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Diabetes Spectrum
Volume 10 Number 1, 1997, Pages 33-38

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In Brief
The stepped hypoglycemic clamp technique has provided a powerful tool
to examine factors that influence how individuals recognize and respond
to hypoglycemia. The method has been used to define the defects in
counterregulatory hormone response induced by intensive treatment of
type I diabetes. The importance of the brain in coordinating such
counterregulatory responses and the impact of intensive treatment on
brain metabolism and function are discussed.

The Brain and Hypoglycemic Counterregulation: Insights From


Hypoglycemic Clamp Studies
Walter P. Borg, MD
Monica A. Borg, MD
William V. Tamborlane, MD

The results of the Diabetes Control and Complication Trial (DCCT) put to rest the longstanding debate
over whether intensive insulin therapy can delay the development of late microvascular and neuropathic
complications of diabetes.1 The benefits of intensive insulin therapy aimed at near-normalization of
glucose levels in type I diabetes have been established, and, as a result, this therapeutic approach has
been recommended as the treatment of choice for most patients with type I diabetes.2 Unfortunately, the
frequency and severity of hypoglycemia is markedly increased by intensive treatment regimens, in spite
of close medical supervision. The DCCT reported a threefold higher incidence of severe hypoglycemia
and coma in those patients assigned to intensified therapy as compared to conventionally-treated
controls.1,3

In the past, iatrogenic hypoglycemia in patients with diabetes was attributed to the so-called
"conventional risk factors," such as excessive or inappropriately timed insulin doses, skipped meals or
snacks, and excessive exercise. However, analysis of the epidemiology of hypoglycemic episodes has
demonstrated that these conventional risk factors are responsible for only a minority of cases.3 It is now

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appreciated that diabetes mellitus is a disease characterized not only by absolute or relative insulin
deficiency, but also by the impairment of hormonal responses that counteract insulin-induced
hypoglycemia. This discovery has renewed interest in the physiology of counterregulation in general
and in the role of central nervous system (CNS) glucose sensors in particular. It has been hoped that in-
depth characterization of the effects of diabetes and its treatment on counterregulatory mechanisms will
eventually lead to strategies or interventions that would eliminate this major obstacle to the benefits of
intensive insulin therapy.

Defective Glucose Counterregulation


in Type I Diabetes
In subjects without diabetes, the earliest and most important response to a fall in blood glucose level is
the suppression of endogenous insulin secretion. In individuals with diabetes who are treated with
exogenous insulin, there is no feedback suppression of plasma insulin levels, and in the presence of
insulin autoantibodies, the hypoglycemic effect of insulin may be prolonged and may impair recovery
from hypoglycemia.4In those without diabetes, if suppression of insulin secretion is insufficient to
stabilize glucose levels, glucagon and epinephrine are the key counterregulatory hormones that
counteract the fall in blood glucose.5 However, just as diabetes destroys the ability of the pancreatic ß-
cell to secrete insulin in response to hyperglycemia, the ability of the a-cell to secrete glucagon in
response to hypoglycemia is lost in many patients with established type I diabetes.6 By contrast,
glucagon responses to other secretagogues, such as amino acids, are unaffected or even increased in
patients with diabetes.

In the absence of a glucagon response, epinephrine becomes the most important hormone for promoting
glucose recovery. Activation of the autonomic nervous system, including stimulation of epinephrine
secretion, serves to alert patients to falling blood glucose levels by inducing the classical warning
symptoms and signs: pounding heart, tremors, hunger, and sweating. In individuals without diabetes,
epinephrine responses alone are sufficient to promote recovery from hypoglycemia, even when
glucagon secretion is blocked by agents such as somatostatin. Unfortunately, diabetes also adversely
affects this line of defense against hypoglycemia. Although deficient epinephrine responses are
commonly observed in long-standing diabetes, this impairment is not simply a consequence of aging.
The epinephrine response to hypoglycemia is similar in healthy elderly subjects and in young adults
without diabetes.7

It has long been recognized that the degree of diabetes control strongly influences how patients
recognize and respond to reductions in plasma glucose levels. Indeed, in his Nobel Lecture delivered in
Stockholm on September 15, 1925, Frederick G. Banting noted that:

"The onset of hypoglycemic symptoms depends not only on the extent, but also on the rapidity, of fall
in blood sugar. The level at which symptoms occur is slightly higher in the diabetic with marked
hyperglycemia than in a patient whose blood sugar is normal. When the blood sugar is suddenly
reduced from a high level, premonitory symptoms may occur with a blood sugar between the normal
levels of 0.100% and 0.080%, while the more marked symptoms of prostration, perspiration, and
incoordination develop between 0.080% and 0.042%. As a patient becomes accustomed to a normal

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blood sugar, the threshold of these reactions becomes lower. One patient who formerly had premonitory
symptoms of hypoglycemia at 0.096% now has no reaction at 0.076%, but symptoms commence
between this level and 0.062%."

With the advent of the insulin pump and multiple injection therapy in the late 1970s and early ’80s, it
became apparent that even lower plasma glucose levels were required to induce hypoglycemic
symptoms in well-controlled, intensively-treated patients with type I diabetes, suggesting that the
threshold for release of epinephrine had been lowered to subnormal values.

Hypoglycemic Clamp Technique


One of the major obstacles in studying counterregulatory hormone responses to hypoglycemia was the
lack of methods that would allow investigators to produce a controlled and reproducible hypoglycemic
stimulus in vivo. Interpretation of the studies in which hypoglycemia was induced by large bolus
injections or continuous infusions of insulin was difficult because of the variations in the rate and the
magnitude of the glucose decline between subjects and in the same subjects studied under different
conditions. To overcome these obstacles, the glucose clamp was modified to provide a standardized
hypoglycemic stimulus in which the rate and magnitude of glucose fall were under the control of the
investigator. With this technique, subjects are studied in the fasting state, and separate intravenous
catheters are inserted for infusion of exogenous glucose and insulin and for obtaining sequential blood
samples. Generally, a fixed rate of insulin is administered in a dose sufficient to obtain the desired
degree of hypoglycemia, and exogenous glucose is infused at a variable rate to control the rate and
degree of fall of plasma glucose. The rate of glucose infusion is adjusted every 5 minutes based on
plasma glucose measurements made at the bedside, and the plasma glucose level is allowed to fall in
one or more steps over several minutes or several hours.

The hypoglycemic clamp technique was initially used in our laboratory to test the hypothesis, proposed
by Banting above, that the rate of glucose decline influences counterregulatory hormone responses to
hypoglycemia in normal subjects and conventionally treated subjects with diabetes.8 In one group of
experiments, plasma glucose was reduced gradually from approximately 90 to 50 mg/dl (4.4 to 2.8 mM)
in 10 mg/dl (0.5 mM) steps over 2 hours. In the other experiment, euglycemia was maintained for 2
hours and then plasma glucose was acutely lowered in one step from 90 to 50 mg/dl over 10–15
minutes. Despite the marked differences in the rate at which plasma glucose declined, no significant
differences were detected in the magnitude of the elevations of any of the counterregulatory hormones
in either healthy volunteers or conventionally-treated subjects with diabetes.8 However, the plasma
glucose level that triggered the release of epinephrine (determined from the study when plasma glucose
was reduced slowly) varied widely between subjects (range: 48–74 mg/dl, or 3.0–4.1 mM). These
observations suggested that individual variations in the glucose thresholds for epinephrine release might
contribute to differences in the plasma glucose levels associated with hypoglycemic symptoms, as
Banting had also indicated.

In two subsequent separate studies, single-step and multiple-step hypoglycemic clamps were used to
examine prospectively the effects of strict glycemic control on epinephrine responses to
hypoglycemia.9,10 In these studies, the magnitude of the epinephrine response to identical reductions in

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plasma glucose was reduced by 50–60% in the patients with type I diabetes after achieving near-normal
glycosylated hemoglobin values with continuous subcutaneous insulin infusion, reaching levels that
were significantly below those in healthy controls. Epinephrine release was impaired after intensive
therapy irrespective of whether glucose was lowered rapidly in one step from 90 to 50 mg/dl9 or
gradually in several steps over 4 hours.10 Indeed, in the latter study, impaired epinephrine release was
shown to be due to a downward shift in the glucose level, which triggered the release of
epinephrine.10Delayed release of other counterregulatory hormones (cortisol, growth hormone, and
norepinephrine) was also observed with intensive insulin treatment, and defective glucagon responses
were not restored. As might be expected from these results, a greater hypoglycemic stimulus was
required to elicit signs and symptoms of hypoglycemia when patients were strictly controlled.10

Because defects in epinephrine release developed after only 2–6 months of intensive therapy in healthy
young patients with diabetes who did not have clinical autonomic neuropathy, it was likely that the
impairment was due to acclimatization to lower ambient glucose concentrations during intensive
management rather than being caused by some other confounding variable. A similar defect in
counterregulatory hormone release was subsequently observed in chronically hypoglycemic insulinoma
patients and in women with diabetes who were aggressively treated during pregnancy.11-12

Further clamp studies have demonstrated that a number of other factors besides the degree of metabolic
control of diabetes influence the glucose threshold for counterregulatory hormone responses (Table
1).13 It is particularly noteworthy that adolescents with and without diabetes have early and exaggerated
epinephrine responses compared to those in adults.14 Never-the-less, in the DCCT,3 being an adolescent
was the only other independent risk factor for the development of severe hypoglycemia besides low
HbA1c level. The large doses of insulin that are typically required in adolescent patients and
irregularities in diet and exercise undoubtedly contributed to the greater frequency of severe
hypoglycemia in this group in the DCCT, even though enhanced counterregulatory responses should
have protected adolescents from hypoglycemia.

Table 1. Factors Influencing


Onset and Magnitude of
Epinephrine Release During
Hypoglycemia

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Early or exaggerated

Poor diabetes control


Children and adolescents
Male Sex
Caffeine

Delayed or reduced

Strict diabetes control with


recurrent hypoglycemia
Prolonged disease duration
Female sex
High-dose insulin infusion

No effect

Insulin species (human or


pork)
Rate of glucose fall

Awareness of Symptoms
Related to Hypoglycemia
Ten or fifteen years ago, hypoglycemic symptoms were broadly divided into early "adrenergic" warning
symptoms and later neuroglycopenic symptoms, if plasma glucose levels continued to fall. By
combining the stepped hypoglycemic clamp with more careful scoring of hypoglycemia-related
symptoms, new insights have been obtained regarding the hormonal and physiological changes
responsible for symptom awareness in subjects with and without diabetes. In subjects without diabetes,
Schwartz and colleagues15 showed that the glycemic threshold for an increase in symptom scores was
53 ± 2 mg/dl (2.9 ± 0.1 mM), significantly lower than the glucose threshold for increases in plasma
epinephrine levels (68 ± 2 mg/dl, or 3.8 ± 0.1 mM). In contrast, in adults with poorly-controlled type I
diabetes, the glycemic threshold for symptoms of hypoglycemia (77 ± 6 mg/dl, or 4.3 ± 0.3 mM) was
higher than that for release of epinephrine,16 suggesting that adults with poorly-controlled diabetes are
able to perceive low blood glucose levels before the adrenergic response is triggered.

Towler and associates17 quantified hypoglycemia-related symptom scores in young adult volunteers
without diabetes under four conditions: 1) clamped euglycemia, 2) clamped hypoglycemia, 3) clamped
hypoglycemia with combined a- and ß-adrenergic blockade, i.e., simultaneous administration of
phentolamine and propranolol, and 4) clamped hypoglycemia with panautonomic adrenergic and
cholinergic blockade with phentolamine, propranolol, and atropine. Subjects’ response to the question

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of overall awareness of hypoglycemia (i.e., blood glucose low) did not change during euglycemia but
did increase during hypoglycemia. Symptom scores that declined significantly during adrenergic
blockade included shaky/tremulous, heart pounding, and nervous/anxious, whereas symptoms of being
sweaty, hungry, and tingling did not change. This indicated that they were cholinergic.
Neuroglycopenic symptoms, i.e., those produced by hypoglycemia but not reduced by panautonomic
blockade, included feeling warm or weak, difficulty thinking/confused, and tired/drowsy. The authors
concluded that cholinergic mechanisms mediate an important and previously uncharacterized
component of the symptoms of hypoglycemia and awareness of hypoglycemia.

Kerr and associates used the clamp technique in a different way to examine individual components of
the hypoglycemia-related symptom complex.18 They compared symptom scores in 10 healthy
volunteers during a hypoglycemic clamp with symptom scores in volunteers during a euglycemic clamp
combined with exogenous infusion of epinephrine, norepinephrine, cortisol, glucagon, and growth
hormone to mimic the plasma hormone profile observed during the hypoglycemic clamp. Although the
hormone infusion caused adrenergic symptoms to increase, as they did during the hypoglycemic clamp,
hunger, sweating, and "feeling low" did not increase. This suggested that these symptoms are specific to
hypoglycemia per se and are not the hormonal action of epinephrine.

Studies examining changes in circulating hormone concentrations during hypoglycemia have


emphasized the importance of adrenomedullary rather than central sympathetic stimulation, since
increments in plasma epinephrine during hypoglycemia greatly exceed those of norepinephrine. A very
different picture emerges, however, when changes in local concentrations of epinephrine and
norepinephrine in peripheral tissues are measured. Maggs and colleagues recently accomplished this by
combining the stepped hypoglycemic clamp with microdialysis techniques to estimate changes in
catecholamine levels in adipose and muscle extracellular fluid during baseline, hyperinsulinemic
euglycemia, and hypoglycemic conditions.19 As expected, plasma catecholamines (unchanged during
euglycemia) rose during hypoglycemia, with plasma epinephrine levels increasing about fivefold more
than plasma norepinephrine levels. In contrast, at the local tissue level, the hypoglycemia-induced
increments in muscle dialysate norepinephrine and epinephrine were nearly identical, suggesting local
generation of norepinephrine. Thus, central sympathetic activation, as manifested by local
norepinephrine release from the sympathetic nerve endings, may play a more important role in
hypoglycemic counterregulation than previously thought.

The Brain and Defective Counterregulation


The hypoglycemic clamp technique has also been used to show that delayed and reduced
counterregulatory hormone responses to hypoglycemia induced by intensive treatment may be due to
iatrogenic hypoglycemia per se. In healthy subjects and in type I diabetes patients, a brief period of
moderate antecedent hypoglycemia reduces hormonal responses and symptoms of hypoglycemia during
experimentally induced hypoglycemia on the following day.20 This sequence of events has been called
iatrogenic hypoglycemia-associated autonomic failure,21 and more recent evidence implicates adaptive
alterations in brain glucose transport or metabolism as its pathophysiological basis.

Since the brain is almost exclusively dependent on circulating glucose for its energy needs,22profound

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hypoglycemia may cause coma, permanent brain damage,23-26 or even death.27-28 It is not surprising,
therefore, that the brain would play an important role in hypoglycemia detection and counterregulation
in order to protect itself.29-31 For example, animal studies have shown that maintenance of normal
cerebral glucose levels by infusion of glucose into the carotid and vertebral arteries during systemic
hypoglycemia markedly reduces the counterregulatory hormone responses observed when CNS, as well
as systemic, glucose concentrations were reduced.32 Hence, it has been hypothesized that the lower
glucose threshold for counterregulatory hormone release caused by recurrent hypoglycemia in type I
diabetes is due to a reciprocal increase in glucose transport across the blood-brain barrier. In non-
diabetic rats, recurrent hypoglycemia increases the efficiency of glucose extraction by the brain33-35 and
also is able to induce defects in counterregulatory hormone responses to hypoglycemia that are
comparable to those in intensively-treated patients with diabetes.36

Boyle and associates used the hypoglycemic glucose clamp in combination with measurements of
cerebral blood flow and brain arteriovenous differences to examine these issues in human subjects. In
volunteers without diabetes, they demonstrated that recurrent insulin-induced hypoglycemia for more
than 56 hours leads to adaptations that allow maintenance of normal brain glucose uptake and induces
defects in counterregulatory responses during mild hypoglycemia. 37Using the same techniques, they
subsequently showed that patients with type I diabetes who have nearly normal glycosylated
hemoglobin values maintain normal glucose uptake in the brain during hypoglycemia. In turn, such
preservation of normal cerebral metabolism may reduce counterregulatory hormone responses and
cause unawareness of hypoglycemia.38

It should also be noted that transport and metabolism of glucose may not be the only brain substrate
affected by diabetes. Studies that have combined clamps with microdialysis techniques have reported
strikingly high concentrations of lactate39 in brain extracellular fluid during hypoglycemia.

Episodes of severe hypoglycemia in children are often followed by reversible unilateral neurological
deficits. It has been proposed that hypoglycemia per se may result in the disturbance of the cerebral
blood flow sufficient to result in transient focal ischemia. To address this issue, Jarjour and colleagues
investigated the effect of mild hypoglycemia on regional cerebral blood flow and cerebrovascular
resistance in right-handed children with type I diabetes, using the intravenous xenon-133 clearance
method.40These results showed that cerebral gray matter blood flow was significantly higher in the
right hemisphere compared to the left during hypoglycemia but not at baseline euglycemia. Such
asymmetrical cerebral blood flow changes may explain the frequent laterality of neurological deficits
after severe hypoglycemia.

Role of the Ventromedial Hypothalamus


The importance of the CNS in hypoglycemic detection and counterregulation has generated interest in
determining the precise location of such glucose sensors in the brain. While various nuclei have been
implicated, data from animal studies suggest that counterregulatory responses during hypoglycemia are
activated, at least in part, via the hypothalamus.41-43 It has been frequently suggested that the
ventromedial hypothalamus (VMH),29 known as a regulator of food intake ("satiety center"),44-45

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contains glucosensitive tissues that could mediate the responses to hypoglycemia.46-47

This hypothesis was based primarily on the observations that injections of 2-deoxy-glucose into the
third ventricle caused hyperglycemia.45 Initially, the VMH was considered a sympathetic center,
controlling mainly catecholamine secretion in response to hypoglycemia.41,48 Glucagon responses were
thought to be triggered by intraislet rather than CNS mechanisms.49,50 It has been demonstrated,
however, that electric stimulation of the VMH caused an increase in plasma glucagon levels.29,51,52
Although these studies did not directly address the role of the VMH during hypoglycemia they
suggested that the VMH could serve as a key center for the activation of hypoglycemic
counterregulation.

Our studies have further established the VMH as a dominant center for sensing of glucopenia. In rats,
focal lesioning of the VMH abolishes hormonal response to systemic hypoglycemia.53 Moreover,
production of local neuroglycopenia by perfusion of 2-deoxy-glucose directly into the VMH of awake
rats triggers the release of counterregulatory hormones in the absence of systemic hypoglycemia.54
Conversely, hormonal responses to systemic hypoglycemia could be suppressed by maintaining normal
glucose concentrations in the VMH by glucose infusions via stereotaxically placed microdialysis
probes.55 Selective prevention of hypoglycemia in the VMH, but not in the remainder of the CNS or
elsewhere, blocked catecholamine and glucagon responses, thus providing strong evidence for these
hypothalamic glucoreceptors. Since preliminary results indicate that counterregulatory hormone
responses to systemic hypoglycemia can also be blocked by infusion of lactate into the VMH, the VMH
may act as a fuel sensor rather than being only a glucose sensor.56

Brain Function and


Recurrent Hypoglycemia
The hypoglycemic clamp has also permitted investigators to examine whether intensive insulin therapy
influences the ability of the brain to function in the face of mild to moderate hypoglycemia. This is of
paramount clinical importance since adaptive increases in brain glucose transport induced by recurrent
mild hypoglycemia could result in a favorable down-shifting of the glucose level at which brain
function becomes impaired.

This issue is controversial, since it has been reported that intensively-treated type I diabetes patients are
more, rather than less, vulnerable to neuroglycopenia than poorly controlled counterparts, when
conventional electroencephalographic (EEG) recordings are used as an endpoint.57 Other studies using
neuropsychological tests to assess cognitive performance during hypoglycemia in type I diabetes
patients have found no change58,59 or a lowering of the plasma glucose level required to provoke
cognitive dysfunction in patients treated intensively.60-62 It should be emphasized that the various tests
of cognitive function used in these studies are likely to assess different brain regions, which may have
different glucose requirements.

In a recent study from our laboratory, brain function was assessed electrophysiologically by measuring
cortical auditory evoked potentials. The P300 waveform, unlike the EEG, which measures the

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spontaneous electrical output of the brain, is generated by the active cognitive processing of stimulus
information. It is referred to as the P300 potential because the peak amplitude normally occurs about
300 milliseconds after the sensory stimulus. It requires the active participation of the subject and
involves higher brain centers, particularly the hippocampus and the parahippocampal gyrus.63

We have compared P300 responses to hypoglycemia in intensively-treated versus conventionally-


treated type I diabetes patients and healthy subjects during stepped hypoglycemia. As expected, glucose
levels triggering hormonal responses and perception of hypoglycemic symptoms were significantly
lower in intensively-treated patients as compared to their poorly-controlled counterparts, and hormonal
responses were suppressed as compared to healthy controls. We also found that a greater reduction in
plasma glucose was required to alter P300 potentials in the intensively-treated patients as compared to
both the conventionally-treated patients with diabetes and the nondiabetic group. Our data are
consistent with those of an earlier report by Ziegler and associates64 that also utilized the P300 to
monitor changes in cognitive function during hypoglycemia in type I diabetes patients. Both studies
suggest that intensively-treated patients are less vulnerable to cortical dysfunction during mild to
moderate hypoglycemia.

If well-controlled, intensively-treated patients are less vulnerable to cortical dysfunction during mild to
moderate hypoglycemia than are poorly-controlled, conventionally-treated patients, why was the
frequency of severe hypoglycemia including seizure and coma so much higher in the intensive
treatment group in the DCCT?1 In well-controlled patients with type I diabetes, it is likely that the same
molecular mechanisms that lead to enhanced cortical functioning in the face of falling plasma glucose
levels also lead to delayed activation of the glucopenic sensing centers in the VMH. When the latter
effect predominates during clinical management, plasma glucose falls to levels below those that can be
compensated for by changes in cortical metabolism.

Summary

Increased frequency of hypoglycemia has emerged as a serious side effect of intensive insulin therapy
aimed at prevention of late diabetic complications. Patients with diabetes are more vulnerable to low
blood glucose levels not only because they are unable to synchronize insulin delivery normally with
meal ingestion and activity, but also because they have defective counterregulatory responses to protect
them against hypoglycemia.

Recently the role of CNS in activation and coordination of the counterregulatory responses to
hypoglycemia has received substantial attention. Many specific techniques have been developed to
investigate the intricate relationships between the brain and glucose homeostasis. Among them, the
euglycemic-hypoglycemic clamp has been proven to be an effective tool in clarifying the role of the
CNS in glucose counterregulation, as well as in investigating the impact of hypoglycemia on brain
function. It appears that intensive treatment of type I diabetes leads to adaptive changes that enhance
substrate availability for cognitive function, but unfortunately this leads to delayed activation of brain

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centers that initiate counterregulatory hormone responses. While our understanding of these issues has
advanced considerably, strategies to prevent the development of hypoglycemia in insulin-treated
patients remain elusive.

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2American Diabetes Association: Position statement: Implications of the Diabetes Control and
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Walter P. Borg, MD, and Monica A. Borg, MD, are post-doctoral fellows in the Department of Internal
Medicine, and William V. Tamborlane, MD, is a professor of pediatrics and director of the Children's
Clinical Research Center at the Yale University School of Medicine, in New Haven, Conn.

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