What is the Insulin Tolerance Test?
The Insulin Tolerance Test (ITT) is a specialized diagnostic procedure used to assess the integrity of the hypothalamic-pituitary-adrenal (HPA) axis and the pituitary's ability to secrete growth hormone (GH) and adrenocorticotropic hormone (ACTH). By administering a controlled dose of insulin to induce hypoglycemia, the body is stimulated to produce GH and cortisol as part of its counter-regulatory response. This makes the ITT the gold standard test for evaluating adrenal insufficiency, hypopituitarism, and growth hormone deficiency.
Though rarely used in routine practice due to safety concerns (e.g., risk of severe hypoglycemia), it remains one of the most sensitive and informative tests for assessing pituitary function. The test must be conducted under strict medical supervision, with continuous monitoring of glucose levels and patient condition.
Table of Contents
Purpose of the Insulin Tolerance Test
The primary purpose of the Insulin Tolerance Test (ITT) is to evaluate the function of the hypothalamic-pituitary-adrenal (HPA) axis and the growth hormone (GH) axis by assessing the body's hormonal response to induced hypoglycemia. By lowering blood glucose through insulin administration, the test stimulates the natural stress response, prompting the release of ACTH and GH from the pituitary gland. It is considered the gold standard for diagnosing certain endocrine disorders.
A. Evaluation of Growth Hormone Deficiency (GHD)
The ITT is widely used to test for GH deficiency, particularly in children with growth failure and adults with suspected adult-onset GHD. In a healthy individual, hypoglycemia triggers the release of GH. A blunted or absent GH response suggests GH deficiency, often due to pituitary or hypothalamic dysfunction.
B. Diagnosis of Hypopituitarism
Hypopituitarism is the partial or complete loss of pituitary hormone function. The ITT evaluates both GH and ACTH secretion. ACTH should stimulate cortisol production by the adrenal glands. An inadequate rise in GH and/or cortisol levels during the test suggests pituitary insufficiency.
C. Assessment of Adrenal Insufficiency
The test can also help diagnose central (secondary) adrenal insufficiency, where the adrenal glands fail to respond due to a lack of ACTH stimulation from the pituitary. A low cortisol response to hypoglycemia in this context indicates impaired adrenal function due to pituitary or hypothalamic disease.
Steps Involved in the Insulin Tolerance Test
The Insulin Tolerance Test (ITT) is a carefully controlled diagnostic procedure performed in a hospital or clinical setting due to the potential dangers associated with induced hypoglycemia. The goal is to assess the body’s neuroendocrine response, specifically growth hormone (GH) and cortisol secretion, to a hypoglycemic stressor. The test should always be conducted by trained medical professionals with emergency resuscitation equipment on hand.
A. Preparation for the Insulin Tolerance Test
1. Fasting: Patients are usually asked to fast for at least 8 hours (typically overnight) to ensure a stable baseline for blood glucose and hormone levels.
2. Medication Review: Medications that affect glucose metabolism, pituitary, or adrenal function (e.g., corticosteroids, hormone replacements, or insulin) may need to be temporarily stopped under medical supervision.
3. Informed Consent & Medical Screening: Due to the test’s risks, patients must give informed consent. A thorough screening is conducted to rule out contraindications such as:
➧ Seizure disorders
➧ Ischemic heart disease
➧ Severe adrenal insufficiency
➧ Poorly controlled diabetes
4. Baseline Vital Signs and Intravenous Access: Vital signs (blood pressure, heart rate, oxygen saturation) are recorded, and an IV line is placed for insulin administration and possible glucose rescue therapy.
B. Procedure of the Insulin Tolerance Test
1. Baseline Measurements: The test begins with drawing baseline blood samples to measure glucose, GH, and cortisol levels. These baseline values are important for comparison with the post-insulin values.
2. Insulin Administration: A dose of regular insulin (typically 0.1–0.15 units/kg IV) is given to induce hypoglycemia. The target blood glucose is usually <2.2 mmol/L (40 mg/dL).
3. Monitoring and Serial Sampling: Blood glucose is measured every 5–10 minutes initially, then every 15–30 minutes. Blood samples for GH and cortisol are drawn at 30, 45, 60, 90, and 120 minutes or as per institutional protocol.
4. Symptom Monitoring: During hypoglycemia, the patient may experience symptoms such as:
➧ Tremors
➧ Sweating
➧ Palpitations
➧ Confusion
➧ Drowsiness
➧ Seizures (rare but possible)
5. Emergency Management: If the patient becomes severely symptomatic or fails to recover appropriately, glucose is administered immediately (IV dextrose or oral sugar), and the test is stopped.
C. Recovery and Post-Test Monitoring
After adequate samples are collected:
➧ Hypoglycemia is reversed with oral or IV glucose.
➧ The patient is observed until fully alert, asymptomatic, and euglycemic.
➧ A light meal is usually provided after the test.
➧ Final vital signs and glucose levels are recorded before discharge.
📝 Note:
➧ The test is contraindicated in certain populations (e.g., elderly, cardiovascular disease, epilepsy).
➧ Alternative tests, such as the glucagon stimulation test or ACTH stimulation test, may be used in high-risk patients.
Interpretation of Results
The Insulin Tolerance Test (ITT) results are interpreted by assessing how much growth hormone (GH) and cortisol levels increase in response to insulin-induced hypoglycemia. Hypoglycemia acts as a physiological stressor, and an appropriate hormonal response indicates an intact hypothalamic-pituitary-adrenal (HPA) axis and growth hormone axis.
A. Growth Hormone (GH) Response
1. Normal Response
GH levels should rise to at least >5 ng/mL (some protocols use >7 or >10 ng/mL) during the test. The exact threshold may vary slightly by laboratory reference range and age of the patient (children may have higher expected peaks).
2. Abnormal Response
A blunted or absent GH rise indicates growth hormone deficiency (GHD). This may result from:
➧ Hypopituitarism
➧ Hypothalamic dysfunction
➧ Congenital or acquired GH deficiency
Note: GH secretion is pulsatile, so multiple time-point sampling is crucial to avoid false negatives.
B. Cortisol Response
1. Normal Response
Cortisol levels should increase to at least 18–20 μg/dL (500–550 nmol/L) within 30–90 minutes of hypoglycemia onset. A peak below this threshold suggests an impaired adrenal response.
2. Abnormal Response
➧ Secondary Adrenal Insufficiency: Inadequate cortisol response due to pituitary failure (low ACTH production).
➧ Tertiary Adrenal Insufficiency: Due to hypothalamic dysfunction (low CRH secretion).
➧ Primary Adrenal Insufficiency (rare in ITT context): If ACTH is high but cortisol remains low (often evaluated using ACTH stimulation test instead).
C. Combined Interpretation
By examining both GH and cortisol responses:
➧ Normal GH + Normal Cortisol: Intact pituitary and adrenal function.
➧ Low GH + Low Cortisol: Suggests hypopituitarism.
➧ Low GH + Normal Cortisol: Isolated GH deficiency.
➧ Normal GH + Low Cortisol: May indicate isolated ACTH deficiency or adrenal insufficiency.
📌 Additional Considerations
➧ Glucose Target: The hypoglycemic stimulus must be adequate, typically blood glucose <2.2 mmol/L (40 mg/dL), for the results to be valid.
➧ Patient Factors: Age, gender, obesity, stress, and comorbidities may affect hormone response.
➧ Alternative Tests: In cases where ITT is contraindicated, alternatives like glucagon stimulation test or the ACTH stimulation test may be used.
Risks and Complications of the Insulin Tolerance Test
The Insulin Tolerance Test (ITT) is a valuable but high-risk diagnostic procedure because it intentionally induces hypoglycemia, which can provoke serious physiological responses. For this reason, the test is performed only in specialized clinical settings under the supervision of trained medical personnel.
1. Severe Hypoglycemia
The primary risk of the ITT is profound hypoglycemia, which is the intended physiological trigger for hormonal assessment. In some cases, this can lead to:
➧ Confusion
➧ Sweating and shaking
➧ Loss of consciousness
➧ Seizures
➧ In rare cases, coma
To manage this, glucose (either oral or intravenous) is readily available, and blood glucose is monitored closely, typically every 15–30 minutes during the test. Emergency protocols are in place to rapidly reverse hypoglycemia if necessary.
2. Cardiovascular Complications
Patients with underlying cardiovascular disease (e.g., coronary artery disease, arrhythmias, or recent myocardial infarction) are at higher risk during the ITT. Hypoglycemia induces a sympathetic nervous system response (release of epinephrine and norepinephrine), which can:
➧ Elevate heart rate and blood pressure
➧ Precipitate arrhythmias
➧ Causes chest pain or angina
This is why such patients are typically excluded from ITT, and alternative tests (like ACTH or glucagon stimulation) are used instead.
3. Neurological Symptoms
Hypoglycemia can also result in:
➧ Dizziness or fainting
➧ Blurred vision
➧ Headache
➧ Seizures (especially in patients with epilepsy or known seizure disorders)
Because of this, ITT is contraindicated in patients with a history of epilepsy or seizure disorders.
4. Gastrointestinal Symptoms
Nausea, vomiting, and a feeling of unease are common side effects during the test. These occur as part of the body’s response to falling glucose levels and the overall stress of hypoglycemia.
Contraindications
The ITT should not be performed in individuals with:
➧ Severe ischemic heart disease
➧ History of seizures or epilepsy
➧ Cerebrovascular disease
➧ Severe malnutrition or frailty
➧ Adrenal crisis or unstable endocrine conditions
Due to these risks, the ITT must be performed under strict medical supervision with immediate access to rescue glucose and emergency medical equipment. It is contraindicated in patients with certain conditions, such as severe heart disease, epilepsy, or uncontrolled adrenal insufficiency.(alert-passed)
Alternatives to the Insulin Tolerance Test (ITT)
Given the risks associated with inducing hypoglycemia during the ITT, several safer and more accessible alternatives have been developed to evaluate growth hormone (GH) deficiency and adrenal insufficiency. These tests are often used when the ITT is contraindicated due to underlying medical conditions or when a less invasive diagnostic approach is preferred.
For Growth Hormone Deficiency
1. Glucagon Stimulation Test (GST): A safer alternative to ITT, especially in patients where ITT is contraindicated. However, its diagnostic accuracy can vary, and BMI-adjusted GH cut-points are important.
2. Growth Hormone-Releasing Hormone (GHRH) and Arginine Test: Considered a strong alternative, though GHRH may not be readily available in all regions.
3. Macimorelin Stimulation Test: An oral ghrelin mimetic that is a newer diagnostic option.
For Adrenal Insufficiency
ACTH Stimulation Test (Synacthen Test): This is the most common and safest test for primary adrenal insufficiency, but it may not always detect secondary or tertiary adrenal insufficiency (pituitary or hypothalamic issues) as effectively as the ITT.
While these alternative tests provide safer options with easier administration, the Insulin Tolerance Test remains the gold standard in certain clinical contexts, particularly when evaluating both the GH axis and HPA axis simultaneously or when other tests yield inconclusive results.
Ultimately, the choice of test depends on:
➧ The clinical question (GH vs cortisol vs both)
➧ Patient risk profile
➧ Availability of test agents and lab resources
➧ Local guidelines and physician expertise
Summary
While the Insulin Tolerance Test remains a gold standard for evaluating the integrity of the hypothalamic-pituitary-adrenal axis and growth hormone secretion, it carries significant risks. Its success and safety depend on careful patient selection, strict monitoring, and experienced clinical supervision.
Despite being uncomfortable and occasionally distressing for patients, when appropriately administered, the ITT can yield critical diagnostic information that supports accurate treatment planning for endocrine disorders, especially hypopituitarism, adrenal insufficiency, and growth hormone deficiency.
