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Translational Endocrinology & Metabolism highlights the intersection of basic science, clinical research,
and patient care that forms the foundation of translational medicine. It represents the collective
expertise of The Endocrine Society, providing bench to bedside information in an integrated
approach. A continuing medical education component is provided for self-assessment and credit.
ENDOCRINOLOGY
& M E TA B O L I S M
HYPOGLYCEMIA
IN DIABETES
UPDATE
TRANSLATIONAL
ENDOCRINOLOGY
& METABOLISM
HYPOGLYCEMIA
IN DIABETES
UPDATE
Editor-in-Chief
R. Paul Robertson, MD
Pacic Northwest Diabetes Research Center
Seattle, Washington
Guest Editor
Elizabeth R. Seaquist, MD
University of Minnesota
Minneapolis, Minnesota
www.endo-society.org
Contents
Contributors
Foreword
11
15
47
89
115
161
163
Continuing Medical
Education Information
Accreditation Statement
The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Endocrine Society has
achieved Accreditation with Commendation.
The Endocrine Society designates this enduring material for a maximum of 4 AMA PRA
Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent
of their participation in the activity.
Disclaimers
The information presented in this activity represents the opinion of the faculty and is not necessarily the ofcial position of The Endocrine Society.
Use of professional judgment:
The educational content in this activity relates to basic principles of diagnosis and therapy
and does not substitute for individual patient assessment based on the health care providers
examination of the patient and consideration of laboratory data and other factors unique to the
patient. Standards in medicine change as new data become available.
Drugs and dosages:
When prescribing medications, the physician is advised to check the product information
sheet accompanying each drug to verify conditions of use and to identify any changes in drug
dosage schedule or contraindications.
Learning Objectives
Upon completion of this educational activity, learners will be able to:
Chapter 1: Epidemiology and Impact of Hypoglycemia on Patients With Diabetes
Identify the predictive factors of hypoglycemic risk.
Examine impaired awareness of hypoglycemia and alterations in counterregulatory defenses
associated with hypoglycemia.
Analyze the clinical and socioeconomic consequences of hypoglycemia.
Chapter 4: Prevention and Management of Hypoglycemia in the Active Patient With
Diabetes
Analyze how exercise affects blood glucose in patients with diabetes mellitus.
Help patients with diabetes mellitus plan for exercise to reduce the risk of hypoglycemia.
Compare different approaches to insulin therapy in the context of exercise in patients with
diabetes mellitus.
Target Audience
This continuing medical education activity should be of substantial interest to endocrinologists
and other physicians and allied healthcare providers treating hypoglycemia.
Statement of Independence
As a provider of continuing medical education (CME) accredited by the Accreditation Council
for Continuing Medical Education, The Endocrine Society has a policy of ensuring that
the content and quality of this educational activity are balanced, independent, objective, and
scientically rigorous. The scientic content of this activity was developed under the supervision of Editor-in-Chief, Dr. Paul Robertson, and Guest Editor, Dr. Elizabeth R. Seaquist.
Disclosure Information
The faculty, committee members, and staff who are in position to control the content of this
activity are required to disclose to The Endocrine Society and to learners any relevant nancial
relationship(s) of the individual or spouse/partner that have occurred within the last 12 months
with any commercial interest(s) whose products or services are related to the CME content.
Financial relationships are dened by remuneration in any amount from the commercial interest(s)
in the form of grants; research support; consulting fees; salary; ownership interest (e.g., stocks,
stock options, or ownership interest excluding diversied mutual funds); honoraria or other
payments for participation in speakers bureaus, advisory boards, or boards of directors; or
other nancial benets. The intent of this disclosure is not to prevent CME planners with relevant nancial relationships from planning or delivery of content, but rather to provide learners
with information that allows them to make their own judgments of whether these nancial relationships may have inuenced the educational activity with regard to exposition or conclusion.
The Endocrine Society has reviewed all disclosures and resolved or managed all identied
conicts of interest, as applicable.
The following faculty reported no relevant nancial relationships: Stephen N. Davis, MBBS,
FRCP, FACP, and Brian M. Frier, BSc (Hons), MD, FRCPE, FRCPG.
The following authors reported relevant nancial relationships: Mark L. Evans, MBBS, MD,
FRCP has sat on advisory boards for and has received travel support from Medtronic, Roche and
CellNovo and received speakers fees from Animas, Abbot Diabetes Care and AstraZeneca.
Simon R. Heller, DM, FRCP has sat on a speaker advisory board and has received a consulting fee from Novo Nordisk; has received consulting fees from Eli Lilly and Sano Aventis and
has sat on an advisory board for Lifescan.
Editor-in-Chief R. Paul Robertson, MD, who planned and reviewed content for this activity,
reported no relevant nancial relationship. Elizabeth R. Seaquist, MD, the guest editor, has
reported relevant nancial relationships with AMG Medical, Sano Adventis and SkyePharma
as a consultant and has received Grant/Research Support from Eli Lilly.
Endocrine Society staff associated with the development of content for this activity reported
no relevant nancial relationships.
|7
Method of Participation
This enduring material is presented in online and print format. To receive a maximum of
4 AMA PRA Category 1 Credit(s) participants must complete an activity evaluation, as well
as a post-test achieving a minimum score of 70%. If learners do not achieve a passing score
of 70%, they have the option to change their answers and make additional attempts to
achieve a passing score. Learners also have the option to clear all answers and start over. To
claim your CME credit, please go to www.endojournals.org/translational.
To complete this activity, participants must:
Have access to a computer with an Internet connection.
Use a major web browser, such as Internet Explorer 7+, Firefox 2+, Safari, Opera, or
Google Chrome; in addition, cookies and Javascript must be enabled in the browsers
options.
The estimated time to complete this activity, including review of material, is 4 hours.
Last Review Date: January 2013
Activity Release Date: May 2013
Activity Expiration Date: May 2016 (date after which this enduring material is no
longer certied for 4 AMA PRA Category 1 Credits)
For questions about content or obtaining CME credit, please contact The Endocrine Society at
education@endo-society.org.
Contributors
Editor-in-Chief
R. Paul Robertson, MD
Pacific Northwest Diabetes
Research Center
Seattle, Washington
Guest Editor
Elizabeth R. Seaquist, MD
University of Minnesota
Minneapolis, Minnesota
Contributing Authors
Stephen N. Davis, MBBS, FRCP, FACP
University of Maryland School
of Medicine
Baltimore, Maryland
Raghavendra Rao, MD
University of Minnesota School
of Medicine
Minneapolis, Minnesota
|9
Foreword
Hypoglycemia is a major concern for patients with diabetes who are treated with insulin or
insulin secretagogues. Its effects can range from inconveniencing symptoms brought on by
counterregulatory hormones to more serious effects such as seizures, tachycardia, and even
death. Repeated episodes may lead to hypoglycemia associated autonomic failure, where the
body fails to mount an appropriate counterregulatory response before profound neuroglycopenia occurs. It is important for clinicians to give their patients up-to-date information to help
prevent hypoglycemia.
This issue of Translational Endocrinology & Metabolism: Hypoglycemia in Diabetes Update
is a comprehensive review of the latest research and knowledge on this condition, opening with
an examination of the impact of hypoglycemia on the lives of patients with diabetes by Brian
Frier and Simon Heller. Vanessa Routh, Casey Donovan, and Sue Ritter explore the role of glucose
sensors in detecting hypoglycemia and hypoglycemia-associated autonomic failure. Rory
McCrimmon and Gulin Oz discuss how the brain responds to repeated hypoglycemia and
how these adaptations may contribute to reduced counterregulatory responses in some diabetic
patients. Stephen N. Davis and Mark L. Evans consider the challenges in balancing exercise
with the risk of hypoglycemia. Finally, Raghavendra Rao and Tamara Hershey examine the
effects of severe hypoglycemic episodes on the brain development in children.
We are certain you will nd the research presented here both interesting to read and useful
to your practice. This issue contains the most current science as well as ideas for working with
your patients. We hope you will enjoy this research and put the ideas here to good use.
R. Paul Robertson, MD
Editor-in-Chief
Translational Endocrinology &
Metabolism
Elizabeth R. Seaquist, MD
Guest Editor
Translational Endocrinology &
Metabolism: Hypoglycemia
in Diabetes
| 11
Abstract
| 13
Epidemiology
The significance of hypoglycemia as an adverse effect of treatment became
apparent within a few years of the introduction of insulin (1). As the
importance of maintaining glucose concentrations as close to normal as
possible began to accumulate, the emerging relationship between tight
glucose control with subcutaneous insulin therapy and the risk of severe
hypoglycemia caused some to question the safety of the approach (2).
These doubts were silenced by the publication of the Diabetes Control and
Complications Trial (DCCT), but the epidemiological data that accompanied the DCCT emphasized the risk from hypoglycemia in those undertaking intensive insulin therapy (3). The data also highlighted the need
for a good understanding of the adverse effects of therapy when agreeing
upon clinical approaches with patients or their relatives.
Systematic epidemiological data began to emerge in the 1980s as hypoglycemic adverse effects became more apparent. The evidence was initially obtained from overnight monitoring of individuals with type 1
diabetes (4) and retrospective questioning of those attending hospital clinics, and it was assumed at the time that the risks of hypoglycemia were
generally confined to this group.
These data suggested that therapy (usually with twice daily insulin) in
patients with type 1 diabetes led to severe hypoglycemia in around 10%
to 30% of patients per year (5). The risk of severe hypoglycemia was also
reported as a rate, usually the number of overall number of episodes
experienced by each patient per year, although both methods failed to
highlight that rates of hypoglycemia are not normally distributed. Most
individuals with either type 1 or insulin-treated type 2 diabetes experience few or no episodes at all, while a small proportion experience hypoglycemia, even severe episodes, very frequently (6). This type of distribution
16
1.0
0.8
0.6
0.4
0.2
0.0
Type 2 treated with
Type 2
SU
ins <2 yrs
Type 2 >5
yrs
Type 1 <5
yrs
Type 1
> 15 yrs
FIG 1-1. Proportion of each group experiencing at least one severe self-reported hypoglycaemic episode during 9-12 months of follow-up. Vertical bars, 95% condence intervals (from
UK Hypoglycaemia Study Group: Risk of hypoglycaemia in types 1 and 2 diabetes: effects of
treatment modalities and their duration. Diabetologia 50:1140-1147, 2007, gure 2).
| 17
in type 1 diabetes (18). Thus, as far more people with type 2 diabetes are
treated with insulin, the clinical problem is correspondingly greater.
18
Renal Impairment
Renal impairment is an important although under-reported contributor
to hypoglycemia. It impairs clearance of insulin and the metabolites of
sulfonylureas. The renal contribution to gluconeogenesis (up to 30%
under some conditions) and glucose reabsorption of filtered glucose are
also relevant. The risk of severe hypoglycemia may be raised by as much
as 2 to 3 times in individuals with type 2 diabetes who have an estimated
glomerular filtration rate (eGFR) less than 60 mL/min (25). Measurement
of renal function is particularly important among patients with type 2 diabetes who experience a severe episode.
Psychosocial Factors
The role of psychosocial factors in determining the risk of hypoglycemia is
increasingly recognized (29). Inappropriate responses of patients to raised
glucose concentrations and their overcorrection with additional doses of
insulin may contribute to loss of hypoglycemia awareness and the risk of
subsequent severe episodes. The potential of anticipating and identifying
these attitudes and developing interventions to address them is currently
the increasing focus of experimental work.
| 19
20
Adults
Elderly
Autonomic/neuroglycopenic
Autonomic
Autonomic
Neuroglycopenic
Neuroglycopenic
Behavioral
Non-specic malaise
Neurological
| 21
level by subjectively rated symptom scores. Experimental studies have generally confirmed clinical observations that cerebral cognitive function (using
sensitive tests such as 4 choice reaction time)
Physiological defenses to
begins to deteriorate at around 55 mg/dL
hypoglycemia are intact at
(3 mmol/L) as blood glucose falls and cerebral
diagnosis but become
glucose delivery diminishes (22) (Figure 1-2).
progressively impaired as
Awareness of hypoglycemia depends upon
diabetes duration increases.
patients recognizing their own peripheral
Other factors may also
autonomic response and taking action before
inuence the rate of decline of
their cognitive dysfunction becomes estabthese defenses, and there
lished in the absence of cerebral glucose
appears to be considerable
delivery. Since both symptom generation
variation in the extent and
(through activation of the autonomic nervous
severity of impaired responses.
system) and cerebral dysfunction reflect neuroglycopenia, it is unsurprising that both
responses occur at comparable low glucose levels. It emphasizes how
important it is for patients to respond to warning symptoms and implies
that a shift in activation of the sympathoadrenal response to a lower blood
glucose could prevent recognition of hypoglycemia.
Glucagon release
Epinephrine release
Sweating, tremor
70
55
35
20
Start of brain
dysfunction
Confusion/loss of
concentration
Coma/seizure
brain damage
FIG 1-2. Glucose thresholds for the normal physiological response to hypoglycemia.
| 23
24
Percentage of subjects
80
2.36
Normal awareness
of hypoglycaemia
Impaired awareness
of hypoglycaemia
60
2.0
1.5
50.5%
40
20
2.5
1.0
20.1%
0.38
0.5
100
0.0
0
Percentage
Events
FIG 1-3. Prevalence and incidence of severe hypoglycemia (SH) in the year preceding a
survey of 518 adults with Type 1 diabetes with and without impaired awareness of hypoglycemia (reproduced from Geddes et al, 2008) (20).
The extent to which antecedent hypoglycemia contributes to the widespread impairment in physiological defenses to hypoglycemia demonstrated by patients is still not entirely clear. However, it may largely account
for the failure of counter-regulatory mechanisms and loss of hypoglycemia
awareness after tightening glycemic control, presumably alongside those
associated with long duration of disease.
The term hypoglycemia-associated autonomic failure (HAAF) has
been proposed by Cryer to describe the phenomenon, and he has highlighted how an initial period of hypoglycemia could lead to a downward
vicious spiral of progressively impaired physiological responses, increasing clusters of hypoglycemic episodes and the development of impaired
hypoglycemia awareness (54). However, the extent to which autonomic
dysfunction (a classical complication of diabetes generated by a different
mechanism) may contribute is uncertain. Interestingly, antecedent exercise
results in impaired sympathoadrenal responses to experimental hypoglycemia, and antecedent hypoglycemia impairs subsequent sympathoadrenal
activation during exercise (55). Furthermore, antecedent hypoglycemia has
been demonstrated to impair some cardiac autonomic reflexes, including
baroceptor sensitivity and sympathoadrenal responses, to lower negative
| 25
26
with restoration of symptoms of hypoglycemia, and in some reports, resetting of glycemic thresholds at higher levels for epinephrine release and
for symptoms. In some studies, investigators demonstrated that the effect
of hypoglycemia avoidance was to reset the threshold for release of epinephrine to a glucose concentration above that for cognitive impairment
(64, 65). Not all studies have demonstrated restoration of epinephrine
responses (66), although, interestingly, symptom scores during hypoglycemia improved despite the reversal program having failed to restore epinephrine release.
The potential to reverse some aspects of diminished hypoglycemia awareness by avoiding hypoglycemic episodes offers a practical solution to the
problem of loss of awareness. The work described above suggests that if
patients can completely eliminate hypoglycemia for just a few weeks,
they will obtain useful clinical benefit. The published studies do not
provide detailed descriptions of the clinical techniques that were used
to avoid hypoglycemic episodes in order to restore normal awareness.
Nevertheless, the relevant features appear to include close and continuing communication with specialist medical and nursing staff and discussing blood glucose targets based on intensive monitoring. Patients
need to be prepared to accept occasional high glucose values and not to
overcorrect with extra doses of insulin. It is important to emphasize that
the approach is not designed to run high blood glucose values but to
avoid hypoglycemic episodes, and at least in the published studies, it
was possible to achieve this without a major deterioration in glycemic
control.
Clinical Consequences
Morbidity of Hypoglycemia
Neurological Consequences
Around 25% of all episodes of severe hypoglycemia result in coma (67),
which is the principal neurological consequence of severe hypoglycemia.
Coma and hypoglycemia-induced seizures can result in serious morbidity
such as fracture-dislocations, soft tissue injuries, and head injury. When
electroencephalography (EEG) is performed during hypoglycemia in resting
subjects who are awake, typical changes that occur include a decrease in
alpha waves, an increase in theta waves, and increased bursts of delta waves
over the cerebral cortex, which are more evident over the anterior part of
the brain (68). The EEG abnormalities are more pronounced in people with
type 1 diabetes than in nondiabetic subjects, and epileptiform activity is
| 27
more common. The theta wave changes persist after normoglycemia has
been restored. Hypoglycemia-induced EEG changes may persist for several
days and can become permanent, particularly after recurrent severe hypoglycemia. This may confound interpretation of the EEG when attempting to
exclude idiopathic epilepsy. Epileptiform seizures can also provoke cardiac
arrhythmias (69, 70), which might cause sudden death in association with
a hypoglycemia-induced seizure. Because hypoglycemia often causes dizziness, lightheadedness, confusion, and mental obtundation, accidents causing personal injury are a common sequela (71), and may result in falls with
fractures or joint dislocations, particularly in frail elderly people who may
have other comorbidities such as osteoporosis and coronary heart disease.
Permanent focal neurological lesions following acute hypoglycemia are
rare, whereas transient and reversible neurological deficits are relatively
common; in individual cases, short-lived structural changes have been
demonstrated using sophisticated neuroimaging (72, 73). Functional
changes may therefore occur within the brain without leaving a permanent cerebral abnormality. Based on anecdotal clinical observation, it
is thought that several hours of exposure to profound neuroglycopenia
are required to produce permanent brain damage. Such a catastrophic
outcome is rare and is usually the consequence of attempted suicide
with deliberate massive insulin overdose (74) or associated with excessive
alcohol consumption (75). Structural abnormalities observed in the brains
of survivors of profound hypoglycemia include cortical and hippocampal
atrophy and ventricular dilatation. These severely brain-damaged individuals have evidence of widespread cognitive impairment or exist in a vegetative state. When hypoglycemic coma is prolonged, predicting prognosis
can be difficult. Elevation of serum markers of brain damage, neuronespecific enolase and S-100, within 24 to 48 hours of the onset of coma,
usually indicates a fatal outcome (76).
Total cerebral blood flow is increased during acute hypoglycemia, and
blood flow is altered acutely within different regions of the brain; it
increases in the frontal cortex, presumably as a compensatory mechanism
to preserve the supply of glucose to this part of the brain, which is very
sensitive to glucose deprivation. These regional vascular changes become
permanent in people who are exposed to recurrent severe hypoglycemia
and in those with impaired awareness of hypoglycemia; they are then
observed during normoglycemia (77). This probably represents an adaptive response of the brain to recurrent exposure to neuroglycopenia. However, the permanent hypoglycemia-induced changes in regional cerebral
blood flow may promote localized neuronal ischemia, particularly if the
cerebral circulation is already compromised by the development of
28
cerebrovascular disease. This risk of cerebral ischemia may then be augmented if the individual is exposed to some other form of hemodynamic
stress that affects the cerebrovascular circulation. Transient ischemic attacks
and hemiplegia are recognized manifestations of hypoglycemia, and in
the elderly they may be misdiagnosed as cerebrovascular disease.
Cognitive function, which includes several forms of mental activity, rapidly becomes impaired when blood glucose declines below 3.0 mmol/L
(54 mg/dL). Complex and attention-demanding cognitive tasks, and those
that require speeded responses are much more affected by hypoglycemia
than simple tasks or those that do not have any time restraint (78, 79).
Although the overall speed of response of the brain to make decisions is
slowed, accuracy is preserved for many tasks (80, 81). Although many
aspects of mental performance become impaired during hypoglycemia,
individual differences exist in the levels at which impairment commences
and in the magnitude of dysfunction that occurs. Recovery of cognitive
function does not occur immediately after the blood glucose returns to
normal, but in some cognitive domains may be delayed for up to 60 minutes (79), which has practical consequences for the performance of tasks
that require complex cognitive functions, such as driving. The profound
and negative effects that hypoglycemia exerts on mood and emotion are
often unrecognized by clinicians (82). Fear of hypoglycemia is common
and is a major obstacle to maintaining strict glycemic control both in type
1 and insulin-treated type 2 diabetes (83).
In adults, the long-term effect of repeated exposure to severe hypoglycemia on cognitive function is less clear. The longitudinal follow-up of the
DCCT showed no differences in cognitive function between the intensive
and standard treatment arms over a period of up to 20 years, despite a
greater frequency of severe hypoglycemia in the intensive arm (84). Similarly, data from a systematic meta-analysis did not show any relationship
between recurrent hypoglycemia and performance in cognitive tests (85).
However, the brain of the very young or elderly person with diabetes may
be much more susceptible to hypoglycemia-induced brain injury (86).
Exposure to hypoglycemia in children with early onset of type 1 diabetes
has been associated with lower verbal IQ (87), and early exposure to
severe hypoglycemia in young children with type 1 diabetes appears to
have adverse long-term effects on cognitive function (88). Cognitive
development may be affected adversely by exposure to hypoglycemia, particularly when accompanied by induced seizures, in very young children
(89). It is possible that repeated exposure to hypoglycemia may accelerate
the onset of dementia in elderly people with type 2 diabetes, but as yet
this remains unproven.
| 29
Mortality
Linking Mortality to Hypoglycemia
It is challenging to calculate accurately the risk of mortality due to hypoglycemia in diabetes. Death certificates are notoriously unreliable in attributing cause of death, with coding often left to hospital clerks who rarely
have appropriate training or access to clinical details (4).
Sustained carbohydrate metabolism continuing postmortem, manifested
by glycogenolysis, raises the blood glucose concentration in major rightsided vessels. Thus, normal or high glucose values on the right side of the
heart do not exclude antemortem hypoglycemia. In contrast, glucose is
also metabolized peripherally; thus low blood glucose is often found after
death in those without diabetes.
The difficulties are reflected in a wide range of published estimates on
hypoglycemic mortality rates. Reports from Scandinavia have estimated
hypoglycemic mortality of between 7% and 10% among young adults,
only slightly lower than mortality rates attributed to diabetic ketoacidosis
(90, 91). Because hypoglycemia is common, however, an individual episode is unlikely to cause death.
30
5.0 mM
2.5 mM
| 31
patients with either type 1 or type 2 diabetes (103, 104), and in both adults
(105) and children (106). Reductions in serum potassium and sympathoadrenal activation both contribute to the effect (107). Thus one possible
mechanism accounting for sudden death in type 1 diabetes is acquired
long QT syndrome caused by insulin-induced hypoglycemia (108).
An additional factor that could contribute to arrhythmic risk during
hypoglycemia is the contribution of autonomic activation, particularly if
the parasympathetic and sympathetic components are affected differentially. Parasympathetic activation (or suppression of sympathetic activation) will cause bradycardia, an arrhythmia reported during nocturnal
episodes (109). Studies using heart rate variability to measure cardiac
sympathetic and parasympathetic tone have reported inconsistent changes
during hypoglycemia (110112), and the additional effect of autonomic
neuropathy is also uncertain (113).
A recent case report of a sudden death during hypoglycemia in a
young male patient with type 1 diabetes during coincidental continuous glucose monitoring is strong additional evidence of an arrhythmic
death (114), but the precise mode of death remains unclear. It is likely
that both genetic and environmental affects combine together, but
important areas of uncertainty, including the factors that are most
important and whether it is possible to identify those at greatest risk,
are still to be determined.
experienced at least 1 severe event had higher mortality ratio than those
with no hypoglycemia in both arms, with a hazard rate of 1.41 (118).
Interestingly, there was also a relationship between a severe hypoglycemic episode and downstream mortality in both VADT and ADVANCE.
However, although all 3 trials have reported a similar association; they
could not establish a causal relationship. In ADVANCE, similar associations were also reported with other outcomes, including microvascular
complications and noncardiac mortality (119). It seems equally possible
that the risk of mortality might be due to residual confounding and be a
marker of ill health and vulnerability.
Indeed the reported data linking hypoglycemia, mortality, and intensive glycemic control are inconsistent and apparently confusing. The
ACCORD trial showed that the relationship between a severe hypoglycemic event and mortality was greater in those randomized to standard
therapy (118). While this observation has been cited to refute a causal
effect of hypoglycemia on mortality, the interpretation does not acknowledge the effect of tight control and repeated hypoglycemia, which is well
known to suppress sympathoadrenal responses to subsequent hypoglycemic episodes. Thus if hypoglycemia has effects on cardiovascular risk
through sympathoadrenal responses, then it might be expected that those
experiencing occasional episodes in the standard group would demonstrate stronger sympathoadrenal activation with a more powerful effect
on the cardiovascular system.
Evidence has also emerged recently of an adverse effect of intensive
glucose control among nondiabetic individuals with critical illness.
Original work in this area suggested that intensive glucose control reduced
mortality in critically ill individuals admitted to a surgical intensive care
unit, but subsequent trials have not been able to reproduce these findings.
Indeed, a recent trial reported increased mortality in those treated intensively (120), and the markedly higher rates of hypoglycemia in this
group have clear potential relevance to the observed outcomes (121).
Subsequent post hoc analyses have confirmed the association between
severe hypoglycemia and mortality, although a causal relationship cannot be established. Furthermore, the fact that the greatest rate of mortality was observed in those who were not taking insulin but who had
experienced hypoglycemia suggests that confounding by vulnerability to
hypoglycemia in those who are the most ill contributes to these findings
(120, 122, 123).
In summary, despite a clear association between hypoglycemia and mortality, it is not yet possible to establish a causal relationship, and important
confounders including increased vulnerability to both hypoglycemia and
| 33
34
less clear, with inconsistent responses following hypoglycemia on interleukin 6 and C-reactive protein (125, 127, 128).
Platelet activation and aggregability are increased following hypoglycemia (125, 127), a mechanism probably mediated by sympathoadrenal
activation (129). Initiation of an acute coronary syndrome may also be
related to the state of the fibrinolytic system, and this also appears to be
activated by hypoglycemia (130). Other work has demonstrated increased
coagulation and reduced fibrinolysis during sustained insulin-induced
episodes (127)
The hemodynamic response following hypoglycemia leads to increases
in heart rate, although this rarely rises above 100 beats per minute, perhaps because of simultaneous parasympathetic activation. Systolic blood
pressure increases, accompanied by a fall in diastolic blood pressure, widening of pulse pressure, an increase in cardiac output, and a fall in peripheral vascular resistance. There is a transient increase in the elasticity of
the arterial system (131), which is diminished in people with type 1 diabetes of longer duration (>15 years), and premature arterial stiffening is
common in diabetes of both types. Accelerating the return of the pressure
wave generated during systole to the heart may diminish diastolic coronary filling. A fall in myocardial blood flow reserve (132) may be of limited clinical significance in a healthy individual but could be critical in a
person with pre-existing coronary heart disease.
There are few reports of clinical hypoglycemic episodes initiating a cardiac ischemic event. Silent ischemia in a diabetic patient with suspected
coronary heart disease has been reported (133), and one study utilizing continuous glucose monitoring reported ischemic electrocardiogram (ECG)
changes during hypoglycemia (some being accompanied by chest pain)
that were not observed when glucose was normal or high (134).
Socioeconomic Consequences
Driving
Because hypoglycemia affects cognitive function and mood, it can affect
many everyday activities that require the interaction of several cognitive
domains. One such important activity is driving; progressive neuroglycopenia interferes with driving performance and can cause road traffic accidents. To investigate the effect on driving performance, hypoglycemia was
induced in adults with type 1 diabetes in a driving simulator, which had
visual, auditory, and kinesthetic feedback to track several performance
variables (135, 136). Driving performance began to deteriorate when
| 35
36
| 37
Severe hypoglycemia does not appear to be a major problem in the workplace among most employees with type 1 diabetes (149). However, many
people with insulin-treated type 2 diabetes have reported problems in
relation to their work following mild hypoglycemia, including not going
to work or arriving late because hypoglycemia (particularly nocturnal)
had occurred outside working hours or it affected work performance to
cause significant loss of productivity (150).
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46
2. Hypoglycemia Detection
Vanessa H. Routh, PhD
Casey M. Donovan, PhD
Sue Ritter, PhD
Introduction
Insulin-induced hypoglycemia is a life-threatening iatrogenic phenomenon that activates multiple neural and humoral corrective systems. When
blood glucose levels begin to fall below 80 mg/dL, a sequential series of
events occurs. Insulin secretion ceases; secretion of glucagon, epinephrine (E), corticosterone, and growth hormone is initiated, and neurogenic
systems trigger food intake. All of these responses are recruited when
glucose decreases to approximately 60 mg/dL. Together, these corrective
responses (counter-regulatory responses or CRR) rapidly restore euglycemia.
Unfortunately, however, the magnitude of the CRR decreases with recurring hypoglycemic episodes, leading to a syndrome known as hypoglycemiaassociated autonomic failure (HAAF). During HAAF, glucose levels can
fall dangerously low without eliciting the behavioral signs that usually
accompany hypoglycemia. HAAF is the major limiting factor of the intensive insulin therapy needed to control the deleterious effects of diabetic
hyperglycemia (1, 2). In order to understand and develop therapies for
HAAF, it is critical to understand the mechanisms underlying hypoglycemia detection and initiation of the CRR.
For many decades, it has been clear that there are glucose sensors located
throughout the body and the central nervous system (CNS) (38). The
goal of this chapter is to describe glucose sensing by central and peripheral
glucose sensors and evidence that supports their roles in hypoglycemia
detection and HAAF. The authors will focus on 3 glucose-sensing systems
that contribute importantly to glucose counterregulation: the ventromedial hypothalamic nucleus (VMN) (9, 10), the hindbrain catecholamine
neurons (11), and the portal-mesenteric vein (PMV) (12).
Acknowledgements: The authors are grateful to Dr. Z. Song for assistance with data collection
for Figure 2-1. The authors also wish to acknowledge the following grant support: VHR: NIH
DK081358, CA139063 and JDRF 4-2010-433; CMD: NIH DK062471 and JDRF 1-2007605; SR: NIH DK040498, DK081546.
48
studies report hypothalamic glucose levels of 1 to 2.5 mM during peripheral euglycemia, ranging from 5 mM during hyperglycemia (blood glucose 20 mM) to 0.2 mM during severe hypoglycemia (blood glucose 2
to 3 mM) (25, 26). Similar glucose concentrations during euglycemia
have been noted in other brain regions (27). Thus, emphasis will be placed
on studies of GE and GI neurons that used physiological glucose concentrations within this range.
GE neurons
GE neurons were first identified in the ventromedial region of the hypothalamus (VMH), a region that contains the VMN and the arcuate (ARC)
nucleus. Thus, there are more data regarding these GE neurons compared
to GE neurons in other locations. In 1990, Ashford et al used the pancreatic beta cell as inspiration for the mechanism by which VMH GE neurons
sense glucose (28). These investigators showed that, like the pancreatic
beta cell, glucose directly depolarizes VMH GE neurons by closing inhibitory ATP-sensitive K+ (KATP) channels (28). Although these early studies used supraphysiological glucose levels, KATP channel-dependent
glucose sensing by VMH GE neurons has stood the test of time (22). However, it is important to note that most neurons, glucose-sensing or not,
possess KATP channels or other ion channels that are regulated by ATP
(29). Thus, the presence of such channels is not sufficient to define a neuron as glucose-sensing.
More recent studies point out further similarities with the pancreatic
beta cell in that both the beta cell and most (but not all) VMH GE neurons
require the low-affinity hexokinase IV isoform glucokinase (GK), which
catalyzes the committed step in glycolysis, to sense glucose (30). The
pancreatic beta cell also uses the low-affinity glucose transporter isoform
2 (GLUT2) to transport glucose into the cell. However, 30% of all VMH
neurons express GLUT2 without regard to glucose sensing capability.
Instead, the insulin-sensitive GLUT4 may play a role, since twice as many
glucose sensing versus nonglucose-sensing neurons express both the
GLUT4 and the insulin receptor (31). The neuronal GLUT3 is expressed
in all VMH neurons (31). Like VMH GE neurons, GE neurons in the
amygdala and dorsal vagal complex (DVC) are GK-dependent. The DVC
GE neurons use the KATP channel to sense glucose, but this has not yet
been demonstrated for amygdalar GE neurons (32, 33). Glucose also
closes an inhibitory ion channel (eg, potassium or chloride) to activate
LH melanocortin-concentrating hormone (MCH) GE neurons. However,
the identity of this inhibitory channel is not known (34).
Hypoglycemia Detection
| 49
The cellular fuel sensor AMP-activated protein kinase (AMPK) may mediate glucose sensing in some GE neurons. A decreased ATP:AMP ratio activates AMPK. AMPK is present in most cells and plays a role in activating
cellular processes that restore intracellular ATP levels. Over the past decade,
much data have emerged regarding a prime role for hypothalamic AMPK in
the regulation of whole-body energy homeostasis (35). AMPK has also been
linked to glucose sensing in several populations of GE neurons. The gonadotropin-releasing hormone (GnRH) neurons in the anterior hypothalamus
are AMPK-dependent GE neurons (36), as are the GnRH-derived immortalized GT1-7 cell line (37). Interestingly, glucose opens a nonselective cation
channel to activate GnRH neurons rather than closing an inhibitory channel such as the KATP channel (36). GT1-7 cells possess the KATP channel
(37). However, whether the KATP channel contributes to glucose sensing
in these cells is not known. Like GnRH neurons, GE neurons found in the
hypothalamic paraventricular nucleus (PVN) and subfornical organ also
use a cation channel rather than the KATP channel to sense glucose (18,
38). Whether glucose sensing in PVN or subfornical organ GE neurons uses
GK or AMPK is not known, although GK is expressed in the PVN (39).
The ARC pro-opiomelanocortin (POMC) neurons may also be AMPKdependent GE neurons, although this is still controversial. Several studies using rats as well as wild-type mice and mice whose POMC neurons
express green fluorescent protein (GFP) suggest that POMC neurons do
not directly sense glucose (4042). On the other hand, other studies using
distinct POMC-GFP and other transgenic mice as well as a POMC-derived
cell line suggest that glucose may directly excite POMC neurons via
AMPK-linked KATP channels. However, several of these studies used
supraphysiological glucose concentrations (4345). In these POMC neurons, AMPK regulation of the hypoxia-sensitive nuclear transcription factor hypoxia-inducible factor 1 alpha may play a role in glucose sensing
(46). In contrast to ARC POMC neurons, glucose sensing by VMN GE neurons is unaffected by AMPK modulators (40).
GE neurons most likely respond to changes in glucose metabolism
(vs the glucose molecule per se), since glycolytic flux through GK, AMPK,
and the KATP channel all depend on intracellular metabolism. Moreover,
inhibition of glucose metabolism also inhibits GE neurons (28). However, it
is also possible that metabolism-independent GE neurons exist. This mechanism may explain glucose sensing in those GE neurons that lack GK (31).
For example, the sodium-glucose cotransporter (SGLT) 1 is also expressed
in about 25% of VMH GE neurons. The SGLT1 couples glucose transport
to an inward (excitatory) sodium current, which could contribute to glucose-induced depolarization (31).
50
GI neurons
As mentioned previously, GI neurons are found in many locations that
also contain GE neurons, including the VMN, ARC, PVN, LH, subfornical
organ (SFO), DVC, and amygdala (18, 24, 32, 33, 38). However, GI neurons have not been found in the anterior hypothalamus where GnRH neurons are located. Since these experiments focused only on the GnRH
neurons, it is possible that GI neurons may be found in other cell populations in this region (36). GI neurons exist in both the ARC and the VMN
regions of the VMH (22, 41). In the ARC, about half of the orexigenic
neuropeptide Y (NPY) neurons are GI neurons (41). Because most NPY
neurons coexpress -aminobutyric acid (GABA), it is possible that the
NPY-GI neurons release GABA (47). On the other hand, VMN GI neurons
may be glutamatergic. Tong et al showed that when the vesicular glutamate transporter, vGlut, was deleted in steroidogenic factor 1 (SF-1; marker
for the VMN) neurons, release of adrenal E and glucagon in response to
hypoglycemia was impaired (50). As will be discussed, the atypical neurotransmitter nitric oxide (NO) may also be released from VMH GI neurons when glucose decreases. Finally, LH GI neurons express the peptide
orexin (51). Thus, in terms of transmitter release, GI neurons are phenotypically diverse.
As discussed previously for GE neurons, GK is also necessary for glucose sensing in the majority of VMH GI neurons (30). Moreover, like GE
neurons, about twice as many VMH GI neurons as nonglucose-sensing
neurons express both the insulin receptor and GLUT4 (31). Reduced
expression of the neuronal insulin receptor is associated with a blunted
response of VMH GI neurons to decreased glucose and impaired glucose
counter-regulation (52). However, while many VMH GE neurons do not
appear to use AMPK to sense glucose, this enzyme is critical for glucose
sensing in VMH GI neurons (53). Moreover, a feed-forward relationship
Hypoglycemia Detection
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between AMPK and NO is essential for VMN (but possibly not ARC-NPY)
GI neurons to sense decreased glucose (53, 54). Decreased glucose activates AMPK, which phosphorylates the neuronal NO synthase (nNOS)
leading to NO production. NO then binds to its receptor, soluble guanylyl
cyclase (sGC) and raises cyclic guanosine monophosphate (cGMP) levels.
Increased cGMP causes a further activation of AMPK, which is necessary
for closure of a chloride channel, possibly the cystic fibrosis transmembrane regulator (CFTR). The reduction in chloride conductance depolarizes GI neurons, leading to increased action potential frequency (53).
The mechanism by which cGMP enhances AMPK activity is not known.
However, it may be via activation of an upstream AMPK kinase as has
been shown for endothelial cells (55). What is clear is that the AMPK-NO
pathway is essential. Blocking nNOS or sGC prevents decreased glucose
or AMPK activators from depolarizing GI neurons. Conversely, AMPK
inhibition prevents cGMP-induced activation of GI neurons (53). Thus, in
VMN GI neurons full AMPK activation requires both a glucose decrease
and AMPK-dependent NO production in order to close the chloride channel. Whether NO in VMN GI neurons is only needed for depolarization in
response to decreased glucose or whether NO might diffuse to adjacent
cells and alter their activity is not known.
Similar mechanisms may confer glucose sensitivity to the hindbrain
catecholamine neurons, which increase cfos expression during hypoglycemia or glucoprivation (56). Blockade of AMPK phosphorylation
and administration of the GK inhibitor, glucosamine, in the hindbrain
both reduce glucoprivic feeding (57). In addition, the glucose analog
2 deoxyglucose (2DG), which cannot be metabolized, mimics the effects
of low glucose in a subgroup of hindbrain catecholamine neurons, indicating their responsiveness to glucose deficit and suggesting a GI phenotype
(56). However, strong support of this supposition will require electrophysiological evidence demonstrating their intrinsic responsiveness to glucose,
which is not available at this time. Therefore, to be conservative, the
authors will refer to these neurons simply as hindbrain catecholamine
(or norepinephrine [NE] and E) neurons.
In addition to the VMH GI neurons, GK is expressed in GI neurons in
the amygdala and DVC; however glucose-sensing mechanisms have not
been fully explored in these regions (32, 33). Interestingly, glucose
appears to open a KATP channel and inhibit SFO GI neurons (18). While
VMH GI neurons use KATP channels to respond to changes in extracellular lactate, this KATP channel does not play a role in glucose sensing (49).
In contrast to the metabolically dependent GI neurons, 2DG inhibits LH
orexin neurons (58). This suggests that LH orexin neurons respond to the
glucose molecule per se. While the identity of this glucose receptor is
unknown, as mentioned previously, the sweet taste receptor and the
SGLT are interesting candidates. Various ion channels have been proposed;
however, the exact mechanism has not been established (59, 60).
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the hypothalamus and the hindbrain have received the greatest attention
with respect to their glucose-sensing potential, due to their demonstrated
roles in control of food intake and metabolism. Glucose sensors within
both hypothalamic and hindbrain sites contribute importantly to glucose
homeostasis, but their roles in this complex process appear to differ, as
will be discussed. In the hypothalamus, the most complete information
regarding hypoglycemia detection and counter-regulation is available
for VMN GE/GI neurons. Prominent among glucoregulatory neurons in
the hindbrain are NE and E neurons. Therefore, the functional characteristics of the VMN and hindbrain glucose sensors will be covered.
54
Hypoglycemia Detection
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56
the VMN, as are those expressing nNOS (84). As mentioned previously, a role
for VMN amino acid transmitters GABA and glutamate has been suggested in
hypoglycemia detection. For example, deleting vGlut in SF-1 neurons that are
specific for the VMN impairs adrenal E and glucagon secretion (50). Moreover, there is considerable overlap between GI neurons and nNOS/NO
signaling (85), and adrenal E release in response to insulin-hypoglycemia
is impaired in nNOS knockout mice that lack VMN GI neurons (10). The
afferent and efferent connections of the VMN are complex and will only be
covered briefly in this chapter. For a complete discourse on the topic, the
reader is referred to an excellent review by Bruce King (84). This review supports an integrative role for the VMN based on its juxtaposition between
autonomic regulatory and higher limbic sites, especially with regard to stress
circuitry. The VMN receives extensive reciprocal input from limbic regions
such as the amygdala and the bed nucleus of the stria terminalis, the latter a
relay within the hypothalamic-pituiitary-adrenal axis. The VMN receives
input from other hypothalamic areas including the LH and the suprachiasmatic nucleus. VMN axons as well as dendrites project widely throughout the
hypothalamus including to the PVN, dorsomedial nucleus, and LH. The VMN
also projects to the midbrain reticular formation (84). It is this latter connection that enables the VMN to provide input to the sympathetic preganglionic
neurons within the intermediolateral column of the spinal cord. Thus, while
the exact phenotype and neurocircuitry influenced by VMN glucose sensing
neurons is not known, the potential for impacting those neural circuits
involved in hypoglycemia detection and the CRR is clear.
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A Control
-54 mV
2.5 mM Glucose
0.1 mM Glucose
-54 mV
10 mV
2.5 mM Glucose
0.5 mM Glucose
1 min
RH
-50 mV
2.5 mM Glucose
0.1 mM Glucose
-50 mV
2.5 mM Glucose
0.5 mM Glucose
RH-AICAR
-52mV
2.5 mM Glucose
0.1 mM Glucose
-52mV
2.5 mM Glucose
0.5 mM Glucose
B
% change in IR
40
30
20
10
0
-10
% change in MP
20
15
a
a
10
5
0
Control
(n=9)
58
RH
(n=6)
RH-AICAR
(n=9)
FIG 2-1. (A) Representative current-clamp recordings of VMN GI neurons in brain slices from
2- to 3-week old male Sprague-Dawley rats. Control and recurrently hypoglycemic (RH) rats were
injected once daily for 3 consecutive days with either saline (control) or insulin (4 U/kg; RH). On
day 4, all rats were sacriced, their brains sliced into 300 m sections, and patch-clamp
recording performed as described previously (80). Brain slices from control and 1 subset of RH
rats were studied in the absence of further treatment. Brain slices from another subset of RH rats
were treated with the AMPK activator, 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside
(AICAR, 0.5 mM) in the bathing medium for 15 minutes (RH-AICAR group). AICAR was then
washed out, and glucose sensitivity was evaluated from 1 to 5 hours after treatment. The top trace
in each group represents the neuronal response to a glucose decrease from 2.5 to 0.1 mM and
the bottom trace a glucose decrease from 2.5 to 0.5 mM. Resting membrane potential is given to
the right of each trace. The downward deections represent the membrane response to a constant
hyperpolarizing pulse of -20 pA given for 500 milliseconds every 3 seconds. VMN GI neurons
from control rats were reversibly activated by glucose decreases to both 0.5 and 0.1 mM,
whereas GI neurons from RH rats were only activated by the maximal glucose decrease to 0.1
mM. AMPK activation (RH-AICAR) completely restored the response to 0.5 mM glucose. (B) The
data in (A) were quantied as the percent change in input resistance (IR) and membrane potential
(MP) in 0.5 mM glucose compared to that in 2.5 mM for each group. In GI neurons from
controls, decreasing glucose to 0.5 mM increased IR and MP by 25% and 8%, respectively.
However, in GI neurons from RH rats, the increase in IR and MP was signicantly reduced or
abolished. Treating the brain slices with AICAR completely restored the response to 0.5 mM
glucose. The data were analyzed by 1 way ANOVA followed by post hoc test. Different letters
represent statistically different groups (P<0.05). (Panel A: Control and RH traces and B: IR values
for control and RH reproduced with permission from Song Z, Routh VH. Recurrent hypoglycemia
reduces the glucose sensitivity of glucose-inhibited neurons in the ventromedial hypothalamus
nucleus (VMN). Am J Physiol Regul Integr Comp Physiol. 2006;291(5):R1283.).
Hypoglycemia Detection
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60
neurons innervating the medial hypothalamus, impairs or abolishes feeding (107), corticosterone (108), and adrenal medullary responses (107) to
both insulin-induced hypoglycemia and 2DG-induced blockade of glycolysis; it also abolishes the suppression of estrous cycles that are normally
induced by chronic glucoprivation (109, 110). DSAP does not impair daily
feeding or feeding stimulated by short-term (overnight) food deprivation
and does not impair feeding in response to mercaptoacetate (107), a drug
that inhibits fatty acid oxidation (111). The feeding deficit caused by the
lesion of hypothalamically projecting catecholamine neurons appears
to be selective for glucoprivic (or counter-regulatory) feeding. The characteristics of glucoprivic responses at the behavioral level provide strong
support for the nonintegrative nature of this control. That is, the hindbrain glucose-sensing neurons, unlike some hypothalamic glucosesensing neurons (42, 49, 112), may not be sensitive to availability of other
metabolic substrates. Glucoprivation stimulates feeding and other CRRs
even in the presence of elevated body adiposity (113), in satiated animals
and during chronic leptin administration (114). Feeding in response to 2DG
is blocked by glucose, but not by coadministration of intravenous fatty
acids (115).
Of the functionally and phenotypically heterogeneous population of
ascending catecholamine neurons, those required for glucoprivic feeding
appear to be those that coexpress NPY. Global deletion of the NPY gene
(Npy) impairs glucoprivic feeding (65, 116), whereas localized lesion of
arcuate neurons coexpressing NPY and agouti gene-related peptide (AgRP)
neurons does not (65, 113). Results using small interfering RNA (siRNA)
technology show that simultaneous (but not separate) silencing of Npy
and Dbh, localized to the area of A1/C1 overlap in the ventrolateral
medulla, reduced the glucoprivic feeding response to only 39% of the
intake of controls injected with nontargeted RNAs and did so without
impairing the feeding response to another metabolic stimulus, mercaptoacetate-induced blockade of fatty acid oxidation (117). These data, combined with the fact that the largest numbers of DBH-NPY coexpressing
neurons are located in the A1 and C1 cell groups in the ventrolateral
medulla, suggest that the latter NE and/or E neurons, rather than those
in the A2/C2 cell group in the dorsomedial medulla (ie, dorsal vagal
complex) are the primary mediators of counter-regulatory feeding. Other
data supporting this localization include the finding that phosphorylation of
AMPK, an energy-sensing mechanism, is increased in response to glucoprivation in A1/C1, but not significantly in the A2 area (23). Phosphorylation
of AMPK is not increased in the A1/C1 area of the hindbrain in rats in
which the catecholamine neurons have been eliminated by PVH injection
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elicited by many different stimuli and by multiple pathways, catecholamine neurons appear to elicit the CRH/corticosterone CRR to glucose
deficit.
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glucoprivation had long latency responses and were largely unmyelinated. More recent work by has shown that separate populations of neurons respond to systemic glucoprivation and to baroreceptive stimulation
and that each population can be manipulated to produce specific glucose
or blood pressure responses (131). Thus, it appears that the physiological
responses of the adrenal medulla are narrowly tuned and tightly controlled by anatomically and physiologically discrete central neurons
driven by distinct sensory signals.
Hindbrain E neurons with cell bodies in C1-C3 and spinal projections
to sympathetic preganglionic neurons of the IML control the adrenal
medullary response to glucoprivation. Selective retrograde destruction
of these bulbospinal E neurons by intraspinal injection of the targeted
toxin, DSAP, abolishes the elevation of plasma E, as well as the hyperglycemic and adrenal medullary c-Fos responses to glucoprivation (106,
107). In addition, Madden et al (132) reported that injection of DSAP
directly into the C1 cell group severely impaired the adrenal medullary
response to systemic glucoprivation, further suggesting that the effects
of intraspinal DSAP injection were not due to nonspecific spinal damage
(as indicated also by the normal response of the controls injected with
unconjugated saporin). Together, these findings indicate that bulbospinal E neurons are required for the adrenal medullary response to glucoprivation and that the C1 cell group is of particular importance for that
response.
It is important to recall that the hindbrain neurons responsible for glucoprivic stimulation of the adrenal medulla do not require forebrain input
for activation by this stimulus, as indicated by experiments in decerebrate
rats (133). Nevertheless, forebrain neurons may contribute to the function
of these hindbrain neurons in the intact animal. For example, these neurons may be a final common path for adrenal medullary control that can
also be activated by other inputs, such as the VMN.
64
A6
C3
C2
A7
A5
Feeding
Corticosterone response
Suppression of estrous cycles
C1
A2
A1
Adrenal medullary
response
Hypoglycemia Detection
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whereas the central and caudal sections of C1 contain neurons that participate in adrenal medullary and feeding responses to glucoprivation.
These features underline the necessity for detailed phenotyping and tracing of anatomical projections of catecholamine neurons for correct assessment of their individual functions.
One common feature of most NE and E neurons is that they are highly
collateralized and distribute their terminals widely throughout the brain
or spinal cord. This makes them well suited for the rapid and highly
orchestrated control of diverse autonomic, behavioral, cognitive, and neuroendocrine responses necessary for survival of glucose deficit. In addition,
catecholamine neurons both innervate orexin cell bodies and coinnervate
many of the same terminal sites as orexin neurons (136). Although the
functional significance of this innervation pattern for glucose counterregulation is uncertain, this pattern is consistent with emerging evidence
suggesting that orexin neurons link homeostatic requirements to appropriate arousal and activity levels (60). Similarly, there is direct interaction
between NPY/AgRP neurons and NE and E neurons, which heavily innervate them. It is accepted that NPY/AgRP neurons play a pivotal role in
integration of metabolic signals and control of daily feeding and energy
homeostasis (137), functions that serve to avert metabolic crisis. Activation of catecholamine neurons by glucoprivation induces expression
of Agrp and Npy (138, 139), an effect one would expect to enhance feeding and other features of these neurons that would be supportive of glucorestoration. The induction of Agrp and Npy by glucoprivation requires
input to AgRP and NPY neurons from hindbrain catecholamine neurons and does not occur in animals in which the catecholamine innervation has been destroyed by DSAP injection. Thus, while NPY/AgRP
neurons are not required for glucoprivic feeding, hyperglycemic or corticosterone responses, activation of their circuitry by hindbrain catecholamine neurons may serve to potentiate feeding or other responses of
importance during acute glucoprivation. In addition, in the PVN DSAPinjected rat, the expression of both Npy and Agrp appears to be chronically
enhanced under basal conditions (139), possibly indicating a role for
these neurons in adaptation to or compensation for the partial loss (ie,
loss of the ascending component) of the catecholamine counter-regulatory
system. This adaptation may confer increased survival potential. These
interconnecting circuits linking NE/E neurons with orexin and NPY/AgRP
neurons provide potential avenues for linking daily feeding and arousal
mechanisms with the circuitry required for hypoglycemia counterregulation.
66
Hypoglycemia Detection
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to the magnitude or temporal development of the glucoprivic challenge, as appears to be the case with the PMV system. Specifically with
respect to adrenal medullary secretion, a lesion of descending catecholaminergic projections to the sympathetic preganglionic neurons abolishes the response to systemic glucoprivation. This suggests that VMH
activation of this response may be mediated by projections to hindbrain
catecholamine neurons. However, it is important to note that decerebration studies have shown that the forebrain is not required for the adrenal
medullary response to hypoglycemia. Specifically with respect to glucagon secretion, the authors have not found that DSAP injections reduce
systemic 2DG-induced glucagon secretion (S Ritter, 2012, unpublished
data). Although the direct effects on glucagon secretion of glucose and
insulin within the pancreas itself may obscure a diminished central effect
in an experiment of this type, these data also may indicate that the VMH
plays a predominant role in central control of glucagon secretion. Finally,
perhaps hindbrain and hypothalamic sites are differentially recruited for the
adrenal E response based on the overall energy needs of the body. For
example, the satiety hormones, leptin and insulin, mask the ability of
VMH GI and GE neurons, respectively, to respond to glucose deficit,
whereas fasting enhances activation of GI neurons by decreased glucose,
in part due to decreased leptin levels (40, 140). Thus one might speculate
that under normal energy balance, hindbrain catecholamine neurons
are dominant with regard to the adrenal E response. However, during
energy deficit, the VMH glucose sensors may be recruited to amplify the
response, potentially via projections to hindbrain catecholamine neurons.
This hierarchical activation for distinct central and peripheral glucose
sensors will be considered in more detail in the conclusion section of this
review. It will be important in future work to confront these apparent
discrepancies and to design incisive experiments to resolve them.
68
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70
portal vein was first reported by Hevener et al (20). By advancing the tip
of the portal cannula adjacent to the liver, they were able to selectively
elevate liver glycemia while maintaining the portal vein hypoglycemic.
When this occurred, there was no effect on the sympathoadrenal response
to hypoglycemia. Only when both the portal vein and liver were normalized, did they observe suppression of the sympathoadrenal response, as
reported earlier. This observation was confirmed when they demonstrated
that normalizing liver glycemia via the hepatic artery during systemic
hypoglycemia had no impact on the CRR (161). Consistent with a portal vein locus for hypoglycemic detection, several studies have demonstrated that selective denervation of the portal vein results in a suppressed
response to insulin-induced hypoglycemia (12, 154, 155). The findings of
Saberi et al (12) extended the locus to include the superior mesenteric
vein. While denervating the portal vein alone was shown to suppress the
adrenal E response by 61%, extending the denervation to include both the
portal and superior mesenteric vein led to 91% suppression. For adrenal
NE, portal-mesenteric denervation not only led to significantly greater
suppression when compared to portal vein denervation alone, it effectively
eliminated the slow-onset response to hypoglycemia. That the hypoglycemic sensing locus includes both the portal and superior mesenteric vein is
not surprising given that they are only distinguished by a single tributary
(ie, the gastrosplenic vein) and demonstrate similar rich innervation by
calcitonin gene-related peptide (CGRP) reactive nerve fibers (12).
Hypoglycemia Detection
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sectioning the hepatic vagus nerve, the purported axis by which portal
vein glucose sensory information reaches the CNS, had no impact on the
sympathoadrenal response to hypoglycemia. Even when all vagal transmission below the diaphragm was eliminated via bilateral subdiaphragmatic vagotomy, the sympathoadrenal response to hypoglycemia remained
fully intact (167). That the glucose sensitive vagal afferents are not
involved in hypoglycemic detection is perhaps not surprising given their
linear response over a wide range of portal vein glucose values (ie, 0
to 28 mM). Increasing portal glucose values from 0 to 28 mM led to a
maximal suppression in hepatic vagal afferent firing rates of 23% to 87%
(148, 162). Extrapolating these findings to glucose concentrations that
define the transition from low euglycemia to deep hypoglycemia (ie, 4.0
to 2.5 mM), the projected increase in firing rate is only 2% to 6% across
the entire range. This modest change in firing rate is inconsistent with the
abrupt and substantial activation of sympathoadrenal output over the
same range of glucose values, leading to a 30-fold increase in plasma E.
While most investigators have focused on vagal glucose sensitive afferents, an earlier report by Schmitt (168) proposed the existence of spinal
glucose-sensitive afferents innervating the portahepatis. Based on the
observed firing rates for LH neurons responding to portal glucose infusion,
Schmitt demonstrated that both spinal transection at T5 and sectioning of
the splanchnic nerve were effective in eliminating the response to portal
glucose infusion, while sectioning both branches of the vagus failed to do
so. The portal vein is richly innervated by spinal afferents as denoted by
CGRP and substance P immunoreactivity (155, 160, 169), which are
largely eliminated by sectioning the celiac-superior mesenteric ganglion
(CSMG) or dorsal root rhizotomy at T8 to T13 (169, 170). Vagotomy, by
contrast, was ineffective in decreasing the content of either CGRP or substance P (SP) in the portal vein (169, 170). Sectioning the CSMG has also
been shown to induce marked blunting of the sympathoadrenal response
to hypoglycemia, indicative of a spinal origin for the portal vein glucose
sensors detecting hypoglycemia (167). Although some vagal afferents
originating from the celiac branch pass through the CSMG, this branching
occurs caudal to the subdiaphragmatic sectioning of the vagus nerve,
which was shown to have no effect on the sympathoadrenal response to
hypoglycemia. Topical application of capsaicin has been shown to substantially reduce CGRP reactivity in the portal vein and with it the ability
for hypoglycemic detection at the portal vein (12, 155). Capsaicin acts
through the transient receptor potential vanilloid receptor 1 (TRPV1)
receptor, which in the abdomen appears to be primarily associated with
spinal afferents, with little expression in vagal afferents (171). Thus,
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74
Translational Studies
The existence of portal-mesenteric glucose sensors has been confirmed in
several species (ie, rat, mouse, guinea pig, and dog), but attempts to confirm their existence in people have proven elusive. As with studies of the
brain, investigators are limited by ethical considerations in directly
accessing the portal-mesenteric vein of people. Several investigators have
attempted to circumvent this limitation by providing an oral glucose load
during a hyperinsulinemic-hypoglycemic clamp. Presumably, the oral
glucose load would work as a portal glucose infusion analogous to the
local irrigation approach. However, this oral glucose approach has yielded
inconsistent findings with reports of suppressed, elevated, and unaffected
CRR (179182). In the absence of portal vein glucose measurements,
explaining these differences remains largely speculative. What is clear is
that that most studies using this approach have demonstrated a sensory
response to the portal glucose load (180182). Further support for portalmesenteric glucose sensing in people derives from the work of Perseghin
et al (183), who reported that the CRR is diminished in people with denervated livers (ie, following liver transplantation). While much remains to
be done, the preponderance of evidence suggests that people, like all other
mammalian species studied to date, retain portal-mesenteric glucose sensors critical for hypoglycemic detection.
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Conclusion
In this review, the authors have presented what is known and some
of what is not known about the 3 primary glucose-sensing areas that
contribute to glucose counter-regulation. In doing so, the authors are
confronted with the fact that present data cannot fully explain how these
distinct glucose-sensing regions are activated, how they interact, or how
their functions are integrated to achieve and preserve glucose homeostasis. However, a very significant conclusion one can draw from analysis of
the specific CRRs discussed in this review is
A very signicant conclusion
that there are multiple glucose sensors that
one can draw from analysis of
operate under different physiological conthe specic CRRs discussed in
ditions. For example, both adrenal E and
this review is that there are
glucagon responses to glucoprivation are
multiple glucose sensors that
influenced by all 3 glucose-sensing regions
operate under different
discussed in this review, but it is apparent
physiological conditions.
that these multiple sites of control are not
equivalent. Rather, different sensors appear
to be activated to varying degrees as the threat posed by hypoglycemia to
the brain changes. When glucose levels decline slowly, the PMV is the
dominant system, with the brain playing a modulatory role. On the other
hand, as the rate of glucose decline increases, so may the relative contribution of the brain, such that, as shown by Saberi et al (12), at very
rapid rates of decline, it is the brain that claims the dominant role.
During rapid hypoglycemia, the hindbrain catecholamine neurons may
play a greater role than the VMN in adrenal E secretion, since ablating
these neurons abolishes the adrenal E response to hypoglycemia. In contrast, most studies indicate that while manipulations of the VMH reduce
or enhance adrenal E secretion by 50% or more, it is never completely
abolished. On the other hand, the VMN may be more important than the
hindbrain in the regulation of glucagon secretion. For example, preventing
increased GABA tone during HAAF may restore glucagon release during
hypoglycemia in diabetic rats in which the glucagon response was previously
considered to be irreversibly impaired even in the absence of HAAF (57).
These and other data point to a hierarchical organization of glucosesensing sites. The potential for hierarchical recruitment of different glucose-sensing areas would be energy-conserving, as glucose reserves would
be allocated judiciously as needed, rather than being wasted by premature
mobilization. Evidence has been reviewed that the PMV glucose sensors
are recruited during slow or modest declines in blood glucose. The fact that
the sensitivity of VMN receptors to glucose deficit appears to be dependent
76
on prior metabolic state is also consistent with a hierarchical organization. Contribution of the VMN to hypoglycemia-induced adrenal medullary secretion appears to be enhanced when overall body energy stores are
low. The evidence for this is that the satiety hormones, insulin and leptin,
profoundly reduce the ability of VMN GE and GI neurons, respectively, to
sense decreased glucose in vitro, whereas fasting significantly enhances
the response of VMN GI neurons to decreased glucose (40, 140). This
hierarchical recruitment of glucose sensors could potentially enhance
both glucagon and sympathoadrenal responses as hypoglycemia becomes
a greater threat to the brain. This hypothesis has not been examined thoroughly. However, it would be reasonable to assume that a system with a
higher threshold for activation by glucose deficit than hypothalamic or
peripheral systems, perhaps with selective sensitivity to glucose availability, and with the ability to elicit a multisystem CRR, such as that provided
by hindbrain catecholamine neurons, would be required to avert or
respond to rapidly developing and profound glucoprivation.
Finally, HAAF may be caused by impaired glucose sensing or by impaired
CRR effector mechanisms. There is strong evidence showing that VMN
glucose sensors become impaired during HAAF (48, 80). Manipulations
that enhance glucose-sensitive signaling pathways in the VMH are associated with enhanced sympathoadrenal and glucagon responses to hypoglycemia, both in the control situations and during HAAF (10, 74, 82, 184).
Antecedent hindbrain glucoprivation also impairs adrenal E and glucagon
secretion (S Ritter, 2012, unpublished data). Similarly, antecedent hypoglycemia localized to the PMV impairs the CRR to slow-onset hypoglycemia
(185). Thus, impaired glucose sensing by any of these 3 key glucosesensing systems is implicated in the development of HAAF. This strongly
suggests that as the circuitry and neuronal phenotypes of VMN, hindbrain
catecholamine, and PMV glucose sensors are more fully revealed, they
will become important therapeutic targets for prevention of HAAF during
intensive insulin therapy.
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3. Cerebral Adaptation to
Recurrent Hypoglycemia
Rory J. McCrimmon, MD, MBChB, FRCP
Glin z, PhD
Abstract
Despite significant technological and pharmacological advancements, insulin
replacement therapy fails to adequately replicate -cell function, so achieving
near-normal glucose levels in type 1 diabetes mellitus (T1D) and long-duration
type 2 diabetes mellitus (T2D) is problematic. In particular, intensive insulin
therapy is frequently accompanied by recurrent hypoglycemia, and this leads
in turn to impaired hypoglycemia awareness and a markedly increased risk of
more severe hypoglycemia. In this review, the authors discuss how the brain
responds to repeated hypoglycemia and how these adaptations may explain, at
least in part, the development of impaired glucose counter-regulation in diabetes. The authors will discuss potential mechanisms that may contribute to the
development of reduced counter-regulatory responses in individuals with T1D
and long-duration T2D, including alterations in glucose uptake or metabolism
by the brain, the use of alternate fuels, changes in hypothalamic activated protein kinase (AMPK) activity and neurotransmitter release, as well as the
role of regulators of the stress response such as opiates and urocortin. Finally,
the authors propose that defective counter-regulation may actually result from
the brain adapting to repeated hypoglycemia and that through preconditioning,
recurrent hypoglycemia is inducing hypoglycemia tolerance.
Introduction
Banting et al (1) provided one of the first descriptions of hypoglycemia when
he wrote that the patient, .may first complain of hunger, or more often
of a sense of weakness or fatigue and, especially if it is his first reaction,
he is conscious of some anxiety, or of what he calls nervousness, or he
may even show the signs of a definite neurosis with loss of emotional
Acknowledgements: The authors thank the postdoctoral fellows, postgraduate students, technical staff, and volunteers who contributed greatly to the research that underpins this review.
Hypoglycemia in Diabetes
Good glycemic control in both T1D (8) and T2D (9) diabetes reduces both
the incidence and progression of long-term microvascular complications.
However, outside of the clinical trial setting, it has been difficult to achieve
near-normalization of glucose levels in people with diabetes. In the Diabetes Control and Complications Trial for instance, less than 5% of subjects in the intensively treated arm maintained normal hemoglobin A1c
(HbA1c) levels (<6.1%, 43 mmol/mol), and the median HbA1c was
7.2% (55 mmol/mol), which is significantly above the nondiabetic range
(8). Normalizing glucose levels in T1D is challenging, because despite a
number of advances in insulin pharmacology and delivery systems, insulin therapy is still essentially a poor replacement for the healthy islet. At
the same time, even when euglycemia is achieved, it is difficult to do so
safely, because intensive insulin therapy results in a markedly increased
risk of severe hypoglycemia. Subjects who underwent intensive insulin
therapy overall had a threefold increased risk of severe hypoglycemia, and
90
this risk increased with tighter glycemic control (10). Similarly in the United
Kingdom Prospective Diabetes Study) of individuals with newly diagnosed
T2D, hypoglycemia became limiting in the intensive therapy arm over
time and as a result median HbA1c levels rose to 8.1% (65 mmol/mol),
a point at which microvascular complications are more likely to develop
(9). In both these trials, it became clear that aggressive management of
T1D with insulin or of T2D with sulphonylureas or insulin was associated
with a significantly increased risk of severe hypoglycemia.
It is now recognized that hypoglycemia in diabetes results from more
than just the inadequacies of modern insulin replacement therapy. In fact,
despite the introduction of insulin analogues, continuous glucose sensors,
and structured education programs, the overDespite the introduction of
all rates of severe hypoglycemia remain
insulin analogues, continuous
essentially unchanged over the last 20 years
glucose sensors, and structured
(11). The risk of severe hypoglycemia in
education programs, the overall
T1D and longer-duration T2D results from
rates of severe hypoglycemia
reduced physiological responses (counterremain essentially unchanged
regulatory deficiency) as well as reduced
over the last 20 years.
symptomatic responses to hypoglycemia
(impaired hypoglycemia awareness). Impaired
hypoglycemia awareness affects around 25% of people with T1D (12),
and when present along with significant deficiencies in the counterregulatory response, markedly increases the risk of severe hypoglycemia
and has limited the ability to achieve good glycemic control. Figure 3-1
illustrates the profound disturbance of glucose homeostasis seen in individuals with T1D despite the technological advances in insulin replacement therapy.
| 91
FIG 3-1. Approximate glucose thresholds for hormonal counter-regulation during insulin-induced
hypoglycemia in nondiabetic individuals (left of axis) and T1D (right of axis) patients who have
undergone intensive insulin therapy. In individuals with T1D, failure to suppress endogenous
insulin secretion, loss of alpha-cell glucagon secretion, and increased threshold (lower glucose)
for counter-regulatory hormone secretion markedly increase their risk of severe hypoglycemia.
increasing lipolysis in fat, and stimulating glycogenolysis and gluconeogenesis (15). Additional responses that are more important as initiators of the
adaptive response to hypoglycemia, but that do not appear to contribute
significantly to the acute response include growth hormone (GH) and
cortisol secretion, which occur below 3.8 mM (70 mg/dL) and 3.2 mM
(60 mg/dL) glucose, respectively (16, 17). These stimulate lipolysis, ketogenesis, and gluconeogenesis. For nondiabetic healthy individuals, the
counter-regulatory response has several fail safes (redundancy), meaning
that hypoglycemia is rarely experienced and only tends to occur during
starvation or ultraendurance sports.
Maintaining glucose homeostasis requires the integration of various
glucose-sensing (GS) systems in both the periphery and central nervous
system (CNS). Fluctuations in peripheral glucose are detected by GS
neurons in the oral cavity, gut, portal/mesenteric vein (PMV), and carotid
body (18). PMV neurons detect changes in blood glucose prior to entry
into the liver from the gut. This information is then relayed through the
vagus nerve and spinal cord to the hindbrain, and from there to higher
brain centers such as the hypothalamus (18). In addition, the hypothalamus, due to its location adjacent to the third ventricle and median eminence, may sample factors from peripheral circulation, including glucose
as well as hormones such as insulin and leptin. It is therefore likely that
within this network glucose and whole-body energy homeostasis are also
integrated, allowing the body to better maintain fuel supplies to essential
organs.
| 93
maintaining glucose, however, does mean that individuals with T1D are
very reliant on protective catecholaminergic responses to hypoglycemia.
94
| 95
Increased glycogen
content/ lactate
metabolism
Increased glucose
uptake/ utilization
Reduced AMPK
activation
Failure to suppress
GABA
Recurrent Hypoglycemia
Increased opioid
regulation of GS
neurons
Enhanced UCN3/ GC
mediated suppression
of GS neurons
Altered serotonin
FIG 3-2. Potential mechanisms through which recurrent hypoglycemia leads to defective glucose
sensing in key brain regions. Several mechanisms have been proposed that may contribute to the
development of defective glucose sensing following recurrent hypoglycemia. Generally, research
has focused on increased fuel metabolism or uptake, enhanced suppression of the stress
response, or altered neurotransmitter release. This list is not exhaustive, and other mechanisms
have also been proposed. Research has largely been conducted in animal studies, and a clear
picture of the molecular mechanisms that leads to defective glucose sensing has yet to emerge.
this area is at best mixed, and as yet, no clear explanation for this phenomenon has emerged (20).
96
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98
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100
Role of AMPK
AMPK is an ancient serine/threonine kinase that plays a critical role in
mediating cellular responses to energy deprivation (79). This makes it an
ideal candidate in any GS system. Certainly, loss of the alpha-2 isoform of
the catalytic subunit of AMPK leads to complete loss of GS capability in
pancreatic beta-cells (80), cultured hypothalamic GS neurons (81), and
hypothalamic proopiomelanocortin/agouti-related peptide POMC/AgRP
neurons (82). Direct pharmacological activation of AMPK, specifically in
| 101
nucleus (ARC) and encapsulating the VMH, where they surround the
glutamatergic neurons (88). Glutamate acts on NMDA, AMPA and kainate
receptors, which are also required for glucose counter-regulation (88), as
ablation of the vesicular glutamate transporter VGLUT2, causes fastinginduced hypoglycemia via defective glucagon secretion (88). This study
induced genetic loss of VGLUT2 in steroidogenic factor-1 (SF-1) neurons.
SF-1 neurons are essential for the development for the mediobasal hypothalamus and are a reasonably specific marker for the VMH. The exact functional
relationship between the GABAergic and glutamatergic neurons and how
this regulates the counter-regulatory response remain to be determined.
These rodent studies raised the possibility that blocking GABA-mediated
inhibition of the counter-regulatory response to hypoglycemia might restore
normal counter-regulatory responses. In a pilot study in healthy, nondiabetic human subjects, Smith and colleagues (89) examined the counterregulatory responses to acute hypoglycemia following the ingestion of
placebo or modafinil, an agent used in narcolepsy that reduces GABA
activity. They reported that autonomic symptom scores and heart rate
were significantly higher with modafinil, while deterioration in performance of 2 cognitive tasks (Stroop and reaction time) was reduced, but
that modafinil had no effect on the counter-regulatory responses to hypoglycemia. The mode of action of modafinil is unclear, however, and it may
act on a number of neurotransmitters. Modafinil also affects monoamine
release and may have been acting directly on sympathetic nerve terminals
and the adrenal gland to enhance catecholamine release. Another recent
study showed that antecedent pharmacologic activation of GABAA receptors with alprazolam blunts neuroendocrine and autonomic nervous system (ANS) responses during next-day hypoglycemia in healthy people
(90), providing support for a role of the GABAergic system in the regulation of the counter-regulatory response. However, the potential for GABA
modulation to amplify counter-regulatory responses to hypoglycemia has
not really been tested in human subjects, although given the importance
of GABA inhibition to many varied neural networks, it seems likely that
selective hypothalamic modulation would be required.
More recent evidence has also suggested that the monoamine neurotransmitter serotonin is involved in counter-regulatory responses. A recent
study in rats has shown that the selective serotonin reuptake inhibitor
(SSRI) sertraline augments epinephrine, norepinephrine, and glucagon
responses to hypoglycemia and prevents blunted epinephrine responses
following RH (91). Furthermore, studies in nondiabetic and T1D patients
have demonstrated a similar amplification of catecholamine responses
following SSRI treatment, although no change in glucagon secretion was
| 103
104
Role of Opioids
Opioids are important mediators of stress and increase during hypoglycemia (105, 106), exercise (107), and psychological stress (108). Studies by
Caprio et al demonstrated that naloxone treatment to block opioid receptors in people amplified the epinephrine and cortisol responses to hypoglycemia (106). More recently naloxone coinfusion in nondiabetic human
subjects during antecedent hypoglycemia was shown to prevent the development defective counter-regulatory responses. The mechanism by which
opioid receptor blockage prevents defects in glucose counter-regulation
are not known and could occur through a hypothalamic, pituitary, or
adrenal effect. In support of the former, naloxone was recently shown
to prevent the induction of mouse hypothalamic Pdk4 and Angptl4
transcripts by RH (109). These genes are thought to induce metabolic
switching from carbohydrate to fat metabolism (110), suggesting opioid
antagonism prevents this adaptation, leading to preserved counter-regulatory
responses for reasons discussed previously. Further research is required to
elucidate the mechanisms by which opioid antagonists prevent the development of defective counter-regulatory responses.
Hypoglycemia Tolerance
In considering the various mechanisms detailed previously (AMPK, glucocorticoids, RCH, UCN, metabolic switching) that may contribute at least
in part to the development of defective hypoglycemia counter-regulation,
| 105
it becomes apparent that many are critical means by which cells adapt
to physiological stressors. The depth (34), duration (35), and frequency
(33, 36) of antecedent hypoglycemia correlate with the magnitude
of the ensuing counter-regulatory deficit, and the defect resolves over
periods of up to 1 week if the hypoglycemic stimulus is not repeated
(37, 38). This is remarkably similar to the classical description of ischemic tolerance that develops in response to ischemic preconditioning
(111). Preconditioning to induce tolerance happens when a nondamaging stressful stimulus is presented to cells, tissues, or organisms to
promote a transient adaptive response so that injury resulting from
subsequent exposure to the harmful stimulus is reduced. Even without preconditioning, cells respond to stressful stimuli by mobilizing a
host of defense and counter-responses to mitigate injury and prevent
death, but adaptive preconditioning ensures the cell is better able to
survive the stress. The degree of ischemic tolerance is also dependent
on the intensity, duration, and frequency of the preconditioning stimulus (111); additionally, the degree of ischemic tolerance shows crosstolerance with other stressors (eg, exercise [112] and temperature ([113]),
and the effect reduces over time unless the preconditioning stimulus is
repeated (111). Thus, the parallels with the impact on glucose counterregulation of antecedent hypoglycemia are clear and support the
concept that this phenomenon (impaired hypoglycemia awareness)
represents a model of hypoglycemia tolerance (or stress habituation)
(Figure 3-3).
The obvious follow-on question is why should an adaptive response
designed to be neuroprotective increase an individuals susceptibility to
severe hypoglycemia? The likely answer is that it does not, but therapeutic hyperinsulinemia does. Therapeutic hyperinsulinemia suppresses
peripheral lipolysis and delivery of gluconeogenic substrates to the liver
and therefore reduces the supply of alternate substrates to the brain. At
the same time, the combination of unregulated hyperinsulinemia and
a hypoglycemia-specific defect in glucagon secretion ensures a more
rapid and severe hypoglycemia (Figure 3-3). Thus, in T1D, hypoglycemia
tolerance develops in the nonphysiological context of hyperinsulinemia,
which prevents appropriate counter-regulation and induces severe hypoglycemia, where at some point cellular defense mechanisms will be
overwhelmed, and cellular death can ensue. The development of reduced
counter-regulatory responses following repeated hypoglycemia can therefore be considered an adaptive response at a cellular level, but maladaptive for individuals with T1D because of their need for insulin replacement
therapy.
106
Therapeutic
Hyperinsulinaemia
Glucagon Defect
Hypoglycaemia
Stress
Starvation
Pre -conditioning
Alternate Fuels
Neuroprotective
Hypoglycaemia Tolerance
FIG 3-3. Development of hypoglycemia tolerance in response to repeated hypoglycemia.
Low glucose initiates 2 broad responses at a cellular and whole-systems level, namely stress
and starvation responses. These act to induce preconditioning and metabolic switching, the
net effect of which is to be neuroprotective, enabling cells/neurons to become more resilient
(tolerant) of subsequent hypoglycemia. However, in T1D, this adaptive response may be
viewed as maladaptive, because an absent glucagon counter-regulatory response, combined
with hyperinsulinemia, ensures that hypoglycemia develops rapidly and is much more severe.
| 107
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Introduction
Despite advances with modern therapies and technology, hypoglycemia
remains a common, unwanted and feared consequence of insulin and oral
insulin secretagogue treatment in diabetes (1, 2). In a recent study, nearly
50% of patients with long-standing type 1 diabetes (T1D) self-reported
episodes of severe hypoglycemia (defined as episodes requiring external
assistance (3) during a 9- to 12-month period. Even in those with type 2
diabetes (T2D), 25% with patients treated with insulin reported severe
hypoglycemia during the same period (4). In general, risk factors for hypoglycemia include hypoglycemia unawareness, long duration, type, and
treatment modality of diabetes. Individual episodes of hypoglycemia can
be precipitated by factors which lead to an absolute or relative excess of
insulin. In insulin-treated patients, aside from an imbalance between carbohydrate intake and insulin dosing, injection site anomalies and alcohol,
exercise, and activity are major etiological factors.
There are a number of mechanisms by which exercise may lead to hypoglycemia in the active patient with diabetes. For example, activity may
consume glucose/carbohydrate stores and increase insulin absorption
from injection sites. The effects of certain activities (eg, household chores,
working in the yard, or dog walking) may be underestimated by patients
who may not perceive these tasks as having a significant exercise effect
on glycemia. During higher intensity exercise, symptoms of hypoglycemia may be difficult to distinguish from the effects of exercise. Risk of
hypoglycemia during exercise is particularly heightened for those with
unawareness of hypoglycemia. As will be discussed, exercise and hypoglycemia unawareness may be interlinked.
Despite the presence of successful role models such as the swimmer
Gary Hall Jr, these challenges may make patients reluctant to consider
exercise despite the significant benefits, such as improved metabolic
control (glycemia, lipids, weight loss, and blood pressure) and improved
well-being (5, 6). Others may overcompensate, deliberately running blood
glucose levels high in an attempt to avoid hypoglycemia during activity.
However, hyperglycemia may interfere with sports performance and carry
broader implications for overall glycemic control where exercise is frequent. In addition, where this is done in an uncontrolled fashion, the
irony is that erratic glycemia may mean that hypoglycemia during or
after exercise is still problematic. In this chapter are discussed the physiological challenges of exercise in diabetes and also strategies for planning safely for exercise to try to minimize risk of hypoglycemia. The
authors have focused largely on T1D, where the challenges of finding
a balance are usually greater than in those not managed with insulin,
although similar principles may apply to patients with T2D managed with
insulin.
116
2. Reduce glucose uptake in peripheral tissues (by the previously mentioned hormones and mechanisms), also serving thereby to conserve
plasma glucose levels.
An additional, but important, mechanism in the defense against falling
plasma glucose is the increase in lipolytic substrate (free fatty acids and
glycerol) resultant on the previously mentioned neuroendocrine and ANS
actions. Free fatty acids can provide energy for hepatic glucose production
and reduce glucose uptake in muscle. Glycerol provides an important gluconeogenic substrate for glucose production during prolonged hypoglycemia. Taken together, it is estimated that lipolysis may provide up to 25%
of the defense against hypoglycemia (8).
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118
| 119
120
into the portal system from the healthy pancreas. Under situations of exercise, this reversed portal-systemic ratio may contribute further to the subnormal hepatic changes in response to exercise. Even where insulin dose
is altered, increased heat and blood flow to skin overlying muscle may
mean that subcutaneous insulin depots are absorbed, paradoxically increasing circulating insulin levels during activity.
| 121
responses tend to be lower during the night (23), and sleep interferes with
the ability to perceive hypoglycemia (24).
Intensity
VO2max (%)
Borg Scale
Light
2039
3554
1011
Moderate
4059
5569
1213
Hard
6084
7089
1416
Very hard
>85
>90
>17
| 123
124
if blood glucose values are higher than the range listed, patients should be
advised to bring down into target before starting exercise because of the
risk of the counter-regulatory hormonal responses to exercise exacerbating hyperglycemia. For similar reasons, patients should not exercise when
ketotic.
Regular blood glucose self-testing during activity, especially where a
new exercise regimen is being performed, is also prudent, perhaps every
30 minutes as a starting guide.
| 125
with this, although delays will remain between changing infusion rates and
alterations in circulating/tissue insulin, so that changes probably need to
be made 45 to 60 minutes in advance of activity.
Where there is a significant possibility of activity resulting in late hypoglycemia, background insulin and/or basal infusion rates for pump users
may need to be adjusted accordingly. With all of these approaches, the
drawbacks include making too little or great an adaptation, resulting in
hypoglycemia or hyperglycemia.
126
10-second sprint performed at the end of the exercise period also minimized the postexercise fall in blood glucose (29).
Drawbacks of this as an approach are that it may not always be practical, and patients still need to address late hypoglycemia occurring after
exercise rather than in the immediate postexercise period.
An Integrated Approach
Combining the described approaches may offer a pragmatic solution, at
least for starting advice for clinicians guiding their patients with T1D. For
example, low-intensity (510 on Borg scale) or moderate-intensity (1113
on Borg scale) activity for up to 20 minutes is best managed by ensuring
that starting glucose is in the high normal range and reducing quickacting insulin prior to exercise (if planned) or carbohydrate intake if
unplanned. More intense activity and/or combination activity and/or
prolonged low-intensity activity for longer than 60 minutes will probably
need a more intensive approach, potentially combining strategies detailed.
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128
| 129
Type 2 Diabetes
As earlier indicated, although the information provided is aimed at T1D,
the physiological principles of the effects of activity on blood glucose are
similar for those with T2D. Insulin-treated T2D patients can follow the
same approaches as detailed for T1D. Patients on sulfonylureas may be at
increased risk of hypoglycemia during activity and have no option to alter
therapy, so they will have to rely on carbohydrate intake and/or perhaps
maximal sprints to prevent hypoglycemia. Alternatively, the challenges of
managing diabetes during activity may mean that some patients prefer to
switch to insulin therapy. Although the risk of hypoglycemia is lower in
those using glucagon-like peptide 1 (GLP-1) analogues and dipeptidyl peptidase IV (DPPIV) inhibitors compared with sulfonylureas and insulin, these
patients are not necessarily immune from activity-induced hypoglycemia.
Summary
In summary, several clinical strategies exist to allow patients with insulintreated diabetes to overcome the inherent challenges of undertaking activity. Depending on the nature of activity or exercise, these may require
careful planning and a phased introduction, with monitoring of the effects
on blood glucose to ensure that activity is performed safely, minimizing
risk of hypoglycemia and/or hyperglycemia.
130
Scenario 2
A 27-year-old woman with a 12-year history of T1D says that she has been
struggling to manage her diabetes during exercise. She has been established on insulin pump therapy for 6 years. She has no evidence for any
| 131
Scenario 3
A 48-year-old man with a 15-year history of T2D treated over last 5 years
with twice-daily 30/70 biphasic insulin says that he has applied and been
offered a place in a marathon running to raise money for the American
Diabetes Association. He is a novice runner and has not taken part in any
organized sport since leaving high school but is keen to use this as an
opportunity to change permanently his lifestyle.
Q. How should he be managed?
A. Although this sounds, at face value, to be a welcome development,
one should carefully analyze the potential risks for him. Check that he
is not hypertensive and has no established cardiovascular disease or
unstable retinopathy. Additionally, one should ensure that he has good
foot care and reasonable glycemic control and no other significant medical problems.
In this case, there were no other issues, and the patient understood
the potential risks involved and the need to be careful and vigilant in
building up his fitness levels slowly. There are many tapering training
regimes available online and in print, and he should choose a conservative one and follow it carefully.
One should remind him about the need for careful foot care. He is
likely to find his diabetes difficult to manage on twice-daily insulin and
most experts would advise changing at least to a basal bolus regimen
with training in how to harness this for flexible insulin dosing including carbohydrate counting, correction values, and other issues. One
author (MLE) finds isophane insulin more useful than longer-acting background insulin because of the ability to alter more rapidly from training to nontraining days. If his health care coverage allows, some find
insulin pump therapy useful for the greater potential to alter insulin dosing, although this carries advantages and disadvantages as set out previously. For example, some distance runners find wearing an insulin pump
cumbersome.
Importantly, the patient is likely to have to adapt his approach, as running distances and time of exercise build up during the approach to a
marathon. There may be little need to alter a great deal as he starts his
training, but as the program progresses, he should expect to have to start
taking extra carbohydrates before training (with insulin, although not
necessarily a full dose as distances build up); during runs, especially once
these extend to an hour or more (perhaps 30 g per 30 minutes as a starting
guide); and after exercise with insulin to replenish glycogen stores, typically 60 to 120 g by the end of his training. Frequent self-monitoring of
| 133
blood glucose to gauge the effects of exercise and his management strategy is essential.
Assuming all goes well, by the race day he should have established how
he manages his diabetes during significant running, albeit submarathon
distances. A typical regimen for a marathon day might be a low glycemic
index (GI) carbohydrate meal 2 to 3 hours before running, with 25% to
50% of usual rapid insulin, aiming to start the race with a blood glucose
around 200 mg/dL. Maintaining hydration is critical, and regular carbohydrate intake (perhaps 30 g every 30 minutes) should take place through
the race. He will need a large carbohydrate meal after finishing (60 to 120 g)
with insulin and ideally a reduction in background insulin that night and
perhaps for the next 24 hours.
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Acknowledgements: The authors studies cited in the manuscript were supported by grants
HD47276 (Rao) and the Dana Foundation, DK064832, DK064832-06S1, DK064832-06S2,
P30 DK056341-11 and UL1 RR024992 (Hershey) from the National Institutes of Health.
FIG 5-1. Diffusion tensor image of healthy age- and gender-matched control (left) and case
(right). Note the difference in microstructural white matter in the splenium of the corpus
callosum (arrows).
138
authors provide a synthesis of the human and animal literature that begins
to unravel important aspects of these difficult questions.
| 139
mice between postnatal day (P) 1 and P14 are used to model the neurological effects of neonatal hypoglycemia (9, 10, 12, 14), while P21 to P28
rats are used to model the effects in young children (11, 15). The advantages of the rodent model are that the gross regional development of the
rodent brain is similar to people, and the human-equivalent developmental stages are known (1, 16) (Figure 5-2). Additionally, the rapid rate of
rodent brain development (adult level of maturity is reached at 2 months
FIG 5-2. Timetable of brain development in people (A) and rats (B). Note that energydemanding processes, such as synaptogenesis and myelination, are mostly postnatal events
in both species, making them potentially vulnerable during hypoglycemia.
140
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FIG 5-3. Compensatory changes and pathogenesis of neuronal injury in the developing brain
during acute hypoglycemia. (Abbreviations: AIF, apoptosis-inducing factor; CBF, cerebral
blood ow; NAD, nicotinamide adenine dinucleotide; NMDA, N-methyl-D-aspartate; PAR,
poly(ADP)ribose polymers; PARP-1, poly(ADP)polymerase-1; ROS, reactive oxygen species).
brain, although all the steps have yet to be established. The major factors
initiating neuronal injury during hypoglycemia are cerebral energy failure,
electroencephalogram isoelectricity, and release of glutamate and aspartate into the extracellular space (Figure 5-3) (17, 30, 31). Binding of these
amino acids to N-methyl-D-aspartate (NMDA) and non-NMDA receptors on
the postsynaptic neuron leads to influx of Ca2+ and altered intracellular
Ca2+ levels, production of reactive oxygen species, altered mitochondrial
permeability, membrane lipid peroxidation, poly(adenosine diphosphate
[ADP]-ribose)polymerase-1 overactivation, release of apoptosis-inducing
factor, and cell death (3235). Additionally, activation of adenosine A1
receptor contributes to neuronal injury (12), and this susceptibility
appears to be unique to the developing brain (12). In the mature brain,
glucose reperfusion and release of vesicular zinc are involved in the production of reactive oxygen species (3638). The involvement of these factors in the pathogenesis of neuronal injury in the developing brain has yet
to be established.
| 143
Age-Related Vulnerability
Is the developing brain more or less vulnerable than the mature brain? On
the one hand, human neonates are able to tolerate acute hypoglycemia
better than adults. Counter-regulatory hormonal changes and increased
cerebral blood flow occur at lower plasma glucose levels (approximately
1.6 mmol/L [30 mg/dL]) in newborn infants (44), as compared with older
children, where such effects are typically seen at a plasma glucose level of
3.6 to 3.9 mmol/L (65 to 70 mg/dL) (45, 46). Relative to the adult, neuronal injury during acute hypoglycemia is less severe in developing rats and
monkeys (9, 47, 48).
On the other hand, recurrent hypoglycemia may be more detrimental to
the developing brain than the mature brain. In persistent hyperinsulinemic hypoglycemia of infancy, the risk of neurodevelopmental deficits is
greater with neonatal onset of the condition, compared with later onset
(49). Whether this is a reflection of more
The developing brain is more
severe hypoglycemia with the former is not
resistant to injury than the
known. Similarly, early onset of hypoglycemature brain during acute
mia increases the risk of neurological defihypoglycemia. However, an
cits in children with T1DM (50). Recurrent
opposite effect is likely after
hypoglycemia in developing rats causes hiprecurrent hypoglycemia.
pocampal dysfunction during the immediate posthypoglycemia period (11), and
increased anxiety, fear-potentiated startle, stress reactivity, and decreased
social play in the long term (13, 51). Conversely, recurrent hypoglycemia in adult rats does not affect hippocampal function, either immediately or in the long term (52, 53), and may in fact, enhance neuronal
function during euglycemia (53) and protect the brain during subsequent hypoglycemia (54). Whether this is also true in people has yet
to be established.
The developmental stage of the brain (Figure 5-2) at the time of recurrent hypoglycemia may be responsible for the differing results during
development and adulthood. By causing frequent energy failure and glutamate depletion (10), recurrent hypoglycemia may irreversibly alter synaptogenesis and connectivity in the developing hippocampus and cerebral
cortex, similar to other postnatal conditions associated with altered energy
and glutamate metabolism in the brain (6, 7). While alternative substrates
may be able to temporarily support energy production during hypoglycemia, they are unable to support synthetic function. The brain weight, cellularity, and protein and myelin contents are decreased in developing rats
subjected to recurrent severe hypoglycemia (55).
144
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Transient Hypoglycemia
Developmental delay in gluconeogenesis and ketogenesis
Prematurity, small-for-gestation
Failure of metabolic adaptation at birth
Maternal drugs (eg, -blockers), birth asphyxia
Transient neonatal hyperinsulinism
Maternal diabetes mellitus, excess dextrose administration during labor,
Rh-isoimmunization, large-for-gestation, stress (eg, birth asphyxia, toxemia
of pregnancy, and sepsis)
Increased energy demand
Sepsis, cardiopulmonary disease, seizures, hypothermia
Drug-induced
Maternal drugs during gestation (eg, alcohol, -blockers, selective serotonin inhibitors,
ritodrine, and sulfonylurea)
Infant/child (eg, alcohol, propranolol, salicylates, sulfonylurea, quinine, quinolone, and
purine analogs)
Other conditions
Neonatal polycythemia, organ injury (eg, hepatic failure)
Persistent Hypoglycemia
Hyperinsulinism
Congenital (eg, autosomal-dominant and -recessive mutations in potassium-adenosine
triphosphate (ATP) channel, glucokinase, and glutamate dehydrogenase)
Insulin therapy for hyperglycemia (eg, T1DM and very low birth weight infants)
Syndromes (eg, Beckwith-Wiedemann syndrome)
Counter-regulatory hormone deciencies
Panhypopituitarism, growth hormone deciency, cortisol deciency, glucagon
deciency
Inborn errors of metabolism
Disorders of carbohydrate metabolism (eg, glycogen storage disease, galactosemia,
fructose-1-6-diphosphatase deciency)
Disorders of fatty acid oxidation and ketogenesis (eg, medium- and long-chain fatty acid
oxidation disorders)
Disorders of amino acid metabolism (eg, maple syrup urine disease and propionic
academia)
(61, 62) and avoids the radiation exposure of CT scan. Most published
studies are case reports in full-term infants with underlying risk factors
for hypoglycemia (Box 5-1) (6264). Infants in these studies had severe
hypoglycemia (typically plasma glucose <1.6 mmol/L [<30 mg/dL])
associated with symptoms, including seizures. Large case series that
include a control group report MRI changes in 33% to 94% of infants after
146
| 147
148
| 149
T1DM Controls
T1DM Controls
T1DM Controls
T1DM Controls
T1DM Controls
2009
2010
2011
2011
In press
Hershey69
Aye110
Perantie109
AntenorDorsey111
T1DM
2008
Ho70
Northam73
T1DM Controls
2007
Perantie72
Groups
Year
First
author
73 30
75 25
27 18
95 49
79 51
62
108 51
Retrospective
Prospective
Retrospective
Retrospective
Retrospective
Retrospective
Retrospective
Design
Analysis
TABLE 5-1. Structural Brain Imaging Findings Associated with Severe Hypoglycemia in youth with T1DM.
150
preterm infants did not find any association between recurrent hypoglycemia during the first 10 days of life and increased risk of neurodevelopmental deficits at 15 years of age (88).
Thus, there is continuing debate whether neonatal hypoglycemia causes
permanent brain injury, especially in the absence of other risk factors
(56). As mentioned previously, most of the studies are case reports without adequate control for comorbidities. Most were performed during an
era when screening for intraventricular hemorrhage or periventricular
leukomalacia was not routine. The two large, long-term studies in preterm
infants were secondary analyses of data collected for a different purpose
(80, 81). In their review, Boluyt et al (79) found that all but 2 of the 18
case-control studies were of poor methodologic quality. Additionally, the
lack of uniformity in subject population, definition and treatment of hypoglycemia, outcome measures, and length of follow-up precludes pooling
of data from these studies. Prospective studies using an optimal design
(79) are necessary to establish the relationship between neonatal hypoglycemia and neurodevelopment.
Postneonatal Period
The potential impact of severe hypoglycemia on cognitive function in
adults and children has been examined for decades. In adults and children,
small cross-sectional studies have found support for the hypothesis that
repeated severe hypoglycemia episodes are associated with lower cognitive function in several domains, including verbal memory and learning,
verbal fluency, visuospatial and visuomotor skills, short-term memory,
and response speed (8993). However, a large, multicenter prospective
study of adults did not find an association between severe hypoglycemia
and cognitive performance on various neuropsychological measures (94,
95). Nevertheless, since most participants were enrolled as adults and had
no previous severe hypoglycemic episodes, this work leaves open the question of how cognitive function is affected by severe hypoglycemia experienced during brain development.
Studies focusing exclusively on children with T1DM have attempted to
fill this gap. In general, the cross-sectional, retrospective studies find that
a higher rate of severe hypoglycemic exposure is associated with poorer
cognitive function, particularly memory and attention, even when controlling for age of onset and hyperglycemia exposure (96102). The most
influential work in this area comes from Elizabeth Northams group in
Australia, which has served to reinforce the findings from these smaller
studies and also clarified some important additional issues for the field
(97, 103105). They assessed a large sample of newly diagnosed children
| 151
with T1DM and followed this cohort and their community controls over
12 years. Importantly, at diagnosis, children with T1DM did not perform
differently than their control group on any cognitive test (104). However,
after 2 years of diabetes, the T1DM group performed worse than controls
on IQ, measures of verbal learning, and speed of processing. Severe hypoglycemia exposure over those 2 years was related to lower memory performance (97, 104). After 6 years of diabetes, groups were still different, and
severe hypoglycemic exposure was related to IQ scores (105). The most
recent analysis from this group reported on differences in cognitive function
after 12 years of diabetes (106). In this analysis, severe hypoglycemia exposure was related to working memory, speed of processing, and verbal skills.
An important caveat to these findings is that the test battery given has had
to change over time, and thus, the analyses presented are necessarily
cross-sectional, and do not reflect within-subject change. In addition, the
data have not been analyzed with respect to the timing of hypoglycemia
exposure during development. Nonetheless, this study has had a significant
impact on the field and suggests that cognitive risks may be associated with
diabetes, hyperglycemia, and hypoglycemia exposure during childhood.
After decades of research of this kind, the field has now progressed
to the point where meta-analyses can be performed. Two meta-analyses
have been published, one of which focuses explicitly on the effect of
severe hypoglycemia on cognitive function during childhood (107). The
other addresses the issue of cognitive function in children with diabetes
more generally (108). Blasetti et al (107) looked at over 1000 children with
T1DM from 12 studies and compared T1DM with and without a history of
severe hypoglycemia. Their analyses found a medium effect size for the
relationship between severe hypoglycemia and lower memory performance.
The analysis also noted small-to-medium effect sizes for learning, intelligence, and verbal tasks. Limitations to this analysis are the same as those
for the individual studies that it relies upon: differing definitions of severe
hypoglycemia, limited information on clinical characteristics of the hypoglycemic events, differing sensitivity and specificity of tasks, failure to
fully account for age of onset or timing of hypoglycemia, and the inherent
limitations of retrospective, cross-sectional designs. In comparison, the
Guadieri meta-analysis (108) examined over 1000 children with T1DM
and approximately, 750 nondiabetic controls from 19 studies (many
of which naturally overlap with the studies in Blasettis analysis). They
found strong effects of early age of onset on learning and memory, attention, and executive function. Their assessment of severe hypoglycemia
was limited to those events that included seizures, and they found only
very small and inconsistent effects. However, their analyses could not
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2.
3.
E. Dead-in-bed syndrome in
persons with type 1 diabetes
mellitus is hypothesized to
result from hypoglycemic
cerebral damage
Prevention and Management of
Hypoglycemia in the Active
Patient With Diabetes
4.
5.
6.
CME Answers: 1, C; 2, A; 3, D; 4, D; 5, B; 6, E.
164