglycemia. Indeed, several animal studies have shown antecedent repeated hypoglycemia, despite clearly attenu-
that days to weeks of chronic hypoglycemia cause upreg- ated hormone responses to hypoglycemia [111]. In
ulation of brain glucose transporters, including both accordance, global blood-to-brain glucose transport, as
GLUT-3 on neuronal membranes [105, 106], and GLUT-1 measured with [1-11C]-glucose PET, remained unaltered in
123
healthy volunteers after exposure to 24 h of moderate neighboring neurons where it is oxidized, especially during
hypoglycemia, albeit interspaced with transient glucose activation [122]. This concept, which bears analogy to the
normalizations during meals [112]. Finally, a 3-OMG-PET cell–cell lactate shuttle, through which skeletal muscle can
study also showed no differences in global brain glucose transport a non-glucose energy source to other organs
transport during hypoglycemia between patients with nor- [123], thus suggests that astrocytes play the primary role in
mal and those with impaired awareness of hypoglycemia brain glucose metabolism. Simpson et al. later came to a
[72]. different conclusion and developed a model that basically
adopts the opposite view, in which neurons are the prin-
Monocarboxylic acid (MCA) uptake cipal site of glucose uptake and metabolism, and the chief
exporter of lactate. This hypothesis was therefore termed
Although glucose is its principal source of energy, the brain the neuron-astrocyte lactate shuttle (NALS) [59] and
may resort to alternative non-glucose fuel substrates under fuelled a heavy debate [124, 125]. The debate on the
glucopenic conditions. These alternative substrates include direction of the lactate shuttle is ongoing with studies
foremost ketones, and lactate, which enter the TCA cycle identifying the neuron as the principal locus of glucose
after conversion to pyruvate or acetyl coenzyme A, and can uptake [126], and other studies indicating that neurons
be metabolized in a similar way as glucose to sustain brain rather than astrocytes are the primary sites for oxidation of
metabolism, and spare glucose. exogenous lactate [119, 127].
Ketones such as beta-hydroxybutyrate and acetoacetate Monocarboxylic acid transporters (MCTs) facilitate the
are synthesized in the liver from fatty acids during pro- uptake of lactate as well as that of acetate and ketone
longed fasting, starvation and severe carbohydrate bodies into the brain, the expression of which may increase
restriction. Under such conditions, up to 60 % of brain following sustained hyperketonemia or recurrent hypo-
energy requirements may be derived from ketone meta- glycemia. A recent study in rats demonstrated a twofold
bolism [113], whereas ketogenic diets can more or less increase in the expression of MCTs 1 and 2 in the cerebral
restore brain energy metabolism and prevent epileptic cortex after the induction of diabetes by streptozotocin.
seizures in patients with GLUT1 deficiency who are unable After 8 weeks of frequent, prolonged endurance training
to transport glucose into the brain [114, 115]. However, and concomitant exposure to hypoglycemia after and
because insulin suppresses the production of ketones, the between exercise sessions, the expression of both trans-
brain is usually unable to use this source of energy during porters increased even further [128]. Such greater transport
insulin-induced hypoglycemia [116]. PET studies with the capacity may explain recent observations in which recur-
use of both ketone and glucose tracers may help to unravel rent exposure to hypoglycemia increased the uptake of 13C-
the complex interaction between the metabolism of ketones labeled lactate into the rat brain under hypoglycemic
and glucose by the brain under different circumstances, conditions [129]. During hypoglycemia, the uptake of both
including hypoglycemia [113]. acetate and lactate into the human brain, as measured by
13
In recent years, it has gradually been recognized that C-MRS during infusion of 13C-labeled acetate or lactate,
lactate plays an important role in the energy metabolism in respectively, was found to be considerably greater in
the brain, particularly during hypoglycemia since both patients with well-controlled type 1 diabetes than in heal-
hypoglycemia and insulin increase plasma levels of lactate, thy controls [97, 130].
at least in healthy subjects [94, 117, 118]. Under basal,
euglycemic, conditions, the contribution of systemic lactate Transport and uptake of other substrates
to cerebral energy metabolism is approximately 8–10 %.
However, the proportional contribution of lactate has been Oral intake of amino acids has been reported to enhance the
reported to increase during strenuous exercise, when glucagon response to hypoglycemia and to improve some
plasma lactate levels rise substantially [119, 120]. The role aspects of cognitive function during hypoglycemia in non-
of lactate in specific areas of the brain includes its diabetic and diabetic subjects [131, 132]. Amino acids
involvement in or interference with hypoglycemia detec- might also serve as a non-glucose substrate that could be
tion in the VMH as stated above. Lactate has also been used by the brain as an alternative fuel and to sustain
found to be a crucially monitored variable in the detection cognitive function during hypoglycemia. Early studies
of energy imbalance in the caudal hindbrain [121]. The showing utilization of amino acids by the rat brain during
importance of lactate for the brain was first highlighted prolonged hypoglycemia and of amino acids contributing
when Pellerin and Magistretti published their astrocyte- to glycogen synthesis in brain cell cultures supported this
neuron lactate shuttle (ANLS) hypothesis. This hypothesis theory [133, 134]. However, data obtained in humans using
posits that glucose is taken up by and metabolized in arteriovenous concentration differences found no evidence
astrocytes to form lactate, after which lactate is exported to that greater availability of amino acids increased its net
123
brain uptake during hypoglycemia [135] or was able to that it enables the investigation of cerebral glucose meta-
offset energy deficit due to reduced glucose supply [136]. bolism in humans in vivo. Since the SNR is relatively low,
A few studies have investigated whether the human most studies employing this technique used large doses of
brain can use lipid substrates to support cerebral metabo- isotopically enriched glucose at high enrichment percent-
lism and brain function during hypoglycemia. Fatty acids ages. Measurements have consequently generally been
can readily cross the blood–brain barrier to be oxidized by performed under hyperglycemic conditions with glucose
the brain, as demonstrated by a 13C-MRS study in rats levels up to 17 mmol/L and plasma C-13 enrichment val-
[137]. In healthy humans, elevated plasma levels of non- ues exceeding 60 %. Under such conditions, Henry et al.
esterified fatty acids and glycerol were found to reduce [93] reported no differences in the TCA cycle rate between
hormonal and symptom responses to hypoglycemia, but patients with type 1 diabetes with impaired awareness of
could not protect against the fall in cognitive function hypoglycemia and healthy controls. More recently, an
[138]. Conversely, in a more recent study, ingestion of improved sensitivity of the 13C-MRS method [142] in
medium-chain triglycerides maintained cognitive function combination with an optimized 13C-glucose infusion pro-
during hypoglycemia without affecting adrenergic or tocol enabled us to study glucose metabolism in the human
symptomatic responses to hypoglycemia in intensively brain during hypoglycemia at lower enrichment values
treated subjects with type 1 diabetes [139]. It should be [143]. With this optimized technique, no differences were
acknowledged, however, that the inferences made with observed in cerebral glucose metabolism between hypo-
respect to the uptake of lipid substrates in the brain were glycemia and euglycemia, neither in healthy controls [94],
indirect and that no neuroimaging studies have been per- nor in patients with type 1 diabetes [144]. Under hypo-
formed that evaluated the effects of these substances on glycemic conditions, however, the TCA cycle rate was
cerebral metabolism more directly. approximately 45 % higher in patients than in healthy
subjects, and inversely related to HbA1c. Appreciating a
low HbA1c as a proxy for a high hypoglycemic burden,
Brain metabolism during hypoglycemia these data suggested a role for prior hypoglycemic expo-
sure in the higher TCA cycle rate in patients with type 1
Glucose metabolism diabetes. Differences in brain glucose levels did not explain
the preservation of brain metabolism and the higher TCA
Both PET and MRS have been used to investigate the cycle rate in the patients, which suggested influx of a non-
effect of hypoglycemia on brain glucose metabolism. PET glucose carbohydrate source [104]. In an animal study by
has been particularly useful in detecting regional differ- Herzog et al. [129], brain glucose transport capacity during
ences in tracer accumulation in the brain, both during hypoglycemia became rate limiting for TCA cycle activity
hypoglycemia [71], and after restoration to euglycemia in control animals, but not in rats exposed to antecedent
[74]. However, rather than focusing on glucose uptake or recurrent hypoglycemia. Explanations for the discrepancy
metabolism, the close link with neuronal activation is then between the human and rodent data include the different
exploited to use the data as input factors for mapping species and the fact that the hypoglycemic condition was
regional brain activity. Thus, the observation that CMRglc more profound in the animals. Indeed, studies in mice
relatively increased during hypoglycemia in patients with suggest that intracellular brain glucose concentrations
type 1 diabetes and normal awareness of hypoglycemia, approach depletion at plasma glucose values between 2 and
and relatively fell in patients with impaired awareness of 3 mmol/L [109].
hypoglycemia, was interpreted as an increase in brain
activation and absence of such a response [72]. When this Glycogen metabolism
increased activation would occur in brain areas involved in
the perception of and the generation of responses to The brain is able to store glycogen and to use this com-
hypoglycemia, the lack of increased activation could then pound when plasma glucose levels are low, although its
underlie loss of hypoglycemic awareness [72, 140]. Sup- capacity to do so is very limited compared to other tissues
port for this hypothesis came from another FDG-PET study such as skeletal muscle and the liver. It was long assumed
[141] and a subsequent analysis of these data [73], as tracer that this presence of glycogen was restricted to astrocytes.
uptake in areas that engage appetite control and food- However, a recent study showed that neurons contain a low
seeking behavior was reduced in patients with impaired but measurable amount of glycogen, the use of which was
compared to patients with intact awareness of found to protect against hypoxic stress, at least in neuronal
hypoglycemia. cell cultures and animal models [145]. Both in rodents
As outlined above, 13C-MRS in combination with [146] and in humans [147], it was shown that brain
infusion of 13C-labeled glucose has the unique property glycogen was used during hypoglycemia, and that its stores
123
were replenished above baseline levels after restoration of than twofold higher brain acetate concentrations in subjects
euglycemia, a phenomenon termed glycogen supercom- with type 1 diabetes compared to healthy controls. This
pensation. It has been speculated that this expanded source greater acetate availability translated into a fraction of
of glucose within the brain could contribute to the devel- oxidative metabolism that resulted from acetate to be
opment of impaired awareness of hypoglycemia by fuelling similarly increased [97]. In accordance, the relative con-
the brain or at least those areas involved in glucose-sensing tribution of acetate to brain metabolism in rats exposed to
during subsequent hypoglycemia [146]. However, prior recurrent antecedent hypoglycemia was also increased
exposure to recurrent hypoglycemia neither facilitated nor during next-day hypoglycemia, indicating that brain sub-
impaired access to glucose from glycogen in the rat brain strate preferences may change rapidly from glucose to
during subsequent hypoglycemia [148]. Additionally, brain alternative substrates if needed [156]. To delineate whether
glycogen content, as measured by 13C-MRS in conjunction this effect was a function of diabetes, prior hypoglycemia
with 13C-glucose administration, was lower rather than or both, the investigators repeated their 13C-acetate study in
higher in patients with type 1 diabetes and hypoglycemia patients with type 1 diabetes with normal or impaired
unawareness [149]. awareness of hypoglycemia and in healthy controls. They
found that absolute rates of acetate metabolism during
Glutamate metabolism hypoglycemia were only higher in the patients with
impaired awareness of hypoglycemic, suggesting that
Glutamate is the major excitatory neurotransmitter in the changes in acetate metabolism are the consequence of prior
brain, but has many other metabolic fates, including the exposure to hypoglycemia rather than of diabetes per se
formation of glutamine, GABA and glutathione [150]. In [96].
addition, a new concept has been introduced by Sonnewald Lactate uses the same MCT as acetate to cross the
[151], who proposed that glutamate degradation in astro- blood–brain barrier. Since plasma levels of lactate are
cytes contributes to most of the lactate that is released from approximately tenfold higher than those of acetate, and
the brain under resting conditions, offering a novel expla- hypoglycemia stimulates the production of lactate [117], it
nation for the concept of aerobic glycolysis in the resting seems plausible that lactate is the more likely substrate for
state [151, 152]. Lastly, glutamate can be oxidized for the brain metabolism when glucose levels are low. Studies
production of energy [150]. To this end, glutamate pro- dating back to the 1990s have shown that exogenous
duction in the brain is tightly coupled to TCA cycle activity administration of lactate attenuates counterregulatory
[153]. Using 1H-MRS, Bischof et al. reported that hypo- responses to and preserves cognitive function during
glycemia reduced the cerebral glutamate to creatine ratio in hypoglycemia, presumably because lactate is used as an
healthy controls, but not in patients with type 1 diabetes alternative source of energy by the brain [157–160]. In
[154]. Similar results were reported by a more recent 1H- agreement, brain lactate concentrations during hypo-
MRS study, were hypoglycemia reduced brain glutamate glycemia, derived from the cerebral uptake of 13C-labelled
levels in healthy controls and in patients with type 1 dia- lactate, were several fold higher in patients with type 1
betes with normal hypoglycemic awareness, but not in diabetes with a history of frequent hypoglycemic episodes
patients with impaired awareness of hypoglycemia [155]. than in non-diabetic subjects [130] and in rats exposed to
The authors concluded that the preservation of brain glu- recurrent hypoglycemia versus those not exposed [129].
tamate during hypoglycemia in the latter group reflected a Surprisingly, the authors found no indication of greater
metabolic adaptation that eliminated the need to oxidize lactate oxidation, as reflected by unchanged 13C fractional
glutamate. They speculated that this adaptation could be enrichments of brain glutamate and glutamine [130]. Data
augmented transport of glucose or of alternative fuels to the from the rodent study, in which lower glucose levels were
brain. achieved than in the human study, suggested that prior
hypoglycemic exposure increased both the uptake and the
Metabolism of monocarboxylic acids oxidation of glucose by the brain, despite the higher lactate
levels [129]. However, when the animal brain was stimu-
As discussed earlier, MRS studies using 13C-labelled lated during hypoglycemia, animals exposed to recurrent
acetate and lactate have clearly suggested that the capacity hypoglycemia had a partial loss of their functional cortical
to transport MCAs over the blood–brain barrier during response, which was only normalized after the adminis-
hypoglycemia is increased in patients with well-controlled tration of lactate. This suggests that the higher capacity for
type 1 diabetes. Indeed, a study during which 13C-acetate lactate transport only becomes critical when the brain is
was infused under hypoglycemic conditions showed more activated during (deep) hypoglycemia.
123
Cerebral blood flow and hypoglycemia functional and metabolic neuroimaging techniques now
suggest that such moderate hypoglycemia neither affects
There is uncertainty as to whether hypoglycemia affects the perfusion to nor the uptake of glucose into the brain, at
global CBF and in what direction. Previous research in least not globally, unless much deeper levels of glucose are
both patients with type 1 diabetes and healthy controls has achieved [102, 109]. In accordance, cerebral glucose
reported either no change in global CBF during hypo- metabolism appears largely maintained during moderate
glycemia [65, 66, 136], a modest increase [161–163], or hypoglycemia [94, 129, 144]. However, on the regional
even a slight decrease [71]. Differences in the plasma level, moderate hypoglycemia causes redistribution of CBF
glucose levels achieved during hypoglycemia and, more to various brain areas involved in the detection of hypo-
importantly, in imaging techniques probably explain many glycemia, particularly the (hypo)thalamus [71, 166–169],
of the discrepancies. Studies that investigated the effect of where enhanced neuronal activation stimulates glucose
hypoglycemia on regional relative changes in CBF seem to uptake and metabolism. Such enhanced neuronal activation
have produced more consistent data. Both in healthy con- has also been found to occur in brain areas involved in
trols [161] and in patients with type 1 diabetes [164], appetitive motivational networks [73], thus linking the
hypoglycemia was found to increase blood flow to the detection of hypoglycemia to a behavioral response.
frontal lobes. This relative redistribution of regional CBF Modern neuroimaging studies have revealed that
was already observed under euglycemic conditions in recurrent hypoglycemia, which typically affects people
patients with type 1 diabetes, and was more pronounced in with type 1 diabetes and underlies the clinical syndrome of
patients who had experienced frequent hypoglycemia impaired awareness of hypoglycemia, may initiate cerebral
[165]. Since the frontal lobes are among the most vulner- adaptations at many different levels. First, there is inter-
able brain areas to suffer structural damage, this may be an ference with the accurate detection of hypoglycemia,
adaptive response to prevent such damage by maintaining probably occurring at the level of the VMH. Brain areas
fuel supply during subsequent hypoglycemia. that control appetite and induce fear and anxiety may not
Hypoglycemia has also been found to increase CBF in become activated during hypoglycemia. Whether locally
the thalamus [71, 166, 167] and hypothalamus [168, 169]. increased glucose uptake in or reduced neuronal activation
Mild or moderate hypoglycemia caused a rise in CBF in the of the hypothalamic area (or both) form the underlying
hypothalamus in healthy non-diabetic subjects, as assessed mechanism remains to be revealed. Importantly, it should
by fMRI [168] or ASL [169], which preceded the rise in be acknowledged that neurovascular coupling may be
counterregulatory hormone responses seen during hypo- altered as a consequence of diabetes per se [171], chronic
glycemia [169]. Interestingly, Mangia et al. found blunting hyperglycemia [172] or microangiopathy [173], thus lim-
of this increase in thalamic perfusion during hypoglycemia iting the interpretation of studies relying on this concept.
in patients with type 1 diabetes with hypoglycemia There is conflicting evidence as to whether recurrent
unawareness, and a correlation between thalamic perfusion hypoglycemia can stimulate brain glucose uptake during
and the adrenaline response to hypoglycemia [167]. In hypoglycemia [65, 66], although most studies employing
contrast, recurrent hypoglycemia enhanced, rather than neuroimaging techniques found no evidence for this sug-
decreased, thalamic perfusion during subsequent hypo- gestion [72, 111, 112]. Nevertheless, patients with type 1
glycemia in healthy controls [170], so that the role of this diabetes, particularly those with impaired awareness of
brain region in the adaptation to hypoglycemia remains hypoglycemia [155], seem better able in maintaining brain
uncertain. (glucose) metabolism during hypoglycemia than healthy
controls [94, 144, 154, 155], probably as a consequence of
prior hypoglycemia [144]. Since profound hypoglycemia
Discussion will eventually cause brain glucose metabolism to deteri-
orate [129], such an adaptation may shift the threshold for
The scientific field of metabolic and functional neu- deterioration of the metabolic rate to lower plasma glucose
roimaging techniques for the brain has tremendously levels.
progressed over the past couple of decades. The application Several mechanisms have been proposed that could
of these techniques to hypoglycemia research has consid- explain the discrepancy between hypoglycemia-induced
erably advanced our understanding of the brain’s responses preservation of cerebral glucose metabolism and the fall in
to hypoglycemia. As plasma glucose falls below levels that glucose availability during hypoglycemia. It seems likely
can be reversed by responses at the level of pancreatic that influx of a non-glucose energy substrate plays a role.
islets, i.e. suppression of insulin release and stimulation of Recent (neuroimaging) studies found little evidence to
that of glucagon, the brain’s sensing abilities are activated support enhanced blood to brain transport of amino acids
to allow timely detection of hypoglycemia. Data from [135, 136] or lipid substrates transport [138, 139] and
123
ketones are unlikely candidates because its production is brain and that of non-glucose alternative fuels, as well as
suppressed by insulin. Also, the lower brain glycogen activation or de-activation of brain areas involved in
content in patients with type 1 diabetes with impaired behavioral responses. It remains to be elucidated whether,
awareness of hypoglycemia compared to controls [149] and if so under which circumstances and in which brain
argues strongly against the glycogen supercompensation areas, the brain uses non-glucose alternative sources of
hypothesis. Several arguments suggest a major role for energy, particularly lactate, and whether this contributes
lactate in preserving brain glucose metabolism during to the emergence of impaired awareness of hypoglycemia.
hypoglycemia. These include: (1) lactate can be used by Such information is needed first to foster personalized
the brain and may even be preferred over glucose under decision-making with respect to glycemic targets, but
non-hypoglycemic conditions [174, 175]; (2) the capacity should eventually lead to treatments that eliminate
for lactate transport over the blood–brain barrier is hypoglycemia from the lives of people with type 1 dia-
increased in patients with impaired awareness of hypo- betes without compromising glucose control.
glycemia and in rats after exposure to hypoglycemia [97,
129]; (3) the use of lactate by glucose-sensing neurons in Acknowledgments We are indebted to Prof. A. Heerschap for his
helpful advice. This work was financially supported by the Dutch
the VMH may interfere with hypoglycemia sensing [54, 56, Diabetes Research Foundation and the European Foundation for the
57]. However, there are data that suggest that lactate is not Study of Diabetes (EFSD).
used as major energy source for the brain during moderate
hypoglycemia, despite greater availability [129, 130]. Also, Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
it is not yet known whether brain uptake or metabolism of creativecommons.org/licenses/by/4.0/), which permits unrestricted
endogenously produced lactate is increased during hypo- use, distribution, and reproduction in any medium, provided you give
glycemia in patients with type 1 diabetes and impaired appropriate credit to the original author(s) and the source, provide a
awareness of hypoglycemia. Finally, it has been suggested link to the Creative Commons license, and indicate if changes were
made.
that lactate may serve as a metabolic regulator or inter-
cellular signaling molecule rather than a fuel, modulating
brain glucose metabolism, oxygen delivery and CBF [176,
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Brain glucose metabolism during hypoglycemia in type 1 diabetes:

Abstract Hypoglycemia is the most frequent complica- Abbreviations

Positron emission tomography can be used to measure

between deoxygenated and oxygenated hemoglobin [82].

concentration of specific metabolites in the tissue exam-

Fig. 4 Linear relationship between plasma and brain glucose levels

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