Basic and Clinical Endocrinology 7th International student edition Edition

18

Hypoglycemic Disorders

John H. Karam MD

Umesh Masharani MRCP (UK)

Circulating plasma glucose concentrations are kept within a relatively narrow range by a complex system of interrelated neural, humoral, and cellular controls. Under the usual metabolic conditions, the central nervous system is wholly dependent on plasma glucose and counteracts declining blood glucose concentrations with a carefully programmed response. This is often associated with a sensation of hunger; and, as the brain receives insufficient glucose to meet its metabolic needs (neuroglycopenia), an autonomic response is triggered to mobilize storage depots of glycogen and fat. In the postabsorptive state, hepatic glycogen reserves and gluconeogenesis from the liver and kidney directly supply the central nervous system with glucose, which is carried across the blood-brain barrier by a specific glucose transport system, while the mobilization of fatty acids from triglyceride depots provides energy for the large mass of skeletal and cardiac muscle, renal cortex, liver, and other tissues that utilize fatty acids as their basic fuel, thus sparing glucose for use by the tissues of the central nervous system.

PATHOPHYSIOLOGY OF THE COUNTERREGULATORY RESPONSE TO NEUROGLYCOPENIA

The plasma concentration of glucose that will signal the need by the central nervous system to mobilize energy reserves depends on a number of factors, such as the status of blood flow to the brain, the integrity of cerebral tissue, the prevailing arterial level of plasma glucose, the rapidity with which plasma glucose concentration falls, and the availability of alternative metabolic fuels.

A hierarchy of responses has been shown to occur as plasma glucose falls in healthy young volunteers, with hormonal counterregulatory responses being triggered at glucose levels slightly higher (approximately 67 mg/dL [3.7 mmol/L]) than those which induce symptoms of hypoglycemia (Figure 18-1). The first symptoms to appear in healthy people are mediated by autonomic neurotransmitters and occur at plasma glucose levels below 60 mg/dL (3.3 mmol/L). The symptoms consist of tremor, anxiety, palpitations, and sweating, which result from sympathetic discharge; and hunger, which is a consequence of parasympathetic vagal response. Ganglionic blockade and cervical cord section or sympathectomy—but not adrenalectomy—ameliorate these symptoms, indicating that they are due to the release of autonomic neurotransmitters and not dependent on adrenal hormones. As plasma glucose falls below 50 mg/dL (2.8 mmol/L), cerebral neuroglycopenia ensues, consisting of impaired cognition, along with weakness, lethargy, confusion, incoordination, and blurred vision. If counterregulatory responses are inadequate to reverse this degree of profound hypoglycemia, convulsions or coma may occur. This can result in brain damage or death, particularly in those who have not adapted to repeated episodes of hypoglycemia (see below).

In elderly people, however, with compromised cerebral blood supply, neuroglycopenic manifestations may be provoked at slightly higher plasma glucose levels. Patients with chronic hyperglycemia, eg, those with poorly controlled insulin-treated diabetes mellitus, may experience symptoms of neuroglycopenia at considerably higher plasma glucose concentrations than persons without diabetes. This has been attributed to a “down-regulated” glucose transport system across the blood-brain barrier. Conversely, in patients exposed to chronic hypoglycemia—eg, those with an insulin-secreting tumor or those with diabetes who are receiving excessively “tight” glycemic control with an insulin pump—adaptation to recurrent hypoglycemia occurs by “up-regulation” of the glucose transporters, which results in “hypoglycemic unawareness” whereby they show greater tolerance to hypoglycemia without manifesting symptoms (Figure 18-2).

Restoring and maintaining an adequate supply of glucose for cerebral function proceeds by a series of neurogenic events that act directly to raise the plasma glucose concentration and to stimulate hormonal responses that augment the adrenergic mobilization of energy stores (Table 18-1).

 

Figure 18-1. Hierarchy of autonomic responses to progressive stepwise reduction in plasma glucose concentration in healthy volunteers. (Adapted from Gerich JE et al: Hypoglycemia unawareness. Endocr Rev 1991;12:356; and from Service FJ: Hypoglycemia disorders. N Engl J Med 1995;332:1144.)

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Counterregulatory Response to Hypoglycemia

  1. INSULIN

Endogenous insulin secretion is lowered both by reduced glucose stimulation to the pancreatic B cell and by sympathetic nervous system inhibition from a combination of alpha-adrenergic neural effects and increased circulating catecholamine levels. This reactive insulinopenia appears to be essential for glucose recovery, as it facilitates the mobilization of energy from existing energy stores (glycogenolysis and lipolysis); increases hepatic enzymes involved in gluconeogenesis and ketogenesis; increases enzymes of the renal cortex, promoting gluconeogenesis; and at the same time prevents muscle tissue from consuming the blood glucose being released from the liver (Chapter 17).

  1. CATECHOLAMINES

Circulating catecholamines—and norepinephrine produced at sympathetic nerve endings—provide muscle tissue with alternative sources of fuel by activating beta-

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adrenergic receptors, resulting in mobilization of muscle glycogen, and by providing increased plasma free fatty acids from lipolysis of adipocyte triglyceride. Metabolism of these free fatty acids provides energy to promote gluconeogenesis in the liver and kidney, thereby adding to plasma glucose levels already raised by the glycogenolytic effect of catecholamines on the liver and their direct stimulation of gluconeogenesis by the renal cortex. Their cardiovascular and other side effects provide a signal that diabetic patients learn to recognize as a warning of their need to rapidly ingest absorbable carbohydrate.

 

Figure 18-2. Glycemic regulation of glucose transporters. The center panel depicts the normal component of the high-affinity glucose transporter 1 (GLUT1) on the vascular cells of the central nervous system during euglycemia. An appropriate amount of glucose diffuses across the blood-brain barrier and is then transported into the neurons by another high-affinity glucose transporter, GLUT3. The upper and lower panels, respectively, show adaptation by either down-regulation of GLUT1 in the face of chronic hyperglycemia (upper panel) or up-regulation of GLUT1 in the presence of chronic hypoglycemia. (GLUT1, glucose transporter 1; GLUT3, glucose transporter 3.)

Table 18-1. Autonomic nervous system response to hypoglycemia.

Alpha-adrenergic effects
   Inhibition of endogenous insulin release
   Increase in cerebral blood flow (peripheral vasoconstriction)
Beta-adrenergic effects
   Hepatic and muscle glycogenolysis
   Stimulation of plasma glucagon release
   Lipolysis to raise plasma free fatty acids
   Impairment of glucose uptake by muscle tissue
   Increase in cerebral blood flow (increase in cardiac output)
Adrenomedullary discharge of catecholamines
   Augmentation of all of the above alpha- and beta-adrenergic effects
Cholinergic effects
   Raises level of pancreatic polypeptide
   Increases motility of stomach
   Produces hunger
   Increases sweating

  1. GLUCAGON

Plasma glucagon is released by the beta-adrenergic effects of both sympathetic innervation and circulating catecholamines on pancreatic A cells as well as by the direct stimulation of A cells by the low plasma glucose concentration itself. Data are available suggesting that a falling-off of intra-islet insulin concentration in subjects with functioning pancreatic B cells can release pancreatic A cells from insulin inhibition and thus augment glucagon release during hypoglycemia. This glucagon release increases hepatic output of glucose by direct glycogenolysis as well as by facilitating the activity of gluconeogenic enzymes in the liver but not in the kidney. As shown in Figure 18-3, plasma glucagon appears to be the key counterregulatory hormone affecting recovery from acute hypoglycemia in nondiabetic humans, with the adrenergic-catecholamine response representing a major backup system. However, in most clinical situations, where hypoglycemia develops more gradually, as with inappropriate dosage of insulin or sulfonylureas, or in cases of insulinoma, the role of glucagon may be less influential. When normal volunteers received a prolonged low-dose insulin infusion to produce a gradual decline in plasma glucose levels without waning of insulin levels, the rise of endogenous glucagon contributed much less to counterregulation than after acute hypoglycemia induced by intravenous insulin, which is followed by rapid waning of insulin levels. This finding suggests that glucagon's role in glucose recovery occurs primarily when the level of insulin wanes.

  1. CORTICOTROPIN AND HYDROCORTISONE

Pituitary ACTH is released in association with the sympathetic nervous system stimulation by neuroglycopenia. This results in elevation of plasma cortisol levels, which in turn permissively facilitates lipolysis and actively promotes protein catabolism and conversion of amino acids to glucose by the liver and kidney.

  1. GROWTH HORMONE

Pituitary growth hormone is also released in response to falling plasma glucose levels. Its role in counteracting hypoglycemia is less well defined, but it is known to antagonize the action of insulin on glucose utilization in muscle cells and to directly activate lipolysis by adipocytes. This increased lipolysis provides fatty acid substrate to the liver and renal cortex which facilitates gluconeogenesis.

  1. CHOLINERGIC NEUROTRANSMITTERS

Acetylcholine is released at parasympathetic nerve endings, and its vagal effects induce the sensation of hunger that signals the need for food to counteract the hypoglycemia. In addition, postsynaptic fibers of the sympathetic nervous system that innervate the sweat glands to signal hypoglycemia also release acetylcholine—in contrast to all other sympathetic postsynaptic fibers, which without exception release norepinephrine.

Maintenance of Euglycemia in the Postabsorptive State

Glucose absorption from the gastrointestinal tract ceases by 4–6 hours after a meal. During the “postabsorptive state”immediately following, glucose must be produced endogenously from previously stored nutrients to meet the requirements of the central nervous system and other glucose-dependent tissues. These include 125 mg of glucose per minute required by the brain and spinal cord as well as an additional 25 mg/min by red blood cells and the renal medulla. It was previously thought that the liver is the only organ involved in glucose production during an overnight fast, but recent data indicate

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that the renal cortex also has the requisite enzymes for production and release of glucose.

 

Figure 18-3. Solid lines show changes in plasma glucose that occur in normal subjects in response to acute intravenous insulin administration. Note the rapid recovery of glucose levels mediated by intact counterregulatory mechanisms. The dashed lines show the response to insulin-induced hypoglycemia in patients with deficiencies of the counterregulatory mechanisms induced as follows: A:Somatostatin infusion (inhibits both glucagon and growth hormone [GH] release). B: Somatostatin infusion plus GH infusion (now with functional isolated glucagon deficiency). C: Somatostatin infusion plus glucagon infusion (isolated GH deficiency). Note return of glucose response to normal, implying that glucagon is the main counterregulatory hormone. D: Bilateral adrenalectomy, leading to epinephrine deficiency, or infusion of phentolamine plus propranolol (alpha and beta blockers, respectively). Note that such deficiencies cause no major abnormality in response to induced hypoglycemia when glucagon is present. E and F: Sympathetic modulation (by phentolamine plus propranolol in E and by bilateral adrenalectomy in F), which seriously impairs the ability to respond to hypoglycemia in the patient made glucagon-deficient by somatostatin infusion. (Reproduced, with permission, from Cryer PE: Glucose counterregulation in man. Diabetes 1981;30:261.)

The liver initially provides glucose by the breakdown of stored hepatic glycogen. However, because these reserves are limited to 80–100 g, they begin to be depleted several hours into the postabsorptive state. Thereafter, hepatic glucose production is augmented by gluconeogenesis—the formation of glucose from amino acids, lactate, and glycerol. These substrates are delivered to the liver and kidney from peripheral stores. Muscle and other structural tissues supply amino acids, mainly alanine; blood cell elements supply lactate, the end product of glycolytic metabolism; and adipose tissue supplies glycerol from lipolysis of triglyceride. In addition, oxidation of the free fatty acids released from adipose cells during lipolysis supplies the energy required for gluconeogenesis and provides ketone bodies, acetoacetate, and β-hydroxybutyrate, which can serve as alternative metabolic fuels for the central nervous system during periods of prolonged fasting. Studies have shown that an insulin infusion does not reduce hepatic glucose production if elevated levels of fatty acids are maintained by intravenous administration of a fat emulsion and heparin, suggesting that fatty acids may be the major mediator of gluconeogenesis.

Role of the Kidney

Although it is generally acknowledged that after fasting for 60 hours the kidney contributes up to 20–25% of endogenous glucose production, its role after an overnight fast remains controversial. One group has found that it produces as much as 25% of the postabsorptive glucose requirement, yet a second group using different methodology found a contribution of no more than 5% in the postabsorptive state. Despite these conflicting findings, it is clear that since the renal medulla removes almost as much glucose as the renal cortex produces, the net renal contribution is minimal in the short-term postabsorptive state as compared to the liver.

The kidney does not have glycogen stores and is dependent on gluconeogenesis as its only source of glucose

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production. Glutamine—rather than alanine—is the predominant amino acid substrate for renal gluconeogenesis. In addition to its contribution to glucose homeostasis after an overnight fast, the kidney also has been shown to be an important contributor to glucose counterregulation in the event of hypoglycemia. While glucagon does not affect the kidney, the counterregulatory rise in catecholamines has been shown to stimulate gluconeogenesis in the renal cortex. As with the liver, insulin inhibits renal gluconeogenesis and glucose release. Hormonal changes that begin early in the postabsorptive state regulate the enzymatic steps necessary for hepatic glycogenolysis and hepatic and renal gluconeogenesis and ensure the delivery of the necessary substrate (Table 18-2). An appropriate fall in circulating insulin levels with a corresponding rise in glucagon is most important; elevations in the counterregulatory hormones cortisol and growth hormone contribute but are less critical. Thus, numerous endocrine and metabolic events interact to provide a continuous source of fuel for proper functioning of the central nervous system. Malfunction of any of these mechanisms can lead to symptomatic hypoglycemia.

Role of PGC-1 in Regulation of Gluconeogenesis

It has long been known that stress-induced catecholamines as well as glucagon generate cAMP, which promotes gluconeogenesis in the liver. Insulin opposes this action but does not seem to do so by directly reducing cAMP levels, and its mode of action has previously been unexplained. Recently, however, discovery of a new protein expressed in liver—peroxisome proliferator activated receptor-gamma coactivator-1 (PGC-1)—has provided new insight into the regulation of gluconeogenesis on a cellular level. PGC-1 has been found to act also as a coactivator of gene expression of key gluconeogenic enzymes. It is believed that cAMP increases expression of PGC-1, which acts as a coactivator with glucocorticoids and a hepatic nuclear factor to stimulate expression of key hormones of gluconeogenesis. Insulin inhibits this process by interfering with PGC-1 expression so that gluconeogenic enzymes are not induced.

Table 18-2. Hormonal changes to maintain euglycemia in the postabsorptive state.

Decreased insulin secretion
   Increases hepatic glycogenolysis
   Increases lipolysis
   Increases hepatic gluconeogenesis
   Decreases muscle uptake of glucose
Increased glucagon secretion
   Increases hepatic glycogenolysis
   Facilitates hepatic gluconeogenesis
Increased cortisol secretion
   Facilitates lipolysis
   Increases protein catabolism
   Augments hepatic gluconeogenesis

CLASSIFICATION OF HYPOGLYCEMIC DISORDERS

Symptomatic Hypoglycemia

A clinical classification of the more common causes of symptomatic hypoglycemia in adults is presented in Table 18-3. (Inborn errors of metabolism that produce hypoglycemia in infants and children are not listed and will not be discussed in this chapter.) This classification is useful in directing diagnostic considerations.

Symptomatic fasting hypoglycemia is a serious and potentially life-threatening problem warranting thorough evaluation. Conditions that produce inappropriate fasting hyperinsulinism are the most common cause of fasting hypoglycemia in otherwise healthy adults. These include insulin-secreting pancreatic B cell tumors and iatrogenic or surreptitious administration of insulin

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or sulfonylureas. In patients with illnesses that produce symptomatic fasting hypoglycemia despite appropriately suppressed insulin levels, the clinical picture is generally dominated by the signs and symptoms of the primary disease, with hypoglycemia often only a late or associated manifestation. This is in contrast to patients with inappropriate hyperinsulinism, who usually appear healthy between hypoglycemic episodes.

Table 18-3. Common causes of symptomatic hypoglycemia in adults.

Fasting
   With hyperinsulinism
      Insulin reaction
      Sulfonylurea overdose
      Surreptitious insulin or sulfonylurea self-administration
      Autoimmune hypoglycemia (idiopathic insulin antibodies, insulin receptor autoantibodies)
      Pentamidine-induced hypoglycemia
      Pancreatic B cell tumors
   Without hyperinsulinism
      Severe hepatic dysfunction
      Chronic renal insufficiency
      Inanition
      Hypocortisolism
      Alcohol use
      Nonpancreatic tumors
Nonfasting
   Alimentary
   Functional
   Noninsulinoma pancreatogenous hypoglycemic syndrome (NIPHS)
   Occult diabetes
   Ethanol ingestion with sugar mixers

Symptoms of nonfasting hypoglycemia in adults, although distressing to the patient, do not in most cases imply serious illness or warrant extensive evaluation. Overstimulation of the B cells postprandially as a result of accelerated glucose absorption after rapid gastric emptying may result in too rapid disposal of glucose, with resulting symptoms of sympathetic nervous system hyperactivity (alimentary hypoglycemia). Other than in patients who have had gastric surgery, this diagnosis may be difficult to establish. A newly described but quite rare disorder of adult nesidioblastosis called noninsulinoma pancreatogenous hypoglycemia syndrome has been found to provoke severe symptoms of hypoglycemia with neuroglycopenia 4–6 hours after meals (see below).

Asymptomatic Hypoglycemia

Hypoglycemia may be seen during prolonged fasting, strenuous exercise, or pregnancy or may occur as a laboratory artifact. In normal men, plasma glucose does not fall below 55 mg/dL (3 mmol/L) during a 72-hour fast. However, for reasons that are not clear, normal women may experience a fall to levels as low as 30 mg/dL (1.7 mmol/L) despite a marked suppression of circulating insulin to less than 5 ľU/mL. They remain asymptomatic in spite of this degree of hypoglycemia, presumably because ketogenesis is able to satisfy the energy needs of the central nervous system. Basal plasma glucose declines progressively during normal pregnancy, and hypoglycemic levels may be reached during prolonged fasting. This may be a consequence of a continuous fetal consumption of glucose and diminished availability of the gluconeogenic substrate alanine. The cause of these diminished alanine levels in pregnancy is unclear. The greatly increased glucose consumption by skeletal muscle that occurs during prolonged strenuous exercise may lead to hypoglycemia despite increases in hepatic glucose production. Whether the hypoglycemia in this circumstance contributes to fatigue or other symptoms in distance runners is unknown.

In vitro consumption of glucose by blood cell elements may give rise to laboratory values in the hypoglycemic range. This can be avoided by adding a small amount of the metabolic inhibitor sodium fluoride to collection tubes used for specimens containing increased numbers of blood cells (as in leukemia, leukemoid reactions, or polycythemia).

CLINICAL PRESENTATION OF HYPOGLYCEMIA

Regardless of the cause, hypoglycemia presents certain common features characterized by Whipple's triad: (1) symptoms and signs of hypoglycemia, (2) an associated plasma glucose level of 45 mg/dL (2.5 mmol/L) or less, and (3) reversibility of symptoms upon administration of glucose.

The symptoms and signs of hypoglycemia are the consequences of neuroglycopenia. They vary depending on the degree of hypoglycemia, the age of the patient, and the rapidity of the decline. In poorly controlled diabetic patients treated with insulin, a precipitous fall in plasma glucose from hyperglycemia toward euglycemia may produce neuroglycopenic symptoms.

  1. ACUTE HYPOGLYCEMIA

A rapid fall in plasma glucose (> 1 mg/dL/min [> 0.06 mmol/L/min]) to low levels often accompanies conditions associated with arterial hyperinsulinism—a condition that leads to increased peripheral glucose uptake and decreased hepatic glucose output. In diabetics, excessive absorption of exogenous insulin either from overtreatment or from rapid mobilization from an injection site during exercise may be responsible. In nondiabetics, reactive hypersecretion of insulin may be the cause, as in postgastrectomy patients with rapid gastric emptying time. The symptoms include anxiety, tremulousness, and feelings of unnaturalness or detachment. These are usually accompanied by palpitations, tachycardia, sweating, and hunger and can progress to neurologic sequelae of ataxia, coma, or convulsions. These warning symptoms of hypoglycemia occur even in the absence of adrenal glands and therefore are due to neurogenic responses to hypoglycemia. The autonomic response has probably evolved as more of an alarm than a counterregulatory mechanism, since glucagon is generally sufficient to provide necessary counterregulation to hypoglycemia once insulin levels wane. In type 1 diabetes, however, the adrenergic system becomes of greater importance since the glucagon response to hypoglycemia is lost in most patients (Chapter 17), and subcutaneous depots of exogenous insulin may prevent inappropriately high levels of insulin from waning.

  1. SUBACUTE AND CHRONIC HYPOGLYCEMIA

A relatively slow fall in plasma glucose accompanies conditions caused primarily by a reduction in hepatic glucose output in response to hyperinsulinism (predominantly within the portal vein [insulinoma]), or to

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the inappropriately sustained effects of long-acting insulin preparations on the liver and kidney in the postabsorptive state, or to metabolic derangements of gluconeogenesis (eg, alcohol hypoglycemia). Symptoms due to hypoglycemia in patients with these conditions may be less apparent, particularly because sympathetic discharge is minimal or delayed until profound hypoglycemia develops. Recurrent hypoglycemic episodes result in hypoglycemic unawareness with impairment of autonomic responses and an increased risk for severe hypoglycemia. These patients develop progressive confusion, inappropriate behavior, lethargy, and drowsiness. If the patient does not eat, seizures or coma may develop—though this is not inevitable, and spontaneous recovery can occur. Because these patients are seldom aware of their degree of functional impairment, a history should be obtained from relatives or friends who have observed the episode. Except for hypothermia (often seen during hypoglycemic coma), there are no identifying characteristics on physical examination. Hypoglycemia will often be misdiagnosed as a seizure disorder, transient ischemic attack, or personality disorder.

Documentation of Low Plasma Glucose Values

With the specific laboratory methods now available, it has been arbitrarily decided that fasting hypoglycemia is present when plasma glucose is 45 mg/dL (2.5 mmol/L) or less after an overnight fast (corresponding to a blood glucose level of 40 mg/dL [2.2 mmol/L] or less). In the fasting state, there is no substantial difference between arterial, venous, or capillary blood samples (in contrast to nonfasting hyperglycemia, in which arteriovenous glucose differences may be considerable because of arterial hyperinsulinism and consequent increases in glucose uptake across capillary beds).

The development of portable blood glucose meters has been of great value for rapid estimation of blood glucose levels, particularly for insulin-treated diabetics undergoing home monitoring. In emergency room or hospital settings, they are helpful in the differential diagnosis of coma, but a sample should also be sent to the laboratory for definitive diagnosis. Although therapeutic decisions to administer glucose can be based on the glucose meter results alone in an emergency situation, such readings are less dependable as the sole laboratory indicator for a definitive diagnosis of hypoglycemia.

Reversibility of Clinical Manifestations of Hypoglycemia with Treatment

Because prolonged hypoglycemia may cause permanent brain damage and death, prompt recognition and treatment are mandatory. (It is prudent to consider the possibility of hypoglycemic coma in most unconscious patients.)

The goal of therapy is to restore normal levels of plasma glucose as rapidly as possible. If the patient is conscious and able to swallow, glucose-containing foods such as candy, orange juice with added sugar, and cookies should be quickly ingested. Fructose, found in many nutrient low-calorie sweeteners for diabetics, should not be used, because although it can be metabolized by neurons, it is not transported across the blood-brain barrier.

If the patient is unconscious, rapid restoration of plasma glucose must be accomplished by giving 20–50 mL of 50% dextrose intravenously over 1–3 minutes (the treatment of choice) or, when intravenous glucose is not available, 1 mg of glucagon intramuscularly or intravenously. Families or friends of insulin-treated diabetics should be instructed in the administration of glucagon intramuscularly for emergency treatment at home. Attempts to feed the patient or to apply glucose-containing jelly to the oral mucosa should be avoided because of the danger of aspiration.

When consciousness is restored, oral feedings should be started immediately. Periodic blood glucose surveillance after a hypoglycemic episode may be needed for 12–24 hours to ensure maintenance of euglycemia. Prevention of recurrent hypoglycemic attacks depends upon proper diagnosis and management of the specific underlying disorder.

SPECIFIC HYPOGLYCEMIC DISORDERS

SYMPTOMATIC FASTING HYPOGLYCEMIA WITH HYPERINSULINISM

  1. Insulin Reaction

It is not surprising that insulin-treated diabetics make up the bulk of the patient population with symptomatic hypoglycemia. Present methods of insulin delivery rely upon subcutaneous depots of mixtures of soluble and insoluble insulin whose absorption varies with the site of injection and the degree of exercise in surrounding muscles. Variations in physical and emotional stresses can alter the response of patients to insulin, as can the cyclic hormonal changes relating to menstruation. A deficient glucagon response to hypoglycemia in diabetes compounds the problem, as does the lack of awareness of hypoglycemic symptoms in older patients, in those with neuropathy, and in those with recurrent

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hypoglycemic episodes, who adapt to lower levels of blood glucose without triggering their autonomic alarm system. (See Figure 18-2 andChapter 17 for further discussion of hypoglycemic unawareness.)

Once the patient's acute hypoglycemic episode is managed, the physician should carefully examine possible correctable factors that may have contributed to the insulin reaction.

Inadequate Food Intake

An insufficient quantity of food or a missed meal is one of the commonest causes of hypoglycemia in insulin-treated diabetics. Until improved insulin delivery systems are available, patients attempting to achieve satisfactory glycemic control should self-monitor their blood glucose levels and eat three regular meals as well as small mid morning, mid afternoon, and bedtime snacks, particularly when they are receiving multiple injections of insulin daily.

Exercise

The insulin-treated diabetic is especially prone to exercise-induced hypoglycemia. In nondiabetics, the enhancement of skeletal muscle glucose uptake (a 20- to 30-fold increase over basal uptake) is compensated for by enhanced hepatic and renal glucose production. This is mediated primarily by a fall in circulating insulin levels consequent to an exercise-induced catecholamine discharge, which inhibits B cell secretion. Such regulation is impossible in the insulin-treated diabetic, whose subcutaneous depot not only continues to release insulin during exercise but also shows an accelerated absorption rate when the injection site is in close proximity to the muscles being exercised. When this occurs, increased levels of circulating insulin compromise the hepatic and renal output of glucose. To prevent hypoglycemia, insulin-treated diabetics must be advised to avoid injections into areas adjacent to muscles most involved in the particular exercise and either to eat supplementary carbohydrate before exercising or to reduce their insulin dose appropriately.

Impaired Glucose Counterregulation in Diabetes

Most patients with type 1 diabetes have a deficient glucagon response to hypoglycemia. They are thus solely dependent on an adrenergic autonomic response to recover from hypoglycemia and particularly to provide them with symptoms they recognize as a warning of impending hypoglycemia and as a signal to ingest sugar or fruit juice. Some patients, especially those with long-standing diabetes, autonomic neuropathy, or a history of recurrent hypoglycemic episodes, lack both a glucagon and an epinephrine response and are virtually defenseless against insulin-induced hypoglycemia. Insulin infusion tests can be used to identify these alterations in glucose counterregulation; however, at present these tests are cumbersome, and their ability to accurately predict which patients will suffer frequent severe and prolonged hypoglycemic episodes is yet to be established. Easier and more reliable methods of identifying such patients are needed. The ability of a patient to spontaneously recover from hypoglycemia may determine whether or not aggressive attempts to maintain euglycemia are associated with undue risk.

Some patients who originally had a normal counterregulatory response to hypoglycemia (except for glucagon) lose this protective response when insulin therapy is intensified to achieve tight control, which may be associated with frequent hypoglycemic events including nocturnal hypoglycemia. The mechanisms for this reduction of hormonal response are unknown but seem to be related to “up-regulated” mechanisms of glucose transport across the blood-brain barrier induced by relatively low circulating blood glucose levels. However, one study could not confirm an increase in glucose transport across the blood-brain barrier in subjects with hypoglycemic unawareness and suggested that the adaptation to chronic hypoglycemia may be on a neuronal level within the brain. Regardless of the mechanism, this defective counterregulation has been shown to be reversible to a considerable degree by careful monitoring of intensive insulin therapy to avoid any blood glucose measurements below 70 mg/dL for a period of 3 weeks or longer.

Inadvertent or Deliberate Insulin Overdosage in Diabetics

Excessive insulin may be administered inadvertently by patients with poor vision or inadequate instruction or understanding of dosage and injection technique. The widespread use of highly concentrated U100 insulin enhances the likelihood of overdosage with relatively small excesses of administered insulin.

Deliberate overdosage may occur in certain maladjusted patients, particularly adolescents, who wish to gain special attention from their families or escape tensions at school or work.

Miscellaneous Causes of Hypoglycemia in Insulin-Treated Diabetics

  1. STRESS

Physical stresses—such as intercurrent illnesses, infection, and surgery—or psychic stresses often require an increased insulin dosage to control hyperglycemia. Reduction

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to prestress doses is necessary to avoid subsequent hypoglycemia when the stresses have abated.

  1. HYPOCORTISOLISM

In patients with type 1 diabetes who have otherwise unexplained hypoglycemic attacks, reduced insulin requirements may indicate unusual causes (eg, Addison's disease).

  1. DIABETIC GASTROPARESIS

Unexplained episodes of postprandial hypoglycemia in insulin-treated diabetics may be due to delayed gastric emptying consequent to autonomic neuropathy. This diagnosis can be established by appropriate radiologic studies of gastric motility using liquid or solid test meals containing radioisotopic markers.

  1. PREGNANCY

Pregnancy, with high fetal glucose consumption, decreases insulin requirements in the first trimester.

  1. RENAL INSUFFICIENCY

Renal insufficiency, through impairment of insulin degradation and renal gluconeogenesis while hepatic gluconeogenesis and food intake are often reduced, also requires a reduction in insulin dosage.

  1. DRUGS

Numerous pharmacologic agents may potentiate the effects of insulin and predispose to hypoglycemia. Common offenders include ethanol, salicylates, and beta-adrenergic blocking drugs. Beta blockade inhibits fatty acid and gluconeogenic substrate release and reduces plasma glucagon levels; furthermore, the symptomatic response is altered, because tachycardia is blocked while hazardous elevations of blood pressure may result during hypoglycemia in response to the unopposed alpha-adrenergic stimulation from circulating catecholamines and neurogenic sympathetic discharge. However, symptoms of sweating, hunger, and uneasiness are not masked by beta-blocking drugs and remain indicators of hypoglycemia in the aware patient.

Therapy with angiotensin-converting enzyme (ACE) inhibitors increases the risk of hypoglycemia in diabetic patients who are taking insulin or sulfonylureas, presumably because these drugs increase sensitivity to circulating insulin by increasing blood flow to muscle.

  1. Sulfonylurea Overdose

Any of the sulfonylurea drugs may produce hypoglycemia. Chlorpropamide, with its prolonged half-life (35 hours), was a common offender, but its use has been curtailed recently because of its numerous adverse effects. Older patients—especially those with impaired hepatic or renal function—are particularly susceptible to sulfonylurea-induced hypoglycemia: Liver dysfunction prolongs the hypoglycemic activity of tolbutamide, acetohexamide, and tolazamide, as well as that of the second-generation compounds glyburide and glipizide; renal insufficiency perpetuates the blood glucose-lowering effects of many sulfonylureas, especially chlorpropamide and glyburide. Elderly patients with gradually decreasing creatinine clearance seem to be more at risk for prolonged and severe hypoglycemia when treated with chlorpropamide or glyburide and less so when treated with shorter-acting agents such as tolbutamide or glipizide. In the presence of other pharmacologic agents such as warfarin, phenylbutazone, or certain sulfonamides, the hypoglycemic effects of sulfonylureas may be markedly prolonged.

  1. Surreptitious Insulin or Sulfonylurea Administration (Factitious Hypoglycemia)

Factitious hypoglycemia should be suspected in any patient with access to insulin or sulfonylurea drugs. It is most commonly seen in health professionals and diabetic patients or their relatives. The reasons for self-induced hypoglycemia vary, with many patients having severe psychiatric disturbances or a need for attention. Inadvertent ingestion of sulfonylureas resulting in clinical hypoglycemia has also been reported, due either to patient error or to a prescription mishap on the part of a pharmacist.

When insulin is used to induce hypoglycemia, an elevated serum insulin level often raises suspicion of an insulin-producing pancreatic B cell tumor. It may be difficult to prove that the insulin is of exogenous origin. The triad of hypoglycemia, high immunoreactive insulin levels, and suppressed plasma C peptide immunoreactivity* is pathognomonic of exogenous insulin administration. The inappropriate presence of circulating antibodies to insulin (usually seen only in insulin-treated individuals), will generally support the diagnosis of factitious hypoglycemia. However, the absence of detectable insulin antibodies does not rule out the possibility of exogenous insulin administration, especially with the advent of human insulins and insulin analogs with low immunogenicity in humans.

When sulfonylurea abuse is suspected, plasma or urine should be screened for its presence. Hypoglycemia with inappropriately elevated levels of serum

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insulin and C-peptide along with detectable sulfonylureas in blood or urine are diagnostic of inadvertent or factitious sulfonylurea overdose. While all first- and second-generation sulfonylureas are measureable in standard chromatographic assays, the third-generation drug glimepiride—as well as other insulin secretagogues such as repaglinide and nateglinide—require special methodology.

Treatment of factitious hypoglycemia involves psychiatric therapy and social counseling.

  1. Autoimmune Hypoglycemia

In recent years, a rare autoimmune disorder has been reported in which patients have circulating insulin antibodies and the paradoxic feature of hypoglycemia. While some of these patients may be surreptitiously administering insulin, in an increasing number of case reports it has not been possible to document exogenous insulin as the inducer of insulin antibodies. More than 200 cases of insulin-antibody-associated hypoglycemia have been reported since 1970, with 90% of cases reported in Japanese patients. HLA class II alleles—DRB1*0406, DQA1*0301, and DQB1*0302—are associated with this syndrome, and these alleles are ten to thirty times more prevalent in Japanese and Koreans, which may explain the higher prevalence of this syndrome in these populations. Hypoglycemia generally occurs 3–4 hours after a meal and follows an early postprandial hyperglycemia. It is attributed to a dissociation of insulin-antibody immune complexes, releasing free insulin. This autoimmune hypoglycemia, which is due to accumulation of high titers of antibodies capable of reacting with endogenous insulin, has been most commonly reported in methimazole-treated patients with Graves' disease from Japan as well as in patients with various other sulfhydryl-containing medications (captopril, penicillamine) and other drugs such as hydralazine, isoniazid, and procainamide. In addition, it has been reported in patients with autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and polymyositis as well as in multiple myeloma and other plasma cell dyscrasias where paraproteins or antibodies cross-react with insulin.

In most cases the hypoglycemia is transient and usually resolves spontaneously within 3–6 months of diagnosis, particularly when the offending medications are stopped. The most consistent therapeutic benefit in management of this syndrome has been achieved by dietary treatment with frequent low-carbohydrate small meals; and prednisone therapy (30–60 mg/d) has been used to lower the titer of insulin antibodies.

Hypoglycemia due to insulin receptor autoantibodies is also an extremely rare syndrome; most cases have occurred in women often with a history of autoimmune disease. Almost all of these patients have also had episodes of insulin-resistant diabetes and acanthosis nigricans. Their hypoglycemia may be either fasting or postprandial and is often severe and is attributed to an agonistic action of the antibody on the insulin receptor. Balance between the antagonistic and agonistic effects of the antibody determines whether insulin-resistant diabetes or hypoglycemia occurs. Hypoglycemia was found to respond to glucocorticoid therapy but not to plasmapheresis or immunosuppression.

  1. Pentamidine-Induced Hypoglycemia

With the use of intravenous pentamidine for treatment of Pneumocystis carinii infection in patients with AIDS, reports of pentamidine-induced hypoglycemia have appeared. The cause of acute hypoglycemia appears to be the drug's lytic effect on B cells, which produces acute hyperinsulinemia in about 10–20% of patients receiving the drug. Physicians treating patients with pentamidine should be aware of the potential complication of acute hypoglycemia, which may be followed later by occasionally persistent insulinopenia and hyperglycemia.

Intravenous glucose should be administered during pentamidine administration and for the period immediately following to prevent or ameliorate hypoglycemic symptoms. Following a complete course of therapy with pentamidine, fasting blood glucose or a subsequent glycohemoglobin should be monitored to assess the extent of pancreatic B cell recovery or residual damage.

Fortunately, with the advent of improved therapies for AIDS, the incidence of pneumocystis pneumonia is decreasing. Moreover, other drugs have been found to be just as effective in treating this pneumonia, so that pentamidine use and its hypoglycemic sequelae have declined in recent years.

  1. Pancreatic B Cell Tumors

Spontaneous fasting hypoglycemia in an otherwise healthy adult is most commonly due to insulinoma, an insulin-secreting tumor of the islets of Langerhans. Eighty percent of these tumors are single and benign; 10% are malignant (if metastases are identified); and the remainder are multiple, with scattered micro- or macroadenomas interspersed within normal islet tissue. (As with some other endocrine tumors, histologic differentiation between benign and malignant cells is difficult, and close follow-up is necessary to ensure the absence of metastases.)

These adenomas may be familial and have been found in conjunction with tumors of the parathyroid glands and the pituitary (multiple endocrine neoplasia

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type 1). (See Chapter 22.) Over 99% of them are located within the pancreas and less than 1% in ectopic pancreatic tissue.

These tumors may appear at any age, though they are most common in the fourth to sixth decades. A slight predominance in women has been reported in some studies, though other ones suggest no sex predilection.

Clinical Findings

The signs and symptoms are chiefly those of subacute neuroglycopenia rather than adrenergic discharge. The typical picture is that of recurrent central nervous system dysfunction at times of exercise or fasting. The preponderance of neuroglycopenic symptoms rather than those more commonly associated with hypoglycemia (adrenergic symptoms) often leads to delayed diagnosis following prolonged psychiatric care or treatment for seizure disorders or transient ischemic attacks. Some patients learn to relieve or prevent their symptoms by taking frequent feedings. Obesity may be the result; however, obesity is seen in less than 30% of patients with insulin-secreting tumors.

Diagnosis of Insulinoma

Experts in this field emphasize that the most important prerequisite to diagnosing an insulinoma is simply to consider it, particularly when facing a clinical presentation of fasting hypoglycemia with symptoms of central nervous system dysfunction such as confusion or abnormal behavior. B cell tumors do not reduce secretion in the presence of hypoglycemia, and a serum insulin level of 5 ľU/mL or more with concomitant plasma glucose values below 45 mg/dL (2.5 mmol/L) suggests an insulinoma. Other causes of hyperinsulinemic hypoglycemia must be considered, however, such as surreptitious administration of insulin or sulfonylureas.

  1. INSULIN ASSAY

Because the insulin radioimmunoassay is crucial in diagnosing insulin-secreting tumors, it is important to be aware of certain limitations in its use. It detects not only human but also beef and pork insulin as well as newer analogs of insulin such as insulin lispro, insulin aspart, and insulin glargine. Therefore, a high serum level may indicate either endogenous or exogenous insulin. (C peptide measurements are necessary to make this distinction.) In addition, the assay is of no value in patients who have taken insulin in the past year or so, as virtually all will have developed low-titer insulin antibodies that will interfere. Falsely low or elevated values will result depending on the method used. Proper collection of samples is also important: If the serum is not separated and then frozen within 1–2 hours, falsely low values will result, because the insulin molecule will undergo proteolytic digestion.

  1. SUPPRESSION TESTS

Failure of endogenous insulin secretion to be suppressed in the presence of hypoglycemia is the hallmark of an insulin-secreting tumor. The most reliable suppression test is the prolonged supervised fast in hospitalized subjects, and this remains the preferred diagnostic maneuver in the workup of suspected insulinomas. A suggested protocol for the supervised fast is set forth in Table 18-4.

In normal men, the blood glucose value will not fall below 55 mg/dL (3.1 mmol/L) during a 72-hour fast, while insulin levels fall below 10 ľU/mL; in some normal women, however, plasma glucose may fall below 30 mg/dL (1.7 mmol/L) (lower limits have not been established), while serum insulin levels also fall appropriately to less than 5 ľU/mL. (These women remain asymptomatic despite this degree of hypoglycemia, presumably because ketogenesis is able to provide sufficient fuel for the central nervous system.) Calculation of ratios of insulin (in ľU/mL) to plasma glucose (in mg/dL) can be useful diagnostically. Nonobese normal subjects maintain a ratio of less than 0.25; obese subjects may have an elevated ratio, but hypoglycemia does not occur with

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fasting. However, most centers no longer calculate this ratio and are relying only on the concentration of insulin being 5 ľU/mL or higher in the presence of hypoglycemia. Virtually all patients with insulin-secreting islet cell tumors will fail to suppress their insulin secretion appropriately and will maintain serum insulin concentrations of 5 ľU/mL or more despite a fall in plasma glucose below 45 mg/dL. The term “72-hour fast” is actually a misnomer in most cases, since the fast should be immediately terminated as soon as symptoms and laboratory confirmation of hypoglycemia are evident. Most patients with insulinomas will experience progressive and symptomatic fasting hypoglycemia with associated elevated insulin levels within 24–36 hours and no evidence of ketonuria. Consequently, one group recommended reducing the duration of the supervised diagnostic fast to no more than 48 hours for cost considerations as well as patient convenience. However, an occasional patient will not demonstrate hypoglycemia until 72 hours have elapsed, and most centers therefore prefer the fast to be supervised up to 72 hours. Brisk exercise during the fast may help precipitate hypoglycemia. Once symptoms of hypoglycemia occur, plasma glucose should be obtained and the fast immediately terminated if plasma glucose is below 45 mg/dL (2.5 mmol/L).

Table 18-4. Suggested hospital protocol for supervised fast in diagnosis of insulinoma.1

1. Obtain baseline serum glucose, insulin, proinsulin, and C-peptide measurements at onset of fast and initiate reliable intravenous access with normal saline.

2. Permit only calorie-free and caffeine-free fluids and encourage activity.

3. Measure all voided urine for acetone.

4. Obtain capillary glucose measurements with a reflectance meter every 4 hours until values < 60 mg/dL are obtained. Then increase the frequency of fingersticks to each hour, and when capillary glucose value is < 49 mg/dL send a venous blood sample to the laboratory for serum glucose, insulin, proinsulin, and C-peptide measurements. Check frequently for manifestations of neuroglycopenia.

5. If symptoms of hypoglycemia occur or if a laboratory value of serum glucose is < 45 mg/dL, conclude the fast with a final blood sample for serum glucose, insulin, proinsulin, C-peptide, and sulfonylurea measurements. Intravenous glucose should then be administered (40–50 mL of 50% dextrose in water over 3–5 minutes through the intravenous access line) and administer calorie-containing liquids and food.

1Adapted, with permission, from Service FJ: Hypoglycemic disorders. N Engl J Med 1995;332:1144.

  1. STIMULATION TESTS

A variety of stimulation tests with intravenous tolbutamide, glucagon, or calcium have been devised to demonstrate exaggerated and prolonged insulin secretion. However, because insulin-secreting tumors have a wide range of granule content and degrees of differentiation, they are variably responsive to these secretagogues. Thus, absence of an excessive insulin secretory response during any of these stimulation tests does not rule out the presence of an insulinoma. In addition, the tolbutamide stimulation test was extremely hazardous to patients with responsive tumors because it induced prolonged and refractory hypoglycemia, and for that reason it is no longer recommended for diagnosis of insulinoma. The glucagon stimulation test is performed as follows: One milligram of glucagon is given intravenously, and serum insulin levels are measured every 5 minutes for 15 minutes. A level exceeding 130 ľU/mL suggests an insulin-secreting tumor. However, only about half of patients with insulinomas will demonstrate this hyperinsulinism, and false-positive results may occur. When an exaggerated increase in serum insulin occurs, the hyperglycemic effect of glucagon may be subnormal, and profound hypoglycemia may subsequently develop by 60 minutes. To prevent this, the patient is fed and may also require intravenous glucose after the 15-minute serum sample is obtained. Nausea is an unpleasant side effect, often occurring several minutes after administration of intravenous glucagon.

  1. ORAL GLUCOSE TOLERANCE TEST

The oral glucose tolerance test is of no value in the diagnosis of insulin-secreting tumors. A common misconception is that patients with insulinomas will have flat glucose tolerance curves, because the tumor will discharge insulin in response to oral glucose. In fact, most insulinomas respond poorly, and curves typical of diabetes are more common. In those rare tumors that do release insulin in response to glucose, a flat curve may result; however, this also can be seen occasionally in normal subjects.

  1. PROINSULIN MEASUREMENTS

Insulinoma cells are poorly differentiated, which affects their ability to process insulin and convert it from proinsulin. Thus, in contrast to normal subjects, whose proinsulin concentration is less than 20% of the total immunoreactive insulin, most patients with insulinoma have elevated levels of proinsulin, representing as much as 30–90% of total immunoreactive insulin. While absolute proinsulin measurements may be elevated in other conditions besides insulinoma (such as in insulin-resistant states), an increased percentage of proinsulin-like components in relation to total insulin immunoreactivity is more specific for insulinoma. However, since this assay of the “percent proinsulin” requires laborious methodology with columns to separate serum protein components, its usefulness is limited. Absolute serum proinsulin measurements are more readily available in commercial laboratories, and their specificity increases considerably if hypoglycemia is achieved during a prolonged supervised fast. In cases where serum insulin measurements are at borderline levels during a fast in a patient with suspected insulinoma, a serum proinsulin that fails to suppress below 0.2 ng/mL in the presence of hypoglycemia is suggestive of the diagnosis.

  1. GLYCOHEMOGLOBIN MEASUREMENTS

Low glycohemoglobin values have been reported in occasional cases of insulinoma, reflecting the presence of chronic hypoglycemia. However, the diagnostic usefulness of glycohemoglobin measurements is limited by the relatively low sensitivity of this test as well as poor accuracy at the lower range of normal in many of the assays. In addition, it is nonspecific for hypoglycemia, with low levels being found in certain hemoglobinopathies and hemolytic states.

  1. TUMOR LOCALIZATION STUDIES

It is imperative that the surgeon be convinced that the diagnosis of insulinoma has been unequivocally made by clinical and laboratory findings. Only then should surgery be considered, as there is no justification in the use of surgery for exploratory purposes or of localization

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techniques as a diagnostic tool. The focus of attention should be directed at the pancreas only, since virtually all insulinomas originate from this tissue; ectopic cancers secreting insulin are unknown in the experience of all major centers, with only one published report describing an atypical insulin-producing tumor believed to have originated from a small-cell carcinoma of the cervix.

  1. Imaging studies—Prior to surgery, a CT scan of the abdomen should be performed to rule out a large tumor of the pancreas or hepatic metastases from a malignant islet cell tumor. Otherwise, radiographic and arteriographic techniques are seldom helpful in localizing insulinomas preoperatively owing to the small size of most of these tumors (averaging 1.5 cm in diameter in one large series). Standard arteriography has many disadvantages since it is a painful and imprecise procedure that exposes insulinoma patients to hypoglycemia and the discomfort of several hours of invasive and expensive radiography. False-positive or false-negative results are quite common, and in most cases a tumor mass that is large enough to “blush” on arteriography is generally large enough for an experienced surgeon to identify by direct visualization or palpation. Currently there is a growing consensus among experts in this field that present techniques for preoperative localization are of limited usefulness and should be replaced by careful intraoperative ultrasonography and palpation by a surgeon experienced in insulinoma surgery.

Small tumors within the pancreas that are not palpable at laparotomy have been localized using intraoperative ultrasound in which a transducer is wrapped in a sterile rubber glove and passed over the exposed pancreatic surface. This is at present probably the most effective method of localizing insulinomas. Intraoperative ultrasound, combined with careful palpation by a surgeon experienced in insulinoma surgery, has a success rate of up to 97% in recent reports and is the sole localizing approach relied upon at many centers. When the insulinoma is not found at the initial surgery, three localization methods are available prior to reoperation.

  1. Localization methods prior to reoperation
  2. Kinetic magnetic resonance imaging—When the insulinoma is not found at the initial surgery, three localization methods are available prior to reoperation:
  3. The least invasive is a kinetic MRI with multiple imaging during gadolinium injection, but its accuracy for small tumors is no better than 40% and its usefulness is therefore limited.
  4. Percutaneous transhepatic pancreatic vein catheterization with insulin assay can also be useful for localizing small insulinomas with about 70% reliability. However, this technique is not widely available, is quite invasive and expensive, and is associated with considerable discomfort and some risk to the patient from intra-abdominal bleeding.
  5. A more acceptable (and the currently favored) localization method correlates imaging from selective arteriography of segments of the pancreas with simultaneous hepatic vein sampling for insulin during a bolus of intra-arterial calcium delivered selectively to these same pancreatic segments. Calcium has been found to be a secretagogue only for neoplastic tissue and not for normal islet tissue, so that a rise in hepatic vein insulin concentration indicates segmental localization of an insulinoma. A step-up of insulin in the hepatic venous effluent regionalizes the hyperinsulinism to the head of the pancreas for the gastroduodenal artery, the uncinate process for the superior mesenteric artery, and the body and tail of the pancreas for the splenic artery. Furthermore, this technique may provide data that are particularly helpful when multiple insulinomas are suspected, as in patients with coexisting pituitary or parathyroid adenomas who develop hypoglycemia, and it has become a major tool in confirming the diagnosis of diffuse islet hyperplasia in the recently described noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) (see below). Since diazoxide might interfere with this test, it should be discontinued for at least 48–72 hours before sampling. An infusion of dextrose may be required, therefore, and patients should be closely monitored during the procedure to avoid hypoglycemia (as well as hyperglycemia, which could affect insulin gradients).

Treatment of Insulinoma

The treatment of choice for insulin-secreting tumors is surgical resection.

  1. SURGICAL TREATMENT

Tumor resection should be performed only by surgeons with extensive experience with removal of islet cell tumors, since these tumors may be small and difficult to recognize. Success rates as high as 97% have been reported without preoperative localization procedures if surgeons have prior experience with insulinomas and utilize preoperative ultrasonography—although in centers with lower referral rates for this rare disorder (and therefore with less experience with its treatment), success rates are less impressive.

After the pancreas is mobilized, inspected, and palpated, it is imaged to assist in locating the tumor and to reassure the surgeon that no additional tumors exist. An additional benefit of intraoperative ultrasonography is its ability to identify the pancreatic duct and its relationship to the tumor so that the duct can be protected during surgery.

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Tumors should be enucleated whenever possible unless they have malignant features (eg, hardness or an appearance of infiltration). When the tumor is in the body or tail of the pancreas and if for some reason enucleation is difficult, a safe and effective alternative is distal resection with preservation of the spleen if possible.

Limited experience with laparoscopy using ultrasound and enucleation suggests that this approach can be successful with a single tumor of the body or tail of the pancreas, but open surgery is required when a tumor is found at the time of laparoscopy to be in the head of the pancreas to ensure that risk of damage to the pancreatic duct is minimized.

  1. Preoperative management—Oral diazoxide, a potent inhibitor of insulin secretion, will maintain euglycemia in most patients with insulin-secreting tumors. It acts by opening the ATP-sensitive potassium channel of the pancreatic B cell and hyperpolarizing the cell membrane. This reduces calcium influx through the voltage-gated calcium channel, thereby reducing insulin release. If there is a delay in scheduling surgery once the diagnosis of insulinoma is made, the use of diazoxide is recommended to prevent or reduce the frequency of hypoglycemic episodes. Doses of 300–400 mg/d (divided) will usually suffice, but an occasional patient will require up to 800 mg/d. Side effects include edema due to sodium retention (which generally necessitates concomitant thiazide administration), gastric irritation, and mild hirsutism.
  2. Treatment during surgery
  3. Glucose need during surgery—An infusion of 5% or 10% dextrose is needed to maintain euglycemia during the surgical procedure. Careful and frequent blood glucose monitoring is needed to determine the infusion rate required in individual patients to avoid hypoglycemia, especially when the insulinoma is being palpated and manipulated prior to removal.
  4. Diazoxide—Diazoxide should be administered preoperatively as well as on the day of surgery in patients who are responsive to it, since the drug greatly reduces the need for glucose supplements and the risk of hypoglycemia during surgery while not masking the glycemic rise indicative of surgical cure.
  5. Postoperative hyperglycemia—Postoperatively, several days of hyperglycemia may ensue. A major cause is probably related to edema and inflammation of the pancreas secondary to its mobilization and manipulation during surgical resection of the insulinoma. However, other possible contributing factors include high levels of counterregulatory hormones induced by the procedure, chronic down-regulation of insulin receptors by the previously high circulating insulin levels from the tumor, and perhaps suppression of normal pancreatic B cells by long-standing hypoglycemia. Small subcutaneous doses of regular insulin may be prescribed every 4–6 hours if plasma glucose exceeds 300 mg/dL (16.7 mmol/L), but in most cases pancreatic insulin secretion recovers after 48–72 hours, and very little insulin replacement is required.
  6. Failure to find the tumor at operation—In approximately 2–5% of patients with biochemically demonstrated autonomous insulin secretion, no tumor can be found at exploratory laparotomy even with intraoperative ultrasound. The tumor will most likely be in the head of the pancreas, since this is the most difficult area for the surgeon to mobilize and explore; therefore, blind distal two-thirds pancreatectomy is seldom successful and, in contrast to former practice, is no longer recommended by most surgeons in this field. Moreover, complete pancreatectomy is quite hazardous and not a reasonable option. These patients should be maintained on diazoxide and referred to a medical center staffed by people with considerable experience, where a calcium stimulation test during selective arteriography can be scheduled prior to reoperation (see above).
  7. MEDICAL TREATMENT

Diazoxide therapy is the treatment of choice in patients with inoperable functioning islet cell carcinomas and in those who are poor candidates for operation. A few patients have been maintained on long-term (over 10 years) diazoxide therapy without apparent ill effects. Hydrochlorothiazide, 25–50 mg daily, should also be prescribed to counteract the edema and hyperkalemia secondary to diazoxide therapy as well as to potentiate its hyperglycemic effect. Frequent carbohydrate feedings (every 2–3 hours) can also be helpful in maintaining euglycemia, though obesity may become a problem.

When patients are unable to tolerate diazoxide because of side effects such as gastrointestinal upset, hirsutism, or edema, a calcium channel blocker such as verapamil (80 mg given orally every 8 hours) may be tried in view of its inhibitory effect on insulin release from insulinoma cells in vitro.

A potent long-acting synthetic octapeptide analog of somatostatin (octreotide) has been used to inhibit release of hormones from a number of endocrine tumors, including inoperable insulinomas, but it has had limited success. Of the five somatostatin receptors (SSTR) that have been identified in humans, SSTR2, which predominates in the anterior pituitary, has a much greater affinity for octreotide than SSTR5, which predominates in the pancreas. This explains why octreotide is much more effective in treating acromegaly than in treating insulinoma, except in the occasional cases where insulinoma cells happen also to express SSTR2. When hypoglycemia persists after attempted

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surgical removal of the insulinoma and if diazoxide or verapamil is poorly tolerated or ineffective, a trial of 50 ľg of octreotide injected subcutaneously twice daily may control the hypoglycemic episodes in conjunction with multiple small carbohydrate feedings.

Streptozocin has proved beneficial in patients with islet cell carcinomas, and with selective arterial administration effective cytotoxic doses have been achieved without the undue renal toxicity that characterized early experience. Benign tumors appear to respond poorly, if at all.

SYMPTOMATIC FASTING HYPOGLYCEMIA WITHOUT HYPERINSULINISM

  1. Disorders Associated with Low Hepatic Glucose Output

Reduced hepatic gluconeogenesis can result from a direct loss of hepatic tissue (acute yellow atrophy from fulminating viral or toxic damage); from disorders reducing amino acid supply to hepatic parenchyma (severe muscle wasting and inanition from anorexia nervosa, chronic starvation, uremia, and glucocorticoid deficit from adrenocortical deficiency); or from inborn errors of carbohydrate metabolism affecting glycogenolytic or gluconeogenic enzymes.

  1. Ethanol Hypoglycemia

Ethanol impairs gluconeogenesis but has no effect on hepatic glycogenolysis. The metabolism of ethanol has been shown to reduce lactate uptake by gluconeogenic tissues by as much as 60%, thereby depriving these tissues of an important substrate for gluconeogenesis. In the patient who is imbibing ethanol but not eating, fasting hypoglycemia may occur after hepatic glycogen stores have been depleted (within 8–12 hours of a fast). No correlation exists between the blood ethanol levels and the degree of hypoglycemia, which may occur while blood ethanol levels are declining. It should be noted that ethanol-induced fasting hypoglycemia may occur at ethanol levels as low as 45 mg/dL (10 mmol/L)—considerably below most states' legal standards (80 mg/dL [17.4 mmol/L]) for being “under the influence.” Most patients present with neuroglycopenic symptoms, which may be difficult to differentiate from the neurotoxic effects of the alcohol. These symptoms in a patient whose breath smells of alcohol may be mistaken for alcoholic stupor. Intravenous dextrose should be administered promptly to all such stuporous or comatose patients. Because hepatic glycogen stores have been depleted by the time hypoglycemia occurs, parenteral glucagon will not be effective. Adequate food intake during alcohol ingestion will prevent this type of hypoglycemia.

  1. Nonpancreatic Tumors

A variety of nonpancreatic tumors have been found to cause fasting hypoglycemia. Most are large and mesenchymal in origin, retroperitoneal fibrosarcoma being the classic prototype. However, hepatocellular carcinomas, adrenocortical carcinomas, hypernephromas, gastrointestinal tumors, lymphomas and leukemias, and a variety of other tumors have also been reported.

Laboratory diagnosis depends upon fasting hypoglycemia associated with serum insulin levels below 5 ľU/mL. The mechanisms by which these tumors produce hypoglycemia have only recently been elucidated. While very large tumors may metabolize substantial amounts of glucose, this does not explain the increased glucose uptake by muscle and the failure of the liver and kidney to adequately compensate by increasing glucose production. The expression and release of an incompletely processed insulin-like growth factor-II (IGF-II) has provided the best explanation for the clinical manifestations of hypoglycemia in many of these cases.

In normal situations, expression of IGF-II by the liver results in a circulating form of the hormone that is immediately complexed by an IGF-binding protein as well as by an acid-labile protein. This tripartite protein complex is generally inactive in adults since it is unable to properly bind to tissue receptors. However, in patients with nonpancreatic tumors associated with hypoglycemia, a larger, immature form of the IGF-II molecule is released. This incompletely processed molecule can bind to the carrier protein but not to the acid-labile component of serum. It therefore remains active and binds to insulin receptors in muscle to promote glucose transport and to insulin receptors in liver and kidney to reduce glucose output. This immature IGF-II complex also binds to receptors for IGF-I in the pancreatic B cell to inhibit insulin secretion and in the pituitary to suppress growth hormone release. With the reduction of growth hormone, there is a consequent lowering of IGF-I levels as well as IGF-I binding protein 3 and the acid-labile protein. The clinical syndrome of nonpancreatic tumor hypoglycemia, therefore, is supported by laboratory documentation of serum insulin levels below 5 ľU/mL with plasma glucose measurements of 45 mg/dL or lower. Values for growth hormone and IGF-I are also decreased. Levels of IGF-II may be increased but often are “normal” in quantity despite the presence of the immature, higher-molecular-weight form of IGF-II, which can only be detected by special laboratory techniques. Treatment is aimed toward the primary tumor, with supportive therapy using frequent

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feedings. Diazoxide is ineffective in reversing the hypoglycemia caused by these tumors.

NONFASTING HYPOGLYCEMIA (Reactive Hypoglycemia)

Reactive hypoglycemia may be classified as early (within 2–3 hours after a meal) or late (3–5 hours). Early (alimentary) hypoglycemia occurs when there is a rapid discharge of ingested carbohydrate into the small bowel followed by rapid glucose absorption and hyperinsulinism. It may be seen after gastrointestinal surgery and is notably associated with the “dumping syndrome” after gastrectomy; occasionally, it is functional and may result from overactivity of the parasympathetic nervous system mediated via the vagus nerve. Late hypoglycemia (occult diabetes) is caused by a delay in early insulin release, which then results in exaggeration of initial hyperglycemia during a glucose tolerance test. As a consequence, an exaggerated insulin response produces late hypoglycemia. Early or late hypoglycemia may also occur as a consequence of ethanol's potentiation of the insulin-secretory response to glucose, as when sugar-containing soft drinks are used as mixers to dilute alcohol in beverages (gin and tonic, rum and cola).

  1. Postgastrectomy Alimentary Hypoglycemia

Reactive hypoglycemia after gastrectomy is a consequence of hyperinsulinism. This results from rapid gastric emptying of ingested food, which produces overstimulation of vagal reflexes and overproduction of beta-cytotropic gastrointestinal hormones, causing arterial hyperinsulinism and consequent acute hypoglycemia. The symptoms are caused by adrenergic hyperactivity in response to the rapidly falling plasma glucose. Treatment is properly directed at avoiding this sequence of events by more frequent feedings with smaller portions of less rapidly assimilated carbohydrate and more slowly absorbed fat or protein. Occasionally, anticholinergic drugs such as propantheline (15 mg orally four times daily) may be useful in reducing vagal overactivity.

  1. Functional Alimentary Hypoglycemia

Early alimentary-type reactive hypoglycemia in a patient who has not undergone surgery is classified as functional. It is most often associated with chronic fatigue, anxiety, irritability, weakness, poor concentration, decreased libido, headaches, hunger after meals, and tremulousness. Whether or not hypoglycemia accounts for these symptoms or occurs at all is difficult to prove.

The usual sequence of events is that the patient presents with a number of nonspecific complaints. Normal laboratory findings and a normal physical examination confirm the initial impression that organic disease is not present, and the symptoms are then attributed to the stresses of modern living. The only form of therapy usually given is reassurance or a mild tranquilizer. When this fails to be of benefit, the patient seeks help elsewhere. Inevitably, the question of hypoglycemia is raised—frequently by the patient, who has heard of the diagnosis from friends or relatives with similar symptoms or has read of it in the lay press. The diagnosis is often supported by the demonstration of hypoglycemia with symptoms during a 5-hour oral glucose tolerance test.

Unfortunately, the precipitation of hypoglycemia with or without symptoms during oral glucose tolerance testing does not distinguish between normal and “hypoglycemic” patients. As many as one-third or more of normal subjects who have never had any symptoms will develop hypoglycemia with or without symptoms during a 5-hour glucose tolerance test. In addition, many patients will develop symptoms in the absence of hypoglycemia. Thus, the test's nonspecificity makes it a highly unreliable tool that is no longer recommended for evaluating patients with suspected episodes of postprandial hypoglycemia. Indeed, the ingestion of a mixed meal did not produce hypoglycemia in 33 patients who had been diagnosed as having reactive hypoglycemia on the basis of oral glucose tolerance testing; this attempt to increase specificity for the diagnosis of reactive hypoglycemia may have resulted in loss of sensitivity.

For increased diagnostic reliability, hypoglycemia should be documented during a spontaneous symptomatic episode in routine daily activity. However, attempts to demonstrate this are almost never successful. Patients should be instructed in the proper use of glucose meters with sufficient “memory” capability to bring results to the physician's office for documentation of the episodes. Personality evaluation often discloses hyperkinetic compulsive behavior in thin, anxious patients.

The foregoing discussion should not be taken to imply that functional reactive hypoglycemia does not occur—merely that at present we have no reliable means of diagnosing it. There is no harm (and there is occasional benefit) in reducing or eliminating the content of refined sugars in the patient's diet while increasing the frequency and reducing the size of meals. However, it should not be expected that these maneuvers will cure the asthenia, since the reflex response to hypoglycemia is only a possibly aggravating feature of a generalized primary hyperactivity. Counseling and support and mild sedation should be the mainstays in therapy, with dietary manipulation only an adjunct.

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  1. Pancreatic Islet Hyperplasia in Adults (Noninsulinoma Pancreatogenous Hypoglycemia Syndrome)

Since 1995, the Mayo Clinic has treated ten adult patients with hyperinsulinemic hypoglycemia who were diagnosed as having generalized islet hyperplasia and nesidioblastosis. Seven of these were men, and hypoglycemia only occurred 2–4 hours after meals and not at all with fasting up to 72 hours. In addition to adrenergic manifestations, the development of severe neuroglycopenic symptoms (including diplopia, dysarthria, confusion, disorientation, and even in some patients convulsions and coma) within 4 hours after meal ingestion distinguishes this syndrome from that of reactive hypoglycemia, in which adrenergic symptoms overwhelmingly predominate, and when neuroglycopenic symptoms occasionally occur (usually with postgastrectomy alimentary hypoglycemia) they are generally mild. Furthermore, the absence of hypoglycemia during a fast distinguishes these patients from those with single or multiple insulinoma. Each patient had a positive response to selective arterial calcium stimulation, but localization data with this test were variable among the patients, incriminating only one, two, or all three arteries as perfusing the site of abnormal tissue.

Workers at the Mayo Clinic have called this disorder noninsulinoma pancreatogenous hypoglycemic syndrome (NIPHS). No mutations were detected in the KIR6.2 and SUR1 genes, which have been abnormal in some cases of children with a syndrome of familial hyperinsulinemic hypoglycemia and which encode the subunits of the pancreatic ATP-sensitive channel affecting glucose-induced insulin secretion. Following gradient-guided partial pancreatectomy, there was no recurrence of symptoms with up to 4 years of follow-up in all seven of the male patients, but for some unexplained reason the three female patients have had varying degrees of transient or persistent symptom recurrence.

  1. Late Hypoglycemia(Occult Diabetes)

This condition is characterized by delay in early insulin release from pancreatic B cells, resulting in initial exaggeration of hyperglycemia during a glucose tolerance test. In response to this hyperglycemia, an exaggerated insulin release produces late hypoglycemia 4–5 hours after ingestion of glucose. These patients are usually quite different from those with early hypoglycemia, being more phlegmatic and often obese and frequently having a family history of diabetes mellitus. In the obese, treatment is directed at reduction to ideal weight. These patients often respond to reduced intake of refined sugars with multiple, spaced small feedings high in dietary fiber. They should be considered early diabetics and advised to have periodic medical evaluations.

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Banarer S, McGregor VP, Cryer PE: Intraislet hyperinsulinemia prevents the glucagon response to hyperglycemia despite an intact autonomic response. Diabetes 2002;51:958.

Bolli GB, Fanelli CG: Physiology of glucose counterregulation to hypoglycemia. Endocrinol Metab Clin North Am 1999;28: 467.

Boukhman MP et al: Localization of insulinomas. Arch Surg 1999; 134:818.

Boyle PJ et al: Adaptation in brain glucose uptake following recurrent hypoglycemia. Proc Natl Acad Sci U S A 1994;91:9352.

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*C peptide, a major portion of the connecting chain of amino acids in proinsulin, remains intact during the conversion of proinsulin (Chapter 17).