Physiology of Hypoglycemia

During typical physiologic conditions, the brain requires a constant and adequate supply of glucose. Under normal postabsorptive conditions (e.g., an overnight fast), the brain accounts for ≈65% of whole body glucose uptake. Following feeding, the amount of glucose taken up by the brain can increase, but insulin does not influence brain glucose kinetics in a similar fashion to other organs such as liver or muscle. Although the brain was classically considered an insulin-insensitive organ, recent work has challenged this concept.¹⁰ Several studies have elegantly demonstrated that insulin can regulate appetite and feeding mechanisms in rodent models.¹⁰ Additionally, insulin administration into areas of the hypothalamus has been demonstrated to regulate hepatic glucose output.¹¹ Furthermore, studies in dogs¹² and mice¹³ have demonstrated direct CNS effects of insulin to amplify autonomic nervous system (ANS) counterregulatory responses to hypoglycemia. Thus, accumulating data indicate that insulin can have direct metabolic effects on certain areas of the brain.

Although typically dependent upon glucose as a fuel, the brain can adapt and utilize other substrates. Thus during periods of fasting, ketone bodies, lactate, and alanine can be used as alternative brain fuels.¹⁴ Several studies have demonstrated, experimentally, that high levels of alternative substrates can be infused during acute hypoglycemia with a concomitant reduction in neuroendocrine and ANS responses. This indicates that the brain has the capacity to switch from glucose to alternative substrates in a matter of hours. However, it should be noted that the concentrations of substrate infused experimentally are far higher than levels observed during most physiologic conditions (the exception is levels of ketone bodies that occur during prolonged fasting).

During hypoglycemia, brain glucose uptake falls. The exact glycemic value for the start of decreased blood-to-brain glucose transport is debated but is thought to be around 3.6 to 3.8 mmol/L in humans. As hypoglycemia deepens (−3 mmol/L), blood-to-brain glucose transport becomes rate limiting for brain glucose metabolism. Glycolytic derived lactate and a small amount of stored astrocytic glycogen can provide a short duration of fuel supply. Recent work has estimated that stored glycogen could provide the brain oxidative fuel for about 20 minutes¹⁵; based on an estimate that blood-to-brain glucose transport could provide up to 90% of the brain’s oxidative requirements during moderate hypoglycemia,¹⁶ it can be seen that the remaining 10% of energy requirements obtained from lactate and glycogen would last only ≈200 minutes, thus emphasizing the need for a continuous and adequate supply of glucose to the brain from the circulation.

Neurohumoral Regulation During Hypoglycemia

Syndromes of Disordered Counterregulatory Responses During Hypoglycemia

Almost immediately after the discovery of the hormone in the early 1920s, hypoglycemia was recognized as an unpleasant and dangerous side effect of insulin therapy. More than 90% of all patients with type 1 diabetes mellitus (DM) have suffered an episode of hypoglycemia. Typically, a patient with type 1 DM will experience 2 to 10 episodes of glucose below 70 mg/dL (3.9 mmol/L) per week and may have glycemic values below 50 mg/dL (2.9 mmol/L) at least 10 times each week. Episodes of major hypoglycemia requiring resuscitative measures from an additional person or hypoglycemic events resulting in seizures or coma have been reported to occur about once every other year to up to three times a year.¹⁷ The duration of type 1 DM plays an important role in increasing the frequency of severe hypoglycemia. Recent data from the UK hypoglycemia study group³³ demonstrate that the frequency of severe hypoglycemia increases from 110 per 100 patient-years after less than 5 years of insulin therapy to 320 episodes per hundred patient-years after insulin therapy for longer than 15 years.

The risk and frequency of hypoglycemia are considered to be much lower in type 2 DM as compared with type 1 DM. This is undoubtedly true in patients with type 2 DM treated with monotherapy or combination therapy of metformin, a thiazolidineodione, a DPP-4 inhibitor, and/or a GLP-1 agonist. However, the incidence of hypoglycemia increases sharply in longer duration (insulin-deficient) type 2 DM. Recent clinical trials investigating insulin replacement strategies in type 2 DM report hypoglycemia in more than 70% of participants.³⁴ Furthermore, the UK hypoglycemia study group reported that patients with type 2 DM receiving insulin for longer than 5 years had rates of severe hypoglycemia of about 70 episodes per 100 patient-years.³³ This rate is slightly higher than the rate of 60 episodes per 100 patient-years reported for patients with type 1 DM in the intensive group of the DCCT.¹⁷ Other studies examining the frequency of severe hypoglycemia in type 2 DM have reported rates of one-third or similar to those occurring in type 1 DM. Furthermore, large recent multicenter studies investigating the effects of glucose control on complications of diabetes in type 2 DM have reported a significant incidence and prevalence of hypoglycemia.^35,36 Thus, severe hypoglycemia continues to be a significant clinical problem for patients with type 1 DM and longer duration type 2 DM (Fig. 21-1).

Death from hypoglycemia can be considered on the one hand to be rare when one considers the very large number of episodes of hypoglycemia that occur in clinical practice. However, mortality does occur during severe hypoglycemia in both type 1 and type 2 DM. Studies investigating the cause of death in patients with type 1 DM have reported that 2% to 10% may have died because of hypoglycemia.2,3 Similar death rates from hypoglycemia have been reported in patients with type 2 DM. The specific mechanism responsible for hypoglycemia-induced death is not currently understood. Possible suggested causes include cardiac arrhythmias, thrombotic events, and brain death. However, it should be noted that in primates, several hours of profoundly low glucose <1 mmol/L is required to induce irreversible brain damage and death.³⁷

Hypoglycemia-Associated Neuroendocrine and Autonomic Failure

As discussed earlier, the four primary physiologic defenses against falling plasma glucose include inhibition of endogenous insulin secretion, release of glucagon and epinephrine, and symptomatic cues to ingest carbohydrate (Fig. 21-2). Unfortunately in patients with diabetes, all of these physiologic defenses can become defective and/or deficient. In type 1 DM and in long duration type 2 DM, the individual becomes critically insulin deficient, and thus the first physiologic line of defense (modulation of endogenous insulin) becomes lost. After varying periods of duration of disease (≈5 years), the ability of individuals with type 1 DM to release glucagon in response to hypoglycemia is lost (Fig. 21-3). This defect also occurs to a similar extent in long duration type 2 DM (Fig. 21-4).³⁸ The mechanism for this finding is currently under intense investigation in humans. Hypotheses include lack of β cell turnoff, a possible specific autonomic nervous system dysfunction, and another as yet unidentified local signaling defect at the level of the α cell. The defect involved in releasing glucagon in type 1 DM is specific for hypoglycemia as the α cells in these individuals are present in normal number and size. In fact underscoring this point, glucagon responses to other metabolic stressors in type 1 DM such as exercise or amino acid infusions are preserved.³⁹ The fact that glucagon responses are preserved during exercise in type 1 DM is interesting in that exercise is also typically associated with a physiologic “β cell switch off.” Whatever the mechanism, unfortunately after a few years’ duration, individuals with type 1 DM lose two of the four primary defenses against falling blood glucose. This leaves a functioning ANS (sympathoadrenal and sympathetic nervous systems) to serve as the primary defense against hypoglycemia in type 1 DM. In some individuals with type 1 DM, the ability to secrete epinephrine in response to hypoglycemia is preserved and can compensate for the lack of glucagon release.⁴⁰ However, it is now clear that epinephrine responses to hypoglycemia are significantly reduced in patients with type 1 DM with intensive metabolic control.⁴¹ This epinephrine deficiency has been determined to be due to previous episodes of hypoglycemia⁴² and is separate from the syndrome of classic diabetic autonomic neuropathy that can occur after many years of suboptimal glycemic control. Models of repeated antecedent hypoglycemia have been demonstrated to produce acute reductions (30% to 50%) in epinephrine, pancreatic polypeptide (a marker of parasympathetic nervous system activity), and muscle sympathetic nerve activity (a direct marker of sympathetic nerve system activation) in individuals with type 1 DM, in those with type 2 DM, and in nondiabetic individuals.⁴³ Additionally, recent (within 24 hours) antecedent hypoglycemia has been found to blunt a wide spectrum of neuroendocrine responses such as glucagon, growth hormone, ACTH, and cortisol during subsequent hypoglycemia⁴⁴ in healthy and diabetic men. Confirming the role of antecedent hypoglycemia in causing blunted counterregulatory responses are a number of studies that prospectively investigated the effects of avoiding hypoglycemia in type 1 DM and following successful removal of an insulinoma.^45–48 In all cases, there were initial blunted, neuroendocrine, ANS, and symptomatic responses to hypoglycemia. However, when patients with type 1 DM were restudied several months later, all showed improved counterregulatory responses to hypoglycemia, and patients with previous insulinomas had counterregulatory defenses restored to normal. Symptomatic responses, the fourth critical physiologic counterregulatory response, were significantly improved in all studies following a period of hypoglycemia avoidance.^45–48 The blunting effects of antecedent hypoglycemia on subsequent counterregulatory responses have been termed by Cryer as “hypoglycemia-associated autonomic failure” (HAAF).

Following identification of this syndrome, a great deal of work has been performed in both animal and human models to further elucidate the mechanisms responsible for and the characteristics of hypoglycemia-associated counterregulatory failure. However, it should be appreciated that HAAF does not occur only in type 1 DM. Work from two independent laboratories has determined that this syndrome also occurs in type 2 DM.49,50 Segel and colleagues clearly demonstrated that moderate antecedent hypoglycemia of 50 mg/dL (2.8 mmol/L) can blunt ANS responses to subsequent hypoglycemia in moderately controlled (HbA1c 8.4%) individuals with type 2 DM.⁴⁹ More recently, Davis and coworkers have demonstrated that even milder antecedent hypoglycemia of only 60 mg/dL (3.3 mmol/L) can blunt ANS responses to subsequent hypoglycemia in patients with type 2 DM with suboptimal (HbA1c ≈10.0%) or intensive glycemic control (HbA1c ≈6.7%).⁵⁰

The great challenge in determining the mechanisms responsible for HAAF is explaining the simultaneous reduction in ANS-neuroendocrine responses and the change in glycemic thresholds that activate the physiologic defenses against falling plasma glucose. As described earlier, the usual physiologic thresholds for activation of ANS-neuroendocrine and symptom responses during hypoglycemia occur in the plasma glucose range between 50 and 80 mg/dL. In individuals with chronic hyperglycemia, symptoms of hypoglycemia can occur at plasma glucose levels between 90 and 140 mg/dL, depending upon the severity of the prevailing hyperglycemia. Simultaneous measurements of ANS-neuroendocrine hormones are in fact elevated during these symptoms, thus the individuals are experiencing the condition of “relative hypoglycemia.” This syndrome occurs because the thresholds for activation of ANS-neuroendocrine responses have been pushed to a higher plasma glucose level by the chronic hyperglycemia. On the other hand, individuals with intensive glucose control and multiple episodes of hypoglycemia often find that the activation of physiologic responses to hypoglycemia is pushed to a lower plasma glucose level. This dangerous condition, called hypoglycemic unawareness, results in inability of patients to recognize a falling plasma glucose until the value is below 50 mg/dL (2.9 mmol/L). In some individuals, a falling plasma glucose level is not recognized at plasma glucose levels of 30 mg/dL. This reduces the interval between first recognition of hypoglycemia and the onset of serious sequelae (such as coma or seizure). Thus, thresholds for the activation of physiologic defenses against hypoglycemia are labile and can change rapidly. The duration and depth of antecedent hypoglycemia required to induce HAAF have been characterized. Repeated episodes or relatively mild (3.9 mmol/L, or 70 mg/dL) and only brief durations (15 to 20 minutes) of hypoglycemia can independently blunt counterregulatory responses to subsequent hypoglycemia.⁵¹ However, one prolonged episode (2 hours) of moderate hypoglycemia (50 mg/dL, or 2.9 mmol/L) is sufficient to induce HAAF within a few hours on the same day.⁵²

Numerous mechanisms responsible for the syndrome of HAAF have been proposed over recent years, with data both supporting and at times contrary to any given hypothesis. Boyle et al. proposed that repeated hypoglycemia increased cerebral glucose uptake in both healthy individuals and patients with type 1 DM, thereby reducing the stimulus for neuroendocrine counterregulatory responses during subsequent hypoglycemia.⁵³ This finding was later challenged by work reporting no increase in blood-to-brain glucose transport following antecedent hypoglycemia.⁵⁴ Other mechanisms that have been proposed include activation of the hypothalamic-pituitary-adrenal axis,^44,55 increases in neurotransmitters such as GABA, and changes in hypothalamic fuel sensors such as glucokinase or AMP kinase (increases and decreases, respectively).⁵⁶ Additionally, experimental evidence demonstrates that alcohol and opioids can downregulate subsequent ANS and neuroendocrine responses to hypoglycemia.⁵⁷ Other physiologic mechanisms also have been found to cause forms of HAAF. These include sleep, exercise, and gender (Fig. 21-5).^43,58 The association between exercise and hypoglycemia in type 1 DM has been both problematic and perplexing. Hypoglycemia can occur during, 1 to 2 hours after, or up to 21 hours after exercise. Traditionally, the explanation for this phenomenon was either a relative or absolute excess of subcutaneously injected insulin (due to an increase in insulin sensitivity following exercise) and/or incomplete glycogen repletion following exercise. Although these factors are important contributors to exercise-associated hypoglycemia, they cannot explain some of the profound episodes of hypoglycemia that occur during or after exercise. Studies from our own laboratory and others have demonstrated that exercise and hypoglycemia could reciprocally blunt subsequent ANS responses to either stress (Fig. 21-6).^59,60 Thus, exercise blunts ANS responses (by 30% to 50%) to subsequent hypoglycemia, and vice versa. This feed-forward vicious cycle of blunted ANS responses between exercise and hypoglycemia can occur after only a few hours and persists for at least 24 hours following either stress (Fig. 21-7).³⁹ Appreciation that deficient counterregulatory responses are also involved in the pathogenesis of exercise-related hypoglycemia explains why this phenomenon can occur many hours after exercise and provides a platform for therapeutic intervention. In general, in an individual with type 1 DM who is experiencing exercise-related hypoglycemia, it is appropriate to consider reducing both basal and mealtime insulin doses. Additionally, slightly raising glycemic targets and ensuring adequate carbohydrate repletion of glycogen stores are useful recommendations.

Gender can also play a large role in modulating ANS and neuroendocrine responses during hypoglycemia.⁵⁸ In premenopausal, nondiabetic, and type 1 DM women, moderate hypoglycemia of ≈50 mg/dL (2.9 mmol/L) produces 30% to 50% reduced ANS responses compared with that seen in age- and body mass index (BMI)-matched men.⁵⁸ However, when postmenopausal women, not on estrogen replacement, were compared with postmenopausal women receiving estrogen and age- and BMI-matched men, it was found that the large sexual dimorphism in ANS (epinephrine, muscle sympathetic nerve activity) and neuroendocrine (glucagon, growth hormone) responses was no longer present in estrogen-deficient women. It therefore would appear that in healthy humans, estrogen is a major mechanism responsible for sexual dimorphic counterregulatory responses during hypoglycemia.⁶¹ It should also be mentioned that women appear to be more resistant than men to the blunting effects of prior hypoglycemia. Thus, antecedent hypoglycemia can have up to a twofold greater suppressive effect on subsequent counterregulatory responses in men than in women.⁶² The mechanism for this intriguing finding is as yet unknown. Many studies have focused on the blunting effects of antecedent hypoglycemia on neuroendocrine and symptom responses during subsequent hypoglycemia. However, an additional component in the spectrum of deficient counterregulatory responses deserves mention. Several laboratories have identified that adrenergic receptors and particularly epinephrine action are downregulated by intensive glucose control and prior hypoglycemia.^63,64 These reduced metabolic (lipolytic, endogenous glucose production, glycogenolysis) and cardiovascular responses contribute to defective counterregulatory defenses against a falling plasma glucose in patients with diabetes. Thus, it should be noted that strategies aimed at increasing epinephrine levels during hypoglycemia will be only partially successful if tissue resistance or adrenoreceptor downregulation to the action of the hormone is present. What is clear from the above wealth of data is that multiple mechanisms can downregulate ANS responses to hypoglycemia, and that this complex model presents numerous targets for therapeutic interventions to stimulate and restore counterregulatory responses during hypoglycemia in patients with diabetes.

Strategies to Improve Counterregulatory Responses During Hypoglycemia

Parallel with studies investigating the mechanisms responsible for HAAF, a number of laboratories have been exploring strategies for improving ANS and neuroendocrine responses during hypoglycemia. These have included preclinical approaches in rodents through to interventions in humans with type 1 DM. As mentioned above, hypothalamic kinases can act as important fuel sensors. Recent work in rats has shown that methods to reduce AMP-activated protein kinase (AMPK) in the ventral medial nucleus of the hypothalamus reduce epinephrine and glucagon responses during hypoglycemia, whereas increases in AMP kinase action can increase responses of these key neuroendocrine hormones during hypoglycemia.⁶⁵ Other approaches to increase neuroendocrine responses during hypoglycemia in man have included amino acid infusions (glucagon) and use of caffeine (epinephrine and symptom responses). Terbutaline before bed has been demonstrated recently to increase plasma glucose levels during the night and to prevent nocturnal hypoglycemia.⁶⁶ Recently, peroxisome-proliferator–activated receptor-γ (PPAR-γ) agonists, which are known to activate AMP kinase and fructose, which under certain conditions can inhibit glucokinase,⁶⁷ have been demonstrated to increase counterregulatory responses in both healthy men and those with type 1 DM. Although at first glance these latter studies may seem unrelated, both may have mechanisms working through hypothalamic fuel sensing. Most recently, studies in conscious rats and healthy and type 1 DM men have highlighted the possible role of serotonergic transmission in modulating counterregulatory responses during hypoglycemia. Prolonged (i.e., weeks) use of two different selective serotonin reuptake inhibitors (sertraline and fluoxetine) has led to dramatic (30% to 60%) increases in ANS (epinephrine) responses during hypoglycemia.⁶⁸

Drug-Induced Hypoglycemia

By far the most common cause of drug-induced hypoglycemia is insulin followed by sulfonylurea, meglitinides, and benzoic acid derivatives (i.e., oral insulin-producing agents). Hypoglycemia induced by oral insulin secretagogues is much less frequent than that caused by insulin but in certain instances can still be common. For example, hypoglycemia can occur in up to ≈35% of patients receiving glyburide or repaglinide. Hypoglycemia rates are less in agents with glucose-dependent insulin secretion (i.e., stimulation of insulin release is reduced during periods of hypoglycemia). Thus, the percentage of patients who experience hypoglycemia when receiving glimepiride, glipizide XL, or nateglinide is lower and is in the range of 5% to 10%. However, combination of even glucose-dependent insulin secretagogues with agents such as insulin or glucagon-like peptide-1 agonists can result in a much higher frequency of hypoglycemia (≥35%). Generally, newer sulfonylureas produce less hypoglycemia than do older first-generation sulfonylureas such as chlorpropamide. Severe hypoglycemia remains relatively uncommon with oral insulin secretagogues at a rate of ≈1.5 per 100 patient-years.³³ Alcohol might be a more common cause of severe hypoglycemia in the United States than sulfonylureas.⁶⁹ Alcohol can cause hypoglycemia in overnight fasted normal volunteers,^70,71 with plasma glucose values as low as 5 mg/dL (0.3 mmol/L)⁷² and mortality rates ranging from 10% in adults to 25% in children.¹¹⁹ In a series of deaths caused by hypoglycemia, alcohol was the most common causative agent.⁷⁴ The most common situation is a glycogen-depleted state, such as occurs in an individual who drinks after a considerable fast, or who drinks and then fasts. In the latter situation, blood alcohol levels can be low or undetectable.

Alcohol induces hypoglycemia by inhibiting gluconeogenesis⁷²; as little as 50 g might be sufficient.^73,76 Its mechanism of action is complex, with evidence of impaired counterregulatory hormone responses⁷¹ and impaired uptake of gluconeogenic precursors,⁷⁷ but the predominantly accepted mechanism is its inhibition of the gluconeogenic process stemming from an increased reduced nicotinamide adenine dinucleotide (NADH)/NAD ratio as a result of the oxidation of alcohol to acetaldehyde and acetate, thus reducing the ability of the liver and kidney to oxidize lactate and glutamate to pyruvate and α-ketoglutarate, respectively.^78–80 Although plasma insulin levels are appropriately suppressed in this condition, because of this inhibition of gluconeogenesis, glucagon and catecholamines are ineffective in increasing glucose release and raising plasma glucose levels.⁸¹ Thus, in a patient with suspected alcohol-induced hypoglycemia, oral or intravenous glucose is the treatment of choice.

Only about 10% of reported cases of drug-induced hypoglycemia have occurred without concomitant insulin, sulfonylurea, or alcohol.⁸² Of these, propranolol,⁸³ sulfonamides,⁸⁴ and salicylates¹⁶⁹ have been reported most frequently. Propranolol and other nonselective β-blockers decrease the ability of the liver and kidney to increase their release of glucose,^85,86 enhance peripheral insulin sensitivity,⁸⁷ and mask symptoms of impending hypoglycemia. The adverse effects of β-adrenergic β-blockers are mediated through β₂-receptors. Recent studies indicate that β₁-selective blockers do not present an increased risk for severe hypoglycemia and therefore should not be considered as being contraindicated in diabetic patients.^87,88

Salicylates can act by inhibiting hepatic glucose release and increasing insulin secretion, although their exact mechanism remains to be determined. Sulfonamides probably act by stimulating insulin release in a manner similar to that of sulfonylureas. Angiotensin-converting enzyme inhibitors⁸⁹and pentamidine⁹⁰ are associated more frequently with hypoglycemia, as their use increases in diabetic patients and those with AIDS, respectively. Angiotensin-converting enzyme inhibitors can increase tissue insulin sensitivity⁹¹ and can decrease the degradation of bradykinin, which has certain insulin-mimetic actions.⁹² Pentamidine is cytotoxic to pancreatic β cells, and hypoglycemia occurs with the release of insulin from degenerating cells, often with subsequent permanent diabetes mellitus.⁹³ Many of the drugs listed in Table 21-2 have been reported to cause hypoglycemia only in association with the use of antidiabetic medications or have been the subject of isolated case reports, and their etiologic significance remains to be established. However, their use in a patient with otherwise unexplained hypoglycemia should be discontinued whenever possible.

Treatment and Strategies to Reduce Hypoglycemia

Neonatal Hypoglycemia

Plasma glucose levels below 70 mg/dL (3.9 mmol/L) commonly occur in newborn infants. It has been estimated that up to 50% of neonates can have plasma glucose levels below 50 mg/dL (2.9 mmol/L) following short-term fasting (up to 8 hours) after birth.¹¹⁵ Over the first 72 hours of life, gluconeogenic pathways mature, and the risk of hypoglycemia in normal infants is removed. However, in addition to the above physiologic causes of neonatal hypoglycemia, numerous pathologic conditions can cause hypoglycemia (Table 21-3).

The most common causes of persistent neonatal hypoglycemia are the congenital hyperinsulinism syndromes. These syndromes have been estimated to occur at a rate of about 1:30,000 births worldwide. However, in certain areas (e.g., Finland, the Arabian Peninsula), these conditions have been reported to occur at much higher rates (≈1:2,100).116,117 Over the past 50 years, congenital hyperinsulinism syndromes have been given a number of titles (e.g., nesidioblastosis, islet dysregulation syndrome, persistent hyperinsulinemic hypoglycemia of infancy). Recently, it has been discovered that nesiodioblastosis can be a normal feature of the pancreas in the neonatal period and is histologically different from the pathologic processes that cause congenital hyperinsulinism. The pathophysiology and the molecular and genetic bases for congenital hyperinsulinism were reviewed recently by De Leon and Stanley.¹¹⁵ Of these, the most frequently occurring involve loss-of-function mutations in the pancreatic β-cell K-ATP channel, Kir6.2 and Sur-1 receptors.

The clinical presentation of infants with congenital hyperinsulinism may be varied but typically involves prolonged and severe hypoglycemia with lethargy, seizures, and apnea, and babies are often large for gestational dates. Typically, hypoglycemia occurs in the fasting or postprandial state, and these infants require large rates of glucose infusion >10 mg/kg/min to prevent severe hypoglycemia. In the glutamate dehydrogenase version of congenital hyperinsulinism, hypoglycemia can occur during both the fasting and the postprandial state. Hypoglycemia in this condition can be precipitated by a protein meal and is characteristically accompanied by elevated ammonia levels. Diagnosis of glutamate dehydrogenase hyperinsulinism typically occurs when the child is several months of age.¹¹⁸

Mitochondrial Fatty Acid Oxidation Disorders

Eleven different mitochondrial fatty acid oxidation disorders¹²⁰ can present with fasting (hypoketotic) or postprandial hypoglycemia. Hepatic oxidation of fatty acids produces energy and acetyl-CoA, both of which are essential for gluconeogenesis. Additionally, fatty acid oxidation is required for hepatic ketone production. However, because of specific defects in mitochondrial fatty acid oxidation, gluconeogenesis is reduced, and this results in hypoglycemia and a lack of ketone bodies. The combination creates a scenario whereby the brain becomes starved of glucose and its primary alternative substrate (ketones), which creates conditions for severe neurologic consequences. Plasma membrane carnitine transporter deficiency is an autosomal recessive disorder that occurs in ≈1:40,000 infants. Low plasma carnitine and acyl carnitine are indicative of this disorder, and treatment with dietary carnitine prevents hypoglycemia. Carnitine palmitoyl transferase I and II (CPT I and CPT II) deficiencies can present as severe, life-threatening events that require frequent feeding and supplementation with dietary medium-chain triglycerides and l-carnitine (CPT II deficiency). Unfortunately, the most severe form of CPT II deficiency can present soon after birth and can be fatal. Medium-chain acetyl-CoA dehydrogenase (MCAD) deficiency is the most common fatty acid oxidation defect and is inherited as an autosomal recessive trait. Hypoglycemia usually occurs during fasting and conditions of stress such as viral illness.^121,122 The presentation can be serious with vomiting, apnea, coma, encephalopathy, and death. It has been estimated that if left undiagnosed, up to 25% of children may die during the presenting event. Blood tests demonstrate elevated medium-chain acylcarnitine. As with other mitochondrial fatty acid oxidation disorders, the enzyme deficiency can be demonstrated diagnostically in fibroblasts. Treatment consists of avoidance of fasting and precipitation of attacks that could lead to neurologic defects and even death. Thus, frequent meals, bedtime snacks, uncooked cornstarch (to avoid nocturnal hypoglycemia), and carnitine supplementation have been used successfully in these children.

Very long chain (VLCAD) and short-chain acyl-CoA dehydrogenase (SCAD) deficiencies can present with serious, sometimes fatal, episodes of hypoglycemia and metabolic acidosis. These defects are also associated with cardiomyopathy (VLCAD), hepatomegaly, and neurologic defects (SCAD). Treatment involves avoidance of fasting and maintenance of glucose levels during stress, with frequent meals enriched with carbohydrate and medium-chain triglycerides. Carnitine supplementation in these conditions is not recommended (VLCAD) or has limited applicability (SCAD).

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiency are also autosomal recessive disorders. Both conditions can present with severe hypoglycemia, encephalopathy, neurologic complications, and death. Both conditions can result in peripheral neuropathy, and LCHAD deficiency can result in pigmentary retinopathy and blindness. Treatment is similar to that provided for the above fatty acid oxidation defects acyl-CoA dehydrogenase and carnitine/acylcarnitine translocase (CACT). Long-chain ketothilase (LCKAT) and 2-4-dienoyl-CoA reductase deficiency are very rare conditions that have been described recently.¹²⁰

Glycogen Storage Diseases

Glycogen synthase and glucose-6-phosphatase deficiencies often present in the neonatal period with hypoglycemia. Additionally, glycogen-phosphorylase deficiency can present later in childhood. Of the three disorders, glucose-6-phosphate deficiency presents with the most severe hypoglycemic phenotype. Treatment to prevent hypoglycemia is similar in all of the glycogen storage disorders.¹²³ Avoidance of hypoglycemia during stress, exercise, and the night involves frequent carbohydrate-containing meals and bedtime snacks. In times of severe stress, intravenous glucose may be required to maintain plasma glucose levels above 70 mg/dL (3.9 mmol/L).

Sepsis, Trauma, and Burns

Initially, the response to the stress of infection is an increase in glucose turnover, with glucose production often exceeding glucose utilization and resulting in mild hyperglycemia. This response involves increases in both glycogenolysis and gluconeogenesis and is largely mediated by glucagon¹²⁴ because adrenergic blockade has no effect on glucose turnover.¹²⁵ As the infection worsens, increased release of endotoxin and its derivatives, complement activation, endoperoxide activation, and release of endogenous inflammatory mediators (tumor necrosis factor-α, interleukins, and other monokines) compromise cardiovascular integrity and cause central venous pooling, inadequate tissue perfusion, and microvascular protein transudation.¹²⁶ At this stage, a decrease in splanchnic and renal blood flow occurs. Despite concomitantly reduced peripheral tissue perfusion, glucose utilization is increased.^127–129 Decreased tissue oxygenation causes increased anaerobic glycolysis, which perpetuates the increased glucose utilization.

The inability of glucose release to keep pace with increased tissue demands results in hypoglycemia. Hepatic glycogen stores are rapidly exhausted; consequently, glucose release becomes solely dependent on gluconeogenesis. However, gluconeogenesis fails to stimulate this process because of a reduction in ANS and neuroendocrine effects.130–132 Factors such as acidosis (which inhibits hepatic gluconeogenesis), increased intracellular calcium (which impairs mitochondrial function and inhibits gluconeogenic enzymes), and siphoning of available energy from gluconeogenesis to support ion transport might be the mechanisms responsible for diminished ANS and neuroendocrine responsiveness.

Appropriate management entails (1) treatment of the underlying infection, (2) restoration of normal peripheral perfusion, and (3) glucose infusion to satisfy tissue demands.

Cardiac Failure

Spontaneous hypoglycemia can occur with severe heart failure133–135; it is rare in adults but not uncommon in infants and children,¹³⁶ in whom reduced hepatic glycogen levels (but normal phosphorylase and glucose-6-phosphatase activity) have been found in liver biopsy specimens. The condition has been attributed to a variety of mechanisms, including reduced gluconeogenesis, poor dietary intake, and gastrointestinal malabsorption, which are present in cardiac failure.

Mellinkoff and Tumulty first described the hypoglycemia of cardiac failure and attributed it to associated hepatic disease.¹³⁷ However, chronic lung disease with right and left heart failure is seen in most patients.¹³⁵ Thus, hypoxemia and low cardiac output may produce hepatic ischemia. Marks and Rose postulated that decreased availability of oxygen would suppress gluconeogenesis by increasing hepatic anaerobic glycolysis (Pasteur effect) and lactate production, thereby resulting in an increased NADH/NAD ratio.¹³⁸ This decreased ratio could compromise gluconeogenesis because NAD is an essential cofactor for several of the enzymatic steps of gluconeogenesis. This attractive hypothesis could explain the association between hypoglycemia and the lactic acidosis of cardiac¹³⁹ and liver¹⁴⁰ disease, as well as the hypoglycemia accompanying other conditions associated with tissue anoxia, such as sepsis and shock.¹⁴¹ Low cardiac output would be expected to limit substrate delivery to the kidneys. In addition to a reduced capacity to produce glucose, increased glucose utilization from increased anaerobic glycolysis and increased energy demands from labored breathing and malnutrition (anorexia) are probably additional important factors. At the present time, no evidence indicates that abnormal counterregulatory hormone responses play a role in the pathogenesis of the hypoglycemia associated with these conditions.

Renal and Hepatic Disease: General Considerations

The liver and kidneys are the only organs that are capable of releasing glucose into the circulation, inasmuch as other tissues generally lack or have minimal amounts of the enzyme glucose-6-phosphatase. Consequently, it would not be surprising that patients with hepatic or renal disease should be prone to hypoglycemia. Nevertheless, it is uncommon for hypoglycemia to occur simply as a result of loss of mass or function of these organs, and when it does occur, the cause is usually multifactorial.72,142 The large capacities of these organs to release glucose into the circulation and their ability to compensate for each other’s shortcomings appear to provide an explanation for this phenomenon.

Normally, the liver accounts for 80% to 85% of all glucose released into the circulation; it can increase its output (initially mainly by glycogenolysis, later by gluconeogenesis) over a sustained period by twofold to threefold (at least for several days, as exemplified by burn patients¹³⁰). Thus, hypoglycemia with an appropriate compensatory increase in hepatic glucose release would be unlikely to develop in anephric individuals because the kidney normally contributes only 15% to 20% of all glucose that is released into the circulation. On the other hand, the kidney can increase its output over a prolonged period by twofold to threefold, as exemplified in humans who have fasted for several weeks.¹⁴³ Animal and human studies indicate that the kidney can acutely increase its output to compensate for decreased hepatic glucose release and vice versa,^144–146 a phenomenon that is referred to as hepatorenal reciprocity.¹⁴⁷ For example, during the anhepatic phase of human liver transplantation, the kidney can maintain normoglycemia without the need for exogenous glucose.¹⁴⁸ Thus, hypoglycemia would be unlikely to develop in patients with hepatic disease until the liver’s capacity to release glucose was reduced beyond the ability of the kidney to compensate. In fact, animal studies indicate that more than 80% of the liver must be removed for hypoglycemia to occur.¹⁴⁹

Glucagon Deficiency

Pancreatectomized individuals, patients with long-standing type 1 diabetes, and those in whom insulin-requiring diabetes develops as a result of chronic pancreatitis or cystic fibrosis are glucagon deficient¹⁸² and prone to severe hypoglycemia during treatment for their diabetes.¹⁸³ An imbalance between insulin and glucagon secretion (relative glucagon deficiency) has been reported in reactive postprandial hypoglycemia.¹⁸⁴ Because of glucagon’s importance, it might have been expected to be a common counterregulatory hormone deficiency. However, the condition is extremely rare, with only two poorly substantiated cases of neonatal hypoglycemia^185,186 and two reported cases in adults.^187,188

Catecholamine Deficiency

Patients with long-standing type 1 diabetes mellitus, adrenalectomized individuals, and those with autonomic neuropathy have impaired catecholamine responses during insulin-induced hypoglycemia,189–191 but their increased risk for hypoglycemia can be compensated for by increases in the secretion of other counterregulatory hormones, in particular, glucagon.¹⁹² Subtle defects in recovery from hypoglycemia have been demonstrated when such compensatory increases have been prevented experimentally.³⁹⁴ However, if glucagon responses to hypoglycemia are impaired simultaneously (e.g., in the patient with type 1 DM), the risk for hypoglycemia markedly increases.¹⁸³

Several cases of neonatal ketotic hypoglycemia and one case in a 5-year-old boy have been attributed to epinephrine deficiency on the basis of low urinary epinephrine excretion.193,194 No cases of hypoglycemia secondary to isolated catecholamine deficiency have been reported in an adult. The hypoglycemia that occurs with propranolol may relate to the drug’s inhibition of lipolysis, which would reduce gluconeogenesis, an important counterregulatory process, and its promotion of increased glucose clearance by peripheral tissues.⁸⁵ It is important to note that acute hypoglycemia can occur during surgical removal of a pheochromocytoma, presumably because of disinhibition of insulin release and abrupt withdrawal of the anti-insulin actions of catecholamines.¹⁹⁵

Cortisol and Growth Hormone Deficiency

Although cortisol and growth hormone have been demonstrated to contribute independently to glucose counterregulation via their actions to promote glucose release and limit glucose uptake,196–199 hypoglycemia does not develop in most adults who lack these hormones. However, serious hypoglycemia often develops in infants and children, who lack these hormones, especially after a period of fasting or during an intercurrent illness.^199–203 In a review of 76 adults with isolated adrenocorticotropic hormone (ACTH) deficiency,²⁰⁴ 24 (≈33%) had hypoglycemia. During prolonged fasting (6 days), adult growth hormone–deficient dwarfs become hypoglycemic,²⁰⁵ as can hypopituitary pregnant women.²⁰⁶ On the other hand, overnight fasting plasma glucose levels have been reported to be normal in glucocorticoid-withdrawn patients with primary adrenal insufficiency²⁰⁷ or panhypopituitarism.²⁰⁸ Acute adrenal insufficiency such as in Sheehan’s syndrome can be manifested as severe hypoglycemia,²⁰⁹ and autoimmune Addison’s disease may be the cause of severe recurrent hypoglycemia in a patient with type 1 diabetes mellitus.²¹⁰

It is important to be aware that malabsorption of glucocorticoids can occur in patients with bowel disease and in patients treated with drugs such as bile acid sequestrants.²¹¹

Autoimmune Hypoglycemia

Of the two types of autoimmune hypoglycemia, one is due to autoantibodies against the insulin receptor, and the other is due to autoantibodies against insulin itself in individuals who have never received exogenous insulin. Both are rare and can produce fasting, as well as postprandial reactive hypoglycemia—primarily the former.212–220

Anti-Insulin Antibody Hypoglycemia

Since 1970, approximately 200 cases of anti-insulin antibody hypoglycemia have been reported, nearly 90% occurring in Japanese patients.²¹³ Associated autoimmune disorders and plasma cell dyscrasias (Graves’ disease, rheumatoid arthritis, polymyositis, and systemic lupus erythematosus) are common. The use of certain drugs (hydralazine, procainamide, penicillamine, interferon-α, and methimazole) has been implicated in initiating the syndrome.²¹⁶

Postprandial hypoglycemia is more common with this syndrome than is fasting hypoglycemia. Circulating insulin levels are increased and C-peptide levels might not be suppressed, as they are in patients who are taking insulin surreptitiously. Hypoglycemia occurs because dissociation of insulin from the antibodies causes prolonged hyperinsulinemia. Unlike the other syndrome of autoimmune hypoglycemia, the course of this condition is benign and self-limited, with remission usually occurring within a year. Simple interventions such as frequent small meals with a low content of simple sugars often suffice.

Pregnancy

Despite a decrease in insulin sensitivity and an increase in glucose turnover to accommodate the needs of the fetus, fasting plasma glucose levels are normally 10% to 15% lower during the third trimester of pregnancy.225,226 Nevertheless, a great number of metabolic changes occur during pregnancy to make a woman more vulnerable to hypoglycemia.²²⁷ Any condition that can cause hypoglycemia in a nonpregnant woman can do so in a pregnant woman. In addition to insulinoma,^228,229 non–islet cell tumors,²³⁰ severe infection,²³¹ poor nutrition,²³² drug-induced sources (e.g., insulin in diabetic patients), and a condition called the HELLP syndrome (characterized by hemolysis, elevated liver enzymes, and a low platelet count) can cause hypoglycemia as a result of fulminating hepatic dysfunction.^233–235

Exercise

Hypoglycemia can develop after prolonged strenuous exercise and has been reported in marathon runners,²³⁶ in normal volunteers after exercise on a bicycle ergometer for 3 hours at 56% of maximal capacity,²³⁷ and in a healthy male subject taking a β-blocker after skiing 15 km in 2 hours.²³⁸ Although coma developed in the latter instance, most instances of exercise-associated hypoglycemia are asymptomatic, self-limited, and readily reversed by carbohydrates.²³⁹

The increased fuel demands of the working muscle necessitate compensatory metabolic processes in the liver and kidney.240–243 Changes in hepatic glycogenolysis and gluconeogenesis have been found to be closely coupled to the increase in glucose uptake produced by the working muscle because of the actions of the pancreatic hormones.²⁴⁰ The exercise-induced increase in glucagon secretion and the concomitant decrease in insulin secretion interact to stimulate hepatic glycogenolysis, whereas the increase in hepatic gluconeogenesis is determined primarily by glucagon’s action to increase hepatic gluconeogenic precursor fractional extraction and the efficiency of intrahepatic conversion to glucose. On the other hand, no evidence has shown that hepatic innervation is essential for the rise in hepatic glucose production. Epinephrine and norepinephrine become important in increasing glucose production during prolonged or heavy exercise, when levels are particularly high. Catecholamines can produce this effect by directly stimulating both hepatic and renal glucose release, by increasing the availability of gluconeogenic precursors, and by increasing lipolysis.

Factitious Hypoglycemia

Factitious hypoglycemia refers to a situation in which an individual intentionally attempts to create the impression of the presence of a hypoglycemic disorder.244–246 This includes diabetic individuals who falsify their self-glucose monitoring, or who overdose or underdose themselves to intentionally create the impression of better than actual glycemic control or brittle diabetes,^247,248 and in cases of child abuse.¹² Generally excluded are inadvertent sulfonylurea ingestion (see drug-induced hypoglycemia), homicides,^249,250 suicide attempts,^251,252 and substance abuse in which the additional use of insulin or sulfonylureas is intended to “obtain a high,” rather than to create the impression of a hypoglycemic disorder.^253–255 These situations nevertheless can present diagnostic challenges.

Since 1947, more than 80 cases of insulin-induced or sulfonylurea-induced factitious hypoglycemia have been described in the literature,245,256–259 but the condition is probably more common than this figure would indicate because most cases go unreported. Indeed, in a survey from the United Kingdom, it was estimated that 12% of cases of spontaneous hypoglycemia referred for investigation were in fact probably factitious.²⁶⁰ In nearly all instances, the individuals had had diabetes; had been a relative, spouse, or friend of a diabetic patient; or were in the medical or paramedical profession. Thus, factitious hypoglycemia should be suspected in individuals or their relatives who have unexplained hypoglycemia and knowledge of and/or access to insulin, sulfonylureas, or meglitinides²⁶¹ and unexplained hypoglycemia. Such patients have generally been healthy women younger than 50 years of age who have an underlying psychological disorder. Because the main differential diagnosis is insulinoma, it is important to consider this condition as a possible cause of unexplained hypoglycemia to avoid unnecessary laboratory workup, which such patients have undergone.

Previously, autoimmune hypoglycemia was a possibility because of the presence of insulin antibodies in patients who are taking animal or impure insulin. Currently, the use of human insulin does not generally result in antibody production, so autoimmune hypoglycemia is no longer a major consideration. Because the main differential is insulinoma, most patients with this condition should undergo a 72-hour fast. Those in whom hypoglycemia develops as a result of surreptitious insulin injection will have inappropriate plasma insulin levels and a suppressed plasma C-peptide level (because of inhibition of endogenous insulin secretion). This finding is diagnostic. Patients taking sulfonylureas or a meglitinide will have inappropriate plasma insulin and C-peptide levels because of stimulation of endogenous insulin secretion, and this pattern will mimic that seen in patients with insulinoma. However, these conditions can be distinguished by a positive urine or plasma assay for sulfonylureas and meglitinides. It is important that samples be collected during hypoglycemia or as close as possible to the event, and that they be analyzed by a laboratory with a sufficiently sensitive assay.²⁵⁰

Many patients who are documented biochemically to have self-induced hypoglycemia will adamantly deny doing so when confronted with the evidence. Nevertheless, psychological counseling with other physicians is warranted to prevent subsequent episodes or substitution of other potentially self-destructive behaviors.²⁴⁶

Non–Islet Cell Tumors

The development of hypoglycemia in a patient with a non–islet cell tumor was first reported in 1930—a mediastinal fibrosarcoma.²⁶² Since that time, it has become apparent that a large variety of non–islet cell tumors are associated with hypoglycemia.^{156,230,263–285}

Tumors of mesenchymal origin are the most commonly reported in Western countries.²⁶⁴ Such tumors generally are large and slow growing, but often malignant. About one third are retroperitoneal, one third are intra-abdominal, and one third are intrathoracic. In South Africa and Asia, hepatomas are the most common non–islet cell tumors associated with hypoglycemia.²⁷²

With one possible exception (a small cell carcinoma of the cervix),²⁸⁶ ectopic production of insulin has never been demonstrated convincingly in patients with this condition.^280,287 Characteristically, circulating plasma insulin and C-peptide levels are suppressed. In some cases, hypoglycemia results mainly from increased glucose utilization by the tumor, and debulking by surgery or by radiation treatment can alleviate or ameliorate the hypoglycemia.^{264,268,279,283} In patients with rapidly growing hepatomas, hypoglycemia can occur as a terminal or near-terminal event, mainly because of inanition. However, in the great majority of cases, hypoglycemia is explained by tumor production of IGF-like molecules,²⁷⁰ in particular, IGF-2 and its isoforms.²⁸⁵ Excessive release of IGF-like molecules by the tumor can increase glucose utilization in tissues such as muscle,^271,274,284 can suppress endogenous glucose production,^278,284 and can reduce or overcome the secretion of counterregulatory hormones.²³⁰

In most cases, diagnosis is not difficult, and patients generally are middle-aged to elderly; the tumor is usually large, and its presence is known before the onset of hypoglycemia or can be readily noted on physical examination and by ultrasonographic, computed tomographic, and nuclear magnetic resonance (NMR) studies. Biochemically, the hypoglycemia is associated with appropriately suppressed plasma insulin and C-peptide levels and increased IGF-2 levels, as well as an increased IGF-2/IGF-1 ratio, because of suppression of growth hormone secretion and hence suppressed IGF-1 release by IGF-2.

Reactive Hypoglycemia

Reactive hypoglycemia refers to hypoglycemia that occurs after meals. Any condition that causes fasting hypoglycemia, for example, insulinoma,²⁸⁸ hypopituitarism,²⁸⁹ alcoholism,^71,290 sulfonylurea ingestion, hypothyroidism,²⁹¹ growth hormone deficiency,²⁹² and cortisol deficiency, can also cause postprandial hypoglycemia.^184,291 Nevertheless, some conditions are associated with hypoglycemia only after meal ingestion. These conditions fall into four categories: alimentary, prediabetes, idiopathic, and functional hypoglycemia.¹⁸⁴

Historical Perspective

Nesidioblastosis, or diffuse hyperplasia of the islets, as a cause of hypoglycemia was first described by Laidlaw in 1937.325,334 In contrast to multiple adenomas that accompany the multiple endocrine neoplasia type I (MEN-I) syndrome, the condition is characterized by diffuse, although not necessarily uniform, hypertrophy and hyperplasia of islet cells (insulin- as well as glucagon- and somatostatin-producing cells), usually associated with differentiation of ductal cells into insulin-producing cells.³³⁵ This condition can cause hypoglycemia in infants as a result of mutations in the sulfonylurea receptor³²³ or in the anatomically linked potassium channel.³²³ However, it has become apparent that the condition can occur in adults independent of these genetic mutations.^{322,324,325,336–340}

Preoperative differentiation from an insulinoma can be difficult but is suggested by negative imaging studies (including intragastric ultrasonography) and ¹⁸F-DOPA PET scan associated with percutaneous transhepatic portal venous sampling, which demonstrates nonselective increases in venous insulin concentrations following calcium injection.

Treatment generally consists of 60% to 90% distal pancreatectomy. Fifty percent of patients undergoing this procedure are cured of hypoglycemia and are normoglycemic. Ten percent develop insulin-requiring diabetes, and the remaining 40% require medication for treatment of hyperglycemia (insulin secretagogue) or persistent hypoglycemia (calcium channel blockers).322,325

Incidence

Insulinoma is a very rare disorder, and nesidioblastosis is even rarer.322,339,340 On the basis of a 60-year experience at the Mayo Clinic, it was estimated that the incidence in Olmsted County, Minnesota, was about eight cases per million patient-years; however, half these cases were found incidentally at autopsy.³⁴¹ Other estimates from Seattle, Washington³⁴²; and Auckland, New Zealand,³⁴³ which emphasize clinically apparent cases, yield an incidence of about one to two cases per million patient-years. The incidence of adult-onset nesidioblastosis would be expected to be only about 0.3 case per million patient-years.^322,344,345

Demographics

Insulinoma occurs somewhat more frequently in women than in men, with an average/median onset at about 45 years of age; most cases occur between the ages of 30 and 70 years. Younger patients generally have had a greater occurrence in association with MEN-I,³⁴⁶ whereas carcinoma has been more frequent in older patients. However, insulinoma is uncommon in those older than 80 years. Although extraordinarily rare in patients with type 1 diabetes mellitus, insulinomas have occurred in several patients with type 2 diabetes.^347–349

Pathophysiology

Hypoglycemia in patients with insulinoma is the result of dysregulated insulin release. Normally, increased plasma insulin levels and hypoglycemia per se³⁵⁰ suppress insulin release. In patients with insulinoma, suppression of insulin release by insulin and hypoglycemia is abnormal, and insulin release can be described as chaotic, often not appropriately increased by hyperglycemia; some patients occasionally have impaired glucose tolerance. Further evidence of abnormal function of the tumorous islets consists of the increased proinsulin-to-insulin ratios and the decreased insulin concentration relative to normal islet tissue.^351–353

In most patients with insulinoma, hypoglycemia occurs as the result of suppression of glucose release rather than increased glucose utilization, inasmuch as plasma insulin concentrations are usually only 50% to threefold above normal levels (but of course inappropriate for the plasma glucose concentration).³⁵⁴ The frequently observed finding that large infusions of glucose are necessary to maintain normoglycemia in patients with insulinoma is probably a result of the creation of a slight hyperglycemia that can stimulate insulin release by some insulinomas. Suppression of normal β cells in islets by insulin released by the tumor, or by repetitive hypoglycemia, can result in glucose intolerance or transient diabetes after removal of the tumor.

Symptoms and Signs

Except in late-diagnosed malignant insulinoma cases in which an abdominal mass and signs of metastasis may be present, the physical examination is usually normal. Symptoms are the result of hypoglycemia. Patients with MEN-I also can exhibit symptoms as a result of hypercalcemia and accompanying hyperparathyroidism or other excessive hormone secretions (islet production of ACTH, gastrin, and vasoactive intestinal peptide).³⁵⁵ Common initial symptoms of patients with insulinoma are confusion, weight gain, weakness, fatigue, headaches, faintness, altered mental state, and altered behavior. Because of their nonspecific and insidious nature, the time between onset of symptoms and diagnosis is about 3 to 5 years, with the world record being 26 years.³⁵⁶ Initially, autonomic symptoms predominate; these are followed later by neuroglycopenic symptoms. Frequency and/or severity increases over time. Patients with insulinoma, similar to those with diabetes mellitus, can acquire the syndrome of hypoglycemia unawareness,³⁵⁷ which is characterized by diminished symptoms, counterregulatory hormone responses, and β-adrenergic sensitivity,³⁵⁸ which are reversed after successful surgical cure.^357,359 Thus, it is not uncommon for a patient with insulinoma with a plasma glucose concentration less than 36 mg/dL (2 mmol/L) to be completely asymptomatic. The development of this condition can make it difficult to exclude hypopituitarism as an initial cause of the hypoglycemia.

Although insulinoma has long been classified as one of the so-called fasting hypoglycemias, it is important to remember that such patients can experience hypoglycemia at any time of day, even 2 to 4 hours after a meal (Table 21-5). Only about a quarter of patients have hypoglycemia episodes solely after an overnight fast during real-life activity, and postprandial hypoglycemia has been reported to be the sole initial feature.²⁸⁸ In contrast, an appreciable proportion of patients with nesidioblastosis may have symptoms only after meal ingestion.³²⁴ Seizures tend to be more common in children, but permanent neurologic sequelae have been observed in about 7% of adults.³⁶⁰ Patients often learn that eating frequently reduces episodes; therefore, weight gain has been observed in about 50% of patients.³⁶⁰

Pathology

About 80% of insulinomas are due to benign single adenomas, which average about 2 cm in diameter; 10% are due to multiple benign adenomas. Diffuse hyperplasia and/or nesidioblastosis is uncommon in adults (i.e., one to two cases per 100 million patient-years) and usually accounts for only 1% to 2% of cases.361,362 Carcinomas account for about 8%. Five percent of insulinomas are associated with MEN-I, in which case the tumor is more likely to be multiple and malignant and to secrete additional hormones ectopically, such as gastrin or ACTH.

Diagnosis

The diagnosis of insulinoma is readily established by the demonstration of fasting hypoglycemia (<50 mg/dL, 2.8 mmol/L), inappropriate plasma insulin (>5 µU/mL, 30 pmol/L) and C-peptide (>0.25 nmol/L, 0.75 pg/mL), and a negative sulfonylurea/meglitinide blood/urine screen. A plasma proinsulin concentration greater than 5 pmol/L can be useful if plasma insulin and C-peptide values are borderline; additionally, measurement of a high proinsulin-to-insulin ratio can be diagnostic.363,364 Various tests have been proposed over the years to rule in or rule out the presence of an insulinoma: the intravenous tolbutamide tolerance test, the glucagon test, the leucine test, and the C-peptide suppression test.^{344,365–368} All suffer from frequent false positives and false negatives and are not recommended. Additionally, a 3- to 5-hour prolonged OGTT can often produce misleading results. In an insulin-sensitive individual, an oral glucose load will evoke an insulin response that will stimulate glucose uptake into peripheral muscles. This will create an arteriovenous difference, with lower glucose levels in mixed venous blood. Thus, sampling venous blood from a peripheral vein after an OGGT can produce glucose values in the hypoglycemic range that are in fact 10 to 30 mg/dL lower than simultaneous arterial glucose values. The “gold standard” remains the classic 72-hour fast. Hypoglycemia will develop in essentially all patients with insulinoma during this test; in fact, 75% will become hypoglycemic within 24 hours and up to 90% over 72 hours.³⁶⁹ The test should be conducted in a hospital under standardized and supervised conditions. It is worth emphasizing that many patients with nesidioblastosis will have a normal 72-hour fast, and their only biochemical abnormality will be postprandial hypoglycemia associated with abnormal plasma insulin and C-peptide levels, which is why it is preferable to begin the 72-hour fast with a standard meal.

The 72-hour Fast

Successful completion of a 72-hour fast without the development of hypoglycemia effectively excludes a serious hypoglycemic disorder except for nesidioblastosis (Table 21-6).³⁷⁰ It is recommended that the patient be hospitalized and supervised to prevent inadvertent caloric consumption or surreptitious drug administration. Admission is preferred before a standard evening meal so that the response to a meal can be assessed, as well as the response to a fast. The patient should be encouraged to be active to simulate real-life situations and prevent sedentary decreases in glucose utilization. Baseline samples for counterregulatory hormones are drawn to assess the adequacy of a response if hypoglycemia should occur subsequently. Blood for a β-hydroxybutyrate level is drawn at the end of the fast to exclude the consumption of calories. Should hypoglycemia occur, anti-insulin antibodies, anti-insulin receptor antibodies, and IGF-2 levels may be useful in assessing the presence of an autoimmune cause or an occult IGF-2–secreting non–islet cell tumor. Interpretation of the results of these determinations is given in Table 21-7.

The above plan represents the ideal approach. Given the practicalities of third-party reimbursement for procedures, an alternative would be to have the patient fast overnight and come to the office or clinic in the morning at around 8:00 am, after a 12- to 14-hour overnight fast, to begin serial testing during the day. If, at the end of the day (i.e., 4:00 pm, after fasting approximately 20 to 22 hours), hypoglycemia has not occurred, then the patient should be admitted for 2 days of serial testing.

Localization

Only after the diagnosis of hypoglycemia associated with inappropriate hyperinsulinemia has been established biochemically should localization studies be performed. Ninety-nine percent of insulinomas occur within the pancreas. Of the rare insulinomas that are not found in the pancreas, most are found in the wall of the duodenum or gastrosplenic omentum.³⁷¹ They average about 2 cm in diameter and appear with equal frequency in the head, body, and tail.^360,372 Although about 75% to 90% can be identified correctly by palpation at surgery,^373,374 preoperative localization generally is recommended to minimize manipulation of the pancreas, shorten operative time, avoid blind partial pancreatectomy when the tumor is not palpable, and assist in reoperations when scarring and fibrosis from prior surgery make palpation difficult.³⁴⁴ Computed tomography and NMR imaging can detect large tumors and stage malignant ones but yield false positives and false negatives; these techniques correctly localize tumors only 50% to 70% of the time.^{344,373–375} Celiac arteriography and transsplenic portal venous sampling have had variable results and are invasive and probably not needed.^344,374,375 Currently, preoperative transabdominal ultrasonography followed by intraoperative ultrasonography is considered the most sensitive and specific approach and has been recommended for routine use; this approach along with palpation can be used to detect over 95% of tumors.^{373,375–377} Recently, dual-phase spiral computed tomography has been reported to detect six of seven tumors ranging in size from 6 to 18 mm.³⁷⁸ In patients who are suspected of having nesidioblastosis, the tests of choice are ¹⁸F-DOPA PET scans and the selective calcium infusion procedure,^339,375 because this test will confirm the diagnosis of pancreatic hyperinsulinism as the probable cause of the hypoglycemia when reliable localization procedures are negative.³²²

Treatment

Surgery is the treatment of choice for insulinoma and nesidioblastosis.322,360,373 For patients with solitary adenomas, enucleation is curative; in cases that are thought to be due to a single adenoma, recurrence or lack of cure could be due to the presence of multiple adenomas. In 5% to 10% of patients, the adenoma is not found; nevertheless, in such cases, partial pancreatectomy can result in cure. Reoperation still might result in cure, but recurrence has been noted up to 18 years after the initial surgery.³⁴¹ Recurrences are more common in patients with MEN-I (up to 20%).³⁴¹ Multiple adenomas, hyperplasia, and malignancy require more extensive surgery. Debulking of a malignant tumor is worthwhile in helping to control hypoglycemia. The major complications of surgery, which include acute pancreatitis (≈10% to 15%), wound infection (5% to 10%), fistulas (10% to 15%), and pseudocysts (5%), are related to the extent of surgery. Reoperations have greater complication and mortality rates (≈15% vs. 5%). Commonly, transient hyperglycemia occurs and lasts up to 2 to 3 weeks because of suppression of normal islet function. Permanent diabetes mellitus can occur after partial pancreatectomy and reoperation. In patients with nesidioblastosis, gradient-directed resection can result in cure of hypoglycemia.

Medical therapy is reserved for operated patients with recurrence who refuse another exploration and for those with inoperable malignant tumors. Diazoxide (100 to 200 mg, three times daily), which inhibits insulin secretion, has been used most widely.³⁷⁹ Approximately 60% (mainly those with benign disease) can be maintained nearly free of symptoms with only occasional hypoglycemia. The main side effects are fluid retention (≈15%) and hirsutism (≈5%); thiazide diuretics can be used to combat fluid retention and enhance hyperglycemic effects. The somatostatin analogue octreotide has been found to be effective in some patients but must be injected.^380,381 Continuous subcutaneous glucagon infusion has also been used.³⁸² Glucocorticoids (to induce insulin resistance) and verapamil, the calcium channel blocker, and phenytoin, the anticonvulsant, both of which inhibit insulin release at high doses, have been used when other measures were ineffective.³⁴⁴

Malignant insulinomas respond poorly to chemotherapy.³⁸³ Streptozocin has been reported to reduce tumor size in about 50% of patients, with fewer than 20% achieving complete remission; although its use prolongs life, streptozocin has considerable renal, hepatic, and hematopoietic toxicity. The addition of fluorouracil has been reported to have advantages over streptozocin alone.³⁸⁴ Mithramycin,³⁸⁵ doxorubicin (Adriamycin),³⁸⁶ and hepatic embolization³⁸⁷ have been tried with some success in refractory cases.

General Approach to the Patient

Treatment and Strategies to Reduce Hypoglycemia

Treatment is aimed at restoring euglycemia, preventing recurrences, and, if possible, alleviating the underlying cause. In an insulin-taking diabetic patient with mild hypoglycemia because of a skipped meal, treatment can simply entail 15 g of oral carbohydrate every 15 minutes until the blood glucose level is above 80.391,392 With more severe hypoglycemia resulting in obtundation, and when oral administration of carbohydrate might result in aspiration, 1 mg of glucagon given subcutaneously or intramuscularly might be sufficient to raise the blood glucose concentration and revive the patient so that oral carbohydrate can be given. Comatose patients should receive intravenous glucose (a 25 g bolus, followed by an infusion to maintain glucose at around 4.3 to 5.5 mmol/L [80 to 100 mg/dL]). A sulfonylurea or meglitinide overdose can result in prolonged hypoglycemia requiring sustained intravenous glucose infusion, which also is aimed at keeping the blood glucose level at approximately 4.5 to 5.5 mmol/L (≈80 mg/dL) to avoid hyperglycemia, causing further stimulation of insulin secretion and setting in motion a vicious cycle. Blood glucose levels should be monitored initially every 30 minutes and subsequently at 1- to 2-hour intervals. Occasionally, diazoxide or a somatostatin analogue might be needed to inhibit insulin secretion.³⁹³ When other drugs are involved, their use should be discontinued if possible (e.g., sulfonamides in a patient with renal insufficiency). In other conditions, the underlying disorder (e.g., sepsis, heart failure, endocrine deficiency) should be treated, and the blood glucose level should be supported.

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