The n e w e ng l a n d j o u r na l of m e dic i n e

REVIEW article

Mechanisms of Disease
Dan L. Longo, M.D., Editor

Mechanisms of Hypoglycemia-Associated
Autonomic Failure in Diabetes
Philip E. Cryer, M.D.

I
atrogenic hypoglycemia is the limiting factor in the glycemic
management of diabetes.1 It causes recurrent illness in most people with type 1
diabetes mellitus and in many with advanced type 2 diabetes mellitus and is
sometimes fatal. It generally precludes maintenance of euglycemia over a lifetime of
diabetes and thus full realization of the benefits of glycemic control. Various mecha-
nisms, discussed in this review, cause a vicious cycle of recurrent hypoglycemia.

C ompromised Defense s ag a ins t H y p o glycemi a

From the Division of Endocrinology, Me- As plasma glucose levels fall, the physiologic defenses against hypoglycemia1,2 are
tabolism and Lipid Research, Washington a decrease in the secretion of the glucose-lowering pancreatic beta-cell hormone
University School of Medicine, St. Louis.
Address reprint requests to Dr. Cryer at insulin, an increase in the secretion of the glucose-raising pancreatic alpha-cell
Campus Box 8127, Washington University hormone glucagon, and in the absence of an increase in glucagon, an increase in
School of Medicine, 660 S. Euclid Ave., St. the secretion of the glucose-raising adrenomedullary hormone epinephrine. The
Louis, MO 63110, or at [email protected].
normal behavioral defense is carbohydrate ingestion, prompted by neurogenic
N Engl J Med 2013;369:362-72. (autonomic) symptoms that largely originate from a sympathetic neural response.1
DOI: 10.1056/NEJMra1215228 These defenses are illustrated in Figure 1. Their effectiveness ensures a continuous
Copyright © 2013 Massachusetts Medical Society.
supply of glucose to the brain.1
In people with diabetes, therapeutic insulin excess caused by treatment with
insulin, sulfonylureas, or glinides can initiate a hypoglycemic episode. Marked
absolute therapeutic insulin excess can occasionally cause hypoglycemia in pa-
tients with intact defenses against hypoglycemia1 (Fig. 2). Typically, however,
hypoglycemia occurs during less marked or even relative therapeutic insulin ex-
cess (insulin levels insufficient to cause hypoglycemia under most conditions but
high enough to cause it in the context of decreased exogenous glucose delivery
or endogenous glucose production, increased glucose use, or increased sensitiv-
ity to insulin1) in patients with compromised defenses against hypoglycemia.
Such patients — those with established type 1 diabetes or advanced type 2 dia-
betes1 — have beta-cell failure or absolute endogenous insulin deficiency (Fig. 2).
As plasma glucose levels fall, the compromised physiologic defenses include fail-
ure of insulin levels to diminish (in the absence of endogenous insulin secretion,
circulating insulin levels are a function of the absorption and clearance of in-
jected insulin, not insulin secretion), failure of glucagon secretion to increase,1,5,6
and attenuated epinephrine secretion1,7-9 (Fig. 2). This combination of compro-
mised physiologic defenses causes the clinical syndrome of defective glucose
counterregulation, which increases the risk of recurrent severe hypoglycemia by
a factor of 25 or more.1
The compromised behavioral defense, as plasma glucose levels fall, is the fail-
ure to ingest carbohydrates because of the absence of symptoms of hypoglycemia;

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 mechanisms of disease

Peripheral
sensors
Central
Decreased nervous
glucose system

Parasympathetic
nervous system
Increased sympathoadrenal outflow
Sympathetic
nervous system
Decreased
insulin Pancreas Increased norepinephrine Increased
(palpitations, acetylcholine
Adrenal tremor, arousal) (sweating, hunger)
Beta cell Alpha cell medulla

Decreased Increased Increased Increased

insulin glucagon epinephrine neurogenic symptoms

(Lost in (Lost in (Often attenuated in type 1 diabetes) (Often attenuated in type 1 diabetes)
type 1 diabetes) type 1 diabetes)

Liver
Increased glycogenolysis
and increased gluconeogenesis
Muscle Kidney Adipose tissue

Increased lactate,
amino acids,
glycerol

Increased Decreased Increased ingestion

glucose production glucose clearance of carbohydrates

Increased glucose

Figure 1. Physiologic and Behavioral Defenses against Hypoglycemia in Humans. COLOR FIGURE

Physiologic defenses against falling glucose concentrations include a decrease in insulin secretion, an increase in Draft 3
glucagon 7/8/13
secretion,
Author Cryer
and an increase in epinephrine secretion. Behavioral defenses include carbohydrate ingestion prompted by neurogenic symptoms.
1 of 5
All
Fig #
these are compromised in patients with absolute endogenous insulin deficiency. Adapted from Cryer.3 Title

ME
DE Longo
Artist Knoper
their absence reflects the attenuation of the sym- (or sleep or prior exercise) causes both defective AUTHOR PLEASE NOTE:
pathoadrenal response (largely the sympathetic glucose counterregulation (by attenuating Figure thehas been redrawn and type has been reset
Please check carefully

neural response)1 (Fig. 2). That attenuation causes adrenomedullary epinephrine response, in Issuethe
date 7/25/13

the clinical syndrome of hypoglycemia unaware- context of an insulin concentration that is not
ness (or impaired awareness of hypoglycemia), reduced and glucagon secretion that is not in-
which increases the risk of recurrent severe hy- creased) and hypoglycemia unawareness (largely
poglycemia by a factor of 6 or more.1 by attenuating the sympathetic neural response)
A pivotal finding is that hypoglycemia attenu- and thus a vicious cycle of recurrent hypoglyce-
ates defenses (including increased epinephrine mia.1,7,8 With regard to the pathophysiological
secretion and symptomatic defenses) against mechanisms of HAAF, one needs to explain not
subsequent hypoglycemia in nondiabetic per- only the lack of a decrease in insulin and of an
sons10 and patients with type 1 diabetes.7 That increase in glucagon but also the attenuated
led to the concept of hypoglycemia-associated sympathoadrenal — adrenomedullary and sym-
autonomic failure (HAAF) in diabetes (Fig. 2). pathetic neural — responses to declining glu-
According to this concept, recent hypoglycemia cose concentrations.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Early Type 2 Diabetes Type 1 Diabetes and Advanced Type 2 Diabetes

(Relative beta-cell failure) (Absolute beta-cell failure)

Marked Relative or
Falling Falling
absolute mild-to-moderate
glucose glucose
therapeutic absolute therapeutic
levels levels
hyperinsulinemia hyperinsulinemia

Isolated episodes Beta-cell No decrease in

of hypoglycemia insulin and no
failure increase in glucagon

Episodes of hypoglycemia
Exercise Sleep

Attenuated sympathoadrenal
responses to hypoglycemia (HAAF)

Decreased adrenomedullary Decreased sympathetic

epinephrine responses neural responses

Defective glucose Hypoglycemia

counterregulation unawareness

Recurrent
hypoglycemia

Figure 2. Schematic Diagram of Hypoglycemia-Associated Autonomic Failure (HAAF) in Diabetes. COLOR FIGURE
Although marked insulin excess can cause occasional episodes of hypoglycemia in patients with Draft relative
3 6/25/13
beta-cell
Author Digard
failure, less marked insulin excess often causes hypoglycemia in patients with hypoglycemia-associated autonomic
Fig # 2 of 5
failure (defective glucose counterregulation and hypoglycemia unawareness). Adapted from Cryer.4
Title

ME
DE Phimister
Loss of Insulin and Glucagon Responses alpha-cell inhibitory signalArtist of Knoper beta-cell insu-
The mechanism underlying the failure of circu- lin1,13 (Fig. 3). The evidence Figure for
has beenthis
AUTHOR PLEASE NOTE:
conclusion
redrawn and type has been reset

lating insulin levels to fall as glucose levels fall in has been reviewed previously 13 Please
and is summa-
check carefully

Issue date 6/27/13

patients with type 1 diabetes or advanced type 2 rized here. First, loss of the insulin response and
diabetes is straightforward. In the absence of en- loss of the glucagon response are correlat-
dogenous insulin secretion (beta-cell failure), cir- ed,6,11,14,15 and they develop early in the course
culating insulin levels are simply a function of of type 1 diabetes6,11 but late in the course of
the absorption and clearance of injected insulin.1 type 2 diabetes.8 Second, the glucagon response
The mechanism of the lack of an increase in to hypoglycemia is not critically dependent on
glucagon is different from that of the attenua- innervation. Normal glucagon secretion in re-
tion of the sympathoadrenal responses.1 Loss of sponse to hypoglycemia occurs in humans with
the glucagon response precedes attenuation of a transplanted (denervated) pancreas,16 as well
the epinephrine response,1,6,11 is independent of as in humans with spinal cord transections17
diabetic autonomic neuropathy,1,7 and is not cor- (and, thus, no sympathoadrenal outflow from
rected by scrupulous avoidance of hypoglyce- the brain to the islets) and dogs with a dener-
mia.1,12 vated pancreas18; glucagon secretion is also
The lack of an increase in alpha-cell glucagon normal in the perfused rodent pancreas and
secretion is also best attributed to beta-cell fail- perfused rodent and human islets. Thus, loss of
ure — specifically, the lack of a decrease in the the glucagon response cannot be attributed to

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 mechanisms of disease

A Normal physiology

Decreased glucose

Beta cells Decreased insulin Alpha cells Increased glucagon

Beta cells Increased insulin Alpha cells Decreased glucagon

Increased glucose

B Pathophysiology in diabetes

Decreased glucose

Beta cells No decrease in insulin Alpha cells No increase in glucagon

Beta cells No increase in insulin Alpha cells Increased glucagon

Increased glucose

Figure 3. Mechanisms of Loss of the Glucagon Response. COLOR FIGURE

Draft 3
Panel A shows the physiological effect of a decrease in insulin coupled with a low glucose concentration in stimulat- 7/08/13
Author Cryer
ing alpha-cell glucagon secretion, and Panel B shows the pathophysiological effect of beta-cell failure and the result-
Fig # 3 of 5
ing loss of a decrease in insulin secretion and loss of an increase in alpha-cell glucagon secretion,
Title
despite a low glu-
13
cose concentration. Adapted from Cryer.
ME
DE Longo
Artist Knoper
AUTHOR PLEASE NOTE:
islet denervation, and the causative abnormality additional intra-islet mechanisms, such
Figure has been redrawn as exces-
and type has been reset
Please check carefully
in type 1 diabetes and advanced type 2 diabetes sive delta-cell secretion of somatostatin. 26
Issue date 7/25/13
must reside within the islets. These data support the conclusion that in
Third, because there is a glucagon response diabetes characterized by an absolute deficiency
to administered amino acids in patients with of endogenous insulin secretion — type 1 diabe-
type 1 diabetes,5,19,20 loss of the glucagon re- tes and advanced type 2 diabetes — the lack of
sponse to hypoglycemia must be the result of a decrease in beta-cell insulin secretion causes
reduced signaling of functional alpha cells to the loss of an increase in alpha-cell glucagon
secrete glucagon during hypoglycemia. Fourth, secretion as glucose concentrations fall in re-
because insulin normally regulates glucagon sponse to therapeutic hyperinsulinemia.1 The
secretion in a reciprocal fashion in humans20-25 lack of a decrease in insulin and the lack of an
and laboratory animals, it follows that loss of increase in glucagon are prerequisites for defec-
beta-cell insulin secretion would result in loss of tive glucose counterregulation but do not cause
the signal of a decrease in insulin to increase defective glucose counterregulation or hypogly-
alpha-cell glucagon secretion, despite a low glu- cemia unawareness. Those two components of
cose level in the alpha cells (Fig. 3). This mecha- HAAF in diabetes develop only when the sympa-
nism for loss of the glucagon response to hypo- thoadrenal and symptomatic responses to hypo-
glycemia does not exclude the possibility of glycemia become attenuated1 (Fig. 2).

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Attenuation of Sympathoadrenal Responses tenuate the sympathoadrenal and symptomatic

Attenuated sympathoadrenal responses to hypo- responses to subsequent hypoglycemia.34,35 How-
glycemia are commonly caused by recent hypo- ever, neither prior cortisol elevations similar to
glycemia1,7,8,10 but can also be caused by sleep27,28 those that occur during hypoglycemia36,37 nor
or prior exercise.29 Unlike the loss of the insulin inhibition of the cortisol response to prior hypo-
and glucagon responses at the islet level, the al- glycemia with metyrapone37 prevents the attenu-
teration resulting in attenuated sympathoadre- ated epinephrine and symptomatic responses to
nal responses must reside within the central subsequent hypoglycemia in humans.
nervous system (CNS) or its afferent or efferent
connections. Brain Fuel–Transport Hypothesis
One limitation of research on the mechanism According to this hypothesis, recent hypoglyce-
underlying attenuated sympathoadrenal respons- mia causes increased blood-to-brain transport of
es in humans has been the need for noninvasive glucose (or of an alternative metabolic fuel) and
methods of measuring human brain function. thus attenuates sympathoadrenal and symptom-
As discussed below, new techniques of positron- atic responses to subsequent hypoglycemia.1
emission tomography (PET), magnetic resonance This hypothesis was initially based on the find-
imaging, and magnetic resonance spectroscopy ing that hypoglycemia persisting for 3 days38 or
are now addressing that need. Other limitations longer39 results in increased expression of glu-
are the failure of many studies to document cose transporter 1 (GLUT-1) in the cerebral vas-
which patients with diabetes have HAAF (i.e., culature and in increased brain glucose uptake in
documented attenuation of the plasma epineph- rats. However, hypoglycemia for just 2 hours re-
rine and neurogenic symptom responses to sults in attenuated sympathoadrenal and symp-
controlled hypoglycemia) and which patients do tomatic responses to subsequent hypoglycemia
not and the failure to study the putative mecha- in humans.10 In addition, brain glucose uptake
nisms of HAAF in both patient groups and non- (calculated from arteriovenous glucose differ-
diabetic controls. A more efficient approach is toences across the brain and estimates of cerebral
study a putative mechanism of HAAF in nondia- blood flow [the Kety–Schmidt technique]) was
betic persons both before a period of hypoglyce- reported to be maintained during a subsequent
mia, when normal plasma epinephrine and episode of hypoglycemia in nondiabetic persons
neurogenic symptom responses to controlled with a prior episode40 and in patients with type 1
hypoglycemia can be documented, and after a diabetes who had relatively low glycated hemo-
period of hypoglycemia, when attenuated re- globin levels and thus probably more recent hy-
sponses can be documented.10,30,31 Incidentally, poglycemia.41 In both instances, however, the
the findings that attenuated sympathoadrenal difference in calculated brain glucose uptake was
and symptomatic responses to hypoglycemia can due to greater estimated cerebral blood flow
be induced by recent hypoglycemia in nondia- rather than increased arteriovenous glucose dif-
betic persons10,30,31 and can be reversed by scru-ferences across the brain.
pulous avoidance of hypoglycemia in patients The glucose-transport hypothesis was not sup-
with diabetes1,12 underscore the fact that these ported by PET measurements. Global blood-to-
key features of HAAF are functional rather than brain glucose transport, measured with [1-11C]
structural (i.e., neuropathic) in origin.1 glucose PET, was not reduced in patients with
Hypotheses regarding CNS-mediated mech- poorly controlled type 1 diabetes42 and was not
anisms of the attenuated sympathoadrenal re- increased after nearly 24 hours of interprandial
sponses to hypoglycemia that cause HAAF in- hypoglycemia,30 which produces a model of
clude the systemic-mediator hypothesis, the brain HAAF (including attenuated epinephrine and
fuel–transport hypothesis, the brain-metabo- neurogenic symptom responses to hypoglyce-
lism hypothesis, and the cerebral-network hy- mia) in nondiabetic persons.30,31 Furthermore,
pothesis.1,32,33 global blood-to-brain [11C]3-O-methylglucose
transport43 and [18F]deoxyglucose transport,44
Systemic-Mediator Hypothesis both measured with PET, were not increased in
This hypothesis holds that increased circulating patients with type 1 diabetes who were thought
cortisol levels or perhaps some other factor dur- to have hypoglycemia unawareness.
ing recent hypoglycemia acts on the brain to at- The brain fuel–transport hypothesis may be

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 mechanisms of disease

flawed. The premise is that hypoglycemia causes under nonphysiologic conditions (infusions of
a decrease in the rate of cerebral glucose metabo- somatostatin, insulin, and 50% glucose) with
lism, which in turn causes an increase in sym- hyperglycemia (approximately 300 mg per deci-
pathoadrenal activity, and that prior hypoglyce- liter [16.7 mmol per liter]),47 and no significant
mia may somehow increase the cerebral transport difference in cortical brain glucose metabolism,
of glucose to the brain, minimizing the decrease as measured with 13C magnetic resonance spec-
in the rate of cerebral glucose metabolism and troscopy under similar nonphysiologic condi-
thus attenuating the increase in sympathoadre- tions with hyperglycemia, between patients with
nal activity. However, there is no evidence that a type 1 diabetes and nondiabetic persons.48 Al-
decrease in the rate of cerebral glucose metabo- though the patients with type 1 diabetes were
lism causes an increase in sympathoadrenal ac- assumed to have HAAF, they were not shown to
tivity (that response could be a signaling event), have attenuated epinephrine and symptomatic
and it is unclear how low the plasma glucose responses to hypoglycemia.
concentration has to be to limit oxidative brain Notably, the same investigative group found
metabolism, but it may be quite low. The rate of no effect of recurrent episodes of hypoglycemia,
blood-to-brain glucose transport exceeds the rate which produced a model of HAAF (attenuated
of cerebral glucose metabolism even at plasma epinephrine and neurogenic symptom responses
glucose concentrations of 65 mg per deciliter to hypoglycemia), on brain glucose concentra-
(3.6 mmol per liter) in humans.30,42 tions measured with 1H magnetic resonance
Extrapolation of the linear relationship be- spectroscopy under similar nonphysiologic condi-
tween plasma and brain glucose concentrations, tions with hyperglycemia.49 Because the brain
the latter measured with 13C magnetic resonance glucose concentration is a direct function of the
spectroscopy, in nondiabetic persons and patients plasma glucose concentration,45 the unaltered
with type 1 diabetes during euglycemia and hy- brain glucose concentration does not support the
poglycemia, as reported by van de Ven and col- conclusion that increased blood-to-brain glucose
leagues,45 suggests that the plasma glucose transport might be the mechanism of HAAF.46
concentration at which the brain glucose con- If the normally small astrocytic brain glyco-
centration would become zero — at which point gen pool1 increases substantially (reflecting gly-
brain glucose metabolism would have to decrease cogen supercompensation) after hypoglycemia,
— is less than 36 mg per deciliter (2.0 mmol per that expanded source of glucose within the brain
liter). An increase in blood-to-brain glucose could result in an attenuated sympathoadrenal
transport would not increase brain glucose me- response during subsequent hypoglycemia.50
tabolism unless it shifted from below to above However, the evidence in rats that brain glyco-
that unknown, but seemingly low, glycemic gen content increases substantially after hypo-
threshold. glycemia has not been confirmed,51 and the
There was no significant difference in brain glycogen-supercompensation hypothesis has not
glucose concentrations between the nondiabetic been supported in humans.52 Brain glycogen
persons and the patients with type 1 diabetes in was not increased in patients with type 1 diabe-
the study by van de Ven and colleagues,45 sug- tes who were selected for hypoglycemia un-
gesting no difference in blood-to-brain glucose awareness. Because brain glycogen synthesis is a
transport. Assuming the patients with type 1 direct function of the plasma glucose concentra-
diabetes did not have HAAF (epinephrine re- tion and blood-to-brain glucose transport, in-
sponses in these patients were similar to those creased blood-to-brain glucose transport should
in nondiabetic persons, and symptoms of hypo- result in increased brain glycogen. That was not
glycemia were not reported), commentators sug- the case in the patients selected for hypoglyce-
gested that blood-to-brain glucose uptake might mia unawareness.52
have been increased in patients with HAAF, if Neurons oxidize lactate,53 but that lactate is
they had been included in the study.46 That in- largely derived from glucose within the brain.1
ference was made on the basis of two observa- An increase in blood-to-brain lactate transport is
tions: a 15% higher occipital–cortical brain a plausible mechanism of HAAF, although, as dis-
glucose concentration in patients with type 1 cussed above regarding glucose, this idea as-
diabetes than in nondiabetic persons, as mea- sumes that a decrease in brain oxidative metabo-
sured with 1H magnetic resonance spectroscopy lism causes an increase in sympathoadrenal

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 The n e w e ng l a n d j o u r na l of m e dic i n e

activity and, if so, lactate metabolism would One or more of these basic clues from a
have to be sufficient to raise brain oxidative v­ ariety of studies may ultimately lead to clinical
metabolism. Lactate infusions resulting in in- strategies that prevent hypoglycemia. Pending
creases in circulating lactate levels by a factor of that, there are clues from studies in humans that
approximately 4 in nondiabetic persons54 and by may lead to strategies that lower the barrier of
approximately 2 in nondiabetic persons and pa- hypoglycemia in diabetes66 (Fig. 4).
tients with type 1 diabetes55,56 reduced epineph- Several agents, such as glucagon, glucagon-
rine responses to, and symptoms of, hypoglyce- stimulating amino acids, β2-adrenergic agonists
mia in both the nondiabetic persons and the (e.g. terbutaline), and adenosine antagonists (e.g.,
patients with type 1 diabetes. Plasma lactate caffeine), are known to raise glucose concentra-
concentrations roughly double during hyperin- tions. Their therapeutic potential is limited be-
sulinemia.20 Arteriovenous measurements have cause their glucose-raising actions are not in-
revealed lactate release from the brain in the creased in response to falling glucose levels.66
euglycemic state and either no lactate uptake57 Nonetheless, the judicious use of such agents
or a small amount of lactate uptake, sufficient to could prove beneficial if their efficacy and safety
compensate for only about 25% of the calculated were demonstrated in randomized clinical trials.
brain glucose energy deficit58 during hyperinsu- Five potential treatments for reversing glu-
linemic hypoglycemia in humans. cose counterregulatory defects66 — selective
Studies of systemic lactate infusions with 13C serotonin-reuptake inhibitors (SSRIs),67,68 adren-
magnetic resonance spectroscopic measurements ergic antagonists,69 an opiate-receptor antago-
in nondiabetic persons have shown brain lactate nist,70,71 fructose,72 and a selective ATP-sensitive
uptake when arterial lactate levels are increased potassium (KATP)–channel agonist73 — are of
by a factor of 4 and increased lactate transport particular interest. All enhance counterregulatory
to the brain when plasma lactate levels are in- responses to falling glucose concentrations.66
creased by a factor of 2.59,60 Indeed, increased SSRIs increase the counterregulatory respons-
brain lactate concentrations without increased es to hypoglycemia in humans67 and rats.68 A
oxidation of lactate have been reported in pa- randomized clinical trial of an SSRI for the pre-
tients with type 1 diabetes.61 Lactate infusions vention of iatrogenic hypoglycemia may be war-
that caused only a small increase in brain lactate ranted. Combined α-adrenergic and β-adrenergic
metabolism were found to result in maintenance blockade prevents the attenuation of sympatho-
of brain glucose metabolism during subsequent adrenal responses the day after hypoglycemia in
hypoglycemia in rats subjected to recurrent hy- humans.69 If that were shown to be predomi-
poglycemia.62 nantly an effect of β1-adrenergic blockade, a
trial of a β1-adrenergic antagonist for the pre-
Brain-Metabolism Hypothesis vention of hypoglycemia in patients with type 1
This hypothesis holds that recent hypoglycemia diabetes would be reasonable and might reduce
alters CNS metabolic regulation, resulting in at- mortality.74 β1-adrenergic blockade would not
tenuated sympathoadrenal responses to declining impair the β2-adrenergic actions of catecho­
plasma glucose concentrations and thus HAAF. lamines, such as their glucose-raising and symp-
Studies of the cellular and molecular biology and tom-generating effects. Infusion of the opioid-
pathophysiology of CNS control of glucose coun- receptor antagonist naloxone increases the plasma
terregulation in rodent models have focused epinephrine response to hypoglycemia and, when
largely, but not exclusively, on the ventromedial administered during hypoglycemia, prevents at-
hypothalamus. Potential mechanisms32,33,63-65 in- tenuation of the plasma epinephrine response to
clude decreased glucose sensing by glucose-excited subsequent hypoglycemia in humans.70,71 Fructose
or glucose-inhibited neurons in the hypothala- infusion amplifies epinephrine and glucagon
mus, elsewhere in the brain, and in the periphery; responses and increases glucose production dur-
decreased activation of AMP kinase; increased ing hypoglycemia in humans.72 Finally, adminis-
glucokinase activity; loss of a decrease in the tration of a selective Kir6.2/SUR-1 K ATP-channel
counterregulatory inhibitor γ-aminobutyric acid; agonist increases the epinephrine response to
loss of an increase in the counterregulatory stim- hypoglycemia in rats.73 However, systemic ad-
ulator glutamine; increased urocortin release; ministration of the nonselective K ATP -channel
and reduced actions of insulin on the brain. agonist diazoxide suppresses the glucagon re-

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 mechanisms of disease

Cure diabetes Prevent diabetes Develop plasma glucose

regulation:
Insulin replacement
Insulin secretion

Eliminate Hypoglycemia

Reverse compromised glucose

counterregulatory defenses

Glucagon Adrenergic antagonist Adenosine antagonist

Amino acids Selective serotonin-reuptake GABA-release inhibitor
β2-adrenergic agonist inhibitor Fructose
Opiate antagonist KATP-channel agonist
Other

Figure 4. Elimination of Hypoglycemia from the Lives of People with Diabetes.

Prevention or cure of diabetes or provision of plasma-glucose–regulated insulin replacement or secretion would
eliminate hypoglycemia. In the meantime, available drugs might reduce the burden of iatrogenic hypoglycemia.
GABA denotes γ-aminobutyric acid, and K ATP ATP-sensitive potassium. Adapted from Cryer.66

sponse and has no effect on the epinephrine re- Recent hypoglycemia attenuates sympathoad-
sponse to hypoglycemia in nondiabetic humans.22 renal responses to subsequent hypoglycemia in
nondiabetic persons10 and in patients with dia-
Cerebral-Network Hypothesis betes,7 an example of habituation of the sympa-
According to this hypothesis, recent hypoglyce- thoadrenal response to hypoglycemia in humans.
mia acts through a network of interconnected Hypoglycemia has been found to increase synap-
brain regions to inhibit hypothalamic activation tic activity in the human dorsal midline thala-
and thus attenuate the sympathoadrenal and mus, among other brain sites,31,75,76 and to in-
symptomatic responses to subsequent hypogly- crease synaptic activity to a greater extent after
cemia.1,31 The cerebral-network hypothesis is recent hypoglycemia only in the dorsal midline
largely based on findings from functional neuro- thalamus (Fig. 5),31 the site of the posterior
imaging in humans during hypoglycemia,43,44 paraventricular nucleus of the thalamus.78 In-
particularly [15O]water PET measurements of re- deed, slightly subphysiologic glucose concentra-
gional cerebral blood flow as an index of region- tions (65 mg per deciliter) increase synaptic
al brain synaptic activity,31,75,76 and the psycho- activity in the dorsal midline thalamus pre-
physiological concept of habituation of the dominantly, perhaps selectively, in humans.80
response to a given stress and its proposed Thus, thalamic synaptic activation may be in-
mechanism.77 The posterior paraventricular nu- volved in the pathogenesis of the attenuated
cleus of the thalamus is a brain site at which sympathoadrenal and symptomatic responses to
previous stress, such as stress induced by re- hypoglycemia that are the key features of HAAF
straint, acts to attenuate responses to subsequent in diabetes.31,80
episodes of that stress in rats.78 Lesions in the Inactivation of the medial prefrontal cortex
posterior paraventricular nucleus of the thalamus has also been reported to prevent habituation
block habituation of the hypothalamic–pituitary– to restraint-induced stress in rats.81 Increased
adrenocortical response to repeated restraint.78 synaptic activity in the medial prefrontal cortex
Habituation of the sympathoadrenal response to (anterior cingulate) occurs during hypoglyce-
repeated restraint-induced stress has also been mia in humans.31,75,76 Thus, the medial pre-
documented in rats.79 frontal cortex, among other regions, may be

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 The n e w e ng l a n d j o u r na l of m e dic i n e

reported in patients with type 1 diabetes and

12
hypoglycemia unawareness, as compared with
those without hypoglycemia unawareness.44 In-
deed, the array of differences in the patterns of
Day 1
[18F]deoxyglucose uptake during hypoglycemia
between patients with hypoglycemia unaware-
ness and those without it44 is consistent with the
Thalamus participation of a widespread cerebral network
0
12
in the pathogenesis of HAAF in diabetes.

Sum m a r y
Day 2
The key feature of HAAF in diabetes is attenuat-
ed sympathoadrenal responses to hypoglycemia,
most often caused by recent hypoglycemia. In the
0
context of the lack of a decrease in insulin and of
Figure 5. Increased Thalamic Response to Hypoglycemia in a Model of HAAF.
an increase in glucagon — both plausibly attrib-
A model of HAAF in humans shows a greater increase in dorsal midline
uted to beta-cell failure — attenuation of the epi-
thalamus activation, as measured with the use of [15O]water positron-emission
tomography, during hypoglycemia on day 2 than during hypoglycemia on nephrine response causes defective glucose coun-
day 1, with interprandial hypoglycemia occurring between the measure- terregulation. Attenuation of the sympathetic
ments on day 1 and day 2. Areas with the greatest activity are yellow, and neural response largely causes hypoglycemia un-
those with the least activity are dark red. Adapted from Arbeláez et al.31 awareness. The precise mechanisms of the attenu-
ated sympathoadrenal responses are not known,
part of the cerebral network involved in the but there are provocative clues, ranging from evi-
­attenuated sympathoadrenal and symptomatic dence that available drugs might lower the bur-
responses to hypoglycemia that characterize den of iatrogenic hypoglycemia and that lactate
HAAF in diabetes. can affect brain metabolism to the notion of al-
A greater decrease in [18F]deoxyglucose up- terations in a cerebral network in the pathogen-
take, measured with the use of PET, in the sub- esis of HAAF.
thalamic region of the brain, centered on the Disclosure forms provided by the author are available with the
hypothalamus, during hypoglycemia has been full text of this article at NEJM.org.

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