Key Points
- Whipple’s triad consists of symptoms and/or signs consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised.
- Because glucose is an obligate metabolic fuel for the brain, maintenance of brain function requires a virtually continuous supply of glucose from the circulation.
Diagnosis and Assessment
- The Endocrine Society recommends evaluation and management of hypoglycemia only in patients in whom Whipple’s triad—symptoms and/or signs consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised—is documented (1|⊕⊕⊕⊕).
Persons Without Diabetes Mellitus
- The Endocrine Society recommends the following strategy in patients with hypoglycemia without diabetes mellitus (1|⊕⊕⊕o):
- Review the history, physical findings, and all available laboratory data seeking clues to specific disorders—drugs, critical illnesses, hormone deficiencies, nonislet cell tumors.
- When the cause of the hypoglycemic disorder is not evident—ie, in a seemingly well individual—measure plasma glucose, insulin, insulin antibodies, C-peptide, proinsulin, and β-hydroxybutyrate concentrations and screen for oral hypoglycemic agents during an episode of spontaneous hypoglycemia and observe the plasma glucose response to IV injection of 1.0 mg glucagon. These steps will distinguish hypoglycemia caused by endogenous (or exogenous) insulin from that caused by other mechanisms.
- When a spontaneous hypoglycemic episode cannot be observed, formally recreate the circumstances in which symptomatic hypoglycemia is likely to occur—ie, during a fast of up to 72 h or after a mixed meal.
- Diagnosis:
- The findings of symptoms, signs, or both with plasma concentrations of glucose less than 55 mg/dL (3.0 mmol/liter), insulin of at least 3.0 μU/mL (18 pmol/liter), C-peptide of at least 0.6 ng/mL (0.2 nmol/liter), and proinsulin of at least 5.0 pmol/liter document endogenous hyperinsulinism.
- β-hydroxybutyrate levels of 2.7 mmol/liter or less and an increase in plasma glucose of at least 25 mg/dL (1.4 mmol/liter) after IV glucagon indicate mediation of the hypoglycemia by insulin (or by an IGF).
- In a patient with documented fasting or postprandial endogenous hyperinsulinemic hypoglycemia, negative screening for oral hypoglycemic agents, and no circulating insulin antibodies, conduct procedures for localizing an insulinoma. These may include computed tomography or magnetic resonance imaging (MRI), transabdominal and endoscopic ultrasonography, and, if necessary, selective pancreatic arterial calcium injections with measurements of hepatic venous insulin levels.
- Tailor treatment to the specific hypoglycemic disorder, taking into account the burden of hypoglycemia on patient well-being and patient preferences.
Table 1. Causes of hypoglycemia in adults
| Sick or medicated individual |
|---|
1. Drugs
|
2. Critical illnesses
|
3. Hormone deficiency
|
| 4. Nonislet cell tumor |
|
5. Endogenous hyperinsulinism
|
| 6. Accidental surreptitious, or malicious hypoglycemia |
Table 2. Drugs other than antihyperglycemic agents and alcohol reported to cause hypoglycemia
| Moderate quality of evidence |
|---|
|
| Low quality of evidence |
|
| Very low quality of evidence |
|
Table 3. Patterns of findings during fasting or after a mixed meal in normal individuals with no symptoms or signs despite relatively low plasma glucose concentrations-ie, Whipple’s triad not documented-and in individuals with hyperinsulinemic (or IGF-mediated) hypoglycemia or hypoglycemia caused by other mechanisms
| Symptoms, signs, or both | Glucose (mg/dL) | Insulin (µU/mL) | C-peptide (nmol/liter) | Proinsulin (pmol/liter) | β-Hydroxy butyrate (mmol/liter) | Glucose increase after glucagon (mg/dL) | Circulating oral hypoglycemic | Antibody to insulin | Diagnostic interpretation |
|---|---|---|---|---|---|---|---|---|---|
| No | <55 | <3 | <0.2 | <5 | >2.7 | <25 | No | No | Normal |
| Yes | <55 | >>3 | <0.2 | <5 | ≤2.7 | >25 | No | Neg (Pos) | Exogenous insulin |
| Yes | <55 | ≥3 | ≥0.2 | ≥5 | ≤2.7 | >25 | No | Neg | Insulinoma, NIPHS, PGBH |
| Yes | <55 | ≥3 | ≥0.2 | ≥5 | ≤2.7 | >25 | Yes | Neg | Oral hypoglycemic agent |
| Yes | <55 | >>3 | >>2a | >>5a | ≤2.7 | >25 | No | Pos | Insulin autoimmune |
| Yes | <55 | <3 | <0.2 | <5 | ≤2.7 | >25 | No | Neg | IGFb |
| Yes | <55 | <3 | <0.2 | <5 | >2.7 | <25 | No | Neg | Not insulin (or IGF)- mediated |
| Neg, negative; Pos, positive; PGBH, post-gastric bypass hypoglycemia. a Free C-peptide and proinsulin concentrations are low. b Increased pro-IGF-II, free IGF-II, IGF-II/IGF-I ratio. | |||||||||
- Suggested protocol for a prolonged diagnostic fast:
- Date the onset of the fast as the time of the last food intake.
- Discontinue all nonessential medications. Allow the patient to drink calorie-free beverages.
- Ensure that the patient is active during waking hours.
- Collect samples for plasma glucose, insulin, C-peptide, proinsulin, and β-hydroxybutyrate every 6 h until the plasma glucose concentration is less than 60 mg/dL (3.3 mmol/liter); at that point the frequency of sampling should be increased to every 1 to 2 h.
- Samples for plasma insulin, C-peptide, and proinsulin should be sent for analysis only in those samples where the plasma glucose concentration is less than 60 mg/dL (3.3 mmol/liter).
- End the fast when the plasma glucose concentration is less than 45 mg/dL (2.5 mmol/liter) and the patient has symptoms and/or signs of hypoglycemia (or if 72 h have elapsed without symptoms).
- Insulin antibodies should be measured, but not necessarily during hypoglycemia.
Notes:
- The decision to end the fast before 72 h should not be based on a low plasma glucose concentration alone in the absence of symptoms or signs, because some healthy individuals, especially women and children, have low glucose levels during prolonged fasting. Alternatively, the fast can be ended when the plasma glucose concentration is less than 55 mg/dL (3.0 mmol/liter) without symptoms or signs if Whipple’s triad was documented unequivocally on a prior occasion.
- A low plasma glucose concentration is a necessary, albeit not in itself sufficient, finding for the diagnosis of hypoglycemia. Therefore, the decision to end the fast should be based on laboratory-measured plasma glucose concentrations, not those estimated with a point-of-care glucose monitor.
- If it is judged necessary to treat urgently because of severe symptoms, obtain samples for all of the following before administering carbohydrates. At the end of the fast, collect samples for plasma glucose, insulin, C-peptide, proinsulin, β-hydroxybutyrate and oral hypoglycemic agents, and then inject 1.0 mg of glucagon IV and measure plasma glucose 10, 20, and 30 min later. (Insulin antibodies should be measured, but not necessarily during hypoglycemia.)
- Suggested protocol for a mixed meal diagnostic test:
- Perform the test after an overnight fast.
- Hold all nonessential medications.
- Use a mixed meal similar to that which the patient reports has caused symptoms (or use a commercial formula mixed meal).
- Collect samples for plasma glucose, insulin, C-peptide, and proinsulin before ingestion and every 30 min through 300 min after ingestion of the meal.
- Observe the patient for symptoms and/or signs of hypoglycemia and ask the patient to keep a written log of all symptoms, timed from the start of meal ingestion.
- Insulin antibodies should be measured, but not necessarily during hypoglycemia.
Notes:
- If possible, avoid treatment until the test is completed.
- A low plasma glucose concentration is a necessary, albeit not in itself sufficient, finding for a diagnosis of hypoglycemia. Therefore, the mixed-meal test should be interpreted on the basis of laboratory-measured plasma glucose concentrations, not those estimated with a point-of-care glucose monitor.
- If it is judged necessary to treat before 300 min because of severe symptoms, obtain samples for all of the following before administering carbohydrates. Samples for plasma insulin, C-peptide, and proinsulin should be sent for analysis only in those samples in which plasma glucose is less than 60 mg/dL (3.3 mmol/ liter), and a sample for measurement of oral hypoglycemic agents and insulin antibodies should be obtained if Whipple’s triad is demonstrated.
Evaluation of Hypoglycemia - Without Diabetes
