A clinical classification of the more common causes of symptomatic hypoglycemia in adults is presented in Table 18–3. 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 β cell tumors and iatrogenic or surreptitious administration of insulin 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. Hypoglycemia, sometimes severe, can also occur postprandially. In patients with gastric surgery, overrapid gastric emptying and accelerated glucose absorption may result in excess insulin secretion, rapid disposal of glucose, and hypoglycemia. An uncommon condition of islet hyperplasia or adult nesidioblastosis called noninsulinoma pancreatogenous hypoglycemia syndrome can result in hypoglycemia 4 to 6 hours after meals.
TABLE 18–3Causes of symptomatic hypoglycemia in adults. |Favorite Table|Download (.pdf) TABLE 18–3 Causes of symptomatic hypoglycemia in adults.
Oral insulin secretagogues (sulfonylureas, repaglinide, nateglinide)
Other drugs (pentamidine)
Autoimmune hypoglycemia (idiopathic insulin antibodies, insulin receptor autoantibodies)
Pancreatic β cell tumors
Severe hepatic dysfunction
Chronic renal insufficiency
After gastric surgery
Noninsulinoma pancreatogenous hypoglycemic syndrome (NIPHS)
Ethanol ingestion with sugar mixers
SPECIFIC HYPOGLYCEMIC DISORDERS
Iatrogenic hypoglycemia is common in type 1 patients and also in insulin treated type 2 patients (see also Chapter 17). Most type 1 patients aiming for HbA1c levels below 7% have on average one to two symptomatic hypoglycemic episodes per week. Severe hypoglycemia is defined as an episode requiring assistance, and in one study, incidence rates were about 12 per 100 patient years for both type 1 and insulin-treated type 2 patients. Sulfonylureas, repaglinide, and nateglinide can also cause hypoglycemia. Increased risk factors include age (70 years and older), renal failure, hepatic failure, and use of the long-acting sulfonylureas. A number of other drug–drug interactions (clarithromycin, salicylates, sulfonamides) can also potentiate the hypoglycemic effects of sulfonylureas. The annual incidence of sulfonylurea-induced hypoglycemia is approximately 0.2 per 1000 patient years.
As β cell failure progresses (early in type 1 and late in type 2 diabetes), patients lose their glucagon response to hypoglycemia. This combination of insulin deficiency and impaired glucagon response makes it harder for patients to achieve HbA1c levels below 7% without occasional hypoglycemia. These hypoglycemic episodes attenuate the sympathoadrenal response to hypoglycemia, with decreased epinephrine release from the adrenal and decreased sympathetic neural responses (hypoglycemic unawareness) and impaired hepatic glucose release. This combination of events is termed hypoglycemia-associated autonomic failure, and it can persist for more than 24 hours after a single episode of hypoglycemia or longer after repeated episodes of hypoglycemia, which in turn increases the risk for recurrent hypoglycemia. About 20% to 25% of type 1 patients have hypoglycemic unawareness. Other factors that increase the risk for hypoglycemia include poor self-management skills. Patients may take too much insulin for the carbohydrates or high glucose adjustment or take the wrong insulin or do not appropriately time insulin administration with food ingestion. They also may not adjust the insulin for acute exercise or take extra carbohydrates for unexpected exercise or reduce insulin doses for improved insulin sensitivity with exercise training. Alcohol can decrease endogenous glucose production and can cause hypoglycemia, especially if it is consumed on an empty stomach. Diabetes complications—gastroparesis, autonomic neuropathy, and renal failure also increase the risk for hypoglycemia.
There are other consequences of hypoglycemia apart from the autonomic and neurogenic symptoms of acute hypoglycemia. In severe cases, hypoglycemia can cause convulsions and coma. Permanent neurological damage is rare. Although cross-sectional studies and case reports have reported intellectual decline with recurrent hypoglycemia, longitudinal studies have not shown significant cognitive dysfunction in adults. In the Diabetes Control and Complications Trial and its follow-up EDIC study, there was no evidence for cognitive decline related to hypoglycemia in 18 years of follow-up. Young children, however, may be more vulnerable to the effects of hypoglycemia on the brain. Hypoglycemia via its autonomic stimulation and catecholamine release increases cardiac output. In patients with cardiac disease, it can also precipitate cardiac arrhythmias, angina, myocardial infarction, and congestive heart failure. Unexpected deaths in type 1 patients are most likely due to hypoglycemia—so-called “dead-in-bed” syndrome. In studies from the United Kingdom and Scandinavian countries, the frequency of such unexplained deaths is about 2 to 6 events per 100,000 patient-years. Hypoglycemia can also exert a psychological toll. Acute hypoglycemia induces mood changes including anxiety and depression. Nocturnal hypoglycemia can lead to fatigue and decreased sense of well-being the following day. Patients who have had severe hypoglycemia may develop a phobia about hypoglycemia and keep their sugars unreasonably high. Hypoglycemia can also impact personal relationships, occupation, driving, and leisure activities. Surveys show that type 1 patients have increased risk of driving mishaps (crashes, moving violations) when compared to nondiabetic spouses; and that these are related to hypoglycemia.
The goal of therapy for hypoglycemia is to restore levels of plasma glucose to normal as rapidly as possible. If the patient is conscious and able to swallow, glucose-containing tablets or gels, or foods such as candy, juices (ie, orange or apple), and cookies should be quickly ingested. Fructose, found in many nutrient low-calorie sweeteners for diabetics, should not be used. While it can be metabolized by neurons, fructose is not transported across the blood–brain barrier.
If the patient is unconscious, rapid restoration of plasma glucose must be accomplished by giving 20 to 50 mL of 50% dextrose intravenously over 1 to 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. Glucagon should not be given if the hypoglycemia is due to sulfonylurea use. Under these circumstances, glucagon can stimulate insulin secretion and worsen the hypoglycemia. Attempts to feed the patient or to apply glucose-containing gels to the oral mucosa should be avoided because of the danger of aspiration. When consciousness is restored, oral feedings should be started immediately. In patients who have taken massive overdoses of sulfonylureas, the response to intravenous dextrose may be inadequate. For these patients, intravenous boluses of diazoxide (150-300 mg) may be tried but can result in hypotension. Intravenous octreotide (100 μg) has also been reported to be of benefit.
Patients on insulin or sulfonylureas should be instructed on how to recognize and treat hypoglycemia and what measures they can take to prevent such episodes. Patients with type 1 and insulin-treated type 2 diabetes should monitor their blood glucose frequently. Hypoglycemia not infrequently occurs at night and patients should avoid taking large doses of short-acting insulin just before going to bed. Patients should from time to time also monitor blood glucose levels in the middle of the night. Hypoglycemia can also occur many hours after strenuous exercise, and patients should be advised to monitor at these times and cut back their insulin doses and/or eat more carbohydrate. Continuous glucose monitoring systems are increasingly used by patients to alert them to falling glucose levels and prevent hypoglycemia. Finally, it is important to individualize glycemic goals. Early in the course of both type 1 and type 2 diabetes when there is still some endogenous β cell function, it is easier to achieve HbA1c levels close to normal with low risk of hypoglycemia. As β cell failure progresses, however, aiming for normality may lead to unacceptably high rates of hypoglycemia. Patients who have had frequent hypoglycemia and have hypoglycemia unawareness should be encouraged to temporarily raise their glycemic targets—as little as 2 to 3 weeks of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and improves the attenuated epinephrine response. Diabetes complications, previous incidence of hypoglycemia, and life expectancy should all be considered in the establishment of glycemic goals.
2. 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 patients with diabetes or their relatives. The reasons for self-induced hypoglycemia vary, with many patients having severe psychiatric disturbances or a pathological 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 pharmacy.
When insulin is used to induce hypoglycemia, an elevated serum insulin level often raises suspicion of an insulin-producing pancreatic β cell tumor. It can be difficult to prove that the insulin is of exogenous origin. The combination of hypoglycemia, high immunoreactive insulin levels, suppressed plasma C-peptide, and suppressed proinsulin level is pathognomonic of exogenous insulin administration in nondiabetic patients. Insulin and C-peptide are secreted into the portal circulation in a 1:1 molar ratio. The liver is the primary site of insulin clearance, and a large fraction of the portal insulin is removed by the liver during first pass transit. C-peptide, on the other hand, is mostly cleared by the kidney at a slower rate than insulin. It follows that normally the molar ratio of insulin to C-peptide is less than 1.0. In the case of factitious hyperinsulinemia, the insulin/C-peptide ratio (pmol/L) will be greater than 1.0. Patients with renal failure may have normal or even high plasma C-peptide levels, but plasma proinsulin levels are suppressed.
When sulfonylurea abuse is suspected, plasma or urine should be screened for its presence. Hypoglycemia with inappropriately elevated levels of serum insulin and C-peptide along with detectable sulfonylureas in blood or urine is diagnostic of inadvertent or factitious sulfonylurea overdose. It is important to use assays which measure not only all the sulfonylureas but also repaglinide and nateglinide.
Patients with factitious hypoglycemia should receive psychiatric treatment and/or psychotherapy.
Numerous pharmacologic agents may potentiate the effects of insulin and predispose to hypoglycemia. Common offenders include fluoroquinolones such as gatifloxacin and levofloxacin, pentamidine, quinine, angiotensin-converting enzyme (ACE) inhibitors, ethanol, salicylates, and beta-adrenergic–blocking drugs. The fluoroquinolones, especially gatifloxacin, act on ATP-sensitive potassium channels (KATP) in the β cell and initially cause hypoglycemia and then hyperglycemia after several days into therapy. Intravenous pentamidine is cytotoxic to pancreatic β cells, resulting in acute insulin release and hypoglycemia. This occurs in about 10% to 20% of patients receiving the drug and may be followed later by persistent insulinopenia and hyperglycemia. Fasting patients taking noncardioselective beta blockade can have an exaggerated hypoglycemic response to starvation. Beta blockade inhibits fatty acid and gluconeogenic substrate release and reduces plasma glucagon levels resulting in hypoglycemia. Also the symptomatic response to hypoglycemia is altered—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. Symptoms of sweating, hunger, and uneasiness are not masked by beta-blocking drugs and remain indicators of hypoglycemia in the aware patient.
Therapy with 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.
Ethanol-associated hypoglycemia has been proposed to occur as a consequence of hepatic alcohol dehydrogenase activity depleting NAD. The resultant change in the redox state (increase in NADH-to-NAD+ ratio) causes a partial block at several points in the gluconeogenic pathway. These include depressed conversion of citric acid cycle metabolites to oxaloacetate; decreased conversion of lactate to pyruvate; and decreased conversion of L-alpha-glycerophosphate to dihydroxyacetone-phosphate.
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 is not effective. Adequate food intake during alcohol ingestion prevents this type of hypoglycemia.
4. 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. 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 10 to 30 times more prevalent in Japanese and Koreans, which may explain the higher prevalence of this syndrome in these populations. Hypoglycemia generally occurs 3 to 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, procainamide, and alpha lipoic acid. 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.
High titers of insulin autoantibodies, usually IgG class, can be detected. Insulin, proinsulin, and C-peptide levels may be elevated, but the results may be erroneous because of the interference of the insulin antibodies with the immunoassays for these peptides.
In most cases the hypoglycemia is transient and usually resolves spontaneously within 3 to 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. 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 antibodies determines whether insulin-resistant diabetes or hypoglycemia occurs. Hypoglycemia was found to respond to glucocorticoid therapy but not to plasmapheresis or immunosuppression.
5. PANCREATIC β CELL TUMORS
Spontaneous fasting hypoglycemia in an otherwise healthy adult is most commonly due to an 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 type 1; see Chapter 22). It has been reported that about 30% of sporadic insulinoma tumors have a somatic mutation in the YY1 gene (T372R) that encodes the transcriptional repressor YY1. Over 99% of them are located within the pancreas and less than 1% in ectopic pancreatic tissue.
These tumors may appear at any age, although they are most common in the fourth to sixth decades. A slight predominance in women has been reported in some studies. However, others suggest that there is no gender predilection.
The most important prerequisite to diagnosing an insulinoma is simply to consider it, particularly when facing a clinical presentation of hypoglycemia with symptoms of central nervous system dysfunction such as confusion or abnormal behavior. Whipple’s triad consists of history of symptoms consistent with hypoglycemia, associated low plasma glucose and relief of symptoms upon ingesting carbohydrates and raising the plasma glucose.
Patients typically complain of feeling tired, experiencing blurred vision, and not thinking clearly. Other symptoms include personality changes, amnesia, and loss of consciousness. The preponderance of neuroglycopenic symptoms, rather than those more commonly associated with the adrenergic symptoms of hypoglycemia can lead to misdiagnoses of psychiatric or neurological disorders. Some patients learn to relieve or prevent their symptoms by taking frequent feedings. Eating or drinking readily absorbable carbohydrates improves the symptoms within approximately 15 minutes. Patients may gain weight but obesity is seen in less than 30% of patients with insulin-secreting tumors.
Timing of the symptoms in relation to meals and exercise should be noted. In insulinoma patients, the symptoms are most likely to occur early in the morning before breakfast or if a meal is missed during the day. Patients occasionally present when they attempt to go on a diet to lose weight. Exercise may precipitate the symptoms, especially if the activity occurs while fasting or some hours after a meal. Some patients develop symptoms in the middle of the night and may have to eat. Partners of patients often provide useful information, especially if the patient requires assistance in treating the hypoglycemic symptoms. Occasionally the emergency services are called when the patient gets severely confused, presents with focal weakness, loses consciousness, or has a seizure. There may be documentation of low fingerstick glucose at the time when symptoms are present with recovery following administration of intravenous glucose. With the ready availability of home blood glucose–monitoring systems, patients sometimes present with documented fingerstick blood glucose levels in 40s and 50s at time of symptoms. Access to diabetic medications (sulfonylureas or insulin) should be explored—does a family member have diabetes, or does the patient or family member work in the medical field? Medication-dispensing errors should be excluded—has the patient’s prescription medication changed in shape or color? Other illnesses that cause hypoglycemia such as renal failure, hepatic failure, Addison disease, or nonislet tumor should be considered. Patients with insulinoma or factitious hypoglycemia usually have a normal physical examination.
If the history is consistent with episodic spontaneous hypoglycemia, patients should be given a home blood glucose monitor and advised to monitor blood glucose levels at the time of symptoms, if it is safe, and before consumption of carbohydrates. Patients with insulinomas frequently will report fingerstick blood glucose levels between 40 mg/dL (2.2 mmol/L) and 50 mg/dL (2.8 mmol/L) at the time of symptoms. The diagnosis, however, cannot be made based on a fingerstick blood glucose since they are not sufficiently accurate—the fingerstick value may differ by as much as 15 mg/dL when the true blood glucose is less than 75 mg/dL. It is necessary to have a low laboratory glucose concomitantly with elevated plasma insulin, proinsulin and C-peptide levels, and a negative sulfonylurea screen. When patients give a history of symptoms after only a short period of food withdrawal or with exercise, then an outpatient assessment can be attempted. The patient should be brought by a family member to the office after an overnight fast and observed in the office. Activity such as walking should be encouraged and fingerstick blood glucose measured repeatedly during observation. If symptoms occur or fingerstick blood glucose is below 50 mg/dL then samples for plasma glucose, insulin, C-peptide, proinsulin, sulfonylurea screen, serum ketones, and antibodies to insulin should be sent. If outpatient observation does not result in symptoms or hypoglycemia and if the clinical suspicion remains high, then the patient should undergo an inpatient, supervised, 72-hour fast.
A suggested protocol for the supervised fast is set forth in Table 18–4. The fast is timed from the last intake of calories. The term 72-hour fast is actually a misnomer in most cases, because the fast should be immediately terminated as soon as symptoms and laboratory confirmation of hypoglycemia are evident. About 43% of patients with insulinomas are symptomatic within the first 12 hours, 67% by 24 hours and 93% to 95% by 48 hours. Since a minority of patients (∼5%-7%) may not demonstrate hypoglycemia after 48 hours of fasting, it is preferable to continue the fast for up to 72 hours. Patients can drink water and decaffeinated, noncaloric drinks. It is important that patients are active (walking) during the fast since exercise may help precipitate hypoglycemia. An intravenous cannula should be placed to allow for blood draws and as a safety precaution, should intravenous dextrose infusion be required. Fingerstick blood glucose levels should be measured at intervals, and blood sent to the laboratory, if the patient is symptomatic or when fingerstick blood glucose levels are below 50 mg/dL. The decision to stop the fast is not always easy. Patients should be carefully monitored for symptoms of hypoglycemia. If the patient is symptomatic and the laboratory glucose is less than 45 mg/dL, then the test can be stopped. If the symptoms are equivocal and the laboratory glucose is in the mid 50s or higher, then the fast should be continued, if the patient is agreeable. At the time of termination of the fast, blood should be sent to the laboratory for plasma glucose, insulin, proinsulin, C-peptide, and serum β-hydoxybutyrate levels and a sulfonylurea screen.
TABLE 18–4Suggested hospital protocol for supervised rapid diagnosis of insulinoma. |Favorite Table|Download (.pdf) TABLE 18–4 Suggested hospital protocol for supervised rapid diagnosis of insulinoma.
(1) Obtain baseline plasma glucose, insulin, proinsulin, betahydroxybutyrate and C-peptide measurements at onset of fast and place intravenous cannula.
(2) Permit only calorie-free and caffeine-free fluids and encourage supervised activity (such as walking).
(3) 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 <45 mg/dL, send a venous blood sample to the laboratory for serum glucose, insulin, proinsulin, betahydroxybutyrate, and C-peptide measurements. Check frequently for manifestations of neuroglycopenia.
(4) If symptoms of hypoglycemia occur or if a laboratory value of plasma glucose is <45 mg/dL or if 72 hours have elapsed, then conclude the fast with a final blood sample for serum glucose, insulin, proinsulin, C-peptide, β-hydroxybutyrate, and sulfonylurea measurements. Then give oral fast-acting carbohydrate followed by a meal. If the patient is confused or unable to take oral agents, administer 50 mL of 50% dextrose intravenously over 3-5 minutes. Do not conclude a fast based simply on basis of a capillary blood glucose measurement—wait for the laboratory glucose value unless the patient is symptomatic and it would be dangerous to wait.
Glucose sample should be collected in sodium fluoride containing tube on ice to prevent glycolysis and the plasma separated immediately upon receipt at the laboratory. Arrange for the laboratory to run the glucose samples “stat.”
In normal men, the blood glucose value does not fall below 55 mg/dL (3.1 mmol/L) during a 72-hour fast, whereas insulin levels fall below 10 μU/mL; in some normal women, however, plasma glucose may fall below 30 mg/dL (1.7 mmol/L) (lower limits have not been established), but serum insulin levels also fall appropriately to less than 5 μU/mL. These women remain asymptomatic despite this degree of hypoglycemia, presumably because ketogenesis is able to provide sufficient fuel for maintenance of central nervous system function.
The diagnostic criteria for insulinoma after a 72-hour fast are listed in Table 18–5. Virtually all patients with insulin-secreting islet cell tumors fail to suppress their insulin secretion appropriately when the plasma glucose is less than 45 mg/dL (see Table 18–5). It is important to be aware of limitations of the particular insulin assay that is used. When radioimmunoassays (RIAs) with a sensitivity of 5 mU/mL are used, patients with insulinomas have plasma insulin concentrations of 6 mU/mL or more. Immunochemiluminometric assays (ICMA) have sensitivities of less than 1 mU/mL, and with these assays, the cutoff for insulinomas is 3 mU/mL or higher. Previous treatment with insulin may lead to development of autoantibodies to insulin that interfere with the assays, leading to falsely low or elevated values depending on the method used. Proper collection of samples is also important. If serum is not separated and frozen within 1 to 2 hours, falsely low values result because the insulin molecule undergoes proteolytic degradation. Plasma insulin levels measured by ICMA may be lower in hemolyzed samples. Calculation of ratios of insulin (μU/mL) to plasma glucose (mg/dL) is not helpful in making the diagnosis.
TABLE 18–5Diagnostic criteria for insulinoma after a 72-hour fast. |Favorite Table|Download (.pdf) TABLE 18–5 Diagnostic criteria for insulinoma after a 72-hour fast.
Plasma insulin (RIA)
Plasma insulin (ICMA)
Sulfonylurea screen (including repaglinide and nateglinide)
<45 mg/dL (2.5 mmol/L)
≥6 uU/mL (36 pmol/L)
≥3 uU/mL (18 pmol/L
≥200 pmol/L (0.2 nmol/L; 0.6 ng/mL)
Factitious use of insulin will result in suppression of endogenous insulin secretion and low C-peptide levels. Elevated circulating proinsulin levels in the presence of fasting hypoglycemia is characteristic of β cell tumors and does not occur in factitious hyperinsulinism. Thus, C-peptide and proinsulin levels (by ICMA) of greater than or equal to 200 pmol/L and greater than or equal to 5 pmol/L, respectively, are characteristic of insulinomas. C-peptide is renally cleared and caution should be used in interpreting elevated levels in the setting of renal failure. Proinsulin normally represents less than 10% of total immunoreactive insulin. Insulinoma cells are poorly differentiated, which affects their ability to process proinsulin to insulin. Thus, most patients with insulinoma have elevated levels of proinsulin, representing as much as 30% to 90% of total immunoreactive insulin. Hyperinsulinemia suppresses ketone production. Plasma β-hydroxybutyrate levels in patients with insulinoma are 2.7 nmol/L or less. A progressive increase in β-hydroxybutyrate levels after 18 hours of fasting is strongly predictive that the fast will be negative. No single hormone measurement (insulin, proinsulin, C-peptide) is 100% sensitive and specific for the diagnosis of insulinoma, and insulinoma cases have been reported with insulin levels below 3 μU/mL (ICMA assay) or proinsulin level below 5 pmol/L. The hormonal assays are also not standardized between labs, and there can be significant variation in the results. Therefore, the diagnosis should be based on multiple biochemical parameters.
A variety of stimulation tests with intravenous tolbutamide, glucagon, or calcium have been devised to demonstrate exaggerated and prolonged insulin secretion in the presence of insulinomas. 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 is extremely hazardous to patients with responsive tumors because it induces prolonged and refractory hypoglycemia. For that reason, it is no longer included in the diagnostic workup of insulinoma.
The hyperinsulinism associated with insulinoma impairs glycogenolysis. Thus, when patients with insulinoma are given 1 mg IV glucagon at the end of the 72-hour fast, there is an increase in plasma glucose within the first 30 minutes. The glucose rise is 25 mg/dL (1.4 mmol/L) or more at 20 to 30 minutes, whereas normal subjects have a lower increment. Intravenous glucagon can also cause an exaggerated release of insulin from insulinomas. Patients are tested after an overnight fast, and serum insulin levels measured every 5 minutes for 15 minutes after 1 mg IV glucagon. A stimulated peak insulin level exceeding 130 μU/mL (780 pmol/L) (∼twice upper limit of peak stimulated normals)\suggests an insulin-secreting tumor. However, only about half of patients with insulinomas have insulin levels above 130 μU/mL and so the test is not so helpful. Also, in some patients the exaggerated insulin secretion can lead to severe hypoglycemia. Nausea is an unpleasant side effect, often occurring several minutes after administration of intravenous glucagon.
The oral glucose tolerance test is of no value in the diagnosis of insulin-secreting tumors. A common misconception is that patients with insulinomas have flat glucose tolerance curves because the tumors 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.
Low HbA1c values have been reported in patients with insulinoma, reflecting the presence of chronic hypoglycemia. There is however considerable overlap with normal patients and no HbA1c value is diagnostic.
Tumor Localization Studies
After the diagnosis of insulinoma has been unequivocally made by clinical and laboratory findings, studies to localize the tumor should be initiated. The focus of attention should be directed at the pancreas only, because virtually all insulinomas originate from this tissue. Ectopic cases are very rare. There are reports of duodenal neuroendocrine tumors secreting insulin. Other ectopic sites include spleen, perisplenic tissue, duodenohepatic ligament, and ligament of Treitz. Ovarian carcinomas and teratomas, small cell carcinomas of the cervix, and bronchial carcinoids have also been reported to secrete insulin. Because of the small size of these tumors (average diameter of 1.5 cm in one large series), imaging studies do not necessarily identify all tumors. A pancreatic dual phase, thin section, helical CT scan can identify 82% to 94% of the lesions. MRI scans with gadolinium can be helpful in detecting a tumor in 85% of cases. One case report suggests that diffusion-weighted MRI can be useful for detecting and localizing small insulinomas, especially those with no hypervascular pattern. 111In-octreotide scans for insulinomas, which typically express somatostatin receptor type 3, are only positive in 50% to 70% of cases. Newer PET/CT scans, using gallium-labeled somtatostatin analogs such as DOTA-1-NaI3-octreotide (DOTA-NOC), which has a higher affinity for somatostatin receptor subtypes 2, 3, and 5, have been reported to be useful in localizing the tumors. Insulinomas express GLP1-receptors and radiolabeled GLP1-receptor agonists such as [Lys(40)(Ahx-hydrazinonicotinamide [HYNIC]-(99m)Tc)NH(2)]-exendin-4 for SPECT/CT have also been reported to visualize the tumors. The optimal imaging study used will depend upon local availability and local radiologic skill. If the imaging study is negative, then an endoscopic ultrasound should be performed. In experienced hands, about 80% to 90% of tumors can be detected. Finally, needle aspiration of the identified lesion can be attempted to confirm the presence of a neuroendocrine tumor. If the tumor is not identified or imaging results are equivocal, then the patient should undergo selective calcium-stimulated angiography, which has been reported to localize the tumor to particular regions of the pancreas approximately 90% of the time. In this test, angiography is combined with injections of calcium gluconate into the gastroduodenal, splenic, and superior mesenteric arteries, and insulin levels are measured in the hepatic vein effluent. The procedure is performed after an overnight fast. Ten percent of calcium gluconate, diluted to a volume of 5 mL normal saline, is injected into the individual arteries (discussed earlier) at a dose of 0.0125 mmol Ca2+/kg body weight (0.005 mmol/kg for obese patients). Five milliliter blood samples are taken from the hepatic effluent at times 0, 30, 60, 90, 120, and 180 seconds after calcium injection. Fingerstick blood glucose levels are measured at intervals and a dextrose infusion is maintained throughout the procedure. Calcium stimulates insulin release from insulinomas but not normal islets. A step-up in insulin levels at 30 or 60 seconds (twofold or greater) regionalizes the source of 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. A less than twofold elevation of insulin in the 120 second sample may represent effects of recirculating calcium and is not considered a positive localization. In a single insulinoma, the response is in one artery alone (Figure 18–4) unless the tumor resides in an area fed by two arteries or if there are multiple insulinomas as in multiple endocrine neoplasia, type 1. Patients who have diffuse islet hyperplasia (the noninsulinoma pancreatogenous hypoglycemia syndrome [NIPHS]) will have positive responses in multiple arteries. Because diazoxide may interfere with this test, it should be discontinued for at least 48 to 72 hours before sampling. Patients should be closely monitored during the procedure to avoid hypoglycemia (as well as hyperglycemia), which could affect insulin gradients. These studies combined with careful intraoperative ultrasonography and palpation by a surgeon experienced in insulinoma surgery correctly identify up to 98% of tumors.
Responses of serum insulin to selective intra-arterial calcium stimulation in a patient with biochemical confirmation of inappropriate hyperinsulinism. 0.0125 mmol/kg calcium gluconate diluted in 5 mL normal saline were bolused into selectively catheterized arteries as indicated and blood samples collected from the hepatic vein at 0, 30, 50, 90, 120, and 180 seconds. An islet cell tumor was removed from the tail of the pancreas.
The treatment of choice for insulin-secreting tumors is surgical resection (Figure 18–5). While waiting for surgery, patients should be given diazoxide, a potent inhibitor of insulin secretion. It acts by opening the KATP channel of the pancreatic β cell and hyperpolarizing the cell membrane. This reduces calcium influx through the voltage-gated calcium channel, thereby reducing insulin release. Divided doses of 300 to 400 mg/d usually suffice, but occasionally a patient may require up to 800 mg/d. A liquid preparation of diazoxide (50 mg/mL) is available in the United States. Side effects include edema due to sodium retention (which generally necessitates concomitant thiazide administration), gastric irritation, and mild hirsutism.
1.4 cm insulinoma resected from the uncinate process of the pancreas. A: CT scan of abdomen; B: View of the 3rd part of the duodenum (bottom) and uncinate process with site of enucleation; C: tumor sectioned in half.
Tumor resection should be performed only by surgeons with extensive experience with removal of islet cell tumors, because these tumors may be small and difficult to recognize. The tumors are enucleated whenever possible unless they have malignant features (eg, hardness or an appearance of infiltration). Preoperative imaging studies, including endoscopic ultrasound, can identify tumors amenable to laparoscopic surgery. Laparoscopic surgery is associated with faster postoperative recovery. Laparoscopic intraoperative ultrasound should be used to confirm the location and depth of the tumor within the pancreas and also note its relationship to the pancreatic duct and splenic vessels. Open surgery is still necessary for some tumors such as those in the head of the pancreas close to the main pancreatic duct. In the very occasional case where the tumor cannot be found at operation despite the use of intraoperative ultrasound, it is no longer advisable to blindly resect the body and tail of the pancreas since a nonpalpable tumor, missed by ultrasound, is most likely embedded within the fleshy head of the pancreas that is left behind with subtotal resections. Most surgeons prefer to close the incision and treat the patient medically and/or repeat the localization studies. Ultrasound-guided ethanol injection into the tumor has been reported to be effective and should be considered for those patients who are poor surgical candidates.
Diazoxide should be administered on the day of surgery in patients who are responsive to it, because the drug greatly reduces the need for glucose supplements and the risk of hypoglycemia during surgery. Typically, it does not mask the glycemic rise indicative of surgical cure. Blood glucose levels should be monitored frequently during the operation, and a 5% or 10% dextrose infusion should be used to maintain euglycemia. Hyperglycemia occurs for a few days postoperatively most likely due 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 downregulation of insulin receptors by the previously high circulating insulin levels from the tumor, and, perhaps, suppression of normal pancreatic β cells by long-standing hypoglycemia. Small subcutaneous doses of regular insulin may be prescribed every 4 to 6 hours if plasma glucose exceeds 300 mg/dL (16.7 mmol/L), but in most cases pancreatic insulin secretion recovers after 48 to 72 hours, and very little insulin replacement is required.
In patients with inoperable functioning islet cell carcinoma with or without hepatic metastasis and in approximately 5% to 10% of MEN 1 cases when subtotal removal of the pancreas has failed to produce cure, the treatment approach is the same as for other types of pancreatic neuroendocrine tumors (PNET). Diazoxide is the treatment of choice in preventing hypoglycemia. Frequent carbohydrate feedings (every 2-3 hours) can also be helpful although weight gain can become a problem. If patients are unable to tolerate diazoxide because of gastrointestinal upset, hirsutism, or edema, the calcium channel-blocker verapamil, which inhibits insulin release from insulinoma cells, can be tried. Somatostatin analogs, such as octreotide or lanreotide, should be considered if diazoxide is ineffective or if there is tumor progression. These drugs not only inhibit insulin secretion but also have antiproliferative activity. Surgery or embolization (bland-, chemo-, or radio-embolization) or thermal ablation (radiofrequency, microwave, or cryoablation) can be used to reduce tumor burden and also provide symptomatic relief. For islet cell carcinomas, chemotherapy regimens can be considered. Representative regimens include combinations of streptozocin, 5–fluorouracil and doxorubicin; capecitabine and oxaliplatin; and capecitabine and temozolomide. There are only limited data regarding efficacy of these regimens. Targeted therapies against multiple steps in the PI3K/AKT/mTor pathway have been shown to be helpful. Everolimus, an inhibitor of mTor, has been approved for treatment of advanced pancreatic neuroendocrine tumors. Sunitinib targets multiple tyrosine kinase inhibitors including vascular endothelial growth factor (VEGF) receptors 2 and 3, platelet-derived growth factor (PDGF) receptors α and β, and c-kit, has been shown to slow growth of pancreatic neuroendocrine tumors. Treatment with radioisotopes (indium-111, yttrium-90, or lutetium-177) linked to a somatostatin analog have been reported to show benefit in a proportion of patients.
6. NONISLET CELL TUMOR HYPOGLYCEMIA (NICTH)
A variety of nonislet cell 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, renal cell carcinomas, gastrointestinal tumors, lymphomas, leukemias, and a variety of other tumors have also been reported.
Laboratory diagnosis depends on fasting hypoglycemia associated with serum insulin levels below 5 μU/mL. In many cases, the hypoglycemia is due to the expression and release of an incompletely processed insulin-like growth factor II (IGF-II) by the tumor (see also Chapter 21). The primary IGF-II translation product is pre-pro-IGF-II consisting of N-terminal signal peptide of 24 amino acids, 67 amino acid mature IGF-II, and an 89 amino acid extension (E-domain) at the C-terminus. Posttranslational processing of pre-pro-IGF-II involves removal of the N-signal sequence, O-glycosylation of one or more threonine residues of the E-domain, and sequential proteolysis of the E-domain. During this process an IGF-II protein with a 21 amino extension of the E-domain (pro-IGF-IIE[68-88]) is a relatively stable intermediate that may be secreted from the cell. Most of the mature IGF-II released from the liver is complexed with IGF-binding protein-3 (IGFBP3) and acid-labile subunit (ALS). This ternary protein complex is generally inactive in adults because it is unable to bind properly to tissue receptors. It is only the free IGF-II (<1%) and that bound in binary complexes (predominantly IGFBP2 and IGFBP3) that is accessible to tissue compartment and available to bind the IGF and insulin receptors. However, in patients with nonpancreatic tumors associated with hypoglycemia, incompletely processed mainly nonglycosylated forms of IGF-II are released—in particular pro-IGF-IIE (68-88) form. These incompletely processed molecules are heterogeneous in size and are also referred to as big IGF-II and have molecular mass of 10 to 17 kDa in contrast to mature IGF-II at 7.5 kDa. Pro-IGF-II can form binary complexes with IGFBPs but have reduced affinity for forming a tertiary complex with ALS. As a consequence, more of the pro-IGF-II is available for binding to the insulin receptors in the muscle to promote glucose transport and to insulin receptors in liver and kidney to reduce glucose output. The increased production of pro-IGF-II by the tumor may also displace processed IGF-II from IGFBPs, increasing free, unbound IGF-II. The IGF-II may bind to receptors for IGF-I in the pancreatic β 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 IGFBP-3 and ALS.
Size exclusion acid chromatography has been the standard method for detection of Pro-IGF-II in NICTH, but the process is time-consuming. Immunoblot analysis after separating the proteins on 16.5% tricine-sodium dodecyl sulphate-polyacrylamide gels is a more rapid and equally sensitive method. The IGF-II antibody used recognizes both mature and pro-IGF-II forms. In normal subjects, most of the IGF-II migrates at 7.5 kDa and a small amount in the 10 to 17 kDa region, whereas with NICTH most of the IGF-II migrates in the 10 to 17 kDa region and a small amount at 7 kDa.
The clinical syndrome of nonislet cell tumor hypoglycemia, therefore, is supported by laboratory documentation of serum insulin levels below 5 μU/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.
Not all the patients with NICTH have elevated pro-IGF-II. Ectopic insulin production has been described (bronchial carcinoid, ovarian carcinoma, teratoma, and small cell carcinoma of the cervix). Hypoglycemia due to IGF-I released from a metastatic large cell carcinoma of the lung has also been reported.
Treatment is aimed toward the primary tumor, with supportive therapy using frequent feedings. Diazoxide is ineffective in reversing the hypoglycemia caused by these tumors.
7. POSTPRANDIAL HYPOGLYCEMIA
Hypoglycemia Following Gastric Surgery
Hypoglycemia sometimes occurs after gastric surgery (gastrectomy, vagotomy, pyloroplasty, gastrojejunostomy, and laparoscopic Nissen fundoplication, Billroth II procedure, and Roux-en-Y gastric bypass), often after patients consume foods containing high levels of carbohydrates. This late dumping syndrome occurs 1 to 3 hours after a meal and is result of rapid delivery of high concentration of carbohydrates in the small bowel and rapid increase in blood glucose. This is countered by a hyperinsulinemic response. The high insulin levels are responsible for the subsequent hypoglycemia. The hypoglycemic symptoms include lightheadedness, sweating, confusion, and even loss of consciousness. It is likely that excessive release of gastrointestinal hormones—such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1)—may play a role in the hyperinsulinemic response. An increased GLP-1 response has been noted in patients after total gastrectomy, esophageal resection, partial gastrectomy, and Roux-en-Y surgery; and a positive correlation has been noted between the rise in plasma GLP-1 and insulin release. It has been reported that treatment with exendin 9-39, a GLP-1 receptor antagonist can prevent post-gastric bypass hypoglycemia. Decreased need for gastric surgery for peptic ulcer disease and newer gastric operations such as proximal gastric vagotomy had reduced the incidence of postgastrectomy syndromes. There has been a resurgence of cases, however, with the popularity of Roux-en-Y gastric bypass surgery for morbid obesity. The prevalence of the syndrome after Roux-en-Y procedure is not known. The University of Minnesota surgery group identified 14 cases of postprandial hypoglycemia in 3082 procedures (0.4%), but it is unclear how many patients may have eluded detection or failed to maintain follow-up.
Patients typically complain of more severe symptoms after consumption of large amounts of readily absorbable carbohydrates. The mixed meal test can be used to precipitate the symptoms. The composition of the mixed meal has not been standardized, and it is reasonable to request the patient to consume a meal that leads to symptoms during everyday life. The University of Minnesota investigators formalized a high carbohydrate and a low carbohydrate test meal (Table 18–6) and showed that in patients with postgastric bypass hypoglycemia, the high carbohydrate meal resulted in hyperglycemia and concomitant hyperinsulinemia at about 30 minutes after a meal. Glucose levels then fell to a nadir (range 28-62 mg/dL) at 90 to 120 minutes. Eating the low carbohydrate meal, however, resulted in very little change in plasma glucose levels and only a modest increase in plasma insulin. The prolonged (5 hour) oral glucose tolerance test is not recommended for evaluation because a large number of healthy subjects will have a false-positive result. There have been case reports of insulinoma and noninsulinoma pancreatogenous hypoglycemia syndrome occurring in patients who present with hypoglycemia post-Roux-en-Y surgery. It is unclear how often this occurs. A careful history may identify those patients who have history of hypoglycemia with exercise or when meals are missed, and these individuals may require a formal 72-hour fast to rule out insulinoma.
TABLE 18–6Test meals for evaluation of postprandial hypoglycemia after Roux-en-Y gastric bypass surgery. |Favorite Table|Download (.pdf) TABLE 18–6 Test meals for evaluation of postprandial hypoglycemia after Roux-en-Y gastric bypass surgery.
|High Carbohydrate Meal (79% Carbohydrate, 11% Fat, and 10% Protein; 405 kcal) ||Low Carbohydrate Meal (2% Carbohydrate, 74% Fat, and 24% Protein; 415 kcal) |
8 oz of orange juice
1 slice of toast with 1 tsp of margarine and 2 tsp of jam
Decaffeinated black coffee or tea (without sugar)
1 egg, a 1-oz sausage patty, and a 0.5-oz slice of cheese
Several different treatments can be tried for the late dumping syndrome. Dietary modification is the best option but may be difficult to sustain for some patients. More frequent meals with smaller portions of less rapidly assimilated carbohydrate and more slowly absorbed fat or protein can be tried. Alpha glucosidase inhibitors (acarbose and miglitol) can be a useful adjunct to a low carbohydrate diet in some patients. Octreotide 50 μg administered subcutaneously two or three times a day 30 minutes prior to each meal has been reported to improve symptoms in patients with severe dumping refractory to other forms of medical interventions. Information regarding long-term octreotide use is however limited. Various surgical procedures to slow down gastric emptying have been reported to improve symptoms, but long-term efficacy studies are lacking. Recently it has been reported that endoscopic gastrojejunal anastomotic reduction to induce delay in gastric pouch emptying in patients with Roux-en-Y surgery improves the dumping syndrome symptoms.
Noninsulinoma Pancreatogenous Hypoglycemia Syndrome (NIPHS)
These are patients with hyperinsulinemic hypoglycemia due to generalized islet hyperplasia. The term adult onset nesidioblastosis has also applied to this clinical entity, and it is very rare. These patients predominantly have symptoms 2 to 4 hours after meals and only rarely while fasting. As in other patients who have frequent hypoglycemia, the symptoms are predominantly those of neuroglycopenia including diplopia, dysarthria, confusion, disorientation, convulsions, and coma. At the time of hypoglycemia, these patients have elevated insulin, C-peptide and proinsulin levels and negative sulfonylurea, repaglinide, and nateglinide screens. Typically these patients have a negative 72-hour fast. Imaging studies are also negative. These patients have a positive selective arterial calcium stimulation test—usually positive for multiple arteries. NIPHS patients do not have mutations in the KIR6.2 and SUR1 genes, which have been abnormal in some cases of children with a syndrome of familial hyperinsulinemic hypoglycemia (discussed later) Gradient-guided partial or subtotal pancreatectomy relieves the hypoglycemic symptoms in the majority of patients.
Late Hypoglycemia of Occult Diabetes
This condition occurs in the occasional patient with impaired glucose tolerance or early type 1 or type 2 diabetes. The patient complains of hypoglycemic symptoms after consuming high carbohydrate meals. In response to an oral glucose tolerance test, they have a delayed insulin secretion pattern which produces late hypoglycemia 4 to 5 hours after ingestion of glucose. In the obese patient, treatment is directed at reduction to ideal weight. These patients often respond to reduced intake of refined sugars with multiple, spaced, small feedings that are high in dietary fiber. Those with impaired glucose tolerance should be advised to have periodic assessment for development of diabetes.
Functional Alimentary Hypoglycemia
Patients present with symptoms suggestive of increased sympathetic activity—anxiety, weakness, tremor, sweating, or palpitations after meals. Physical examination and laboratory tests are normal. Previously many of these patients underwent a 5-hour oral glucose tolerance test and the detection of glucose levels in the 50s was determined to be responsible for the symptoms, and the recommendation was to modify the diet. It is now recognized that at least 10% of normal subjects who do not have any symptoms have nadir glucose levels less than 50 mg/dL during a 4- to 6-hour oral glucose tolerance test. In a study comparing responses to an oral glucose tolerance test with the response to a mixed meal test, none of the patients who had plasma glucose levels less than 50 mg/dL on oral glucose testing had low glucose values with the mixed meal. Thus, it is not recommended that these patients undergo either a prolonged oral glucose tolerance test or a mixed meal test. The patients should instead be given home blood glucose monitors (with memories) and instructed to monitor fingerstick glucose levels at the time of symptoms. Only patients who have symptoms when their fingerstick blood glucose is low (<50 mg/dL) and who have resolution of symptoms when the glucose is raised by consumption of readily absorbable carbohydrate need additional evaluation. Patients who do not have evidence for low glucose levels at the time of symptoms are generally reassured by their findings. Counseling and support should be the mainstays of therapy in this group, with dietary manipulation used only as an adjunctive form of therapy.
8. DISORDERS ASSOCIATED WITH LOW HEPATIC GLUCOSE OUTPUT
Reduced hepatic gluconeogenesis can result from a direct loss of hepatic tissue (acute yellow atrophy from fulminant viral hepatitis or toxic damage), from disorders that reduce amino acid substrate for hepatic gluconeogenesis (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.
Hypoglycemia is common in children, and prompt diagnosis and effective treatment are required to prevent seizures and brain injury in this vulnerable population. The most common cause of pediatric hypoglycemia is diabetes mellitus. Persistent hypoglycemia, however, is most often the result of a congenital defect in regulation of insulin, cortisol, or growth hormone, or an inborn error of metabolism of glucose, glycogen, or fatty acids. Pediatric hypoglycemia presents a unique challenge of distinguishing between hypoglycemia of the normal transitional glucose metabolism in the newborn and hypoglycemia that persists or presents for the first time after 3 days of life. Diagnosis of the cause of hypoglycemia relies primarily on laboratory investigations (a “critical sample”) at the time of a hypoglycemic episode and Figure 18–6 shows an algorithm for elucidating a diagnosis from these results. Persistent hypoglycemia may result from: (1) a deficiency in one or more counterregulatory hormones including hypopituitarism; (2) defects in glycogenolysis, gluconeogenesis, or fatty acid oxidation; or (3) congenital hyperinsulinism.
Algorithm to approach hypoglycemia. Shows how information from the critical sample can be used to determine major categories of hypoglycemia. BOHB, beta hydroxybutyrate; FFA, free fatty acids; GH, growth hormone.
As with adults, hyperinsulinism is the most frequent cause of persistent hypoglycemia in infants and children. As compared to adults, where the most common cause of hyperinsulinism is an insulin-secreting adenoma, in infants hyperinsulinism most likely stems from an underlying genetic disorder. This condition has been referenced in various ways, including persistent hyperinsulinemic hypoglycemia of infancy or islet dysregulation syndrome, but hereafter will be referred to as congenital hyperinsulinism. Transient congenital hyperinsulinism is a common disorder in the immediate neonatal period. Persistent disorders are rarer, occurring in approximately 1 in 50,000. This problem was originally attributed to an anomaly in islet development, termed nesidioblastosis, a reference to endocrine cell budding from pancreatic ducts. However, this budding has since been noted to represent a normal developmental process during the first year of life. Recent advances in our understanding of the regulation of insulin secretion have begun to elucidate the underlying pathophysiology of this complex disease (Table 18–7). Monogenic forms of congenital hyperinsulinism have now been attributed to mutations in eleven different genes. However, depending on the series cited, genetic mutation analysis is negative in 50% or more of cases and higher in those who are diazoxide-responsive. Timely diagnosis and aggressive treatment are essential to prevent long-term neurologic sequelae from hypoglycemia in the affected individual.
TABLE 18–7Types of congenital hyperinsulinism and their causes. |Favorite Table|Download (.pdf) TABLE 18–7 Types of congenital hyperinsulinism and their causes.
Transitional neonatal hypoglycemia
Infants of diabetic mothers
Small or Large for gestational age, asphyxia, and stress in infants
Defects in ATP-dependent potassium channel
Sulfonylurea receptor (SUR) (ABCC8)
Focal vs diffuse disease
Glutamate dehydrogenase (GDH)
Hexokinase 1 (HK1)
Pyruvate transporter (MCT1) (Exercise-induced)
Short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD)
Hepatocyte nuclear factor (HNF) 1A and HNF 4A
Uncoupling protein 2 (UCP2)
Phosphoglucomutase 1 (PGM1)
A. Transitional neonatal hypoglycemia
It has been long recognized that plasma glucose concentrations are lower in the first few days of life in normal newborns than at older ages. Immediately after birth mean plasma glucose levels drop by 25 to 30 mg/dL and reach a nadir in the first day of life at 55 to 65 mg/dL. These glucose concentrations remain stable and are relatively unaffected by the timing of the first feeding or frequency of feedings in the first day of life. They subsequently increase over the next couple of days to reach the normal range of older children. This hypoglycemia is characterized be suppressed ketogenesis and lipolysis and a large glycemic response to intravenous glucagon injection, consistent with hyperinsulinism due to an apparent incomplete suppression of insulin secretion. This transitional neonatal hyperinsulinism may reflect a persistent reduction of the glucose threshold for insulin secretion, a normal finding in utero thought to optimize fetal growth.
B. Infants of diabetic mothers
The fetuses of mothers with poorly regulated diabetes are exposed to sustained hyperglycemia, leading to increased fetal insulin secretion, with resultant macrosomia. This increased insulin secretion persists postpartum and usually resolves after several days. As a result, infants of diabetic mothers are at high risk of developing hypoglycemia after birth. An added risk of hypoglycemia is associated with being large for gestational age at birth, mothers who required insulin during pregnancy, or mothers who were hyperglycemic during labor. They can usually be managed with early, frequent feedings or intravenous glucose until insulin secretion has normalized, often 1 to 2 days after birth.
C. Small or large for gestational age, asphyxiation, and other conditions in newborns
Various perinatal stresses are known to induce more severe and prolonged hyperinsulinism. Small-for-gestational age as well as large-for-gestational age and asphyxiated newborns, usually from toxemic mothers, frequently experience hyperinsulinism and hypoglycemia. Hyperinsulinism is also reported in erythroblastosis fetalis, sepsis, cerebral hemorrhage, prematurity, and severely stressed newborns (low Apgar scores). Hypoglycemia usually resolves within a period of several days or weeks but may persist in these settings for 6 to 12 months. Some newborns with Beckwith-Wiedemann syndrome and Soto syndrome (also known as cerebral gigantism) show β cell hyperplasia and experience transient hypoglycemia from hyperinsulinism.
Persistent hyperinsulinism, continuing for more than several weeks, results from a group of heterogeneous disorders, rather than a single entity, and the various subtypes are discussed below. These forms may be classified in a variety of different ways, including usual time of presentation (shortly after birth vs after months to years of life); mode of genetic transmission (autosomal recessive vs dominant); or anatomic (focal vs diffuse). In this section, the forms are grouped into defects in the pancreatic β cell KATP channel, defects affecting intracellular metabolism, and several other miscellaneous conditions or syndromes.
Sulfonylurea receptor and Kir6.2—The most common cause and the severe form of congenital hyperinsulinism appears to be related to defects in the pancreatic β cell KATP channel. This channel consists of a multimer of two proteins, the sulfonylurea receptor (SUR1), a member of the ATP-binding cassette superfamily, and Kir6.2, a member of a family of inwardly rectifying potassium channels. With increases in intracellular ATP, the channel closes, leading to membrane depolarization and insulin secretion (see Chapter 17). Inactivating mutations of either component of the channel result in a non-functional KATP channel, inappropriate β cell depolarization, and secretion of insulin, even in the face of low glucose concentrations.
The two genes, ABCC8 and KCNJ11, encoding the channel components, SUR1 and Kir6.2, respectively, are located in tandem on chromosome 11p15. Numerous mutations have now been described and appear to occur more frequently in ABCC8 than KCNJ11. They are usually autosomal recessive mutations, which result in complete absence of KATP channels by blocking trafficking to the plasma membrane. Dominant mutations are missense defects, which allow normal trafficking of the channel to the plasma membrane but act in a dominant negative manner to impair channel activity. The severity of the impairment manifests varying degrees of diazoxide responsiveness. Sequencing of these molecules is available commercially and may not be merely of academic interest: patients harboring some ABCC8 or KCNJ11 mutations do not respond well to medical therapy. Thus, knowledge of the underlying defect may influence treatment decisions for a particular patient as well as inform the family about risk to future children. Relative to other forms of congenital hyperinsulinism, patients with defects in the KATP channel often present early in life, with more marked clinical symptomatology, including macrosomia. They experience early onset and severe hypoglycemia that requires high rates of glucose infusion to normalize serum glucose concentrations and typically require pancreatectomy to restore euglycemia.
Focal versus diffuse disease—Two histologically distinct forms of congenital hyperinsulinism due to KATP channel mutations have been described, a diffuse form, mentioned above, which constitutes 35% to 70% of cases, depending on the series cited, and a focal form (focal adenomatous hyperplasia). The clinical differences between the two forms are subtle; children with the focal form are more likely to have a delay in diagnosis and hypoglycemic seizures. Diagnosis of the focal form is made by perioperative palpation and visualization by an experienced surgeon and histologic examination. 18F DOPA positron emission tomography may also be of utility in preoperative localization of focal lesions. Histologic examination of the focal form reveals focal hyperplasia, with hypertrophied β cells harboring giant nuclei, in contrast to the diffuse form, where all the islets of Langerhans are irregular in size and contain hypertrophied β cells. The molecular explanation for the focal defect is based on a two genetic hit model, in which the child harbors a paternally inherited recessive KATP mutant allele, in either ABCC8 or KCNJ11, and subsequently has an embryonic pancreas-limited chromosome recombination of 11p15.1 that results in a pancreatic lesion with paternal isodisomy (two copies of the paternally inherited recessive KATP mutant) and biallelic loss of function of KATP channel. Paternal isodisomy of the KATP mutation and the adjacent Beckwith-Weidemann syndrome (BWS) locus leads to islet overgrowth due expression and suppression of imprinted growth regulatory genes (IGF2, H19, p57/CDKN1C). The distinction between these two forms of hyperinsulinism has potentially important implications for therapy, because patients with focal disease are not responsive to diazoxide but may be cured with more limited partial pancreatectomy, whereas those with the diffuse form who are not responsive to diazoxide require more aggressive near-total resection, which may result in diabetes. Such patients can only be fully evaluated and treated at centers with a team of endocrinologists, interventional radiologists, pathologists, and surgeons with expertise in this disorder.
The second most common form of congenital hyperinsulinism is the hyperinsulinism-hyperammonemia syndrome, which results from activating mutations of the glutamate dehydrogenase (GDH) gene. This condition is inherited in autosomal dominant fashion. This enzyme mediates oxidative deamination of glutamate to alpha ketoglutarate. Activating mutations impair GDH sensitivity to guanosine triphosphate, an allosteric inhibitor, and increase sensitivity to leucine, an allosteric activator. With increased GDH activity, increased production of alpha ketoglutarate with subsequent oxidation in the Krebs cycle generates increased ATP, which in turn activates the KATP channel and leads to membrane depolarization and insulin secretion. GDH is also expressed in the liver and kidney. Overactivity of GDH in the kidney leads to increased renal ammonia production. Thus, one hallmark of this defect is a chronic mild elevation in serum ammonia concentrations with an increase up to 3 to 5 times normal in response to a protein load. The patients with GDH mutations usually have a milder course than those with defects in the KATP channel, often presenting outside of the neonatal period. CNS manifestations include absence seizures and behavior disturbances. They often have postprandial hypoglycemia, particularly in response to higher protein loads, but may also manifest fasting hypoglycemia. They usually respond well to diazoxide, and many are able to eventually discontinue treatment.
The third most common form of congenital hyperinsulinism results from mutations in glucokinase, the first and rate-limiting step in glycolysis, and an enzyme that is considered to play an essential role in glucose sensing by the β cell. Dominant activating mutations have been described that result in increased rates of glycolysis at lower glucose concentrations. The resultant increase in the intracellular ATP/ADP ratio increases insulin secretion at any given serum glucose concentration, resulting in fasting hypoglycemia. They usually respond poorly to diazoxide. By contrast, individuals heterozygous for inactivating mutations have a form of maturity onset diabetes of the young (MODY).
Two rare forms of congenital hyperinsulinism involve the expression of genes that are not normally expressed in β cells to ensure appropriate insulin secretion. Hexokinase 1 (HK1) has a higher affinity for glucose than glucokinase, and its absence in β cells prevents insulin release at low glucose concentrations. Expression of hexokinase leads to elevations in basal insulin secretion, even at low glucose concentrations, increasing the potential for hypoglycemia. This dominant form of hyperinsulinism is responsive to diazoxide therapy. The loss of normal suppression of monocarboxylate transporter 1 (MCT1) expression in β cells leads to exercise-induced hyperinsulinism. In the setting of anaerobic exercise, the abnormal expression of MCT1 in the pancreatic beta cell allows pyruvate and lactate influx and subsequently leads to ATP generation and an inappropriate, rapid rise in insulin secretion. Therapy is largely focused on prevention with increased ingestion of carbohydrates during and following exercise.
Another autosomal recessive form of congenital hyperinsulinism results from mutations in the gene encoding the short chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD). Mutations of SCHAD cause loss of an inhibitory interaction with GDH that results in a hyperinsulinism phenotype similar to that seen with activating GDH mutations but without hyperammonemia and CNS manifestations. This recessive defect is responsive to diazoxide.
For some time, dominant inactivating mutations of the transcription factors hepatocyte nuclear factor (HNF) 1A and HNF 4A have been associated with MODY3 and MODY1, respectively. Recently, individuals bearing these mutations have been shown to manifest hyperinsulinism in early infancy, yet progress to MODY in early adulthood. The mechanism(s) underlying this transition from early hyperinsulinism and to subsequent islet failure remain unknown; animal models suggest that chronic activation of beta cells may herald later beta cell failure.
Dominant inactivating mutations of uncoupling protein 2 (UCP2) have been reported in a small number of cases of hyperinsulinism. UCP2 functions as a carrier to remove 4 carbon intermediates from the mitochondrial matrix and suppress glucose oxidation. It is assumed that reduced activity of UCP2 enhances glucose oxidation and subsequently increases insulin secretion. Phosphoglucomutase 1 (PGM1) plays an important role in regulating insulin response to glucose. Recessive inactivating mutations cause a form of glycogen storage disease that is associated with ketotic, fasting hypoglycemia, post-prandial hyperinsulinemic hypoglycemia, and abnormal protein glycosylation.
Congenital disorders in glycosylation have also been linked with congenital hyperinsulinism. The mechanism is unclear, although hypoglycosylation of the SUR with a resultant defect in trafficking to the cell membrane has been offered as a possible explanation. Nonetheless, these patients appear to be responsive to diazoxide, suggesting that at least some functional KATP channels reach the cell surface. Affected individuals have multisystem disorders, including neurologic defects.
The cardinal symptoms of congenital hyperinsulinism are recurrent episodes of hypoglycemia and can occur from any time after birth until several years of age, or manifest even later in life, depending on the nature and severity of the defect. However, hyperinsulinism presenting in adolescence is more likely due to an insulinoma. As in adults, the symptoms of hypoglycemia are secondary to adrenergic responses or neuroglycopenia. However, in neonates and infants, symptoms are difficult to detect and may be less specific. They may include tremors, cyanosis, hypothermia, apnea or irregular breathing, lethargy, apathy, limpness, refusal to eat, high-pitched cries, and seizures of any type. Even if newborns appear asymptomatic, hypoglycemia can be severe.
The differential diagnosis for pediatric hypoglycemia is quite long and includes deficiencies in counterregulatory hormones (eg, growth hormone, ACTH, glucocorticoids); defects in gluconeogenesis, glycogen synthesis, and breakdown; and disorders in fatty acid metabolism. Hyperinsulinism is suspected in hypoglycemic newborns or infants who require unusually high glucose infusion rates (12-30 mg/kg/min) to maintain blood glucose levels in the target range. Macrosomia may be another clue to hyperinsulinism, although it is not always present. The crucial diagnostic step is to obtain a critical blood sample for glucose, insulin, growth hormone, cortisol, blood gases, lactate, free fatty acids, and ketones (β-hydroxybutyrate [BOHB]) during hypoglycemia (see Figure 18–6). Insulin levels must often be measured during several episodes of hypoglycemia because insulin levels at times of hypoglycemia are not always elevated to diagnostic levels. In fact, even if not elevated, insulin levels that are inappropriately measurable during episodes of hypoglycemia are still consistent with the diagnosis. As in adults, the hallmarks of hyperinsulinism include measurable plasma insulin in the face of hypoglycemia (glucose <50 mg/dL), low or unmeasurable ketones (BOHB <15 mg/dL [<1.5 mmol/L]) and free fatty acids (<28-42 mg/dL [<1.0-1.5 mmol/L]), and hyperresponsiveness to glucagon challenge, with the glycemic response to 0.5 to 1 mg (30 μg/kg) of parenteral glucagon of more than 30 mg/dL (with glucose monitored every 15 minutes for up to 45 minutes after glucagon injection).
Management of children with congenital hyperinsulinism remains one of the most challenging problems for pediatric endocrinologists, and affected children should be transferred to a tertiary center that has experience in managing such children. Patients may require high glucose infusion rates to maintain euglycemia, and thus a secure central line is usually necessary. They also require frequent glucose monitoring, extensive ongoing laboratory assessment to establish the underlying diagnosis, and a series of medical and/or surgical interventions to effect a cure.
Hypoglycemia in infancy has to be treated aggressively in order to prevent long-term neurologic sequelae. Relative to adults, younger children (up to age 5-6 years) appear to be especially vulnerable to such damage. Those with hyperinsulinism are particularly at risk, because ketone bodies are not present as an alternative fuel source. The therapeutic goal is to achieve glucose levels above 70 mg/dL while the infant is on an appropriate feeding schedule for age. Infants receiving appropriate therapy must be able to support a fast for at least 6 hours without hypoglycemia. In selected cases in which food refusal or intercurrent illness is a problem, hypoglycemia can be prevented by placing a gastrostomy tube to administer enteral feedings on a regular basis or with intermittent low dose intramuscular or subcutaneous glucagon injections until oral feeding resumes.
For acute management of hypoglycemia, stabilization of blood glucoses may require infusion rates of glucose up to 20 to 30 mg/kg/min, well above the 4 to 8 mg/kg/min needed to stabilize most neonates. Some centers employ aggressive enteral feeding, using frequent feeds or continuous feeding via nasogastric or gastrostomy tube, with or without cornstarch, as a means to avoid hypoglycemia. The following drugs are also used in the medical management of hyperinsulinemic hypoglycemia.
Diazoxide—Diazoxide is the drug of choice in infants who cannot be weaned from intravenous glucose. Diazoxide increases blood glucose by stabilizing the KATP channel in the open state, thereby inhibiting membrane depolarization and insulin secretion. Functionally intact SUR1 and Kir6.2 proteins are necessary for the full action of the drug, and thus, patients with channel defects often do not respond, whereas those with other forms of hyperinsulinism do exhibit salutary responses. Diazoxide also increases catecholamine release, which suppresses insulin release and inhibits insulin’s actions peripherally. The initial recommended dose is 10 to 15 mg/kg/d divided every 8 hours, up to a maximal dose of 20 mg/kg/d. Positive responses are usually seen within 48 hours if they are going to occur. Diazoxide has several important side effects that should be considered. Fluid retention can be managed by simultaneous administration of thiazide diuretics. Hypertrichosis and coarse facial changes may become quite striking and can be reduced only by decreasing the dose or discontinuing the diazoxide altogether. Hyperuricemia, leukopenia, and thrombocytopenia are rare, but routine serum studies must be monitored while therapy continues. Diazoxide is also an antihypertensive drug, but these effects are rarely encountered with oral administration.
Depending on the study cited, diazoxide appears to be efficacious in only one-fourth to one-half of the patients with hyperinsulinism and appears to be less likely to work in those patients presenting in the immediate newborn period, a population that often has more marked defects in KATP channel activity. Thus, in those patients with persistent hyperinsulinism, determining whether mutations are present in SUR1 or Kir6.2 may help anticipate the response to medical therapy and predict the need for more definitive surgical intervention.
Somatostatin analogs—These are usually a second-line approach, for those unresponsive to diazoxide. Somatostatin acts via a G protein–coupled receptor to lower intracellular calcium and to hyperpolarize the β cell membrane, thereby inhibiting insulin release. Somatostatin has a half-life of only 1 to 3 minutes, but the synthetic analog octreotide may be administered at intervals of up to 8 hours or via continuous subcutaneous infusion and is efficacious in some patients with congenital hyperinsulinism. A starting dose of 5 to 10 μg/kg/d, administered either as an intermittent bolus or via continuous subcutaneous infusion in a pump, often produces salutary initial responses, but because of tachyphylaxis due to somatostatin receptor downregulation, the dose sometimes has to be increased to as much as 40 μg/kg/d or dosed intermittently to provide a daily period of time off drug. Some physicians advocate octreotide in patients who fail to respond to diazoxide therapy alone. However, optimal control of blood glucose often cannot be achieved by adding octreotide. Nonetheless, the medication may help stabilize blood glucose concentrations in the period prior to pancreatectomy and may prove efficacious postoperatively in those patients who have persistent hyperinsulinism even with reduced β cell mass. There are some reports of long-term success (>5 years) with octreotide alone.
Short-term side effects are mostly self-limited within the first several weeks of therapy. Octreotide has nonspecific effects on the gastrointestinal tract, including decreased perfusion of the splanchnic circulation, gallbladder contractility, and bile secretion. Short-term effects may include necrotizing enterocolitis in young infants, vomiting, abdominal distension, and steatorrhea, with later risk of cholelithiasis. Possible inhibitory effects of octreotide on other hormonal axes, including effects on the pituitary somatotrope, adrenal, and thyroid, raise concerns about its long-term use, although some centers report successful and uneventful use for years without significant problems.
Glucagon—Glucagon has a place in the management of hyperinsulinism during initial stabilization of the hypoglycemic infant in the intensive care unit or prior to surgery. This agent stimulates hepatic glycogenolysis and is very effective in these patients with congenital hyperinsulinism because their glycogen stores are replete. A variety of regimens have been shown to be effective, including a bolus of 0.2 mg intravenously in cases of severe hypoglycemia followed by a continuous infusion at a dose of 2 to 10 mg/kg/h. An intramuscular glucagon injection may also be used as an emergency treatment of recurrent hypoglycemic episodes at home. Attempts have been made to administer glucagon continuously via subcutaneous infusion with limited success due to solubility issues. Newer formulations are in various development stages and show promise for sustained outpatient therapy options.
Pancreatectomy is undertaken when maintenance of euglycemia cannot be achieved with medical treatment alone. The extent of the pancreatectomy required depends on the form of the hyperinsulinism. Some infants may have a focal rather than diffuse form and may require only selective resection of the affected pancreatic tissue in order to effect a cure. Unfortunately, only a limited number of medical centers around the world are now equipped to conduct the pre- and perioperative evaluation to distinguish focal from diffuse disease.
The diffuse form of hyperinsulinism requires more aggressive resections. The β cell mass reduction frequently fails to achieve euglycemia, and medical therapy may have to be continued to address hyper- or hypoglycemia. If hypoglycemia persists, repeated surgical interventions may be required to remove residual and/or ectopic pancreatic tissue. Potential surgical complications include intraoperative injury to the common bile duct and adhesions with intestinal obstruction. Additional complications include exocrine pancreatic insufficiency, often requiring oral supplements at mealtimes, and diabetes mellitus.
NON-INSULIN DEPENDENT HYPOGLYCEMIA
Other remaining causes of persistent hypoglycemia in children are accounted for by deficiencies in one or more counterregulatory hormones or inborn errors of metabolism. Although several hormones are involved in the maintanence of euglycemia and produce hyperglycemic responses in excess, only deficiencies of cortisol or growth hormone have been shown to manifest hypoglycemia, which is characterized by elevated serum ketones levels. Associated physical examination findings are consistent with hypopituitarism, including microphallus, cleft lip and/or palate, neonatal jaundice, and short stature. Glycogen storage diseases (GSD) are inherited defects of glycogen synthesis or degradation. Most cases will manifest in later infancy or childhood. Ketotic hypoglycemia along with failure to thrive and hepatomegaly occur with the hepatic types of GSD (I, III, VI, IX). The most severe hepatic GSD is GSD I, which is a defect in glucose-6-phosphatase activity, the final step in glycogenolytic and gluconeogenic pathways. Lactic academia and hyperuricemia are unique to GSD I due to impaired gluconeogenesis, which is not affected in the other GSD types. Disorders of gluconeogenesis manifest hypoglycemia during episodes of significant metabolic decompensation and are associated with characteristic urine organic acid patterns and ketosis. Fatty acid oxidation provides a significant energy source for gluconeogenesis and therefore, defects in fatty acid oxidation manifest hypoglycemia during prolonged fasting that is characterized by low ketone levels. The treatment of inborn errors of metabolism to prevent hypoglycemia is focused on decreasing the duration of fasting by frequent or continuous feeding or use of uncooked cornstarch to provide a slowly digested form of carbohydrate.
Neurologic sequelae are the major concern with severe hypoglycemia during infancy and childhood. Multiple episodes of hypoglycemia are more often associated with sequelae than one severe hypoglycemic episode with convulsions. At least one-third of patients with congenital hyperinsulinism suffer from developmental delay based on follow-up via a telephone survey.
Patients with the familial form of congenital hyperinsulinism who harbor mutations in the SUR receptor may be at additional neurologic risk. The SUR is expressed in the brain, and defects in this molecule could potentially interfere with neural development. The role of this receptor in the brain, however, has yet to be elucidated.
Affected individuals also appear to be at higher risk for later development of diabetes. This problem may be related to reduced β cell mass following pancreatectomy or from β cell apoptosis following chronic depolarization in subjects who harbor channel defects.