Sei sulla pagina 1di 7


Hypoglycemia in Type 1 and Type 2 Diabetes:

Physiology, Pathophysiology, and Management
Vanessa J. Briscoe, PhD, and Stephen N. Davis, MD

patients versus conventionally treated Predictors for hypoglycemia for the

ypoglycemia is one of the most
feared complications of diabetes patients.11 An intensively treated individ- insulin-treated type 2 diabetic subjects
treatment. Unfortunately, the ual with type 1 diabetes can experience included a history of previous hypo-
threat and incidence of iatrogenic hypo- up to 10 episodes of symptomatic hypo- glycemia (P < 0.0001) and duration of
glycemia is increased in attempts to glycemia per week and severe temporar- insulin treatment (P = 0.014). Self-
achieve euglycemia as recommended by ily disabling hypoglycemia at least once reports of severe hypoglycemia in type 2
current treatment guidelines. These rec- a year.1,11,12 An estimated 2–4% of deaths diabetic subjects were lower than in type
ommendations are based on results from of people with type 1 diabetes have been 1 diabetic subjects. The authors also con-
two landmark studies, the Diabetes attributed to hypoglycemia.4 Hypo- cluded that hypoglycemia occurs more
Control and Complications Trial glycemia is also relatively common in often than previously reported2 in
(DCCT) and U.K. Prospective Diabetes type 2 diabetes, with prevalence rates of insulin-treated type 2 diabetes and with
Study (UKPDS), which demonstrated 70–80% in clinical trials using insulin to sufficient frequency to cause significant
the benefits of intensive glycemic con- achieve good metabolic control.2 morbidity.
trol in type 1 and type 2 diabetes, Donnelly et al.13 randomly surveyed
respectively.1,2 These studies proved that individuals (n = 267) with type 1 dia- Clinical Impact of Iatrogenic
microvascular and some macrovascular betes and insulin-treated type 2 diabetes Hypoglycemia
complications could be reduced by rig- to prospectively record hypoglycemic The brain depends on a continual supply
orous metabolic control. However, the events encountered over a 4-week peri- of glucose and is vulnerable to any glu-
associated increased frequency of hypo- od. Of the 267 subjects, 155 reported cose deprivation.5,8,9 Unable to synthe-
glycemia has limited the clinical imple- 572 incidents of hypoglycemia. The type size or store this primary source of ener-
mentation of such intensive therapy 1 diabetic subjects reported a rate of 43 gy, the brain is one of the first organs
because of the pharmacokinetic imper- events per patient per year, whereas sub- affected by lowered blood glucose lev-
fections of available treatment jects with type 2 diabetes reported a rate els.5,8,9 Once plasma glucose concentra-
regimens.3–5 of 16 events per patient per year. For tions fall below the physiological range
Hypoglycemia commonly occurs in individuals with type 1 diabetes, predic- at a glycemic threshold of ~ 70 mg/dl,5 a
clinical practice. Approximately 90% of tors of hypoglycemia included a history sequence of responses is activated that
all patients who receive insulin have of previous hypoglycemia (P = 0.006). includes release of neuroendocrine hor-
experienced hypoglycemic episodes.6 mones (also called counterregulatory or
Nonetheless, the combination of under- IN BRIEF anti-insulin hormones), stimulation of
standing the physiological counter- the autonomic nervous system (ANS),
The threat and incidence of hypo-
regulatory responses induced by hypo- and production of neurogenic and neu-
glycemia is the major limiting factor
glycemia and monitoring glycemic ther- roglycopenic symptoms to protect the
in intensive glycemic control for
apy can help reduce the prevalence of brain and limit systematic effects of
both type 1 and type 2 diabetes. This
iatrogenic hypoglycemia.3–10 hypoglycemia.
article reviews the physiology of the
The normal physiological counter-
normal counterregulatory responses
Prevalence of Hypoglycemia regulatory response to hypoglycemia
to hypoglycemia and the deficient
in Diabetes consists of suppression of insulin release
counterregulatory defenses that occur
Surveys investigating the prevalence of and secretion of glucagon and pancreatic
in patients with diabetes. Treatment
hypoglycemia have provided some polypeptide from the pancreas, epineph-
paradigms for establishing good
alarming results. The DCCT reported a rine from the adrenal medullae, norepi-
glycemic control while limiting
threefold increase in severe hypo- nephrine from sympathetic postgan-
hypoglycemia are also discussed.
glycemia and coma in intensively treated glionic nerve terminals and adrenal

CLINICAL DIABETES • Volume 24, Number 3, 2006 115


medulla, cortisol from the adrenal cor- Symptoms of Hypoglycemia include shakiness, anxiety, nervousness,
tex, and growth hormone from the ante- For people with type 1 diabetes and palpitations, sweating, dry mouth, pallor,
rior pituitary gland.7 In humans, inhibi- many with advanced type 2 diabetes, and pupil dilation.4,5,9 The cholinergic-
tion of insulin secretion is the initial hypoglycemia is a fact of life.1–5 Those mediated symptoms include diaphoresis,
defense against falling glucose and attempting to achieve better glycemic hunger, and paresthesias.3–5 However, it
occurs at a plasma glucose concentration control suffer many episodes of mild to should be noted that epinephrine infu-
of ~ 80 mg/dl. moderate hypoglycemia. Although the sion in the presence of euglycemia to
Glucagon and epinephrine are the level of plasma glucose that indicates achieve levels commonly seen during
primary fast-acting hormones in the hypoglycemia is sometimes debated, it hypoglycemia only produces 20% of the
defense against acute hypoglycemia. may be best defined in a physiological total neurogenic symptom scores found
Glucagon acts to increase endogenous context as a plasma glucose of < 70 during hypoglycemia. This indicates that
glucose production and does so via mg/dl (< 60 mg/dl whole blood). This the genesis of hypoglycemic symptoms
increases in hepatic glycogenolysis and is because the glycemic threshold for is multifocal and is probably mainly gen-
gluconeogenesis, providing three carbon activation of the anti-insulin neuroen- erated from central nervous system
glucose substrates (lactate, pyruvate, ala- docrine counterregulatory response (CNS) efferent pathways.14
nine, and glycerol). Epinephrine can also occurs at a plasma glucose of 70 mg/dl. Neuroglycopenic symptoms occur
acutely increase endogenous glucose Additionally, antecedent hypoglycemia as a result of brain neuronal glucose
production. Epinephrine has effects simi- of 70 mg/dl has been demonstrated to deprivation.3–5,9,10 Evidence of neurogly-
lar to glucagon on hepatic glucose pro- reduce counterregulatory responses to copenia can be the signal most often
duction but can also stimulate net renal subsequent hypoglycemia.3–7 recognized by patients’ family and
glucose production. Additionally, epi- Symptoms of hypoglycemia are friends. These symptoms include abnor-
nephrine has an important physiological divided into two categories. Neurogenic mal mentation, irritability, confusion,
function in reducing insulin-stimulated (autonomic) symptoms are triggered by difficulty speaking, ataxia, paresthesias,
glucose uptake. a falling glucose level and cause patients headaches, stupor, and eventually (if
During the prolonged hypoglycemia to recognize that they are experiencing a untreated) seizures, coma, and even
that is usually observed in clinical prac- hypoglycemic episode.5,7,8 These symp- death.3–5,9 Neuroglycopenic symptoms
tice, it is the reduced glucose uptake in toms are activated by the ANS and are can also include transient focal neuro-
peripheral tissues that contributes most mediated in part by sympathoadrenal logical deficits (e.g., diplopia, hemi-
to the preservation of circulating glucose release of catecholamines (norepineph- paresis)3–5 (Table 1).
levels and hence the defense against rine and epinephrine) from the adrenal
hypoglycemia. Activation of the sympa- medullae and acetylcholine from post- Hypoglycemia and Glycemic
thetic nervous system (via both circulat- synaptic sympathetic nerve endings.5,8 Thresholds
ing catecholamines and direct innerva- Neurogenic symptoms and signs associ- The glycemic thresholds responsible for
tion) results in increased lipolysis in ated with elevated epinephrine levels the activation of the physiological
adipocytes. The increased release of free
fatty acids (FFAs) results in significant Table 1. Symptoms of Hypoglycemia
glucose sparing (because tissues can oxi-
dize FFAs instead of glucose). In fact, Neurogenic (ANS) Symptoms Neuroglycopenic Symptoms
the contribution of FFAs has been esti- (Caused by Falling Glucose Level) (Caused by Brain Neuronal Glucose
mated to be 25% of the total defense Deprivation)
against hypoglycemia.3–7
Shakiness Abnormal mentation
Growth hormone and cortisol play a
Trembling Irritability
modest role in the metabolic defense
Anxiety Confusion
against acute hypoglycemia but become
Nervousness Difficulty in thinking
more important during prolonged hypo-
Palpitations Difficulty speaking
glycemia.7 In fact, the counterregulatory
Clamminess Ataxia
actions of growth hormone and cortisol
Sweating Paresthesias
on increasing glucose production and
Dry mouth Headaches
restraining glucose disposal do not
Hunger Stupor
become evident until 4 hours after the
Pallor Seizures
onset of hypoglycemia. Even so, their
Pupil dilation Coma
counterregulatory actions are only ~
Death (if untreated)
20% compared to that of epinephrine.7

116 Volume 24, Number 3, 2006 • CLINICAL DIABETES


defenses against hypoglycemia are symptomatic response to subsequent clamp studies, neuroendocrine responses
dynamic rather than static.7 Thus, hypoglycemia.18 for the two groups were similar. Howev-
patients with a higher hemoglobin A1c The above studies combined with er, symptoms began earlier in the
(A1C) may perceive symptoms of hypo- conceptually similar results from differ- younger men and were more intense.
glycemia at a higher plasma glucose ing laboratories allowed the term “hypo- Measures of psychomotor coordination
level than those with more intensive con- glycemia-associated autonomic failure” deteriorated earlier in the older subjects
trol.8 In fact, these patients may generate to be coined. This syndrome includes and to a greater degree. The usual 10–20
hypoglycemic symptoms even when reduced neuroendocrine counterregula- mg/dl plasma glucose difference
their plasma glucose is above the normal tory responses to hypoglycemia and low- between the subjective awareness of
range. This phenomenon is called “rela- ered glycemic thresholds for activation hypoglycemia and the onset of cognitive
tive hypoglycemia” and is associated of physiological defenses against hypo- dysfunction was lost in the older men.
with release of counterregulatory hor- glycemia, which together lead to a con- This altered counterregulatory effect
mones. This phenomenon commonly dition of hypoglycemic unawareness. may contribute to the altered cognitive
occurs when patients undergo intensifi- Glycemic thresholds are shifted to lower response to reductions in blood glucose.
cation of their glucose control. This syn- plasma glucose levels in intensively Thus, the lower glycemic threshold to
drome is self-limiting and usually takes treated type 1 and type 2 diabetic indi- hypoglycemia in older people may limit
2–4 weeks for the brain to readjust to the viduals,10,18–21 which further limits efforts the time available to self-treat and there-
improved and thus relatively reduced cir- to attain euglycemia.3,4 by increase the risk of developing inca-
culating glucose levels.8–10,15,16 pacitating neuroglycopenia.22,25 Addi-
The opposite is true in intensively Counterregulatory Hormone tionally, these neurological symptoms of
controlled individuals with diabetes. Responses to Hypoglycemia in Older hypoglycemia may be misinterpreted in
They may not recognize hypoglycemia Adults older patients because of coexisting ill-
until their plasma glucose is consider- The risk of severe or fatal hypoglycemia nesses, such as cerebrovascular diseases
ably lower than the normal physiologi- associated with the use of oral hypo- or dementia.22,25
cal glycemic thresholds.5,10 The glycemic agents and insulin increases
changes in glycemic thresholds can be exponentially with age.22,23 Also, older Counterregulatory Hormone
caused acutely by antecedent hypo- adults with comorbidities, those using Responses to Hypoglycemia
glycemia and chronically by persistent multiple medications, and those who are in Women
hyperglycemia.1–5 frequently hospitalized are at greater There is a large sexual dimorphism in
To test the hypothesis that hypo- risk for iatrogenic hypoglycemia.24 Most counterregulatory responses to hypo-
glycemia itself causes reduced neuroen- people with type 2 diabetes are > 60 glycemia. It has been clearly demonstrat-
docrine and symptomatic responses to years of age.8 Therefore, it is important ed that both healthy young women and
subsequent hypoglycemia, Heller and to appreciate the idiosyncratic and age- women with type 1 diabetes have
Cryer17 measured counterregulatory specific manifestations of hypoglycemic reduced neuroendocrine, ANS, and meta-
responses during repeated hypoglycemic symptoms.9 bolic (endogenous glucose production)
clamp studies. These seminal experi- Meneilly et al.22 have investigated counterregulatory responses compared to
ments determined that two episodes of the effects of age on counterregulatory age- and BMI-matched men.26–30
antecedent moderate hypoglycemia responses during clamped hypo- This is not because of differences in
(50 mg/dl) resulted in significant reduc- glycemia. Older adults with type 2 dia- glycemic thresholds for activation of
tions of plasma epinephrine, glucagon, betes demonstrated reduced glucagon countrerregulatory responses. In a series
pancreatic polypeptide, and cortisol and growth hormone responses but of separate glucose clamps at glycemic
responses to next-day hypoglycemia. increased epinephrine and cortisol targets of 90, 70, 60, and 50 mg/dl,
Neurogenic and neuroglycopenic symp- responses when compared to age- Davis et al.29 demonstrated that reduced
tom responses were also reduced after matched nondiabetic control subjects. CNS drive is responsible for the sexual
antecedent hypoglycemia. A later study18 However, hypoglycemic symptom dimorphic responses to hypoglycemia
investigated the effects of morning hypo- scores were similar in both groups at all occurring in women. In a subsequent
glycemia on neuroendocrine and meta- levels of glycemia. study, Sandoval et al.30 determined that
bolic responses to subsequent afternoon Matyka et al.,25 on the other hand, estrogen is the mechanism responsible
hypoglycemia. These experiments found differences in hypoglycemic for this sexual dimorphism.
demonstrated that only one episode of symptom responses when comparing Despite this, the prevalence of hypo-
prolonged, moderate hypoglycemia can healthy older men aged 60–70 years glycemic episodes in type 1 diabetes is
also produce substantial blunting of with younger men aged 22–26 years. similar for men and women.1 This appar-
counterregulatory hormones and the During hyperinsulinemic-hypoglycemic ent paradox may be explained by the fact

CLINICAL DIABETES • Volume 24, Number 3, 2006 117


that women may be more resistant than Mechanisms of Counterregulatory hypoglycemia-associated autonomic
men to the blunting effects of antecedent Responses to Hypoglycemia failure also have reduced adrenergic sen-
hypoglycemia on the ANS.30 Thus, two in Type 1 Diabetes sitivity (i.e., tissue responsiveness to cir-
episodes of antecedent hypoglycemia in Epinephrine (not glucagon) is the main culating epinephrine). Korytkowski et
men will cause a twofold greater blunt- defense against hypoglycemia in al.34 demonstrated that type 1 diabetic
ing of counterregulatory responses to patients with type 1 diabetes of > 5 subjects with blunted counterregulatory
subsequent hypoglycemia compared to years’ duration. This is because the pan- responses to hypoglycemia had reduced
women, with the result being that the creatic -cell glucagon secretory -adrenergic sensitivity compared to
usual sexual dimorphic response to response to hypoglycemia is irreversibly patients with normal counterregulatory
hypoglycemia is eliminated. lost.3–6 responses to hypoglycemia and healthy
Unfortunately, epinephrine responses control subjects. Aftab-Guy et al.14 also
Exercise-Related Hypoglycemia to hypoglycemia also become impaired demonstrated that patients with type dia-
Hypoglycemia can occur during, 1–2 in type 1 diabetic patients undergoing betes had reduced whole-body tissue
hours after, or up to 17 hours after exer- intensive insulin treatment. This places sensitivity to epinephrine, which was
cise. The mechanisms responsible for intensively treated type 1 diabetic exacerbated by intensive glycemic con-
this phenomenon have been the subject patients at a significant risk for recurrent trol. This reduced tissue sensitivity to
of recent work.7 Aerobic exercise results hypoglycemia.31,32 These frequent bouts epinephrine resulted in lower endoge-
in an increase in both insulin- and of hypoglycemia further reduce the nous glucose production and less inhibi-
non–insulin-medicated glucose uptake. counterregulatory responses to future tion of insulin-stimulated glucose
During moderate-intensity exercise hypoglycemia by ≥ 50%. This creates a uptake. The above data may be interpret-
in nondiabetic individuals, endogenous vicious cycle of iatrogenic hypo- ed to indicate that reduced tissue respon-
insulin secretion is reduced by 40–60%. glycemia–associated autonomic failure, siveness to epinephrine is an additional
Thus, reductions are recommended in whereby hypoglycemia induces further contributor to the syndrome of hypo-
replacement insulin doses during exer- hypoglycemia.3–5,31 glycemia-associated autonomic failure
cise (basal and/or preprandial insulin). Davis et al.33 demonstrated that the Fritsche et al.35 demonstrated that if
This can be supplemented with oral magnitude of antecedent hypoglycemia hypoglycemic episodes are avoided for
intake of 10–20 g of carbohydrate every produced proportional blunting of coun- 4 months, -adrenergic sensitivity and
30–60 minutes depending on the inten- terregulatory responses to subsequent hypoglycemic symptom responses
sity of exercise. Insulin sensitivity hypoglycemia. In other words, the increase, despite a persistently blunted
increases ~ 2 hours after moderate- greater the depth of antecedent hypo- epinephrine response to hypoglycemia.
intensity exercise. Thus, consideration glycemia, the greater the magnitude of This may indicate that increases in -
should be given to reducing basal and/or subsequent counterregulatory failure. adrenergic sensitivity are a prelude to
prandial insulin doses for 24 hours after The ANS is exquisitely sensitive to restoration of endocrine and autonomic
exercise. the effects of antecedent hypoglycemia. function when hypoglycemic episodes
Additionally, recent studies have Two episodes of hypoglycemia of only are avoided.7 Although controversial,
demonstrated that there is a vicious cycle 70 mg/dl can blunt subsequent counter- other studies have also reported that
of counterregulatory failure between regulatory responses by ~ 30% in men. some or all of the features of hypo-
exercise and hypoglycemia.7 Thus, two Similarly, short durations (20 minutes) glycemia-associated autonomic failure
episodes of prolonged, moderate-intensi- of antecedent hypoglycemia also pro- (i.e., blunted neuroendocrine counter-
ty exercise can reduce ANS and neu- duce significant blunting of subsequent regulatory responses) can be reversed
roendocrine responses by 50% during counterrregulatory responses.33 The with strict avoidance of antecedent
subsequent hypoglycemia. Similarly, reduction in ANS counterregulatory hypoglycemia.3–5,36–38
two episodes of antecedent hypo- responses has significant clinical conse-
glycemia can reduce counterregulatory quences because type 1 diabetic patients Mechanisms of Counterregulatory
responses during subsequent exercise by with deficient glucagon and epinephrine Responses to Hypoglycemia
40–50%.7 Therefore, individuals who responses to hypoglycemia have a ≥ 25- in Type 2 Diabetes
have had a previous episode of hypo- fold risk of hypoglycemia during inten- Type 2 diabetes is a heterogeneous dis-
glycemia are at greater risk of hypo- sive insulin therapy.1 ease affecting a range of individuals
glycemia during exercise. This may be Hypoglycemia-associated autonomic from children to older adults. Therapies
countered by temporarily increasing failure is an acutely acquired syndrome include diet, oral medications, glucagon-
glycemic targets, reducing preexercise that should be differentiated from classi- like peptide-1 analogs, insulin, or combi-
insulin, and consuming appropriate cal diabetic autonomic neuropathy.3–6,19,31 nation therapies and vary depending on
amounts of carbohydrate. It is also possible that patients with patients’ progressive -cell failure.39

118 Volume 24, Number 3, 2006 • CLINICAL DIABETES


Hence, the clinical effect of hypo- role of facilitator as they help patients Table 2. Hypoglycemia Risk
glycemia-associated autonomic failure in navigate through the maze of diabetes Factors
type 2 diabetes is less well established,3–5 self-care.
and results differ considerably with The topic of hypoglycemia has prior- • Missed or delayed meal
respect to age, comorbidity, treatment ity and demands to be routinely • Eating less food at a meal than
modality (diet versus oral hypoglycemic addressed with patients receiving med- planned
agents versus insulin), metabolic control, ications that may themselves or in com- • Vigorous exercise without carbohy-
body fat composition, and the presence bination cause hypoglycemia. Lack of drate compensation
of diabetic neuropathies.39,40 understanding of the diabetes-related • Taking too much diabetes medicine
However, Segel et al.40 tested the therapeutic regimen will contribute to (e.g., insulin, insulin secretagogues,
hypothesis that there are neuroen- repeated incidents of hypoglycemia.42–47 and meglitinides)
docrine changes in glycemic responses Patients must understand time action • Drinking alcohol
to hypoglycemia in individuals with profiles of their diabetes medications and
advanced type 2 diabetes. They reported realize that excessive treatment can be insulin. Substitution of preprandial regu-
that the glucagon response to falling harmful. Providers should urge patients lar insulin with rapid-acting insulin (e.g.,
plasma glucose was virtually absent in to wear potentially lifesaving diabetes glulisine, lispro, or aspart) reduces the
advanced insulin-treated type 2 dia- alert identification. frequency of daytime hypoglycemia.43,44
betes. Glycemic thresholds for auto- Blood glucose monitoring is funda- Similarly, substitution of a long-acting
nomic and symptomatic responses to mentally important for people who expe- insulin analog (e.g., glargine or detemir)
hypoglycemia were also shifted to low- rience hypoglycemic episodes, especial- for intermediate-acting insulins such as
er glucose concentrations by recent ly before they perform critical tasks such NPH, lente, or premix 70/30 or 50/50
antecedent hypoglycemia. as driving.41,42 Also, in older individuals also reduces the frequency of nocturnal
Hence, patients with advanced type 2 with diabetes who have comorbidities and daytime hypoglycemia.44
diabetes, like those with type 1 diabetes, such as dementia, cerebral vascular acci- Insulin pump therapy (continuous
are at risk for hypoglycemia-associated dent, or depression, consideration should subcutaneous insulin infusion) that uses
autonomic failure and the resultant be given to these confounding factors.48 rapid-acting insulin analogs can cause
vicious cycle of recurrent iatrogenic Factors that may predispose such both nocturnal and morning fasting
hypoglycemia.31,40 patients to hypoglycemia include hypoglycemia. With nocturnal hypo-
increased polypharmacy or medication glycemia, the basal insulin infusion rate
Reducing the Risk of Iatrogenic nonadherence, impaired renal or hepatic may be problematic, whereas with fast-
Hypoglycemia metabolism, and poor or erratic nutri- ing or daytime hypoglycemia, the
Fear of hypoglycemia is the major con- tion.22,23,41,42 Hence, the American Geri- preprandial insulin bolus doses, the basal
cern of patients receiving endogenous or atrics Society has recommended an A1C insulin infusion rate, or both may be
exogenous insulin replacement therapy. of ≤ 7% for healthy older adults and an causing the problem.44
Furthermore, patients receiving intensive A1C of ≤ 8% for the frail elderly.48 Insulin secretagogues—sulfony-
insulin therapy have about a threefold If patients report a history of hypo- lureas, repaglinide, and nateglinide—can
greater incidence of severe disabling glycemia, details regarding the time of also produce hypoglycemia related to
hypoglycemia than those receiving con- episodes need to be identified and the absolute or relative insulin excess. How-
ventional insulin therapy.1,41 treatment regimen adjusted accordingly ever, the sulfonylureas may pose the
Education regarding all aspects of (Table 2). If these events go without greatest risk of hypoglycemia in patients
diabetes care is important in the preven- intervention, the risk of recurrent severe with altered renal or hepatic function and
tion and treatment of hypoglycemia. hypoglycemia is high.45 in older adults.42 Hence, agents such as
Carbohydrate counting, insulin and oral Injected insulin can produce absolute glimepiride, glipizide XL, or nateglinide
medication dosing, concomitant medica- or relative insulin excess largely because that are shorter-acting and have glucose-
tions, alcohol intake, exercise, and even of dosing and pharmacokinetics.42 With a dependent insulin secretion would be
driving should be included in the discus- basal-bolus insulin regimen, morning preferable to reduce hypoglycemic
sion. Education will help alleviate fear of fasting hypoglycemia implicates the risks.42
hypoglycemia that may impede ideal long- or intermediate-acting insulin. Hypoglycemia unawareness (loss of
glycemic control.42 Reducing iatrogenic Daytime hypoglycemia may be caused warning symptoms of hypoglycemia)
hypoglycemia will involve patient by the rapid-, short-, or longer-acting implies recurrent hypoglycemia.42
empowerment and anticipatory guidance insulins, depending on the regimen. Assessment of frequency and severity of
by both patients and health care Nocturnal hypoglycemia may also be hypoglycemia is required at each clinic
providers. Providers will also take on the caused by regular and longer-acting visit. Additionally, inquiring at what

CLINICAL DIABETES • Volume 24, Number 3, 2006 119


blood glucose level patients can first Table 3. Tips for Preventing Hypoglycemia
sense low plasma glucose will provide
an assessment of hypoglycemia • If blood glucose is < 70 mg/dl, give 15–20 g of quick-acting carbohydrate (1–2
unawareness. teaspoons of sugar or honey, 1/2 cup of regular soda, 5–6 pieces of hard candy,
If there is still no apparent cause glucose gel or tablets as directed, or 1 cup of milk).
from the history or blood glucose log,
patients may be experiencing hypo- • Test blood glucose 15 minutes after treatment. If it is still < 70 mg/dl, re-treat
glycemia during the night.41,42 Indeed, with 15 g of additional carbohydrate.
nighttime hypoglycemia can be a com-
• If blood glucose is not < 70 mg/dl but it is > 1 hour until the next meal, have a
mon occurrence in people with type 1
snack with starch and protein (crackers and peanut butter, crackers and cheese,
diabetes.1,45 Sleep can preclude detec-
half of a sandwich, or crackers and a cup of milk).
tion of symptoms warning of impending
hypoglycemia.41,42 Approaches to the • Keep glucagon injection kit available for patients who are unconscious or unable
problem of nocturnal hypoglycemia to take in oral carbohydrate. Instruct family members and caregivers about how
include insulin regimen adjustments, to safely administer glucagon. Emergency glucagon kits are available with pre-
such as the use of rapid-acting rather scription only.
than regular insulin during the day and a
long-acting basal insulin. Administra- raise the blood glucose by 50 mg/dl in continuous glucose infusion and fre-
tion of bedtime snacks may be also ~ 15 minutes. The glycemic response to quent feedings.41,42
appropriate.41,42,45 oral glucose is transient; therefore,
If a diagnosis of hypoglycemic ingestion of a small complex carbohy- Conclusions
unawareness is made, the solution will drate snack shortly after the plasma glu- The threat and incidence of iatrogenic
involve the acceptance of somewhat cose concentration rises is generally hypoglycemia is a major limiting factor
higher glucose levels in the short term. advisable, especially if the next meal is in intensive glycemic management of
At least a 3-week period of meticulous longer than 1 hour away. diabetes. Nonetheless, it is possible to
avoidance of hypoglycemia could be Hypoglycemic patients who are both improve glycemic control and min-
attempted with the goal of encouraging unconscious or unable because of neuro- imize hypoglycemic risks by under-
a return to awareness of hypo- glycopenia to take in oral carbohydrates standing the physiological counterregu-
glycemia.1–5 With the return of sympto- can be treated with a parental glucagon latory responses and aggressively moni-
matic hypoglycemia, patients can once injection. Glucagon kits require a pre- toring glycemic therapy.
more work toward achieving better scription. Glucagon acts by mobilizing Hypoglycemia is problematic in type
glycemic control. glucose stores from the liver via 1 diabetes during aggressive glycemic
Review of patients’ self-monitoring glycogenolysis. Thus, it is less effective therapy and in advanced type 2 diabetes
of blood glucose log will help interpret in glycogen-depleted states (e.g., pro- because of compromised glucose coun-
blood glucose patterns. Patients should longed starvation or alcohol ingestion). terregulatory systems. Therefore, educa-
always have a rapidly available source of It is important that a glucagon kit be tion concerning self-monitoring of blood
glucose with them to treat hypoglycemia available for use and that patients’ family glucose, diet, physiological insulin
at the first sign of a low glucose (Table members or caregivers are knowledge- replacement, medication, and lifestyle
3). Hypoglycemia (plasma glucose < 70 able in its use. One does not need to be a are important to maintain good glycemic
mg/dl), including asymptomatic hypo- health care professional to administer control, avoid hypoglycemia, and pre-
glycemia and most episodes of mild to glucagon. Instruction regarding the vent long-term complications.
moderate symptomatic hypoglycemia, is potential side effects of glucagon (i.e.,
effectively self-treated by ingestion of vomiting) is important. This will prevent REFERENCES
some form of glucose. Pure glucose is any surprise and subsequent hesitancy to 1
The DCCT Research Group: The effect of
preferred, although any form of carbohy- use it in the future. Also, care should be intensive treatment of diabetes on the develop-
ment and progression of long term complication
drate that contains glucose will raise taken to ensure that the kit has not in insulin-dependent diabetes mellitus. N Engl J
plasma glucose. expired. Med 329:977–986, 1993
The “rule of 15” is a helpful treat- Intravenous glucose is the prefer- The U.K. Prospective Diabetes Study Group:
Intensive blood-glucose control with sulfony-
ment regimen when patients are able to able treatment of severe iatrogenic lureas or insulin compared with conventional
self-treat. Typically, 15 g of carbohy- hypoglycemia, particularly that caused treatment and risk of complication in patients
with type 2 diabetes. Lancet 352:837–853, 1998
drate (rapidly absorbing forms of glu- by a sulfonylurea. These reactions are
cose such as glucose gel, sugar-contain- more likely to occur in elderly patients Cryer PE: Hypoglycemia risk reduction in
type 1 diabetes. Exp Clin Endocrinol Diabetes
ing soda, or glucose tablets) should and are often prolonged and require 109:S412–S423, 2001

120 Volume 24, Number 3, 2006 • CLINICAL DIABETES


4 21 36
Cryer PE: Current concepts: Diverse causes Spyer G, Hattersley AT, MacDonald IA, Cranston I, Lomas J, Maran A, Macdonald
of hypoglycemia-associated autonomic failure in Amiel S, MacLeod KM: Hypoglycaemic counter- I, Amiel SA: Restoration of hypoglycemia aware-
diabetes. N Engl J Med 350:2272–2279, 2004 regulation at normal blood glucose concentra- ness in patients with long-duration insulin-
tions in patients with well controlled type 2 dia- dependent diabetes. Lancet 344:283–287, 1994
Cryer PE, Davis SN, Shamoon H: Hypo- betes. Lancet 356:1970–1974, 2000 37
glycemia in diabetes. Diabetes Care Fanelli C, Pampanelli S, Epifano L, Ram-
26:1902–1912, 2003 Meneilly GS, Cheung E, Tuokko H: Altered botti AM, Ciofetta M, Modarelli F, DiVincenzo
6 responses to hypoglycemia of healthy elderly A, Annibale B, Lepore M, Lalli C, Sindaco P,
Cryer PE: Hypoglycemia: Pathophysiology, people. Diabetes 43:403–410, 1994 Brunetti P, Bolli G: Relative roles of insulin and
Diagnosis, and Treatment. New York, Oxford
University Press, 1997 23 hypoglycemia on induction of neuroendocrine
Jaap AJ, Jones GC, McCrimmon RJ, Deary responses to, symptoms of, and deterioration of
7 IJ, Frier BM: Perceived symptoms of hypogly-
Diedrich L, Sandoval D, Davis SN: Hypo- cognitive function in hypoglycemia in male and
caemia in elderly type 2 diabetic patients treated
glycemia associated autonomic failure. Clin with insulin. Diabet Med 15:398–401, 1998 female humans. Diabetologia 37:797–807, 1994
Auton Res 12:358–365, 2002 38
Shorr RI, Ray WA, Daugherty JR, Griffin Dagogo-Jack S, Rattarasarn C, Cryer PE:
Zammitt NN, Frier BM: Hypoglycemia in MR: Incidence and risk factors for serious hypo- Reversal of hypoglycemia unawareness, but not
type 2 diabetes. Diabetes Care 28:2948–2961, glycemia in older persons using insulin or sul- defective glucose counterregulation, in IDDM.
2005 fonylureas. Arch Intern Med 157:1681–1686, Diabetes 43:1426–1434, 1994
McAuley V, Deary IJ, Freier BM: Symptoms 1997 39
de Galan BE, Hoekstra JBL: Glucose coun-
of hypoglycemia in people with diabetes. Diabet 25
Matyka K, Evans M, Lomas J, Cranston I, terregulation in type 2 diabetes mellitus. Diabet
Med 18:690–705, 2001 MacDonald I, Amiel SA: Altered hierarchy of Med 18:519–527, 2001
Amiel SA, Sherwin RS, Simonson DC, protective responses against severe hypoglycemia 40
Segel SA, Paramore DS, Cryer PE: Hypo-
Tamborlane WV: Effect of intensive insulin thera- in normal aging in healthy men. Diabetes Care glycemia-associated autonomic failure in
py on glycemic thresholds for counterregulatory 20:135–141, 1997 advanced type 2 diabetes. Diabetes 51:724–732,
hormone release. Diabetes 37:901-907, 1988 26
Amiel SA, Maran A, Powrie JK, Umpleby 2002
The DCCT Research Group: Hypoglycemia AM, MacDonald IA: Gender differences in coun- 41
The DCCT Research Group: Epidemiology
in the Diabetes Control and Complications Trial. terregulation to hypoglycemia. Diabetologia of severe hypoglycemia in the diabetes control
Diabetes 46:271–286, 1997 36:460–464, 1993 and complication trial. Am J Med 90:450–459,
12 27
Davis SN, Goldstein RE, Price L, Jacobs J, 1991
Hepburn DA, MacLeod KM, Pell AC, Scou-
gal IJ, Frier BM: Frequency and symptoms of Cherringon AD: The effects of insulin on the 42
Gabriely I, Shamoon H: Hypoglycemia in
hypoglycaemia experienced by patients with type counterregulatory response to equivalent hypo- diabetes: common, often unrecognized. Cleve-
2 diabetes treated with insulin. Diabet Med glycemia in patients with insulin-dependent dia- land Clin J Med 71:335–342, 2004
10:231–237, 1993 betes mellitus. J Clin Endocrinol Metab
77:1300–1307, 1993 Cryer PE, Childs BP: Negotiating the barri-
Donnelly LA, Morris AD, Frier BM, Ellis 28 er of hypoglycemia in diabetes. Diabetes Spec-
JD, Donnan PT, Durrant R, Band MM, Reekie G, Diamond MP, Jones T, Caprio S, Hallarman trum 15:20–27, 2002
Leese P: Frequency and predictors of hypogly- L, Diamond MC, Addabbo M, Tamborlane WV,
caemia in type 1 and insulin-treated type 2 dia- Sherwin RS: Gender influences counterregulatory 44
Heller SR, Amiel SA, Mansell P: Effect of
betes: a population-based study. Diabet Med hormone responses to hypoglycemia. Metabolism the fast-acting insulin analog lispro on the risk of
22:749–755, 2005 42:1568–1572, 1993 nocturnal hypoglycemia during intensified insulin
14 29
Davis SN, Fowler S, Costa F: Hypo- therapy. Diabetes Care 22:1607–1611, 1999
Aftab-Guy D, Sandoval D, Richardson MA,
Tate D, Davis SN: Effects of glycemic control on glycemic counterregulatory responses differ 45
Ratner RE, Hirsch IB, Neifing JL, Garg SK,
target organ responses to epinephrine in type 1 between men and women with type 1 diabetes. Mecca TE, Wilson CA: Less hypoglycemia with
diabetes. Am J Physiol Endocrinol Metab Diabetes 49:65–72, 2000 insulin glargine in intensive insulin therapy for
289:E258–E265, 2005 30
Sandoval DA, Ertl AC, Richardson MA, type 1 diabetes. Diabetes Care 23:639–643, 2000
Korzon-Burakowska A, Hopkins D, Matyka Tate DB, Davis SN: Estrogen blunts neuroen- 46
docrine and metabolic responses to hypo- Muhlhause I, Overmann H, Bender R, Bott
K, Lomas J, Pernet A, Macdonald I, Amiel S: U, Berger M: Risk factors of severe hypo-
Effects of glycemic control on protective respons- glycemia. Diabetes 52:1749–1755, 2003
glycemia in adult patients with type 1 diabetes—
es against hypoglycemia in type 2 diabetes. Dia- 31
Cryer PE: Mechanisms of hypoglycemia- a prospective population based study. Diabetolo-
betes Care 21:283–290, 1998 associated autonomic failure and its component gia 41:1274–1282, 1998
Boyle PJ, Schwartz NS, Shah SD, Clutter syndromes in diabetes. Diabetes 54:3592–3598, 47
2005 Perriello G, DeFeo P, Torlone E, Fanelli C,
WE, Cryer PE: Plasma glucose concentrations at Santeusanio F, Brunetti P, Bolli GB: The dawn
the onset of hypoglycemic symptoms in patients 32
phenomenon in type 1 (insulin-dependent) dia-
White NH, Skor A, Cryer PE, Levandoski L,
with poorly controlled diabetes and in nondiabet-
Dier DM, Santiago JV: Identification of type 1 betes mellitus: magnitude, frequency, variability,
ics. N Engl J Med 318:1487–1492, 1988
diabetic patients at increased risk for hypo- and dependency on glucose counterregulation and
Heller SR, Cryer PE: Reduced neuroen- glycemia during intensive therapy. N Engl J Med insulin sensitivity. Diabetologia 34:21–28, 1991
docrine and symptomatic responses to subsequent 308:485–491, 1993 48
hypoglycemia after 1 episode of hypoglycemia in Wright EE: Treat to target: ABCs for the
nondiabetic humans. Diabetes 4:223–226, 1991
Davis SN, Shavers C, Mosqueda-Garcia R, elderly. DOC News 3:4, 2006
Costa F: Effects of differing antecedent hypo-
Davis SN, Tate D: Effects of morning hypo- glycemia on subsequent counterregulation in nor-
glycemia on neuroendocrine and metabolic mal humans. Diabetes 46:1328–1335, 1997
responses to subsequent afternoon hypoglycemia 34
Vanessa J. Briscoe, PhD, is a clinical
in normal man. J Clin Endocrinol Metab Korytkowski MT, Mokan M, Veneman TE,
Mitrakou A, Cryer PE, Gerich JE: Reduced beta- research nurse practitioner, and Stephen
86:2043–2050, 2001
adrenergic sensitivity in patients with type 1 dia- N. Davis, MD, is chief of the Division of
Dagogo-Jack SE, Craft S, Cryer PE: Hypo- betes and hypoglycemia unawareness. Diabetes
glycemia-associated autonomic failure in insulin- Care 21:1939–1943, 1998 Diabetes, Endocrinology and Metabo-
dependent diabetes mellitus. J Clin Invest 35
Fritsche A, Stefan N, Haring H, Gerich J,
lism and Rudolph Kampmeier Professor
91:819–828, 1993
Stumvoll M: Avoidance of hypoglycemia restores of Medicine and Molecular Physiology
Segel SA, Paramore DS, Cryer PE: Defec- hypoglycemia awareness by increasing beta- and Biophysics at the Vanderbilt School
tive glucose counterregulation in type 2 diabetes adrenergic sensitivity in type 1 diabetes. Ann
(Abstract). Diabetes 49: A131, 2000 Intern Med 134:729-736, 2001 of Medicine in Nashville, Tenn.

CLINICAL DIABETES • Volume 24, Number 3, 2006 121