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Non-Diabetic Hypoglycemia

, MBBS and , MD, PhD.

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Last Update: May 20, 2020.

ABSTRACT

Objective: To describe the evaluation and management of hypoglycemia in patients without diabetes mellitus. Methods: Review of the literature for the evaluation and management of non-diabetic hypoglycemia using Medline and PubMed. Results: Hypoglycemia (glucose <55 mg/dL [3.0 mmol/L]) is uncommon in people without diabetes. Whipple’s triad (low plasma glucose concentration, clinical signs/symptoms consistent with hypoglycemia, and resolution of signs or symptoms when the plasma glucose concentration increases) should be documented in patients prior to initiating an evaluation. Medications should be reviewed. Critical illnesses, malnutrition, hormone deficiencies especially adrenal insufficiency, and non-islet cell tumors secreting IGF-II need be considered in those who are ill. Hypoglycemia can also follow bariatric surgery. In apparently healthy individuals, endogenous hyperinsulinism due to insulinoma, functional β-cell disorders, or the insulin autoimmune syndrome are possible, as are accidental, surreptitious or factitious causes of hypoglycemia. Tests performed during hypoglycemia can establish the cause in those whom illness or medications are excluded. Testing should be done at the time of spontaneous development of symptoms. If this is not possible, it can be done in the setting of a prolonged supervised fast or during a mixed meal test. Endogenous hyperinsulinism is supported by insulin ≥3 uU/mL, c-peptide ≥0.2 nmol/L, proinsulin ≥5 pmol/L, β-hydroxybutyrate ≤2.7 mmol/L and undetectable sulfonylurea/meglitinide in the setting of hypoglycemia. The use of glucagon tolerance tests, c-peptide suppression tests, anti-insulin antibody testing, and continuous glucose monitoring are discussed. Congenital causes of hypoglycemia, diagnosed primarily in neonates and children, are also reviewed. Treatment of hypoglycemia is tailored to the etiology. Conclusions: Accurate diagnosis is needed to direct nutritional, medical, and/or surgical treatment for non-diabetic hypoglycemia. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Hypoglycemia is uncommon in older children and adults who are not being treated for diabetes mellitus, and may be due to varied or multiple etiologies. Different causes of hypoglycemia should be considered in adults who are apparently healthy compared to those who are ill. Whipple’s triad (low plasma glucose concentration, clinical signs or symptoms consistent with hypoglycemia, and resolution of signs or symptoms when the plasma glucose concentration increases) should be documented prior to initiating an evaluation (1-3). Appropriate blood tests performed at the time of hypoglycemia can establish the etiology in those for whom illness or medications are not a readily apparent cause. Testing should be done at the time of spontaneous development of symptoms when feasible. If this is not possible, testing can be performed in the setting of a prolonged supervised fast or during a mixed meal test as described in this review. Additional diagnostic tests are also discussed. Treatment of hypoglycemia should be tailored to its cause and may include dietary, medical, and/or surgical therapies. The diagnosis and evaluation of neonates and infants with hypoglycemia will also be briefly reviewed.

PHYSIOLOGY

Glucose is the solitary source of energy for the brain under normal conditions (4). In order to maintain proper brain function, plasma glucose must be maintained within a relatively narrow range. Redundant counter-regulatory mechanisms are in place to prevent or correct hypoglycemia. As glucose levels decline, major defense mechanisms include a decrease in insulin secretion, an increase in glucagon secretion, and an increase in epinephrine secretion. Increased cortisol and growth hormone secretion are observed during prolonged hypoglycemia. These hormonal changes cause a reduction in peripheral glucose utilization, an increase in hepatic glucose output (from glycogenolysis +/- gluconeogenesis), and an increase in the availability of alternative fuels. Protein breakdown produces a rise in levels of the gluconeogenic amino acids alanine and glutamine, and lipolysis results in a rise in plasma free fatty acids levels and urine and plasma ketone levels. The plasma concentration of β-hydroxybutyrate reflects ketogenesis.

If these defenses fail and plasma glucose levels continue to fall, symptoms prompting food ingestion will develop. Symptoms typically develop at a plasma glucose of 55 mg/dL (3.0 mmol/L) in otherwise healthy individuals (5-6). At glucose levels of 55 mg/dL (3.0 mmol/L) and lower, insulin secretion is normally almost completely suppressed. Lower plasma glucose levels occur in healthy individuals without symptoms or signs during extended fasting when there is use of alternative fuels such as ketones (1). Because of this variability there is not a single plasma glucose concentration that defines hypoglycemia. In type 1 and longstanding type 2 diabetes the counter-regulatory responses to hypoglycemia are frequently impaired and shift to lower thresholds (1,7-8), but these thresholds have not been as well studied in patients with chronic hypoglycemia in the absence of diabetes.

SIGNS AND SYMPTOMS

Low blood glucose concentrations lead to sympathoadrenergic activation and neuroglycopenia (6,9-11). Awareness of hypoglycemia is mainly due to the perception of neurogenic symptoms (12). Symptomatic hypoglycemia is diagnosed clinically using Whipple’s triad: symptoms of hypoglycemia, plasma glucose concentration <55 mg/dL (3.0 mmol/L), and resolution of those symptoms after the plasma glucose concentration is raised. The most common symptoms of hypoglycemia are listed in Table 1. The presence of neuroglycopenic symptoms in patients without diabetes is strongly suggestive of a hypoglycemic disorder (1). Conversely, there is a low likelihood of a hypoglycemia disorder in those with the presence of neurogenic symptoms in the absence of a low plasma glucose concentration (12). Capillary blood glucose measurements should not be used in the evaluation of hypoglycemia due to poor accuracy (1). Symptoms of hypoglycemia may be absent in patients with hypoglycemia unawareness which is thought to be due to a decreased sympathetic response related to recurrent hypoglycemia, prior exercise, or sleep (1,7-9).

Table 1.

Symptoms of Hypoglycemia

NeurogenicNeuroglycopenic
Sweating
Warmth
Anxiety
Tremor
Nausea
Palpitations
Tachycardia
Hunger
Behavioral changes
Visual changes
Confusion/difficulty speaking
Dizziness/lightheadedness
Lethargy
Seizure
Loss of consciousness
Coma

DIFFERENTIAL DIAGNOSIS

In individuals with hypoglycemia in the absence of diabetes mellitus the differential diagnosis is broad (Table 2). Multiple etiologies may be present concurrently. Different causes of hypoglycemia should be considered in patients who are apparently healthy compared to those who are ill. Drugs, critical illnesses, hormone deficiencies, and non-islet cell tumors should be considered in those who are ill or taking medications. In apparently healthy individuals, endogenous hyperinsulinism due to insulinoma, functional β-cell disorders, or insulin autoimmune conditions are possible, as are accidental, surreptitious or factitious causes of hypoglycemia. Hypoglycemia in patients who have had bariatric surgery is increasingly recognized as the frequency of these operations has grown. Artifactual hypoglycemia can occur if blood samples are improperly handled (lack of antiglycolytic agent in the collection tube) and there is a delay in processing.

Drugs are the most common cause of hypoglycemia (Table 3) (1). Drug-induced hypoglycemia is more common in older patients with underlying comorbidities and in those taking glucose lowering medications, especially insulin, the sulfonylurea drugs glyburide, glipizide, and glimepiride, and the meglitinides (13-15). Accidental, surreptitious or malicious hypoglycemia due to administration of insulin or insulin secretagogues needs to be considered. Non-selective β blockers can impair hepatic and renal glucose output and have been associated with the development of hypoglycemia. Pentamidine can cause direct injury to pancreatic β cells, causing an acute release of insulin. Case reports also suggest that ACE inhibitors can cause hypoglycemia (16). Several mechanisms have been proposed. Using euglycemic glucose-clamp studies, enhanced insulin sensitivity during treatment with captopril was shown (17), Captopril can also reduce the insulin-induced rise in epinephrine and norepinephrine (18).

Quinolone use has been associated with the development of hypoglycemia. Case reports have described hypoglycemia in patients who were taking ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin. Gatifloxacin was withdrawn from the US market because of reports of severe hypoglycemia. The risk of hypoglycemia is increased in the setting of renal insufficiency or with the concomitant use of a sulfonylurea drug. There are data suggesting that fluoroquinolones, to varying degrees, increase insulin secretion by inhibiting the Kir6.2 subunit of the ATP-sensitive K+ channels in pancreatic β cells (19).

Deficiencies in counter-regulatory hormones (cortisol, glucagon and epinephrine) may result in hypoglycemia. These deficiencies are uncommon in patients without type 1 or advanced type 2 diabetes, and usually present with additional signs and/or symptoms (1). Since any condition that results in ACTH deficiency or directly interferes with cortisol secretion can cause hypoglycemia, primary and secondary adrenal insufficiency, for which simple treatment is available, should be considered. Adrenal insufficiency has multiple potential etiologies, including but not limited to autoimmune and infectious causes, as well as hemorrhage or infarction. An 8 AM cortisol level, with or without a simultaneous adrenocorticotropin (ACTH) level can be used as a screening test for adrenal insufficiency. Early morning cortisol values over 18 mcg/dL predict a normal response to ACTH stimulation and further testing for adrenal insufficiency is not needed. Cortisol values below 5 mcg/dL are suggestive of adrenal insufficiency. Cortisol values that are intermediate warrant further testing with ACTH stimulation (20-21). ACTH stimulation testing with either standard (250 mcg) or low dose (1 mcg) synthetic ACTH (cosyntropin) should be done unless the basal cortisol level has ruled out adrenal insufficiency. Serum cortisol concentrations should rise to ≥ 18 mcg/dL after either 30 or 60 minutes following the standard 250 mcg dose, and after 20 or 30 minutes following the low 1 mcg dose. Most patients can be evaluated by the standard 250 mcg ACTH stimulation test; however, the 1 mcg stimulation test may be preferable in patients with recent onset of suspected ACTH deficiency (21-22). Hypoglycemia associated with cortisol or growth hormone deficiency may present after a prolonged fast.

Critical illness, including sepsis and organ failure is a common setting for hypoglycemia. Dysglycemia in the setting of sepsis is common and thought to be initiated by activation of proinflammatory mediators and counter-regulatory hormones (23-27). Hyperglycemia results from increased hepatic gluconeogenesis and insulin resistance which exceeds the increase in glucose uptake by peripheral tissue and macrophage rich organs (liver, lung and spleen). Hypoglycemia is also common in critically ill patients with sepsis. Although this is usually related to insulin therapy, hypoglycemia can occur in the absence of insulin treatment and is associated with illness severity and mortality. Hypoglycemia that occurs in sepsis in the absence of exogenous insulin use is related to increases in glucose utilization which exceed production (26-27). Risk is higher with poor nutritional status including inadequate oral intake and in those requiring hemodialysis.

Hypoglycemia related to hepatic disease is primarily observed in the setting of massive and rapid hepatic destruction. Hypoglycemia can occur with viral hepatitis (28), but is atypical in other forms of liver disease. Hypoglycemia in acute liver failure is due to both impaired gluconeogenesis and depletion of hepatic glycogen stores and is associated with an increased risk of mortality. Glycogen storage diseases, which are caused by abnormalities in the enzymatic processes of glycogen storage or breakdown, are rare inherited diseases which may result in hypoglycemia. These represent a diverse group of illnesses which can present at varying ages from neonate to adult, and have distinct characteristics and treatments (29-31).

Hypoglycemia is common in patients with renal failure and can be seen in those with and without diabetes (32-33). The etiology of hypoglycemia in renal failure is multifactorial with decreased renal gluconeogenesis, decreased caloric intake, decreased renal clearance of insulin, and decreased metabolism of other medications that can cause hypoglycemia. Concurrent hepatic disease or sepsis are all possible contributing factors (24, 33-35). Insulin sensitivity may improve in uremic patients after starting renal replacement therapy, and this can contribute to an increased risk for hypoglycemia (36). In patients receiving hemodialysis, hypoglycemia is reduced with the addition of glucose to dialysis solutions (37).

Severe cardiac failure is sometimes accompanied by hypoglycemia. The pathogenesis of this is not well understood. Inhibited gluconeogenesis due to hepatic congestion as well as decreased glycogen stores from inadequate nutritional intake and reduced gastrointestinal absorption are proposed mechanisms (38-40).

Alcohol causes hypoglycemia primarily by inhibiting gluconeogenesis. Hypoglycemia can occur in individuals who drink alcohol in the setting of poor nutrition and depleted glycogen stores (1,23). Alcohol blunts the response of growth hormone to hypoglycemia (41). Alcohol can also increase the insulin response to a glucose load, which may result in postprandial hypoglycemia after eating a small meal (42). Alcohol-induced hypoglycemia is usually associated with elevated levels of β-hydroxybutyrate and low insulin and c-peptide levels.

Malnutrition, in the setting of body fat and muscle depletion, can also cause hypoglycemia due to limited substrates for gluconeogenesis and glycogenolysis (43-44). This has been observed in patients with eating disorders such as anorexia nervosa, mental health conditions, malabsorption, alcohol and substance use disorders and during starvation. Additional risk factors for malnutrition include homelessness, food insecurity, natural disasters, and child or elder abuse. After a prolonged period of poor caloric intake, the reintroduction of nutrients can cause a variety of metabolic and electrolyte disturbances. This is referred to as the Refeeding Syndrome, which is also sometimes associated with postprandial hypoglycemia (45-46).

Endogenous hyperinsulinism is a rare cause of hypoglycemia that can result from an insulinoma or pancreatic islet nesidioblastosis (1). Insulinomas primarily cause hypoglycemia in the fasting state, but may cause symptoms in the postprandial period as well. The incidence is 1/250,000 patient-years. Less than 10% are malignant, multiple or present in patients with the multiple endocrine neoplasia type 1 (MEN-1) syndrome (1). At the time of hypoglycemia, insulin, c-peptide and proinsulin levels are elevated and β-hydroxybutyrate levels are low (see Diagnostic Tests below).

Non-insulinoma pancreatogenous hypoglycemia typically causes hypoglycemia in the postprandial state. These patients have diffuse islet involvement with nesidioblastosis (islet hypertrophy, hyperplasia and enlarged and hyperchromatic β-cell nuclei) (47). Rarely, a genetic mutation causing hyperinsulinemia is diagnosed in adults, as was reported for a 20- year-old man with hyperinsulinemic hypoglycemia found to have a mutation in the ABCC8 gene affecting insulin secretion (48).

Hypoglycemia in patients with non-islet cell tumors is associated with high circulating levels of pro-IGF-II, also called “big” IGF-II (49). Overproduction of IGF-1 (50) as well as glucagon-like peptide 1 (GLP1) and somatostatin have also been reported (51-53). Hypoglycemia has been described in a variety of tumors but particularly in tumors of mesenchymal origin which are typically large and clinically apparent. Pro-IGF-II binds poorly to its binding proteins, enters tissue spaces and causes hypoglycemia due to its insulin-like actions. Growth hormone secretion is suppressed with resulting low IGF-1 levels, and pro IGFII to IGF II and IGF-II to IGF-I ratios are elevated (49-51). Endogenous insulin secretion is appropriately suppressed (1). There can be increased glucose utilization by the tumors as well.

Some patients who have had bariatric surgery for the treatment of obesity, most commonly Roux-en-Y gastric bypass surgery, will develop hypoglycemia. In one study, the incidence of hypoglycemia was 9.1% and 7.9% at 12 months and 60 months respectively after Roux-en-Y gastric bypass surgery (54). Inappropriate high post-prandial insulin and GLP-1 levels and alterations in glucagon levels as well as in GI function have been described (55-56). In a small study, use of a GLP-1 receptor antagonist decreased postprandial insulin secretion, correcting hypoglycemia (57).

Hypoglycemia may be “reactive”, related to the abnormal transport of food to the small intestine (56, 58-60). Children who have had a Nissen fundoplication with percutaneous endoscopic gastrostomy (PEG) tube can develop hypoglycemia related to the development of the dumping syndrome.

The insulin autoimmune syndrome or Hirata’s disease is characterized by the presence of antibodies to insulin and/or proinsulin or the insulin receptor (1,12, 62, 63). Antibodies to native insulin occur primarily in patients of Japanese and Korean descent, but have been reported in Caucasians as well. Exposure to sulfhydryl containing drugs such as clopidogrel or α-lipoic acid which also contains sulfur can cause the insulin autoimmune syndrome. It is hypothesized that the sulfhydryl group disrupts the insulin disulfide bond, increasing its immunogenicity (64). Late postprandial hypoglycemia occurs as insulin secreted in response to the meal disassociates from antibodies (1). The antibodies found in the insulin autoimmune syndrome can interfere with immunoassays of pancreatic hormones (63). The diagnosis is made with documentation of elevated insulin antibody levels in the absence of exposure to exogenous insulin, or elevated insulin receptor antibody levels. These patients may have other autoimmune diseases as well. Rarely, mutations in the insulin receptor gene cause hypoglycemia.

Table 2.

Causes of Hypoglycemia in Adults

Drugs - see Table 3
Hepatic, renal or cardiac failure
Sepsis, trauma, burns
Malnutrition
Hormonal deficiencies (cortisol, glucagon, epinephrine)
Non-islet cell tumors (primarily IGF-II secreting tumors)
Insulinoma (insulin-secreting tumors)
Non-insulinoma pancreatogenous hypoglycemia (NIPHS)
Post gastric bypass surgery
Insulin antibodies
Insulin receptor antibodies
Accidental, surreptitious or malicious hypoglycemia
Genetic disorders – see Table 6

Adapted from: Cryer, PE, et al. Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 94:709-728, 2009.

Table 3.

Drugs Associated with Hypoglycemia

Insulin
Insulin secretagogues (especially sulfonylureas, meglitinides)
Alcohol
Cibenzoline
Glucagon (during endoscopy)
Indomethacin
Pentamidine
Quinine
Fluoroquinolones
Artemisinins
Sulfonamides
IGF-1
Lithium
Hydroxychloroquine
Salicylates
Angiotensin converting enzyme inhibitors
Nonselective β-adrenergic receptor antagonists
The following are supported by lower quality evidence:
Angiotensin receptor antagonists
Gabapentin
Mifepristone
Disopyramide
Heparin
6-Mercaptopurine

Adapted from: Cryer, PE, et al. Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 94:709-728, 2009.

DIAGNOSTIC TESTS

Clinical practice guidelines for the evaluation and management of adult hypoglycemic disorders were published by the Endocrine Society in 2009 (1). The testing approach is also discussed in the Endotext chapter on pancreatic islet function testing (65).

Initial Evaluation

Evaluation should be conducted in patients in whom Whipple’s triad (low plasma glucose concentration, clinical signs or symptoms consistent with hypoglycemia, and resolution of signs or symptoms when the plasma glucose concentration increases) is documented. Patients with hypoglycemia typically present with a history of “spells” concerning for hypoglycemia, or have an incidental low plasma glucose measurement.

The first step is to review the patient’s history in detail, including the types of symptoms, timing of episodes and relation to food ingestion, comorbid conditions, medications and social history.

When adrenal insufficiency is considered, a morning cortisol level +/- ACTH level should be performed, followed by an ACTH stimulation test when the cortisol level is indeterminate (discussed above). If the cause of hypoglycemia is not apparent, further laboratory testing is indicated. Capillary blood glucose measurements should not be used in the diagnosis of hypoglycemic disorders due to their poor accuracy in these situations.

If possible, testing should be done during a time of symptomatic hypoglycemia. Simultaneous measurements of plasma glucose, insulin, c-peptide, proinsulin, and β-hydroxybutyrate and a screen for oral hypoglycemic agents (sulfonylureas and meglitinides) should be performed (Table 4). Glucagon, 1 mg IV, should then be administered with careful follow up of the glucose response every 10 minutes for 30 minutes. These tests distinguish between hypoglycemia due to hyperinsulinism (endogenous and exogenous) and other causes.

If testing cannot be performed during a spontaneous episode of hypoglycemia, either a fast of up to 72 hours or a mixed meal test done in a monitored setting followed by administration of glucagon is the most useful diagnostic strategy. The choice of test is based on the circumstances in which hypoglycemia is most likely to occur.

The 72-Hour Fast

The gold standard test in the evaluation of hypoglycemia is the 72-hour supervised fast. The purpose of the fast is twofold. The first is to diagnose hypoglycemia as the cause of the patient's symptoms. The second is an attempt to determine the etiology of the hypoglycemia. Due to the risk of hypoglycemia, patients should be admitted to the hospital to undergo the fast in a monitored setting. The fast can be initiated in a carefully monitored outpatient facility, with the patient entering the hospital if the fast is not terminated prior to the closing of the site.

During a 72 hour fast, patients are allowed no food but can consume non-caloric caffeine-free beverages. The onset of the fast is the time of the last food consumption. During the fast all non-essential medications should be discontinued. Simultaneous insulin, c-peptide and glucose samples are obtained at the beginning of the fast and every 4-6 hours. When the plasma glucose falls to <60 mg/dL, specimens should be taken every 1-2 hours under close supervision. Patients should continue activity when they are awake. The fast continues until the plasma glucose falls below 45 mg/dL (2.5 mmol/l) [plasma glucose less than 55 mg/dL (3.0 mmol/L) is an alternative end point if Whipple’s triad has been previously documented] and symptoms of neuroglucopenia develop. At this time insulin, glucose, c-peptide, oral insulin secretagogues, proinsulin and β-hydroxybutyrate levels are obtained and the fast is terminated (1). Additional samples for insulin antibodies, anti-insulin receptor antibodies, IGF-1/IGF-2 and plasma cortisol, glucagon or growth hormone can also be obtained if a non-islet cell tumor, autoimmune etiology, or hormone deficiency is suspected. A glucagon tolerance test is then frequently performed to aid in diagnosis [Glucagon, 1 mg intravenously, administered with careful follow up of the glucose response every 10 minutes for 30 minutes]. Further details regarding the glucagon tolerance test are below. Patients are fed at the conclusion of the test.

The diagnosis of endogenous hyperinsulinism is supported if insulin, c-peptide and proinsulin levels are inappropriately elevated in the setting of hypoglycemia (Table 4). β-hydroxybutyrate <2.7 mmol/L, and an increase in plasma glucose ≥25 mg/dL (1.4 mmol/L) after intravenous glucagon indicate mediation of the hypoglycemia by either insulin (endogenous or exogenous) or an IGF excess (1). It has been suggested that an amended insulin:glucose ratio, which subtracts 30 mg/dL (1.7 mmol/L) from the measured glucose, may be helpful in ruling out suspected insulinomas, but this remains controversial (66-67).

In patients with laboratory assessments consistent with endogenous hyperinsulinism, negative screening for oral hypoglycemic agents (sulfonylureas/meglitinide) and negative insulin antibodies are suggestive of an insulinoma, non-insulinoma pancreatogenous hypoglycemia (NIPHS), or post gastric bypass hypoglycemia.

Table 4.

Distinguishing Causes of Symptomatic Hypoglycemia [glucose < 55 mg/dl (3.0 mmol/l)] After a Prolonged Fast

Insulin (µU/mL)C-peptide (nmol/L)Proinsulin (pmol/L)Oral hypoglycemic medicationInterpretation
»3<0.2<5NoExogenous insulin
≥3≥0.2≥5NoEndogenous insulina
≥3≥0.2≥5YesOral hypoglycemic (drug-induced)
a Insulinoma, non-insulinoma pancreatogenous hypoglycemia (NIPHS), post gastric bypass hypoglycemia.

Adapted from: Cryer, PE, et al. Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 94:709-728, 2009

Approximately 75% of patients with insulinomas are diagnosed after a 24 hour fast and 90-94% at 48 hours. Although some experts advocate conducting the prolonged fast for only 48 hours others disagree, arguing that prolonging the fast up to 72 hours minimizes misdiagnosis and maximizes the probability of diagnosing an insulinoma (68-69).

Limitations of the prolonged fast:

  • Normal subjects, especially young women, can occasionally have plasma glucose levels <40 mg/dL (2.2 mmol/L)
  • Rare insulinomas suppress the release of insulin in response to hypoglycemia
  • Insulin levels can sometimes be artificially elevated in the presence of anti-insulin antibodies.

Glucagon Tolerance Test

The glucagon tolerance test serves as a supplemental study to aid in determining the etiology of hypoglycemia. Following an overnight fast (or at the conclusion of the prolonged fast), 1 mg of glucagon is injected intravenously over 2 minutes. Plasma glucose and insulin levels are measured at baseline, and either 10, 20, and 30 minutes after glucagon, or at 3, 5, 10, 15, 20, and 30 minutes after glucagon injection.

In the hypoglycemic patient at the conclusion of the prolonged fast, an increase in plasma glucose of >25 mg/dL (1.4 mmol/L) post-glucagon suggests an insulin-mediated etiology (12).

In normal patients, maximum insulin response occurs rapidly and usually does not exceed 100 uU/mL (peak insulin 61+19 uU/mL at 3-15 minutes), and the serum glucose levels peak at 20-30 minutes (140 +24 mg/dL) (70).

Insulinoma patients demonstrate an exaggerated insulin response to glucagon, with values often exceeding 160 uU/mL within 15-30 minutes of the injection (peak insulin 93-343 uU/mL at 15 minutes) (70).

Patients with malnutrition or hepatic disease may be unable to have a hyperglycemic response to glucagon due to depleted hepatic glycogen stores. Insulin responses in these subjects may be increased but not to the degree seen in subjects with an insulinoma. Drugs such as diazoxide, hydrochlorothiazide, and diphenylhydantoin can cause false negative results (70). Patients with non-islet cell tumors such as hemangiopericytomas and meningeal sarcomas can have similar glucose elevations (30 mg/dL) as individuals with insulinomas following glucagon injection (71).

Another limitation for the glucagon stimulation test is the failure of some insulinoma patients to hypersecrete insulin following glucagon injection. This problem was reported in 8% of patients with insulinomas in one study (70). In addition, patients with cirrhosis with portocaval anastomosis can have peak insulin levels that are indistinguishable from subjects with insulinomas. Obese individuals and patients with acromegaly can also have exaggerated peak insulin responses, as can patients treated with sulfonylurea drugs and aminophylline. An additional disadvantage of this test is the danger of causing hypoglycemia after 90-180 minutes, as well as inducing nausea and vomiting. Because of the possibility of severe hypoglycemia, a physician needs to be present during the test.

Mixed Meal Testing

For patients with hypoglycemic symptoms several hours after meals, a mixed meal test may be performed. This test has not been well standardized. This test is typically done after an overnight fast. Patients eat a meal similar to one that provokes their symptoms. If this is not possible then a commercial mixed meal may be used. Patients are then observed for several hours. Samples for plasma glucose, insulin, c-peptide, and proinsulin are collected prior to the meal and every 30 - 60 minutes thereafter for 5 hours. If symptoms occur prior to the end of the test then additional samples for the above are collected prior to administration of carbohydrates. If Whipple’s triad is demonstrated, testing for oral hypoglycemic drugs and testing for insulin antibodies should be done. Interpretation of test results is the same as for the 72-hour fast or spontaneous hypoglycemia (Table 4).

Continuous Glucose Monitoring

Continuous glucose monitoring (CGM) devices measure interstitial glucose concentrations and are used by individuals with diabetes to help guide treatment. In patients who have had Roux-en-Y gastric surgery, use of CGM was reported to detect more hypoglycemia than the mixed meal tolerance test (72-73). Whereas these devices may be helpful in detecting hypoglycemia in selected patients, their use is not recommended for the diagnosis of hypoglycemic disorders in people without diabetes.

Testing for Autoimmune Hypoglycemia

The insulin autoimmune syndrome is a rare condition where antibodies, either directed against insulin or against the insulin receptor, are responsible for hypoglycemia. Autoimmune hypoglycemia due to insulin antibodies should be suspected when the hypoglycemia is associated with high insulin levels (usually >100 uU/mL) and incompletely suppressed C-peptide levels. Insulin levels are rarely >100 uU/mL when the hypoglycemia is due to an insulinoma. Although these elevated insulin levels can be observed with exogenous insulin administration, the associated c-peptide levels are usually extremely low. Autoimmune hypoglycemia is most often seen in people of Japanese or Korean descent, but has been described in other populations (74).

Autoimmune hypoglycemia may also be due to antibodies to the insulin receptor. These patients will have mildly elevated insulin levels (thought to be due to decreased clearance of insulin) and suppressed c-peptide levels. Other autoimmune conditions may be present as well (63). Antibodies to insulin and/or proinsulin and insulin receptor antibodies can interfere with the measurements of pancreatic hormones using immunoassays (63). Insulin, proinsulin and/or insulin receptor antibody testing is needed to confirm the diagnosis of autoimmune hypoglycemia. This testing does not need to be done at the time of hypoglycemia.

C-Peptide Suppression Test

C-peptide and insulin are secreted in equimolar concentrations in the pancreas, making c-peptide levels a good marker of endogenous insulin secretion. The c-peptide suppression test is rarely used to test for an insulinoma but can provide supplemental diagnostic information, especially if the results of a supervised fast are not definitive. The c-peptide suppression test must be carefully administered, since the patient is given intravenous insulin to induce hypoglycemia. The advantage of the test is that it is of much shorter duration than the supervised fast.

The c-peptide suppression test is performed following an overnight fast. The procedure is to infuse regular insulin, 0.125 U/kg body weight, intravenously over 60 minutes. Blood samples are obtained from the contralateral arm at 0, 30, 60, 90, and 120 minutes for determination of insulin, c-peptide, and plasma glucose levels. An abnormal result is a lower percentage decrease of c-peptide at 60 minutes compared to normative data appropriately adjusted for the patient's body mass index and age (75). For example, an abnormal result for a 45-year-old with a BMI of 25-29 kg/m2 would be <61% suppression of c-peptide at 60 minutes (76). An alternative method (Regular insulin 0.075 IU/kg/hr infused intravenously over 2 hours) using a different classification plot has been proposed (77) but few data using it have been published.

Limitations of this test include the fact that some patients with a documented insulinoma have normal c-peptide levels including normal percent decrease in c-peptide levels. There is also the danger of inducing severe hypoglycemia. In addition, little data concerning the reliability, sensitivity, and safety of this test are published.

Imaging

When endogenous hyperinsulininemic hypoglycemia is present, imaging studies are performed. These may include computed tomography (CT), magnetic resonance imaging (MRI), transabdominal and endoscopic ultrasonography, and/or positron emission tomography (PET) imaging with or without fluorine-18-l-3,4-dihydroxyphenylalanine (18F-DOPA) or GLP-1 receptor analog tracers. Imaging studies are successful in identifying approximately 75% of insulinomas (78). Intraoperative pancreatic ultrasonography may also be used to localize small insulinomas not otherwise found with other imaging modalities. Insulinomas are often less than 1.0 cm, so negative imaging does not exclude the diagnosis (79-83). For infants and children with biochemical evidence of congenital hyperinsulinism, imaging with 18F-DOPA-PET/CT has been used to differentiate between diffuse and focal pancreatic disease and help direct surgery.

Selective Pancreatic Calcium Stimulation with Hepatic Venous Sampling

In patients with endogenous hyperinsulinemic hypoglycemia, it is sometimes difficult to distinguish between insulinoma and non-insulinoma pancreatogenous hypoglycemia. When noninvasive imaging studies are negative or equivocal, selective arterial calcium injections with measurements of hepatic venous insulin levels can be used to help differentiate insulinoma from diffuse nesidioblastosis (84-90).

TREATMENT

Immediate treatment should be focused on reversing the hypoglycemia. If the patient is able to ingest carbohydrates 15 to 20 grams of glucose should be given every 15 minutes until the hypoglycemia has resolved. If the patient is unable to ingest carbohydrates, or if the hypoglycemic episode is severe, parenteral glucose should be administered. In a healthcare setting intravenous dextrose is used. Twenty-five gram boluses of 50% dextrose are given until the hypoglycemia has resolved. If needed, an infusion of 10% or 20% dextrose can be used to sustain euglycemia in patients with recurrent episodes of hypoglycemia. In the outpatient setting, glucagon, given intranasal or as a subcutaneous or intramuscular injection, is used to correct hypoglycemia. Glucose gel and other forms of oral glucose should be used in impaired patients with caution and only in circumstances where no alternative is available, as they pose an aspiration risk.

Long-term treatment should be tailored to the specific hypoglycemic disorder, considering the burden of hypoglycemia on well-being and patient preferences. Offending medications should be discontinued and underlying illnesses treated, whenever possible.

Dietary Treatment

In non-insulinoma pancreatogenous hypoglycemia, including patients with post Roux-en-Y gastric bypass hypoglycemia, dietary interventions may be helpful. Frequent feedings and a low carbohydrate diet are common recommendations (61, 91-92). Low carbohydrate diets are broadly defined in the literature, with the macronutrient content from carbohydrates ranging from 2% to 30% (92-93). In post Roux-en-Y gastric bypass hypoglycemia, restriction of carbohydrates, avoidance of high glycemic index foods and simple sugars, and the addition of protein and fat to each meal are recommended. Gastrostomy tube feeding can be considered in patients with post Roux-en-Y gastric bypass hypoglycemia refractory to dietary modifications (94)

Medical Treatment

Medical treatment with α-glucosidase inhibitors, calcium channel blockers, diazoxide, or somatostatin analogs can be used if resection is not possible in patients with hyperinsulinism, or as a temporizing measure (Table 5). Sirolimus (mTOR) has been used successfully in congenital hyperinsulinism, and glucocorticoids and growth hormone have been used in non-islet cell tumor hypoglycemia.

Alpha glucosidase inhibitors (acarbose, miglitol) delay the digestion of ingested carbohydrates, resulting in lower blood glucose concentrations after meals. Acarbose has been used to lessen the hyperinsulinism in post Roux-en-Y gastric bypass hypoglycemia. Acarbose is typically prescribed as 50 mg three times daily with meals (61, 92, 95).

Calcium channel blockers may be helpful in patients with hypoglycemia by inhibiting glucose stimulated insulin secretion from the pancreatic β cells; verapamil 80 mg twice daily has been reported in the literature, but other agents such as diltiazem and nifedipine have been used as well (61, 95).

Diazoxide inhibits insulin secretion by opening the ATP-dependent potassium channel of the β cell in the pancreas. Diazoxide is given orally as 3-8 mg/kg/day divided every 8-12 hours up to 1200 mg/day. Diazoxide may cause edema, dizziness, nausea, and hirsutism, and the dose should be reduced in the presence of renal insufficiency (61, 96-97)

Somatostatin analogs (octreotide and lanreotide) inhibit insulin secretion when given in high doses, but may not be as effective as diazoxide (98-99). Octreotide is given as a subcutaneous injection 100 mcg twice daily up to 1500 mcg daily, whereas the longer acting lanreotide is given monthly.

Chemotherapy has been used to treat insulinomas and non-islet cell tumors with varying degrees of success. 177Lu-Dotatate (lutetium[Lu-177]-DOTA-Tyr3-ostreotide) was given successfully to treat hypoglycemia associated with a neuroendocine tumor in a patient who failed the usual medical and surgical treatments (100). Radiotherapy can also be used in non-islet cell tumors.

Table 5.

Common Medication Treatment Options for Serious Hypoglycemia

Medication ClassNameRouteDosage
Alpha-glucosidase inhibitor/Carbohydrate digestion and glucose absorption delayedAcarboseOral50 mg three times daily with meals
Calcium channel blocker/Insulin secretion inhibitorVerapamilOral80 mg twice daily
Vasodilator/Insulin secretion inhibitorDiazoxideOral3-8 mg/kg/day
Somatostatin analog/Insulin secretion inhibitorOctreotide
Lanreotide
Subcutaneous
Subcutaneous
100 mcg twice daily
120 mg every 4 weeks

Autoimmune hypoglycemic conditions may be treated with either glucocorticoids or immunosuppressants, but these disorders may be self-limited. Providing glucose by ingestion of uncooked cornstarch or intragastric glucose infusion may be necessary in some patients.

Surgical Treatment

Surgical resection can be curative for insulinomas. Surgery can also alleviate hypoglycemia in non-islet cell tumors, even if the cancer cannot be cured. Partial pancreatectomy can be considered in patients with non-insulinoma pancreatogenous hypoglycemia. Results of selective arterial calcium stimulation testing and/or 18F-DOPA-PET/CT scanning have been used to guide the area(s) of resection when partial pancreatectomy is needed. Roux-en-Y gastric bypass reversal can also be considered in patients with post Roux-en-Y gastric bypass hypoglycemia refractory to dietary modifications (94).

HYPOGLYCEMIA IN NEONATES AND INFANTS

The presence of hypoglycemia in neonates and infants may be transient, especially during the first 2-3 days of life (Table 6). This is generally observed in newborns with prematurity, perinatal stress and/or a history of maternal diabetes. The Pediatric Endocrine Society (101) recommends focusing on treating hypoglycemia during the first 48 hours of life, and initiating a more complete diagnostic evaluation if hypoglycemia persists. The glucose threshold for evaluating hypoglycemia in this age group is controversial, with recommendations including <60 mg/dL (3.3 mmol/L) and <47 mg/dL (2.6 mmol/L). Whipple’s triad is of limited use in infants since they cannot communicate hypoglycemia. In neonates and infants, signs and symptoms of hypoglycemia can include lethargy, irritability, poor feeding, seizures or myoclonic jerks, respiratory distress, hypotonia, sweating and hypothermia.

Causes of hypoglycemia in the newborn period are listed in Table 6 and reviewed in more detail in references 31, 101-103. For the evaluation of hypoglycemia in this age group, particular attention is directed towards family history, congenital syndromes, genetic defects, and hormonal deficiencies. In addition to the evaluation recommended for adults (physical exam, liver, thyroid and renal function, pituitary/adrenal evaluation as indicated, simultaneous measurements of plasma glucose, insulin, c-peptide, proinsulin, and β-hydroxybutyrate, screen for oral hypoglycemic drugs, and glucagon stimulation; Table 4), measures of bicarbonate, free fatty acids, ammonia, lactate, total and free carnitine and acyl carnitine profile, plasma amino acids, IGFBP-1, urine for reducing substance and organic acids should be considered.

When hyperinsulinemic hypoglycemia is suspected, a carefully supervised fast can be conducted, with laboratory testing performed when the plasma glucose level is <50 mg/dL (2.8 mmol/L), followed by a glucagon challenge with measurements of the glucose response. Genetic mutation analysis when available is indicated in specific cases (e.g. to confirm a diagnosis, for genetic counseling and prenatal testing). Treatments are dependent upon the etiology of the hypoglycemia. Treatment options are discussed in the guidelines by the Pediatric Endocrine Society (101).

Table 6.

Causes of Hypoglycemia in Neonates and Infants

Transitional (transient) neonatal hyperinsulinemic hypoketotic hypoglycemia:
Prematurity, small for gestational age
Placental insufficiency and intrauterine growth restriction
Maternal diabetes and/or large for gestational age
Perinatal stress, birth asphyxia
Maternal use of glucose-lowering drugs and β blockers
Congenital hyperinsulinism
Monogenic defects affecting insulin secretion (e.g. in ABCC8, KCNJ11, GLUD1, GCK,
HADH1, UCP2, MCT1, HNF4A, HK1, or PCM1 genes)
Genetic syndromes: Beckwith-Wiedemann, Kabuki, Turner, Fanconi-Bickel
Congenital disorders of glycosylation
Autoimmune (anti-insulin or anti-insulin receptor antibodies)
Insulin receptor inactivation
Hormonal deficiencies (cortisol, growth hormone, glucagon, epinephrine) e.g. hypopituitarism,
adrenal insufficiency including genetic disorders i.e. 3β-hydroxysteroid dehydrogenase II
deficiency, growth hormone deficiency
Hyperthyroidism
Hereditary fructose intolerance
Galactosemia
Maple syrup urine disease
Glycogen storage diseases e.g. glycogen synthase deficiency (fasting hypoglycemia with high
glucose and lactate immediate post eating)
Other causes of impaired hepatic glucose production e.g. glucose-6-phosphate translocase
deficiency, debrancher deficiency, hepatic phosphorylase deficiency, fructose1,6
diphosphatase deficiency, phosphoenolpyruvate deficiency, pyruvate carboxylase deficiency
Additional metabolic defects e.g. carnitine acyl transferase deficiency, hepatic hydroxymethyl
glutaryl coenzyme A lyase deficiency, very long chain, long chain, medium chain and short
chain acyl-coenzyme A dehydrogenase deficiencies
Drugs and toxins- see Table 3
Systemic diseases, sepsis, trauma, burns
Malnutrition
Accidental, surreptitious or malicious hypoglycemia

GUIDELINES

  1. Cryer PE, Axelrod L, Grossman AB, Heller SR, Montori VM, Seaquist ER, Service FJ. Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2009;94:709–728. [PubMed: 19088155]
  2. Thornton PS, Stanley CA, De Leon DD, Harris D, Haymond MW, Hussain K, Levitsky LL, Murad MH, Rozance PJ, Simmons RA, Sterling MA, Weinstein DA, White NH, Wolfsdorf JI. Recommendations from the Pediatric Endocrine Society for Evaluation and Management of Persistent Hypoglycemia in Neonates, Infants and Children. J Pediatr. 2015;167:238–245. [PubMed: 25957977]
  3. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101:364–89. [PMC free article: PMC4880116] [PubMed: 26760044]

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