Insulin-induced hypoglycemia test protocol

INTRODUCTION — The diagnosis of adrenal insufficiency usually can be made by the findings of low morning serum cortisol and a subnormal response to synthetic corticotropin (ACTH [1-24]) [1,2]. In very rare circumstances, however, other tests, such as insulin-induced hypoglycemia, can be utilized to evaluate the pituitary-adrenal response to stress, particularly when recent onset of ACTH deficiency is suspected as the cause of adrenal insufficiency. Compared with other tests for the diagnosis of adrenal insufficiency, the insulin-induced hypoglycemia test is more difficult to perform, poses greater risk, and is much more expensive. As a result, it is infrequently performed in clinical practice for the assessment of pituitary-adrenal function.

Details of insulin-induced hypoglycemia test (also referred to as the "insulin tolerance test" or "ITT") in adults will be reviewed here. Additional information on the diagnosis of adrenal insufficiency, the evaluation of patients after pituitary surgery, and diagnostic testing for adult growth hormone deficiency is reviewed separately. (See "Diagnosis of adrenal insufficiency in adults" and "Determining the etiology of adrenal insufficiency in adults" and "Treatment of gonadotroph and other clinically nonfunctioning adenomas", section on 'First evaluation post-discharge' and "Growth hormone deficiency in adults".)

CLINICAL USES — The rationale for the insulin-induced hypoglycemia test (insulin tolerance test [ITT]) is that hypoglycemia induced by insulin administration is a sufficient stress to stimulate corticotropin-releasing hormone (CRH), corticotropin (ACTH), and therefore cortisol secretion. One advantage of this test is that the results correlate relatively well with the serum cortisol response to surgical stress. Although this is a valid test of the hypothalamic-pituitary-adrenal response to stress, in most settings, the ACTH stimulation test provides nearly the same information, is much less difficult and less expensive to perform, and is without risk to the patient. Nonetheless, the ITT may have utility in specific clinical settings. (See "Diagnosis of adrenal insufficiency in adults" and "Determining the etiology of adrenal insufficiency in adults".)

Recent pituitary surgery — Recent pituitary surgery is the main clinical scenario in which the ACTH stimulation test has limited diagnostic utility. If ACTH deficiency occurs as a result of transsphenoidal surgery, the cortisol response to exogenous ACTH stimulation may be normal in the first month or two after surgery. An abnormal response does not evolve until the volume of the adrenal cortex has decreased significantly. In this setting, the ITT may be a better test to diagnose ACTH deficiency because the ACTH response to hypoglycemia may be lost in the early postoperative period [3]. (See "Treatment of gonadotroph and other clinically nonfunctioning adenomas", section on 'First evaluation post-discharge' and "Diagnosis of adrenal insufficiency in adults", section on 'Recent ACTH deficiency'.)

●ITT versus other dynamic tests – Available data suggest that ACTH stimulation tests are not ideal to test for adrenal insufficiency in the immediate postoperative period and that at one month after surgery, ACTH stimulation tests may under- or overdiagnose adrenal insufficiency depending on the dose of synthetic corticotropin utilized [3-5].

Although the overnight metyrapone test may also be used to diagnose adrenal insufficiency in the postoperative setting [6], this test is available in few medical centers. The overnight metyrapone test, when performed six weeks after transsphenoidal surgery, correlates well with the cortisol response to insulin-induced hypoglycemia [6]. This test confers fewer risks than the ITT and may be preferred where available. (See "Metyrapone stimulation tests".)

●Long-term predictive utility of the ITT – A normal cortisol response to the ITT is a strong predictor of intact hypothalamic-pituitary-adrenal axis function. However, an abnormal cortisol response to insulin-induced hypoglycemia in the immediate postoperative period may not predict long-term axis dysfunction. In one study of 36 patients with an abnormal response to ITT at three months after surgery, 20 patients had a normal response at 12 months [7]. In another study, all six patients with an abnormal response to ITT in the immediate postoperative period had a normal response at three months [3]. By contrast, very few patients with an initially normal response to insulin or ACTH progress to an abnormal function [5,7,8].

Growth hormone deficiency: Not recommended — We do not suggest the insulin-induced hypoglycemia test for the evaluation of growth hormone deficiency. It was more commonly used in the past, but its disadvantages are that it requires constant supervision by a clinician and the symptoms of hypoglycemia can be very unpleasant for the patient. In fact, none of the tests for secondary adrenal insufficiency (ACTH or CRH stimulation; insulin-induced hypoglycemia) seem to perform well in patients with growth hormone deficiency. This issue is discussed in more detail separately [9]. (See "Growth hormone deficiency in adults", section on 'Insulin-induced hypoglycemia'.)

PRACTICAL ASPECTS

Contraindications — This test is contraindicated in patients with coronary heart disease, cerebrovascular disease, or epilepsy; if coronary disease is suspected, appropriate evaluation must be performed before considering the insulin tolerance test (ITT). (See "Screening for coronary heart disease".)

Procedure — The patient fasts for at least eight hours before the test and must remain supine during the procedure. An experienced clinician must be present at all times to monitor for complications related to hypoglycemia (chest pain, tachycardia, and/or neuroglycopenic symptoms [confusion, seizures]). A syringe containing 50 percent glucose solution should be at the bedside. An intravenous line is established, and insulin is injected intravenously. The usual dose is 0.15 units/kg of regular insulin, but different doses may be indicated in certain patients [10]:

●In patients thought to have hypopituitarism or primary adrenal insufficiency, the insulin dose is decreased to 0.1 units/kg because these conditions may be associated with decreased release of other counterregulatory hormones such as epinephrine and growth hormone.

●In patients with obesity, diabetes mellitus, or suspected acromegaly or Cushing syndrome, the dose is increased to 0.2 units/kg. However, coronary disease must be ruled out before performing the test, particularly at this higher dose.

●In premenopausal women, the test can be performed at any phase of the menstrual cycle as there are no cycle effects on the hypothalamic-pituitary-adrenal axis response to insulin-induced hypoglycemia [11].

Blood is obtained for bedside measurement of serum glucose and for laboratory measurement of serum glucose and cortisol levels (and for plasma corticotropin [ACTH], if indicated) immediately before insulin is injected and every 15 minutes thereafter. The final, definitive blood sample for measurement of ACTH and cortisol should be obtained 5 to 10 minutes after the patient begins to perspire or, if it can reliably be measured, when the serum glucose falls below 35 mg/dL (1.9 mmol/L). As noted, there is no clear consensus about the glucose nadir necessary for optimal test performance. While many use 35 mg/dL (1.9 mmol/L), others use 40 or 45 mg/dL (2.2 or 2.4 mmol/L) [6,12].

●Almost all patients have some degree of perspiration. If the patient does not perspire, the adequacy of the stress stimulus must remain suspect regardless of the serum glucose concentration.

●Most patients also have a hyperactive precordium (but not tachycardia or hypotension, because they are supine), and feelings of hunger, drowsiness, detachment, or anxiety. The last is common and sometimes severe, and many patients find this an unpleasant experience.

The nadir in blood glucose usually occurs 30 to 45 minutes after insulin injection. If adequate hypoglycemia is not achieved, a second similar dose of regular insulin should be injected intravenously. Adequate hypoglycemia should be achieved within the subsequent 30 to 45 minutes.

Ideally, an automated glucose oxidase analyzer or calibrated and validated point of care device should be available at the bedside. Unfortunately, most glucose oxidase strips, whether read visually or with a glucose meter, are inaccurate at low serum glucose concentrations, tending to underestimate them, leading to premature termination of the test.

Patients with primary or secondary adrenal insufficiency or longstanding diabetes mellitus have an impaired compensatory response to hypoglycemia. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

●Therefore, the test should be stopped when the serum glucose concentration decreases to or below 35 mg/dL (1.9 mmol/L). In addition to stopping the test, sweetened orange juice or cola should be given by mouth.

●If hypoglycemic symptoms are severe, administration of 25 g of 50 percent glucose should be administered intravenously (see "Hypoglycemia in adults with diabetes mellitus", section on 'With IV access'). The solution should be infused over a period of one minute (slowly, because of its hypertonicity) if seizure, chest pain, confusion, disorientation, or other potentially serious complications occur; this will result in hyperglycemia within 30 seconds.

●Blood should be drawn for measurement of cortisol when glucose is given and 15 minutes later as levels continue to increase despite increasing serum glucose concentrations [13].

Normal reference values — The criteria for a normal serum cortisol response in individuals without adrenal insufficiency ranged from 18 to approximately 22 mcg/dL (500 to 600 nmol/L) in multiple studies using different assays and various methods. The newer, more specific cortisol immunoassays and tandem mass spectrometry (LC-MS/MS) methods may give significantly lower cortisol results (as much as 25 percent lower) [14]. Because of this, serum cortisol cutoffs for any stimulation test must be individualized to the method used in the clinical laboratory [15-18]. The highest (peak) serum cortisol is used to interpret the response, rather than the cortisol increment [13]. (See "Diagnosis of adrenal insufficiency in adults" and "Diagnosis of adrenal insufficiency in adults", section on 'ACTH stimulation tests'.)

Plasma ACTH also can be measured. The normal plasma ACTH response has not been carefully defined, but the peak concentration should exceed 150 pg/mL (33 pmol/L) [19-23].

There is increasing evidence that the salivary cortisol response to insulin-induced hypoglycemia can provide useful information, although definitive cutoffs have yet to be established [24-26].

Interpretation — An inadequate cortisol response can be due to hypopituitarism of any etiology, including hypothalamic corticotropin-releasing hormone (CRH) deficiency, isolated ACTH deficiency, partial or panhypopituitarism, or hypothalamic-pituitary suppression from use of opioids or synthetic glucocorticoids [1,27-29]; it also can be due to primary adrenal insufficiency when serum cortisol levels rather than plasma ACTH values are used as the endpoints of the test. However, false-negative results in patients who have partial adrenal insufficiency can occur because hypoglycemia is such a potent stimulus that it may obscure a partial defect. (See "Causes of secondary and tertiary adrenal insufficiency in adults" and "Causes of primary adrenal insufficiency (Addison disease)".)

●Hypoglycemia is a stronger stimulus of ACTH secretion than is hypocortisolemia (as induced by metyrapone). Consequently, patients may have a normal response to hypoglycemia, but an inadequate response to metyrapone, which can detect subtle defects in ACTH secretion. The reverse is almost never true.

●The low-dose (1 mcg) one-hour ACTH stimulation test does not result in maximally stimulating plasma ACTH concentrations. Thus, as with metyrapone, patients may have a normal serum cortisol response to hypoglycemia (or to the high-dose cosyntropin test), but an inadequate response to low-dose cosyntropin.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Adrenal insufficiency" and "Society guideline links: Growth hormone deficiency and other growth disorders".)

SUMMARY

●Clinical utility – Although insulin-induced hypoglycemia is a valid and perhaps the most physiologically rational test of hypothalamic-pituitary-adrenal response to stress, there is little, if any, reason for performing the test in clinical practice except in patients with suspected recent corticotropin (ACTH) deficiency (eg, recent pituitary surgery). (See 'Clinical uses' above.)

●Practical aspects – The test is relatively safe (if a clinician is present) in patients with no history of seizures or cardiovascular or cerebrovascular disease, but otherwise should not be performed. (See 'Practical aspects' above.)

●Test procedure – Insulin (usually at a dose of 0.15 units/kg [in patients with low basal cortisol levels, the dose should be reduced to 0.1 units/kg]) is given with the aim to achieve hypoglycemia of 35 to 45 mg/dL (1.9 to 2.5 mmol/L) or less. (See 'Procedure' above.)

Cortisol concentrations are measured at 0, 30, and 45 minutes after insulin is given and, when appropriate, 15 minutes after glucose has been given to reduce symptoms of hypoglycemia. It may also be useful to measure the plasma ACTH response. (See 'Normal reference values' above.)

●Interpretation of results

•Adequacy of cortisol response – The criteria for a normal serum cortisol response range from 18 to approximately 22 mcg/dL (500 to 600 nmol/L) in studies using different assays and various methods to establish a normal reference range. Newer, more specific cortisol assays have cutoffs approximately 25 percent lower. Failure to reach this level is indicative of an inadequate response only if the serum glucose decreased to 35 to 45 mg/dL (1.9 to 2.5 mmol/L) or less. If this degree of hypoglycemia was not achieved and the cortisol is inadequate, the test was ended prematurely and must be repeated. It is the peak serum cortisol concentration that is achieved rather than the increment that is important. (See 'Interpretation' above.)

•Underlying etiology – An inadequate cortisol response can be due to hypopituitarism of any etiology, including hypothalamic corticotropin-releasing hormone (CRH) deficiency, isolated ACTH deficiency, partial or panhypopituitarism, or hypothalamic-pituitary suppression from use of opioids or synthetic glucocorticoids; it can also be due to primary adrenal insufficiency. However, false-negative results in patients who have partial adrenal insufficiency can occur because hypoglycemia is such a potent stimulus that it may obscure a partial defect. (See 'Interpretation' above.)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.