Hypoglycemia is the major, and most feared, complication of the pharmacological therapies
for diabetes. In health, hypoglycemia sufficient to cause clinically relevant impairment
of cognitive function or cardiac rhythm is prevented by highly efficient counterregulatory
mechanisms that culminate in restoration of circulating glucose concentrations. In
the accompanying article, McCrimmon (1) has summarized our current understanding of
how these mechanisms may be initiated and coordinated by central glucose sensing,
described the possible molecular mechanisms of neuronal glucose sensing, and alluded
to the defective performance of these mechanisms in insulin-treated diabetes.
The principle clinical correlate of defective brain glucose sensing in diabetes is
the change in the patient's awareness of the plasma glucose concentration. The clinical
phenomenon of loss of awareness of hypoglycemia, and its associated increase in risk
of severe hypoglycemia, is accompanied by measurable defects in the counterregulatory
stress responses attributed at least in part to failure of central glucose sensing.
As McCrimmon explains, the main determinant of the plasma glucose concentrations at
which the brain responds actively to hypoglycemia appears to be the recent antecedent
glucose exposure. Thus, people accustomed to chronic hyperglycemia may activate symptomatic
stress responses as the glucose concentration falls within the physiological range—a
barrier for some to tighten glucose control effectively. More extensively explored
is the phenomenon of hypoglycemia unawareness, in which the body only mounts a protective
counterregulatory response to falling blood glucose at glucose concentrations well
below the physiologic norm. Added to the failure of glucagon responses to hypoglycemia
that occurs early in type 1 diabetes, such additional counterregulatory failure may
leave the patient symptom free and defenseless until plasma glucose concentrations
are insufficient to support normal higher brain function. Confusion becomes the first
sign of the hypoglycemia, and severe episodes (those in which the person is rendered
incapable of self-treatment) ensue. In this article, we will look at the insights
clinical research has provided into such hypoglycemia unawareness, how the clinical
and laboratory research data have influenced our understanding and management of problematic
hypoglycemia in those with diabetes, and the implications of the basic science for
future diabetes management.
Hypoglycemia unawareness
Hypoglycemia unawareness and its associated increase in risk of severe hypoglycemia
came to prominence with the publication of the three-fold increase in severe hypoglycemia
seen in the intensively treated arm of the Diabetes Control and Complications Trial
(DCCT). In that randomized controlled trial of intensive versus what was then conventional
insulin therapy, severe hypoglycemia was not only more common in a curvilinear fashion
with lower glycated hemoglobin, but there was also a significantly higher risk in
the intensively treated group at any given achieved glycated hemoglobin (2). Such
data have given rise to the perception that hypoglycemia unawareness and high risk
of severe hypoglycemia are inextricably linked to tight glycemic control. In fact,
this is not the case. Some people with diabetes and consistently high glycated hemoglobin
can experience recurrent severe hypoglycemia. People who choose to set their glucose
targets high to diminish risk of severe hypoglycemia do not always achieve their aim.
Contemporaneously with the DCCT, the Düsseldorf program of structured education for
people with type 1 diabetes was consistently achieving reductions in glycated hemoglobin
with significantly reduced rates of severe hypoglycemia (3), perhaps the best definition
of good glycemic control that we have. Although many studies find an inverse correlation
between glycated hemoglobin and rate of severe hypoglycemia, this is not always the
case. Table 1 lists factors associated with increased risk of severe hypoglycemia
in clinical practice. One of the best predictors is an absence of C-peptide; another
even stronger predictor is having a history of severe hypoglycemia (4). In those with
type 2 diabetes, increasing age and the presence of comorbidities are proven additional
risk factors, which may be relevant to those with all types of diabetes (5).
Table 1
Contributors to increased risk of severe hypoglycemia
Loss of endogenous insulin secretion
Inability to reduce circulating insulin concentrations
Loss of signal to α-cells to increase glucagon secretion
Possible loss of C-peptide or amylin effects
Primary failure of hormones raising blood glucose concentrations
Hypopituitarism
Adrenal cortical failure
Isolated growth hormone deficiency
Defective glucose counterregulation
Loss of glucagon response to hypoglycaemia (1b)
Delayed onset of counterregulatory response secondary to antecedent hypoglycemia experience
Prolongation of insulin effect
Exogenous insulin injection
Insulin secretagogues
Renal impairment
Hypothyroidism
Liver failure
High levels of insulin-binding antibodies
Rare activating insulin receptor autoantibodies
Exaggerated mismatch between insulin and nutrient absorption
Primary gastrointestinal disease with malabsorption, e.g., celiac disease
Delayed insulin administration
Lifestyle contributors to individual episodes of severe hypoglycemia
Acute increase in muscle glucose uptake during exercise
Depletion of liver and muscle glycogen by vigorous/prolonged exercise
Suppression of gluconeogenesis by alcohol
Use of drugs enhancing effects of insulin secretagogues
Loss of endogenous insulin and hypoglycemia risk
Lack of C-peptide indicates a complete deficiency of endogenous insulin. Its association
with increased risk of severe hypoglycemia may relate to the loss of capacity for
even vestigial reduction of an endogenous insulin response to hypoglycemia. In support
of this, islet transplantation can restore protection from severe hypoglycemia even
when the patient remains insulin requiring and on exogenous insulin, despite apparently
not restoring glucagon responses to the falling glucose (6). Persistence of insulin
effect has long been known to impair counterregulation and was considered to be the
mechanism of increased risk of severe hypoglycemia posed by high levels of insulin
antibodies in the days before monocomponent and human insulins (7). Loss of the cessation
of endogenous insulin secretion as a paracrine signal to the α-cell to release glucagon
may be another important contributory factor that makes total loss of all endogenous
insulin secretion a high risk for severe hypoglycemia. Certainly, maintaining intraislet
insulin with a sulfonylurea during hypoglycemia markedly attenuates the glucagon response
(8). Amylin, which in healthy subjects is cosecreted with insulin, does not appear
to affect counterregulation (9), although it may smooth out glucose profiles in subjects
with type 1 diabetes (10). The evidence suggests that glucagon responses are lost
in those with type 1 diabetes within the first 5 years and that at least in some people,
catecholamine responses are also diminished over a longer diabetes duration (7). In
those with type 2 diabetes, the glucagon deficit appears to develop in parallel with
defective responses of endogenous insulin (11). Whereas no therapeutic maneuvers short
of whole pancreas transplantation can restore glucagon responses to hypoglycemia in
those with type 1 diabetes, some restoration of other defects can be made based on
our current understanding of how they arise.
The role of antecedent hypoglycemia
The link between defective glucose counterregulation and high risk of severe hypoglycemia
is not only intuitive, it has been well demonstrated experimentally. Ryder et al.
(12) showed that failure to arrest a glucose fall during an unopposed insulin infusion
was associated with failure of the counterregulatory hormone response to the hypoglycemia
(and incidentally had no causal relationship with diabetic autonomic neuropathy) and
also with clinical problems with severe hypoglycemia. White et al. (13) used failure
to counterregulate during insulin infusion as a successful predictor of future problematic
hypoglycemia in subsequent application of intensified insulin therapy. Although it
was initially hoped that improved glycemic control might enhance counterregulation,
perhaps restoring defective glucagon responses to hypoglycemia, this did not occur.
Indeed, the early methods of insulin intensification, such as those used in DCCT,
were associated with increasing counterregulatory failure. Defective counterregulation
appeared to be induced by the tightened glucose control (Fig. 1) (14,15).
Figure 1
Epinephrine responses to controlled induced hypoglycemia before (△) and after (○)
intensification of diabetes control. The hatched area shows the response of a group
of healthy individuals who were slightly older than the diabetic subjects. Reprinted
with permission from Amiel et al. (14).
A seminal study showed that the glucose concentration required to induce secretion
of catecholamines in hypoglycemia could be lowered in healthy volunteers by prior
exposure to two episodes of experimental hypoglycemia the preceding day (16). This
work has since been repeated in people with type 1 and type 2 diabetes and appears
consistent. There is some dispute about the degree of antecedent hypoglycemia required
to induce the problem. Experimental reduction of arterial plasma glucose to only 3.9
mmol/l induces defects primarily in the glucagon responses to subsequent hypoglycemia,
but this response is of little relevance to the insulin-deficient patient, although
increases in epinephrine and muscle sympathetic nerve activity were also reduced (17).
Reductions in plasma glucose to just below the physiological range (3.3 mmol/l) have
more extreme effects on the catecholamine, pancreatic polypeptide, growth hormone,
endogenous glucose production, and lipolytic responses to hypoglycemia, although at
least 30 min of exposure to lower glucose concentrations is required to affect subjective
awareness, at least in experimental models (18). In type 2 diabetes, a recent study
has shown reduction of exaggerated counterregulatory hormone responses by improved
glycemic control, with a further defect inducible by a single experimental exposure
to a plasma glucose of 3.3 mmol/l (19).
Perhaps of greater clinical relevance has been the demonstration that awareness could
be restored to the hypoglycemia unaware by avoidance of all exposure to a plasma glucose
of <3 mmol/l. This was demonstrated not just in people with short duration diabetes
and tight control but also in people with long duration diabetes, both using and far
from using intensified therapy regimens (20). It is of interest to note that whereas
most studies showed at least some restoration of both counterregulatory hormone responses
to hypoglycemia as well as restoration of subjective awareness, one study showed recovery
of awareness alone without any impact on defective catecholamine responses (21). This
dissociation between the counterregulatory hormone responses and subjective awareness
is explored below.
Cortical activation in hypoglycemia perception
McCrimmon rightly focuses his paper on current research on the molecular mechanisms
of glucose sensing in the brain centers that respond to a change in glucose supply
with a change in action potential brain regions such as the nuclei of the hypothalamus
(1). These neurons are critical sensors and coordinators of the counterregulatory
response. However, subjective awareness of hypoglycemia and the ability to respond
to such awareness by taking on carbohydrates is the diabetic patient's best defense
against severe hypoglycemia. Whereas the mechanisms that drive symptomatic counterregulatory
responses may have origins in many brain regions, the perception of symptoms is clearly
a cortical activity.
Neuroimaging studies in human subjects have consistently failed to show an increase
in brain glucose uptake at euglycemia or hypoglycemia in those accustomed to hypoglycemia
who are hypoglycemia unaware. This is in contrast to studies showing upregulation
of glucose transporters in animal models of antecedent hypoglycemia experience and
two human studies estimating global brain glucose uptake from cross-brain arteriovenous
difference measurements after prolonged or recurrent hypoglycemia. Importantly, human
global brain imaging does show cortical as well as brain stem activation during hypoglycemia.
Teves et al. (22) showed an increase in regional brain perfusion using [15O]-H2O water
positron emission tomography (PET) in anterior cingulate cortex and thalamus during
hypoglycemia in healthy volunteers. Although primary changes in cerebral blood flow
do not directly alter rates of cerebral metabolism, changes in regional brain perfusion
detected by water PET are thought to be driven by regional changes in neuronal activation
and their associated regional changes in cerebral metabolism and thus form a surrogate
marker of neuronal activation. Bingham et al. (23), using [11C]-3-O-methyl-d-glucose
PET, also showed an increase in glucose tracer uptake in the prefrontal cortex and
anterior cingulate cortex during hypoglycemia sufficient to lower global brain glucose
content in subjects with type 1 diabetes. Importantly, in the latter study, cerebral
metabolic rate for glucose in the brain showed a relative rise in aware subjects versus
a relative fall in unaware subjects. This is explained by understanding that the tracer
uptake and metabolism are reflecting neuronal activity rather than insulin-stimulated
glucose uptake, with the increased glucose uptake reflecting the involvement of cortical
brain regions in the generation or detection of symptoms. The anterior cingulate cortex
is an important brain region for interoception, monitoring the body's internal state,
and is activated during increase in sympathetic nervous system activation. In the
study by Bingham et al., the relative fall in the surrogate marker of neuronal activation
was associated with failure of subjective awareness and not with complete failure
of hormonal stress response.
A possible additional clinical significance of changes in the cortical response to
acute hypoglycemia was illustrated in a recent analysis of 18-fluoro-deoxy-glucose
uptake during hypoglycemia that differentiated between the aware and unaware (24).
Engagement of appetite control and reward-seeking networks involved in food seeking
was seen, but the responses of these networks were measurably reduced in hypoglycemia
unawareness, with failure of amygdala and orbifrontal cortex responses in particular
(Fig. 2). This suggests habituation of higher behavioral responses to hypoglycemia,
akin to stress desensitization, being a basis for unawareness. If confirmed, this
would argue that the hypoglycemia-unaware person is unaware both of the hypoglycemia
itself but also of its dangers and unpleasantness. This may have important therapeutic
implications.
Figure 2
Regions of enhanced 18-fluoro-deoxy-glucose uptake during hypoglycemia displayed on
magnetic resonance imaging brain slices. A: Relatively greater 18-fluoro-deoxy-glucose
uptake in amygdala, cerebellum, and brainstem in people with type 1 diabetes and hypoglycemia
awareness than in people with type 1 diabetes and hypoglycemia unawareness, consistent
with a greater anxiety and vigilance response in the former. B: Relatively reduced
18-fluoro-deoxy-glucose uptake in the right lateral orbitolfrontal cortex in people
with good awareness of hypoglycemia compared with those who are unaware. The reduced
activation of this brain region in those with awareness suggested by these data is
compatible with the recognition of the unpleasantness or danger of the stimulus encouraging
behavior to avoid hypoglycemia in future. This seems to be significantly less effective
in those who are unaware. Reprinted with permission from Mason et al. (28).
Role of nonglucose substrates for brain metabolism in hypoglycemia unawareness
McCrimmon describes the evidence showing the ability of nonglucose fuels, particularly
ketones and lactate, to sustain cerebral function during hypoglycemia, and such information
is used clinically in treating some forms of epilepsy with ketogenic diets. Infusions
of lactate and ketones can sustain cortical function and delay counterregulation during
induced hypoglycemia (25,26), and lactate infusion reduced brain glucose uptake in
a neuroimaging study (27). Neuroimaging data shows an upregulation of transporters
for monocarboxylic acid transporters in hypoglycemia unawareness, the concept being
that because the neurons are better able to use lactate during hypoglycemia, there
is less neuronal drive for counterregulation (28). As yet, neuroimaging data have
compared diabetic subjects with hypoglycemia unawareness only with nondiabetic control
subjects, so the effect of diabetes alone remains uncertain. If, however, the effect
is associated with reduced awareness and delayed counterregulation, it is likely that
there are regional differences in its importance across the brain because of the absence
of protection from severe hypoglycemia in those who are hypoglycemia unaware. Clinically,
it is difficult to see how these data may be exploited. It is difficult to raise lactate
levels with current agents such as metformin in healthy subjects.
Alanine has also been shown to support some aspects of cognitive function during hypoglycemia
(29). It may appear paradoxical that it also enhances the counterregulatory responses
to hypoglycemia, but this is restricted to the glucagon responses, which are exaggerated
(30). A similar potentially beneficial effect is seen with oral amino acid ingestion.
The increase in blood glucose concentration from a bedtime snack is transient (the
main function of the snack being to counteract the tail action of the pre–evening
meal insulin), but including protein has been suggested to enhance the defenses against
nocturnal hypoglycemia by providing amino acid. In contrast to alanine, raising circulating
fatty acids with intralipid impacts only on the centrally mediated hormonal responses
to hypoglycemia with no effect on cognition, a combination unlikely to be exploitable
therapeutically (31).
The risk of repeat hypoglycemia
Anecdotally, many patients experiencing hypoglycemia will describe how episodes tend
to occur in clusters with great variation in the weekly frequency. This may of course
be caused by a subacute change in insulin requirement related to other factors such
as lifestyle events. Cox et al. (32) have identified that greater changes in glucose
excursions are seen in the 48 h before severe hypoglycemia in patients at high risk
and that a given episode of severe hypoglycemia is preceded by a significant increase
in the frequency of low blood glucose measurements converted into a low blood glucose
index. The increased risk of a second hypoglycemic episode occurring within 24 h of
a first episode is also likely to be enhanced by the downregulation of symptomatic
stress responses induced by the first episode. George et al. (33) showed that only
norepinephrine responses were still impaired 48 h after an index hypoglycemia exposure
in type 1 diabetic patients, although generalized reduction in response is seen within
24 h. If, as some authorities suggest, brain glycogen is important in the defenses
against severe hypoglycemia and it takes 24 h to restore them after hypoglycemia (34),
this could be another contributory factor.
Therapeutic strategies for improving the defenses against hypoglycemia
Avoiding hypoglycemic experience.
Based on the evidence that exposure to antecedent hypoglycemia induces and maintains
counterregulatory failure and hypoglycemia unawareness and that restoration of counterregulatory
responses or awareness of early hypoglycemia is achieved by hypoglycemia avoidance,
helping insulin users to minimize hypoglycemia exposure is an important focus for
current research. Education programs that apparently focused exclusively on this showed
success in reducing hypoglycemia experience (35). However, a particularly impressive
combination of improved glycated hemoglobin and large reduction in severe hypoglycemia
rate sustained over at ≥3 years was achieved by the Düsseldorf program and has since
been reproduced in other countries, including the U.K., where it was translated into
Dose Adjustment for Normal Eating (DAFNE) (36
–38). These are 5 day in- or outpatient programs delivered to small groups of patients
in which principles of adult education are used to transfer skills in insulin dose
adjustment to the insulin users. The courses share a common curriculum delivered by
trained educators, and the best regularly undergo quality control by peer review and
are audited. The insulin regimens are based on tested algorithms for dose adjustment.
Patients are taught to use premeal and prebed blood glucose tests to adjust doses,
correcting instantly for readings that are out of target and also prospectively by
reflecting on the results of the previous few days. The regimens are now not of themselves
remarkable. They stress providing meal insulin and basal insulin requirements independently,
allowing flexibility of meal timing without loss of glycemic control. Patients use
carbohydrate counting to determine meal doses, which are described in ratios of insulin
units required per unit carbohydrate consumed at any meal. Much of the course is spent
perfecting the art of accurate carbohydrate counting using food models, food plates,
exercises, and real meals. Sessions also discuss other factors that influence diabetes
control, provide algorithms for adjusting for these factors, and explain the rationale
for the glucose targets chosen. A recent audit of the U.K.'s DAFNE program has shown
that awareness of hypoglycemia can be restored to nearly half the patients entering
the program with hypoglycemia unawareness at 1 year post-training (38). Although a
causal link between reduced hypoglycemia experience and restored awareness is not
proven by these data, it is a plausible hypothesis. It is unlikely that one single
element of the Düsseldorf-based programs is responsible for their success. The explicit
splitting of basal insulin replacement from meal replacement using algorithms developed
by experimentation, the support of the small-group education delivery and use of adult
education techniques, and the opportunity to take time to learn how insulin works
with food all are likely to be important. That a clinical audit of the U.K.'s DAFNE
program has recently shown a beneficial impact on depression and anxiety in participants
highlights the complex nature of these interventions (38).
Technology has helped as well. Meta-analyses have failed to show a significant impact
on diabetes control of the newer insulin analogues in either type 1 or type 2 diabetes
(39,40). However, in studies, the flatter action profiles of the long-acting analogues,
insulin glargine and detemir, and the highly peaked shorter duration of action of
the rapid-acting analogues, humalog and insulin aspart, consistently show less hypoglycemia,
especially at night. Clinical benefits may best be seen when they are properly used
in people at increased risk of hypoglycemia problems. Continuous subcutaneous insulin
infusion has long been associated in clinical observational studies with reduced frequency
of severe hypoglycemia, and this is supported by a series of randomized controlled
trials and a recent meta-analysis (41). No one has specifically shown that pump therapy
per se has been able to restore counterregulatory failure, but it seems a likely association
of the improved experience of severe hypoglycemia. Most recently, the availability
of real-time glucose monitoring, by which the patient can observe the direction and
rate of change of plasma glucose in real time using an electrode inserted into the
interstitial fluid of the subcutaneous space, has shown an ability to improve glycated
hemoglobin (with no increased risk of hypoglycemia) in adults actively practicing
intensified insulin therapy, primarily with insulin infusion (42).
The evidence supports the hypothesis that all the above strategies may be diminishing
the risk of severe hypoglycemia by reducing the frequency of exposure to hypoglycemia
of any kind. This would be expected to improve hypoglycemia awareness and counterregulatory
responses. Although it is not clear what constitutes the degree of hypoglycemia experience
that creates risk, in a study by Cranston et al. (20) showing restoration of both
hormonal and symptom responses to experimentally induced hypoglycemia, the investigation
was not performed until the patients had demonstrated a 3-week absence of exposure
(on conventional intermittent home blood glucose monitoring) to plasma glucose concentrations
<3 mmol/l. Coincidentally, 2.8–3 mmol/l is the arterialised plasma glucose concentration
in clamp-induced experimental hypoglycemia at which cognitive function first becomes
detectable (as a deterioration in complex reaction time) (43). Perhaps for these reasons,
the European Medicines Agency (EMEA), responsible for the scientific evaluation of
applications for European marketing authorization for medicinal products, has chosen
<3 mmol/l as its definition of hypoglycemia when examining side effects of diabetes
therapies (44). This strategy is in contrast to the definition favored by an American
Diabetes Association workgroup of <4 mmol/l (45) based on the evidence of activation
of endogenous counterregulatory responses (increased glucagon and reduced endogenous
insulin in health) and the ability of experimental exposure of 3.9 mmol/l to induce
some defects in the counterregulatory response to subsequent hypoglycemia. Because
3.9 mmol/l lies within the physiological range and the pancreatic responses to hypoglycemia
are impaired in insulin-deficient diabetes anyway (as far as we know irretrievably),
most clinical guidelines use 3.5 mmol/l as the defining value of hypoglycemia requiring
treatment. This is important because defining a patient as experiencing significant
hypoglycemia has implications on their employment and leisure opportunities. In particular,
labeling a person as being hypoglycemia unaware has important implications for those
individuals, and defining the glucose measurement below which appearance of symptoms
should be identified as having inadequate awareness is fraught with pitfalls. Practically,
and given the inaccuracies of home blood glucose measurement, the definition of hypoglycemia
unawareness should not be applied to people who are fully aware of hypoglycemia at
3– 4 mmol/l or even slightly less. The diagnosis is best made clinically on the basis
of the person's ability to recognize and successfully treat episodes of hypoglycemia,
almost irrespective of the glucose concentration measured at the time.
Despite good evidence of restoration of hypoglycemia awareness by hypoglycemia avoidance
in research studies, translating this into sustainable benefit is not universally
successful. Whereas about half of patients entering a DAFNE program who have hypoglycemia
unawareness were hypoglycemia aware 1 year later, about half still reported themselves
as being hypoglycemia unaware (38). The adaptation of the hedonic aspects of the stress
response to hypoglycemia in those who were unaware seen in the neuroimaging studies
described above is consistent with the failure of any central signal that hypoglycemia
is unpleasant or dangerous. This aspect of unawareness is likely to reduce motivation
for making behavioral changes directed at hypoglycemia avoidance. There are some early
clinic data to suggest that the ability to change insulin regimens to avoid hypoglycemia
is impaired in those who are hypoglycemia unaware (46). This may explain the failure
of purely educational strategies to reduce problematic hypoglycemia in everyone. It
is not known whether the changes in the cortical responses to hypoglycemia are part
of the hypoglycemia-induced syndrome of unawareness and counterregulatory deficit,
in which case they should be reversible, or whether they reflect a predisposition
to respond to stress in this manner. The potential for therapies directed at reversing
behavior patterns engendered by stress desensitization to help people with intractable
hypoglycemia unawareness needs urgent investigation.
Future directions for adjunctive therapies to protect against severe hypoglycemia.
Despite its lack of universal or lasting success, avoidance of hypoglycemia remains
the most proven and effective strategy for reducing an individual's risk of severe
hypoglycemia. Research into improving our ability to avoid exposure to subphysiological
glucose concentrations remains a top priority. Current therapeutic strategies should
target avoidance of exposure to low glucose concentrations and ways of achieving this
including ruling out or treating predisposing comorbidities, use of structured patient
education around insulin usage and hypoglycemia avoidance as well as use of pump therapy,
glucose monitoring strategies, and even for intractable problems, consideration of
replacement of active islet tissue by transplantation. However, complete protection
against hypoglycemia remains an elusive goal, and research continues into other nonglycemic
strategies that might give further protection.
Based on an understanding of the mechanisms of glucose sensing and normal counterregulation,
people are beginning to test the use of pharmacological agents to defend against severe
hypoglycemia. To counteract the observed defect in catecholamine responses to hypoglycemia
in those with long-standing type 1 diabetes, Cryer and colleagues (47) examined the
ability of the β2-adrenergic agonist terbutaline to diminish the risk of nocturnal
hypoglycemia. The first study did reduce hypoglycemia rates but at the expense of
a generalized elevation of the blood glucose through the night. More recently a lower
dose has been tried that achieved a better balance, but the effects of elevating background
catecholamine action will require careful further testing.
McCrimmon describes three molecular pathways implicated in glucose sensing and the
initiation of counterregulation: the AMP-activated protein kinase (AMPK); the ATP-sensitive
K+ (KATP) channels, and the corticotropin-releasing hormone receptor family (1). Some
of these may be amenable to pharmacological manipulation.
The methylxanthine derivatives antagonize central adenosine A2 receptors and increase
intracellular cAMP, activating AMPK. They are associated with enhanced neuronal activation,
alertness, and catecholamine secretion; drive the hepatic glucose response to adrenaline
and glucagon; induce vasopressor responses; and reduce cerebral blood flow. Their
cerebral effects, enhanced neuronal activation, and reduced cerebral blood flow are
the reverse of the effects of hypoglycemia. Nevertheless, both caffeine and theophylline
have been shown to enhance symptomatic and hormonal responses to hypoglycemia, effects
which some have suggested may relate to a greater degree of neuroglycopenia at any
given blood glucose concentration by limiting the increase in cerebral blood flow
that hypoglycemia should elicit. Both agents have been shown to increase counterregulatory
responses. In the case of theophylline, 2 weeks of therapy resulted in loss of the
ability of the drug to enhance the catecholamine responses to hypoglycemia but preservation
of the enhancement of vascular, sweating, and symptomatic responses (48). It is not,
however, known whether the therapy was associated with changes in glycemic control
as a contributory mechanism. In the case of caffeine, again some of its apparently
beneficial effects on subjective awareness of hypoglycemia are retained (49), but
this may be at least in part because it reduces the frequency of hypoglycemia, as
shown by continuous glucose monitoring (50). Caffeine may also exacerbate aspects
of cortical function deficits in susceptible individuals while helping preserve others
during hypoglycemia (51). Other drugs that activate AMPK directly or activate adenylate
cyclase may also be worth investigating. These include metformin and prostacyclin.
The complexity of manipulation of the molecular mechanisms of glucose sensing is illustrated
by examining attempts to exploit the involvement of the KATP channels in neuronal
glucose sensing to enhance counterregulatory responses. Intracerebrovascular administration
of the KATP channel opener diazoxide increases counterregulatory hormone responses,
and sulfonylurea reduces them (1). In a human study, however, a single dose of the
sulfonylurea glibenclamide had equivocal effect on normal glucose counterregulatory
hormone release but diminished the cognitive dysfunction seen with the hypoglycemia,
compatible with the presence of sulfonylurea receptors in the cortex (52). Further
work needs to be done in this area, including apparently paradoxical studies of the
effects of both ATP channel openers such as diazoxide-like agents and closers such
as glibenclamide.
A possible final common pathway through which glucose sensing may affect counterregulatory
stress responses is through manipulating brain concentrations of the inhibitory neurotransmitter
γ-aminobutyric acid (GABA), disinhibiting the stress responses. As described by McCrimmon
in an animal study, localized blocade of γ-aminobutyric acid–receptor-A1 receptors
in the glucose-sensing ventromedial hypothalamus can enhance glucagon and epinephrine
responses to hypoglycemia, although growth hormone and cortisol responses were unaffected
(1). In a single-dose healthy volunteer study, modafinil, which diminishes brain GABA
levels by noradrenergic stimulation of serotonergic neurons, enhanced heart rate responses
and symptom scores during hypoglycemia and supported some aspects of cognitive function
(53). It had no effect on catecholamine or glucagon responses. Modafinil is used to
support higher brain function in narcolepsy, and its actions in the hypoglycemia study
may be exclusively cortical. In contrast, selective serotonin reuptake inhibitors,
by blocking also neuronal norepinephrine transport, can enhance sympathetic outflow
activity, and in experimental human studies, high-dose fluoxetine for 6 weeks prior
to induced hypoglycemia enhanced epinephrine and muscle sympathetic nerve activity
in hypoglycemia but had no effect on subjective awareness (54). The clinical benefit
of these observations is uncertain. As yet, there has been no clinical translation
of the emerging data on the corticotropin-releasing factor receptor involvement in
glucose sensing.
Further implications of the research into glucose sensing and impact on other pharmacological
therapies in diabetes.
The investigation of the molecular mechanisms for glucose sensing have implications
for drug development in diabetes apart from the protection from hypoglycemia. In the
search for better therapies for hyperglycemia, agents that are likely to affect glucose
sensing are actively being explored. Current initiatives include the development of
activators of glucokinase, which may be expected to lower plasma glucose by enhancement
of liver glucose uptake and by enhancement of insulin secretion (55). If the glucokinase
activators have access to the central nervous system, they may also alter hypoglycemia
sensing. Similarly, sodium-glucose transporters are a target for therapeutic blood
glucose lowering by encouraging renal excretion of glucose (56). Sodium-glucose cotransporters
(SGLTs) are found in gut and in the brain, including the ventromedial hypothalamus
(VMH) (1). Phlorizin, a nonselective inhibitor of SGLTs too toxic for human use, inhibits
glucose-induced excitation of ventromedial hypothalamus neurons; therefore, SGLT inhibition
may paradoxically stimulate a stress response that might be expected to exaggerate
the counterregulatory hormone response, although this has not been tested.
SUMMARY AND CONCLUSIONS
Hypoglycemia remains a significant limitation to optimal treatment of diabetes with
insulin and insulin secretagogues. Current research into the physiology of hypoglycemic
counterregulation has helped us understand how to reduce risk of severe hypoglycemia,
but much remains to be understood and exploited. In those with type 1 diabetes, risk
for hypoglycemia is increased by the completeness of the insulin deficiency as well
as the associated failure of glucagon responses to hypoglycemia and additional failure
of other counterregulatory mechanisms created at least in part by repeated exposure
to modest hypoglycemia itself. For those with long duration type 2 diabetes, hypoglycemia
risk also increases with increasing insulin deficiency. Teaching patients to use insulin
flexibly around changes in diet, exercise, alcohol ingestion, and other factors influencing
insulin requirements and sensitivity can improve glycemic control while reducing hypoglycemia
risk. Thereafter, increasing use of technology in both insulin delivery and, more
recently, glucose sensing may be helpful. For the patient with truly intractable hypoglycemia,
replacement of functional islet tissue by islet or organ transplantation is also a
current therapeutic option. For the future, research into agents that may influence
glucose sensing or cerebral and peripheral metabolism may offer new ways of enhancing
defenses against hypoglycemia in the delivery of truly good glycemic control.