3129Hypoglycemia CHAPTER 406

Hypoglycemia is most commonly caused by insulin or insulin-producing

drugs used to treat diabetes mellitus or by exposure to other drugs,

including alcohol. However, a number of other disorders, including

critical organ failure, sepsis and inanition, hormone deficiencies,

non-β-cell tumors, insulinoma, and prior gastric surgery, can cause

hypoglycemia (Table 406-1). Hypoglycemia may be documented by

Whipple’s triad: (1) symptoms consistent with hypoglycemia, (2) a low

plasma glucose concentration measured with a precise method, and (3)

relief of symptoms after the plasma glucose level is raised. The lower

limit of the fasting plasma glucose concentration is normally ~70 mg/dL

(~3.9 mmol/L), but lower venous glucose levels occur normally, late

after a meal, during pregnancy, and during prolonged fasting (>24 h).

Severe hypoglycemia can cause serious morbidity and increase the risk

for serious cardiovascular events and mortality during and after the initial hypoglycemic episode. It should be considered in any patient with

episodes of confusion, an altered level of consciousness, or a seizure.

■ SYSTEMIC GLUCOSE BALANCE AND

GLUCOSE COUNTERREGULATION

Glucose is an obligate metabolic fuel for the brain under physiologic

conditions. The brain cannot synthesize glucose or store more than

a few minutes’ supply as glycogen and therefore requires a continuous supply of glucose from the arterial circulation. As the arterial

plasma glucose concentration falls below the physiologic range, bloodto-brain glucose transport becomes insufficient to support brain

energy metabolism and function. However, multiple integrated glucose

406 Hypoglycemia

Stephen N. Davis, Philip E. Cryer

TABLE 406-1 Causes of Hypoglycemia in Adults

Ill or Medicated Individual

1. Drugs

Insulin or insulin secretagogues

Alcohol

Others

2. Critical illness

Hepatic, renal, or cardiac failure

Sepsis

Inanition

3. Hormone deficiency

Cortisol

Growth hormone

Glucagon and epinephrine (in insulin-deficient diabetes)

4. Non–islet cell tumor (e.g., mesenchymal tumors)

Seemingly Well Individual

5. Endogenous hyperinsulinism

Insulinoma

Functional β-cell disorders (nesidioblastosis)

Noninsulinoma pancreatogenous hypoglycemia

Post–gastric bypass hypoglycemia

Insulin autoimmune hypoglycemia

Antibody to insulin

Antibody to insulin receptor

Insulin secretagogues

Other

6. Disorders of gluconeogenesis and fatty acid oxidation

7. Exercise

8. Accidental, surreptitious, or malicious hypoglycemia

Source: Modified with permission from PE Cryer et al: Evaluation and management

of adult hypoglycemic disorders: An Endocrine Society clinical practice guideline.

J Clin Endocrinol Metab 94:709, 2009.

counterregulatory mechanisms normally prevent or rapidly correct

hypoglycemia.

Plasma glucose concentrations are normally maintained within a

relatively narrow range—roughly 70–110 mg/dL (3.9–6.1 mmol/L)

in the fasting state, with transient higher excursions after a meal—

despite wide variations in exogenous glucose delivery from meals and

in endogenous glucose utilization by, for example, exercising muscle.

Between meals and during fasting, plasma glucose levels are maintained by endogenous glucose production, hepatic glycogenolysis, and

hepatic (and renal) gluconeogenesis (Fig. 406-1). Although hepatic

glycogen stores are usually sufficient to maintain plasma glucose levels

for ~8 h, this period can be shorter if glucose demand is increased by

exercise or if glycogen stores are depleted by illness or starvation.

Gluconeogenesis normally requires low insulin levels and the presence of anti-insulin (counterregulatory) hormones together with a

coordinated supply of precursors from muscle and adipose tissue to

the liver and kidneys. Muscle provides lactate, pyruvate, alanine, glutamine, and other amino acids. Triglycerides in adipose tissue are broken

down into fatty acids and glycerol, which is a gluconeogenic precursor.

Fatty acids provide an alternative oxidative fuel to tissues other than the

brain (which requires glucose).

Systemic glucose balance, maintenance of the normal plasma

glucose concentration, is accomplished by a network of hormones,

neural signals, and substrate effects that regulate endogenous glucose

production and glucose utilization by tissues other than the brain

(Chap. 403). Among the regulatory factors, insulin plays a dominant

role (Table 406-2; Fig. 406-1). As plasma glucose levels decline within

the physiologic range, pancreatic β-cell insulin secretion decreases,

thereby increasing hepatic glycogenolysis and hepatic (and renal)

gluconeogenesis. Low insulin levels also reduce glucose utilization in

peripheral tissues, inducing lipolysis and proteolysis and consequently

releasing gluconeogenic precursors. Thus, a decrease in insulin secretion is the first defense against hypoglycemia.

As plasma glucose levels decline just below the physiologic range,

glucose counterregulatory (plasma glucose–raising) hormones are

released (Table 406-2; Fig. 406-1). Among these, pancreatic α-cell glucagon and adrenomedullary epinephrine play a primary role. Glucagon

stimulates hepatic glycogenolysis and gluconeogenesis. Adrenomedullary epinephrine also stimulates hepatic glycogenolysis and gluconeogenesis (and renal gluconeogenesis) but limits peripheral uptake of

glucose and stimulates lipolysis with production of glycerol and fatty

acids. Epinephrine becomes critical when glucagon is deficient. When

hypoglycemia is prolonged beyond ~4 h, cortisol and growth hormone

also support glucose production and restrict glucose utilization to a

limited amount (both mechanisms are reduced by ~80% compared

to epinephrine). Thus, cortisol and growth hormone play no role in

defense against acute hypoglycemia.

As plasma glucose levels fall further, symptoms prompt behavioral defense against hypoglycemia, including the ingestion of food

(Table 406-2; Fig. 406-1). The normal glycemic thresholds for these

responses to decreasing plasma glucose concentrations are shown in

Table 406-2. However, these thresholds are dynamic. They shift to

higher-than-normal glucose levels in people with poorly controlled

diabetes, who can experience symptoms of hypoglycemia when their

glucose levels decline toward the normal range. On the other hand,

thresholds shift to lower-than-normal glucose levels in people with

recurrent hypoglycemia; i.e., patients with intensively treated diabetes

or an insulinoma have symptoms at glucose levels lower than those that

cause symptoms in healthy individuals.

Clinical Manifestations Neuroglycopenic manifestations of

hypoglycemia are the direct result of central nervous system glucose

deprivation. These features include behavioral changes, confusion,

fatigue, seizure, loss of consciousness, cardiac arrhythmias, and, if

hypoglycemia is severe, death. Neurogenic (or autonomic) manifestations of hypoglycemia result from the perception of physiologic

changes caused by the central nervous system–mediated sympathoadrenal discharge that is triggered by hypoglycemia. They include adrenergic symptoms (mediated largely by norepinephrine released from

3130 PART 12 Endocrinology and Metabolism

and nondiabetic individuals. These responses increase platelet aggregation, reduce fibrinolytic balance (increase plasminogen activator

inhibitor-1), and increase intravascular coagulation. Hypoglycemia

also reduces protective nitric oxide–mediated arterial vasodilator

mechanisms in healthy, T1DM, and T2DM individuals.

■ HYPOGLYCEMIA IN DIABETES

Impact and Frequency Hypoglycemia is the limiting factor in the

glycemic management of diabetes mellitus. First, it causes recurrent

morbidity in most people with T1DM and in many with advanced

T2DM, and it is sometimes fatal. Second, it precludes maintenance

of euglycemia over a lifetime of diabetes and, thus, full realization of

the well-established microvascular benefits of glycemic control. Third,

it causes a vicious cycle of recurrent hypoglycemia by producing

hypoglycemia-associated autonomic failure—i.e., the clinical syndromes of defective glucose counterregulation and of hypoglycemia

unawareness.

Brain

Pituitary

Growth

hormone

(ACTH)

Adrenal

cortex

Cortisol

Pancreas

Arterial glucose

Insulin

Liver

Kidneys Glucose

production

Arterial

glucose Muscle Fat

Gluconeogenic

precursor (lactate,

amino acids, glycerol)

Glucagon

Sympathoadrenal

outflow

Sympathetic

postganglionic

neurons

Adrenal

medullae

Epinephrine

Norepinephrine

Acetylcholine

Glucose

clearance

Symptoms

(Ingestion)

FIGURE 406-1 Physiology of glucose counterregulation: Mechanisms that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes, the

key counterregulatory responses—suppression of insulin and increases in glucagon—are lost, and stimulation of sympathoadrenal outflow is attenuated. ACTH,

adrenocorticotropic hormone.

sympathetic postganglionic neurons but perhaps also by epinephrine

released from the adrenal medullae), such as palpitations, tremor, and

anxiety, as well as cholinergic symptoms (mediated by acetylcholine

released from sympathetic postganglionic neurons), such as sweating,

hunger, and paresthesias. Clearly, these are nonspecific symptoms.

Their attribution to hypoglycemia requires that the corresponding

plasma glucose concentration be low and that the symptoms resolve

after the glucose level is raised (as delineated by Whipple’s triad).

Common signs of hypoglycemia include diaphoresis and pallor.

Heart rate and systolic blood pressure are typically increased but may

not be raised in an individual who has experienced repeated, recent

episodes of hypoglycemia. Neuroglycopenic manifestations are often

observable. Transient focal neurologic deficits occur occasionally. Permanent neurologic deficits are rare.

Etiology and Pathophysiology Hypoglycemia activates proinflammatory, procoagulant, and proatherothrombotic responses in

type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM),

TABLE 406-2 Physiologic Responses to Decreasing Plasma Glucose Concentrations

RESPONSE

GLYCEMIC THRESHOLD,

mmoL/L (mg/dL) PHYSIOLOGIC ↓ EFFECTS

ROLE IN PREVENTION OR CORRECTION OF HYPOGLYCEMIA

(GLUCOSE COUNTERREGULATION)

↓ Insulin 4.4–4.7 (80–85) ↑ Ra

 (↓ Rd

), increased lipolysis;

↑ FFA

↑ Glycerol

Primary glucose regulatory factor/first defense against hypoglycemia

↑ Glucagon 3.6–3.9 (65–70) ↑ Ra Primary glucose counterregulatory factor/second defense against

hypoglycemia

↑ Epinephrine 3.6–3.9 (65–70) ↑ Ra, ↓ Rc, increased lipolysis;

↑ FFA and glycerol

Third defense against hypoglycemia; critical when glucagon is deficient

↑ Cortisol and growth

hormone

3.6–3.9 (65–70) ↑ Ra, ↓ Rc Involved in defense against prolonged hypoglycemia; not critical

Symptoms 2.8–3.1 (50–55) Recognition of hypoglycemia Prompt behavioral defense against hypoglycemia (food ingestion)

↓ Cognition <2.8 (<50) — Compromises behavioral defense against hypoglycemia

Note: Ra

, rate of glucose appearance, glucose production by the liver and kidneys; Rc

, rate of glucose clearance, glucose utilization relative to the ambient plasma glucose

by insulin-sensitive tissues; Rd

, rate of glucose disappearance, glucose utilization by insulin-sensitive tissues such as skeletal muscle. Rd

 by the brain is not altered by

insulin, glucagon, epinephrine, cortisol, or growth hormone.

Abbreviation: FFA, free fatty acids.

Source: Reproduced with permission from PE Cryer, in S Melmed et al: Williams Textbook of Endocrinology, 12th ed. New York, NY: Elsevier; 2012.

3131Hypoglycemia CHAPTER 406

Hypoglycemia is a fact of life for people with T1DM if treated with

insulin, sulfonylurea, or glinides. They suffer an average of two episodes of symptomatic hypoglycemia per week and at least one episode

of severe, at least temporarily disabling hypoglycemia each year. An

estimated 6–10% of people with T1DM die as a result of hypoglycemia.

The incidence of hypoglycemia is lower in T2DM than in T1DM. However, its prevalence in insulin-requiring T2DM is surprisingly high.

Recent studies have revealed a hypoglycemia prevalence approaching

70%. In fact, as patients with T2DM outnumber those with T1DM

by ten- to twentyfold, the prevalence of hypoglycemia is now greater

in T2DM. Hypoglycemia can occur at any hemoglobin A1c (HbA1C)

level. Although severe hypoglycemia occurs twice as frequently at

lower HbA1C levels in T1DM, it still occurs at HbA1C levels >8%. In

insulin-requiring T2DM, severe hypoglycemia can occur at lower

HbA1C values but also importantly at values of 8–10%. Severe hypoglycemia in T2DM carries an increased risk of severe cardiovascular

and cerebrovascular morbidity and mortality for up to 1 year after

the event. The risk of severe hypoglycemia and a subsequent cardiovascular adverse event is, in fact, relatively increased when trying to

improve glucose control in some T2DM individuals with persistently

raised HbA1C values. Therefore, improvements in glycemic control in

these individuals should be performed incrementally and carefully

to avoid episodes of hypoglycemia. Insulin, sulfonylureas, or glinides

can cause hypoglycemia in T2DM. Metformin, thiazolidinediones,

α-glucosidase inhibitors, glucagon-like peptide 1 (GLP-1) receptor

agonists, sodium-glucose cotransporter-2 inhibitors, and dipeptidyl

peptidase IV (DPP-IV) inhibitors do not cause hypoglycemia. However, they increase the risk when combined with a sulfonylurea, glinide,

or insulin. Notably, the frequency of hypoglycemia approaches that in

T1DM as persons with T2DM develop absolute insulin deficiency and

require more complex treatment with insulin.

Conventional Risk Factors The conventional risk factors for

hypoglycemia in diabetes are identified on the basis of relative or absolute insulin excess. This occurs when (1) insulin (or

insulin secretagogue) doses are excessive, ill-timed,

or of the wrong type; (2) the influx of exogenous

glucose is reduced (e.g., during an overnight fast,

periods of temporary fasting, or after missed meals

or snacks); (3) insulin-independent glucose utilization is increased (e.g., during exercise); (4) sensitivity

to insulin is increased (e.g., with improved glycemic

control, in the middle of the night, after exercise, or

with increased fitness or weight loss); (5) endogenous glucose production is reduced (e.g., after alcohol ingestion); and (6) insulin clearance is reduced

(e.g., in renal failure). However, these conventional

risk factors alone explain a minority of episodes;

other factors are typically involved.

Hypoglycemia-Associated Autonomic Failure

(HAAF) While marked insulin excess alone can

cause hypoglycemia, iatrogenic hypoglycemia in diabetes (T1DM and/or T2DM) is typically the result

of the interplay of relative or absolute therapeutic

insulin excess and compromised physiologic and

behavioral defenses against falling plasma glucose

concentrations (Table 406-2; Fig. 406-2). Defective

glucose counterregulation compromises physiologic

defense (particularly decrements in insulin and increments in glucagon and epinephrine), and hypoglycemia unawareness compromises behavioral defense

(ingestion of carbohydrate).

DEFECTIVE GLUCOSE COUNTERREGULATION In

the setting of absolute endogenous insulin deficiency,

insulin levels do not decrease as plasma glucose levels fall; thus, the first defense against hypoglycemia is

lost. After a few years of disease duration in T1DM,

glucagon levels do not increase as plasma glucose levels fall; a second

defense against hypoglycemia is lost. Reduced glucagon responses to

hypoglycemia also occur in long-duration T2DM. However, pancreatic

alpha cells that produce glucagon are present in the same number and

size in T1DM as compared to age-matched nondiabetic individuals.

Thus, the defect that restricts glucagon release during hypoglycemia

in T1DM (and presumably in long-standing T2DM) appears to be

a signaling defect, as glucagon responses to other physiologic stress

in T1DM (e.g., exercise) are preserved. Finally, the increase in epinephrine levels, the third critical defense against acute hypoglycemia, is

typically attenuated. The glycemic threshold for the sympathoadrenal

(adrenomedullary epinephrine and sympathetic neural norepinephrine) response is shifted to lower plasma glucose concentrations. That

shift is typically the result of recent antecedent iatrogenic hypoglycemia. In the setting of absent decrements in insulin and of absent increments in glucagon, the attenuated increment in epinephrine causes

the clinical syndrome of defective glucose counterregulation. Affected

patients are at ≥25-fold greater risk of severe iatrogenic hypoglycemia

during intensive glycemic therapy for their diabetes than are patients

with normal epinephrine responses. This functional—and potentially

reversible—disorder is distinct from classic diabetic autonomic neuropathy, which also includes all of the above pathophysiologic defects,

and is a structural and irreversible disorder.

HYPOGLYCEMIA UNAWARENESS The attenuated sympathoadrenal

response (largely the reduced sympathetic neural response) to hypoglycemia causes the clinical syndrome of hypoglycemia unawareness—i.e.,

loss of the warning adrenergic and cholinergic symptoms that previously allowed the patient to recognize developing hypoglycemia and

therefore to abort the episode by ingesting carbohydrates. Affected

patients are at a sixfold increased risk of severe iatrogenic hypoglycemia during intensive glycemic therapy of their diabetes.

HAAF IN DIABETES The concept of HAAF in diabetes posits that

recent antecedent iatrogenic hypoglycemia (or sleep or prior exercise)

Early T2DM

(Relative β-cell failure)

Marked absolute therapeutic

hyperinsulinemia →

Falling glucose levels

Isolated episodes

of hypoglycemia

Advanced T2DM and T1DM

(Absolute β-cell failure)

Relative or mild-moderate absolute

therapeutic hyperinsulinemia →

Falling glucose levels

Attenuated sympathoadrenal

responses to hypoglycemia

(HAAF)

β-cell failure → No ↓

insulin and no ↑ glucagon

Episodes of hypoglycemia

Exercise Sleep

↓ Adrenomedullary

epinephrine responses

↓ Sympathetic

neural responses

Hypoglycemia

unawareness

Defective glucose

counterregulation

Recurrent

hypoglycemia

FIGURE 406-2 Hypoglycemia-associated autonomic failure (HAAF) in insulin-deficient diabetes. T1DM,

type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. (Modified from PE Cryer: Hypoglycemia in

Diabetes. Pathophysiology, Prevalence, and Prevention, 2nd ed. © American Diabetes Association, 2012.)

3132 PART 12 Endocrinology and Metabolism

causes both defective glucose counterregulation (by reducing the epinephrine response to a given level of subsequent hypoglycemia in the

setting of absent insulin and glucagon responses) and hypoglycemia

unawareness (by reducing the sympathoadrenal response to a given

level of subsequent hypoglycemia). These impaired responses, which

can occur in individuals with either T1DM or T2DM, create a vicious

cycle of recurrent iatrogenic hypoglycemia (Fig. 406-2). Hypoglycemia

unawareness and, to some limited extent, the reduced epinephrine

component of defective glucose counterregulation can be reversible by

as little as 2–3 weeks of scrupulous avoidance of hypoglycemia in most

affected patients.

On the basis of this pathophysiology, additional risk factors for

hypoglycemia in diabetes include (1) absolute insulin deficiency,

indicating that insulin levels will not decrease and glucagon levels will

not increase as plasma glucose levels fall; (2) a history of severe hypoglycemia or of hypoglycemia unawareness, implying recent antecedent

hypoglycemia, as well as prior exercise or sleep, indicating that the

sympathoadrenal response will be attenuated; (3) impaired renal function resulting in reduced clearance of exogenous and endogenous insulin; (4) classical diabetic autonomic neuropathy; and (5) lower HbA1C

or lower glycemic goals even at elevated HbA1C levels (8–10%), as they

represent an increased probability of recent antecedent hypoglycemia.

Hypoglycemia Risk Factor Reduction Several recent, multicenter, randomized controlled trials investigating the potential benefits

of tight glucose control in either inpatient or outpatient settings have

reported a high prevalence of severe hypoglycemia. In the NICESUGAR study, attempts to control in-hospital plasma glucose values

toward physiologic levels resulted in increased mortality risk. The

ADVANCE and ACCORD studies and the Veterans Affairs Diabetes

Trial (VADT) also found a significant incidence of severe hypoglycemia among T2DM patients. Severe hypoglycemia with accompanying

serious cardiovascular morbidity and mortality also occurred in the

standard (e.g., not receiving intensified treatment) control group in

all of the above studies and in another large study in prediabetic and

T2DM individuals (ORIGIN). Thus, as stated above, severe hypoglycemia can and does occur at HbA1c values of 8–10% in both T1DM

and T2DM. Somewhat surprisingly, all three studies found little or no

benefit of intensive glucose control to reduce macrovascular events in

T2DM. In fact, the ACCORD study was ended early because of the

increased mortality rate in the intensive glucose control arm. Whether

iatrogenic hypoglycemia was the cause of the increased mortality risk is

not known. In light of these findings, some new recommendations and

paradigms have been formulated. Whereas there is little debate regarding the need to reduce hyperglycemia in the hospital, the glycemic

maintenance goals in critical care settings have been modified to stay

between 140 and 180 mg/dL. Similar glycemic targets are also recommended in non–critically ill patients by a number of expert societies,

although some recommend even more strict glucose control down to

108 mg/dL. Accordingly, the benefits of insulin therapy and reduced

hyperglycemia can be obtained while the prevalence of hypoglycemia

is reduced.

Similarly, evidence exists that intensive glucose control can reduce

the prevalence of microvascular disease in both T1DM and T2DM.

These benefits need to be weighed against the increased prevalence of

hypoglycemia. Certainly, the level of glucose control (i.e., the HbA1c

value, symptoms of hyper- and hypoglycemia, and home glucose

values) should be evaluated for each patient. Multicenter trials have

demonstrated that individuals with recently diagnosed T1DM or

T2DM can have better glycemic control with less hypoglycemia. In

addition, there is still long-term benefit in reducing HbA1c values from

higher to lower, albeit still above recommended levels. Perhaps a reasonable therapeutic goal is the lowest HbA1c level that does not cause

severe hypoglycemia and that preserves awareness of hypoglycemia.

Pancreatic transplantation (both whole organ and islet cell) has been

used in part as a treatment for severe hypoglycemia. Generally, rates of

hypoglycemia are reduced after transplantation. This decrease appears

to be due to increased physiologic insulin and glucagon responses

during hypoglycemia.

The use of continuous glucose monitors (CGMs), either alone or

in combination with continuous subcutaneous infusion via a wearable

pump, offers promise as a method of reducing hypoglycemia while

improving HbA1c. Specifically, continuous glucose monitoring coupled

with temporary discontinuation of subcutaneous insulin infusion when

the monitor predicts a low glucose concentration is particularly promising. Studies investigating the use of CGM during inpatient care for both

insulin-requiring pediatric and adult patients with diabetes are ongoing.

Furthermore, progress utilizing a portable wearable “artificial pancreas”

incorporating continuous glucose sensor modulation of either insulin

alone or bi-hormonal delivery of both insulin and glucagon has been

established. Additionally, stem cell–derived β cells also offer promise of

novel therapeutic interventions to reduce hypoglycemia.

Other interventions to stimulate counterregulatory responses, such

as selective serotonin reuptake inhibitors, β-adrenergic receptor antagonists, opiate receptor antagonists, and fructose, remain experimental

and have not been assessed in large-scale clinical trials.

Thus, intensive glycemic therapy (Chap. 404) needs to be applied

along with the patient’s education and empowerment, frequent selfmonitoring of blood glucose, flexible insulin (and other drug) regimens

(including the use of insulin analogues, both short- and longer-acting),

individualized glycemic goals, and ongoing professional guidance, support, and consideration of both the conventional risk factors and those

indicative of compromised glucose counterregulation. Given a history

of hypoglycemia unawareness, a 2- to 3-week period of scrupulous

avoidance of hypoglycemia is indicated.

■ HYPOGLYCEMIA WITHOUT DIABETES

There are many causes of hypoglycemia (Table 406-1). Because hypoglycemia is common in insulin- or insulin secretagogue–treated diabetes, it is often reasonable to assume that a clinically suspicious episode

is the result of hypoglycemia. On the other hand, because hypoglycemia is rare in the absence of relevant drug-treated diabetes (pregnancy

and during severe episodes of morning sickness), it is reasonable to

conclude that a hypoglycemic disorder is present only in patients in

whom Whipple’s triad can be demonstrated.

Particularly when patients are ill or medicated, the initial diagnostic

focus should be on the possibility of drug involvement and then on critical illnesses, hormone deficiency, or non–islet cell tumor hypoglycemia. In the absence of any of these etiologic factors and in a seemingly

well individual, the focus should shift to possible endogenous hyperinsulinism or accidental, surreptitious, or even malicious hypoglycemia.

Drugs Insulin and insulin secretagogues suppress glucose production and stimulate glucose utilization. Ethanol blocks gluconeogenesis

but not glycogenolysis. Thus, alcohol-induced hypoglycemia typically

occurs after a several-day ethanol binge during which the person eats

little food, with consequent glycogen depletion. Ethanol is usually

measurable in blood at the time of presentation, but its levels correlate

poorly with plasma glucose concentrations. Because gluconeogenesis

becomes the predominant route of glucose production during prolonged hypoglycemia, alcohol can contribute to the progression of

hypoglycemia in patients with insulin-treated diabetes.

Many other drugs have been associated with hypoglycemia. These

include commonly used drugs such as angiotensin-converting enzyme

inhibitors and angiotensin receptor antagonists, β-adrenergic receptor antagonists, quinolone antibiotics, indomethacin, quinine, and

sulfonamides.

Critical Illness Among hospitalized patients, serious illnesses such

as renal, hepatic, or cardiac failure; sepsis; and inanition are second

only to drugs as causes of hypoglycemia.

Rapid and extensive hepatic destruction (e.g., toxic hepatitis) causes

fasting hypoglycemia because the liver is the major site of endogenous

glucose production. The mechanism of hypoglycemia in patients

with cardiac failure is unknown. Hepatic congestion and hypoxia

may be involved. Although the kidneys are a source of glucose production, hypoglycemia in patients with renal failure is also caused by

the reduced clearance of insulin (thereby inappropriately increasing

3133Hypoglycemia CHAPTER 406

insulin relative to the prevailing glucose levels) and the reduced mobilization of gluconeogenic precursors in renal failure.

Sepsis is a relatively common cause of hypoglycemia. Increased glucose utilization is induced by cytokine production in macrophage-rich

tissues such as the liver, spleen, and lung. Hypoglycemia develops if

glucose production fails to keep pace. Cytokine-induced inhibition

of gluconeogenesis in the setting of nutritional glycogen depletion, in

combination with hepatic and renal hypoperfusion, may also contribute to hypoglycemia.

Hypoglycemia can be seen with starvation. Due to brain conversion

and utilization of alternative substrates, such as lactate, pyruvate, and

ketone bodies, there is only a modest counterregulatory neuroendocrine and autonomic nervous system response. During periods of prolonged starvation (fasting) plasma glucose levels are lower in women as

compared to men, perhaps because of loss of whole-body fat stores and

subsequent depletion of gluconeogenic precursors (e.g., amino acids),

necessitating increased glucose utilization.

Hormone Deficiencies Neither cortisol nor growth hormone is

critical to the prevention of hypoglycemia, at least in adults. Nonetheless, hypoglycemia can occur with prolonged fasting in patients

with primary adrenocortical failure (Addison’s disease) or hypopituitarism. Anorexia and weight loss are typical features of chronic

cortisol deficiency and likely result in glycogen depletion. Cortisol

deficiency is associated with impaired gluconeogenesis and low levels

of gluconeogenic precursors; these associations suggest that substrate-limited gluconeogenesis, in the setting of glycogen depletion,

is the cause of hypoglycemia. Growth hormone deficiency can cause

hypoglycemia in young children. In addition to extended fasting,

high rates of glucose utilization (e.g., during exercise or in pregnancy)

or low rates of glucose production (e.g., after alcohol ingestion) can

precipitate hypoglycemia in adults with previously unrecognized

hypopituitarism.

Hypoglycemia is not a feature of the epinephrine-deficient state that

results from bilateral adrenalectomy when glucocorticoid replacement

is adequate, nor does it occur during pharmacologic adrenergic blockade when other glucoregulatory systems are intact. Combined deficiencies of glucagon and epinephrine play a key role in the pathogenesis of

iatrogenic hypoglycemia in people with insulin-deficient diabetes, as

discussed earlier. Otherwise, deficiencies of these hormones are not usually considered in the differential diagnosis of a hypoglycemic disorder.

Non–β-Cell Tumors Fasting hypoglycemia, often termed non–

islet cell tumor hypoglycemia, occurs occasionally in patients with large

mesenchymal or epithelial tumors (e.g., hepatomas, adrenocortical

carcinomas, carcinoids). The glucose kinetic patterns resemble those of

hyperinsulinism (see next), but insulin secretion is suppressed appropriately during hypoglycemia. In most instances, hypoglycemia is due

to overproduction of an incompletely processed form of insulin-like

growth factor II (“big IGF-II”) that does not complex normally with

circulating binding proteins and thus more readily gains access to target tissues. The tumors are usually apparent clinically, plasma ratios of

IGF-II to IGF-I are high, and free IGF-II levels (and levels of pro-IGF-II

[1–21]) are elevated. Curative surgery is seldom possible, but reduction

of tumor bulk may ameliorate hypoglycemia. Therapy with a glucocorticoid, growth hormone, or both has also been reported to alleviate

hypoglycemia. Hypoglycemia attributed to ectopic IGF-I production

has been reported but is rare.

Endogenous Hyperinsulinism Hypoglycemia due to endogenous hyperinsulinism can be caused by (1) a primary β-cell disorder—

typically a β-cell tumor (insulinoma), sometimes multiple insulinomas,

or a functional β-cell disorder with β-cell hypertrophy or hyperplasia; (2)

an antibody to insulin or to the insulin receptor; (3) a β-cell secretagogue

such as a sulfonylurea; or perhaps (4) ectopic insulin secretion, among

other very rare mechanisms. None of these causes are common.

The fundamental pathophysiologic feature of endogenous hyperinsulinism caused by a primary β-cell disorder or an insulin secretagogue is the failure of insulin secretion to fall to very low levels during

hypoglycemia. This feature is assessed by measurement of plasma

insulin, C-peptide (the connecting peptide that is cleaved from proinsulin to produce insulin), proinsulin, and glucose concentrations

during hypoglycemia. Insulin, C-peptide, and proinsulin levels need

not be high relative to normal, euglycemic values; rather, they are

inappropriately high in the setting of a low plasma glucose concentration. Critical diagnostic findings are a plasma insulin concentration

≥3 μU/mL (≥18 pmol/L), a plasma C-peptide concentration ≥0.6 ng/

mL (≥0.2 nmol/L), and a plasma proinsulin concentration ≥5.0 pmol/L

when the plasma glucose concentration is <55 mg/dL (<3.0 mmol/L)

with symptoms of hypoglycemia. A low plasma β-hydroxybutyrate

concentration (≤2.7 mmol/L) and an increment in plasma glucose

level of >25 mg/dL (>1.4 mmol/L) after IV administration of glucagon

(1.0 mg) indicate increased insulin (or IGF) actions.

The diagnostic strategy is (1) to measure plasma glucose, insulin,

C-peptide, proinsulin, and β-hydroxybutyrate concentrations and to

screen for circulating oral hypoglycemic agents during an episode

of hypoglycemia and (2) to assess symptoms during the episode and

seek their resolution following correction of hypoglycemia by glucose

(either oral or parenteral) or by IV injection of glucagon (i.e., to document Whipple’s triad). This is straightforward if the patient is hypoglycemic when seen. Since endogenous hyperinsulinemic disorders

usually, but not invariably, cause fasting hypoglycemia, a diagnostic

episode may develop after a relatively short outpatient fast. Serial

sampling during an inpatient diagnostic fast of up to 72 h or after a

mixed meal is more problematic. An alternative is to give patients a

detailed list of the required measurements and ask them to present to

an ambulatory care center or emergency room, with the list, during a

symptomatic episode. Obviously, a normal plasma glucose concentration during a symptomatic episode indicates that the symptoms are not

the result of hypoglycemia.

An insulinoma—an insulin-secreting pancreatic islet β-cell tumor—

is the prototypical cause of endogenous hyperinsulinism and therefore

should be sought in patients with a compatible clinical syndrome.

However, insulinoma is not the only cause of endogenous hyperinsulinism. Some patients with fasting endogenous hyperinsulinemic

hypoglycemia have diffuse islet involvement with β-cell hypertrophy

and sometimes hyperplasia. This pattern is commonly referred to as

nesidioblastosis, although β-cells budding from ducts are not invariably

found. Other patients have a similar islet pattern but with postprandial hypoglycemia, a disorder termed noninsulinoma pancreatogenous

hypoglycemia. Post–gastric bypass postprandial hypoglycemia, which

most often follows Roux-en-Y gastric bypass, is also characterized

by diffuse islet involvement and endogenous hyperinsulinism. Multiple pathophysiologic mechanisms have been suggested including

exaggerated GLP-1 responses to meals resulting in hyperinsulinemia,

hypoglucagonemia, and hypoglycemia. However, other mechanisms

may be responsible for the relative hyperinsulinemia, such as reduced

insulin clearance and reduced glucagon responses to hypoglycemia.

The relevant pathogenesis has not been clearly established. However,

if medical treatment with agents such as an α-glucosidase inhibitor,

diazoxide, or octreotide fail, partial pancreatectomy may be required.

Autoimmune hypoglycemias include those caused by an antibody to

insulin that binds postmeal insulin and then gradually disassociates,

with consequent late postprandial hypoglycemia. Alternatively, an

insulin receptor antibody can function as an agonist. The presence of

an insulin secretagogue, such as a sulfonylurea or a glinide, results in

a clinical and biochemical pattern similar to that of an insulinoma but

can be distinguished by the presence of the circulating secretagogue.

Finally, there are reports of very rare phenomena such as ectopic

insulin secretion, a gain-of-function insulin receptor mutation, and

exercise-induced hyperinsulinemia.

Insulinomas are uncommon, with an estimated yearly incidence of 1

in 250,000. Because >90% of insulinomas are benign, they are a treatable

cause of potentially fatal hypoglycemia. The median age at presentation

is 50 years in sporadic cases, but the tumor usually presents in the third

decade when it is a component of multiple endocrine neoplasia type 1

(Chap. 388). More than 99% of insulinomas are within the substance

of the pancreas, and the tumors are usually small (<2.0 cm in diameter

3134 PART 12 Endocrinology and Metabolism

in 90% of cases). Therefore, they come to clinical attention because of

hypoglycemia rather than mass effects. CT or MRI detects ~70–80%

of insulinomas. These methods detect metastases in the roughly 10%

of patients with a malignant insulinoma. Transabdominal ultrasound

often identifies insulinomas, and endoscopic ultrasound has a sensitivity of ~90%. Somatostatin receptor scintigraphy is thought to detect

insulinomas in about half of patients. Selective pancreatic arterial

calcium injections, with the endpoint of a sharp increase in hepatic

venous insulin levels, regionalize insulinomas with high sensitivity, but

this invasive procedure is seldom necessary except to confirm endogenous hyperinsulinism in the diffuse islet disorders. Intraoperative pancreatic ultrasonography almost invariably localizes insulinomas that

are not readily palpable by the surgeon. Surgical resection of a solitary

insulinoma is generally curative. Diazoxide, which inhibits insulin

secretion, or the somatostatin analogue octreotide can be used to

treat hypoglycemia in patients with unresectable tumors; everolimus,

an mTOR (mammalian target of rapamycin) inhibitor, has also been

successful in combination with the above approaches.

■ ACCIDENTAL, SURREPTITIOUS,

OR MALICIOUS HYPOGLYCEMIA

Accidental ingestion of an insulin secretagogue (e.g., as the result of a

pharmacy or other medical error) or even accidental administration of

insulin can occur. Factitious hypoglycemia, caused by surreptitious or

even malicious administration of insulin or an insulin secretagogue,

shares many clinical and laboratory features with insulinoma. It is

most common among health care workers, patients with diabetes or

their relatives, and people with a history of other factitious illnesses.

However, it should be considered in all patients being evaluated for

hypoglycemia of obscure cause. Ingestion of an insulin secretagogue

causes hypoglycemia with increased C-peptide levels, whereas exogenous insulin causes hypoglycemia with low C-peptide levels, reflecting

suppression of insulin secretion.

Analytical error in the measurement of plasma glucose concentrations is rare. On the other hand, hand-held and continuous glucose

monitors used to guide treatment of diabetes are not quantitative

instruments, particularly at low glucose levels, and should not be used

for the definitive diagnosis of hypoglycemia. Even with a quantitative

method, low measured glucose concentrations can be artifactual—e.g.,

the result of continued glucose metabolism by the formed elements of

the blood ex vivo, particularly in the presence of leukocytosis, erythrocytosis, or thrombocytosis or with delayed separation of the serum

from the formed elements (pseudohypoglycemia).

■ INBORN ERRORS OF METABOLISM

CAUSING HYPOGLYCEMIA

Nondiabetic hypoglycemia also results from inborn errors of metabolism. Such hypoglycemia most commonly occurs in infancy but can

also occur in adulthood. Cases in adults can be classified into those

resulting in fasting hypoglycemia, postprandial hypoglycemia, and

exercise-induced hypoglycemia.

Fasting Hypoglycemia Although rare, disorders of glycogenolysis

can result in fasting hypoglycemia. These disorders include glycogen

storage disease (GSD) of types 0, I, III, and IV and Fanconi-Bickel

syndrome (Chap. 419). Patients with GSD types I and III characteristically have high blood lactate levels before and after meals, respectively.

Both groups have hypertriglyceridemia, but ketones are high in GSD

type III. Defects in fatty acid oxidation also result in fasting hypoglycemia. These defects can include (1) defects in the carnitine cycle; (2)

fatty-acid β-oxidation disorders; (3) electron transfer disturbances;

and (4) ketogenesis disorders. Finally, defects in gluconeogenesis

(fructose-1,6-biphosphatase) have been reported to result in recurrent

hypoglycemia and lactic acidosis.

Postprandial Hypoglycemia Inborn errors of metabolism resulting in postprandial hypoglycemia are also rare. These errors include (1)

glucokinase, SUR1, and Kir6.2 potassium channel mutations; (2) congenital disorders of glycosylation; and (3) inherited fructose intolerance.

Exercise-Induced Hypoglycemia Exercise-induced hypoglycemia, by definition, follows exercise. It results in hyperinsulinemia

caused by increased activity of monocarboxylate transporter 1 in β cells.

APPROACH TO THE PATIENT

Hypoglycemia

In addition to the recognition and documentation of hypoglycemia

as well as its treatment (often on an urgent basis), diagnosis of the

hypoglycemic mechanism is critical for the selection of therapy that

prevents, or at least minimizes, recurrent hypoglycemia.

RECOGNITION AND DOCUMENTATION

Hypoglycemia is suspected in patients with typical symptoms; in

the presence of confusion, an altered level of consciousness, or a

seizure; or in a clinical setting in which hypoglycemia is known

to occur. Blood should be drawn, whenever possible, before the

administration of glucose to allow documentation of a low plasma

glucose concentration. Convincing documentation of hypoglycemia requires the fulfillment of Whipple’s triad. Thus, the ideal

time to measure the plasma glucose level is during a symptomatic

episode. A normal glucose level excludes hypoglycemia as the cause

of the symptoms. A low glucose level confirms that hypoglycemia

is the cause of the symptoms, provided the latter resolve after

the glucose level is raised. When the cause of the hypoglycemic

episode is obscure, additional measurements—made while the

glucose level is low and before treatment—should include plasma

insulin, C-peptide, proinsulin, and β-hydroxybutyrate levels; also

critical are screening for circulating oral hypoglycemic agents and

assessment of symptoms before and after the plasma glucose concentration is raised.

When the history suggests prior hypoglycemia and no potential mechanism is apparent, the diagnostic strategy is to evaluate

the patient as just described and assess for Whipple’s triad during

and after an episode of hypoglycemia. On the other hand, while it

cannot be ignored, a distinctly low plasma glucose concentration

measured in a patient without corresponding symptoms raises the

possibility of an artifact (pseudohypoglycemia).

DIAGNOSIS OF THE HYPOGLYCEMIC MECHANISM

In a patient with documented hypoglycemia, a plausible hypoglycemic mechanism can often be deduced from the history, physical

examination, and available laboratory data (Table 406-1). Drugs,

particularly alcohol or agents used to treat diabetes, should be the

first consideration—even in the absence of known use of a relevant

drug—given the possibility of surreptitious, accidental, or malicious

drug administration. Other considerations include evidence of a

relevant critical illness, hormone deficiencies (less commonly),

and a non-β-cell tumor that can be pursued diagnostically (rarely).

Absent one of these mechanisms in an otherwise seemingly well

individual, the care provider should consider endogenous hyperinsulinism and proceed with measurements and assessment of

symptoms during spontaneous hypoglycemia or under conditions

that might elicit hypoglycemia.

URGENT TREATMENT

If the patient is able and willing, oral treatment with glucose tablets or glucose-containing fluids, candy, or food is appropriate. A

reasonable initial dose is 15–20 g of glucose. If the patient is unable

or unwilling (because of neuroglycopenia) to take carbohydrates

orally, parenteral therapy is necessary. IV administration of glucose (25 g) should be followed by a glucose infusion guided by

serial plasma glucose measurements. If IV therapy is not practical,

SC or IM glucagon (1.0 mg in adults) can be used, particularly in

patients with T1DM. Because it acts by stimulating glycogenolysis, glucagon is ineffective in glycogen-depleted individuals (e.g.,

those with alcohol-induced hypoglycemia). Glucagon also stimulates insulin secretion and is therefore less useful in T2DM. The