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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 7 3408-3412
Copyright © 2004 by The Endocrine Society

Usefulness of Homeostasis Model Assessment for Identifying Subjects at Risk for Hypoglycemia Failure during the Insulin Hypoglycemia Test

Gemma Francisco, Cristina Hernández, Rosa Galard and Rafael Simó

Endocrinology Division (G.F., C.H., R.S.) and Biochemistry Department (R.G.), Hospital Univesitari Vall d’Hebron, 08035 Barcelona, Spain

Address all correspondence and requests for reprints to: Rafael Simó, M.D., Endocrinology Division, Hospital Universitari Vall d’Hebron, Pg. Vall d’Hebron 119-129, 08035 Barcelona, Spain. E-mail: rsimo{at}hg.vhebron.es.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
One of the main problems of the insulin hypoglycemia test (IHT) is the failure to achieve an adequate hypoglycemia (blood glucose, <45 mg/dl) with the standard dose of insulin used. The aim of the study was to identify by means of homeostasis model assessment (HOMA) the subjects at risk for hypoglycemia failure during IHT. For this purpose 32 patients in whom an IHT was performed were prospectively included. Receiver operating characteristics curve analyses were performed to assess the sensitivity and specificity of both insulinemia and HOMA. Eight patients (25%) did not reach adequate hypoglycemia. A serum insulin concentration above 17.7 µIU/ml or a HOMA value above 4.38 identified those subjects who would not reach adequate hypoglycemia with a probability of 75%. By contrast, when the levels of either insulinemia or HOMA were lower than the cut-off points mentioned above, the probability that individuals would reach sufficient hypoglycemia was 89.5%. In conclusion, quantitative estimate of insulin resistance by HOMA is a simple and reliable method that permits identification of individuals at risk of not reaching adequate hypoglycemia during IHT. In these patients, either alternative tests or a higher dose of insulin should be considered.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE COMBINED ASSESSMENT of GH and ACTH reserve in adults is best achieved by the insulin-induced hypoglycemia test (IHT), which assesses the integrated central and peripheral responses to this stressful event. However, it is unpleasant and time and resource consuming, and should be performed in an experienced endocrine unit under adequate supervision (1). In addition, it is contraindicated in frail elderly subjects and patients with ischemic heart disease or epilepsy. For all of these reasons, in recent years low dose ACTH and glucagon stimulation tests have been suggested as safer alternatives with comparable cortisol responses to IHT (2, 3, 4, 5). The low dose (1 µg) ACTH stimulation test is quick, insensitive to interference from diet or medication, simple to interpret, and reliable, and it can be applied to people of all ages without fear of untoward effects. However, it does not allow evaluation of GH reserve. By contrast, the glucagon stimulation test has some side-effects (i.e. nausea and vomiting), but permits a reliable assessment of both ACTH and GH pituitary reserve. Nevertheless, although hypoglycemia cannot be considered as a truly physiological stimulus to the human hypothalamic-pituitary-adrenal (HPA) axis, IHT is considered a means by which physical stresses may be simulated, and it has become the gold standard test for determining the need for cortisol (6, 7, 8) and GH replacement (9, 10) in patients with hypothalamic-pituitary disease.

A question of major importance is the relationship between the degree of hypoglycemia and the hormone response (11, 12). There is a lack of consensus regarding the specific hypoglycemic threshold that should be achieved during IHT. The current values for defining an adequate hypoglycemia are less than 40 mg/dl (2.2 mmol/liter) (1, 13, 14, 15, 16, 17, 18) or less than 45 mg/dl (2.5 mmol/liter) (8, 19), although a cut-off as high as 50 mg/dl (2.8 mmol/liter) (7) has been also used. Whatever cut-off value is selected, one of the main problems of IHT remains the failure to achieve adequate hypoglycemia with the standard dose of insulin (0.15 IU/kg body weight). For this reason, it seems advisable to identify beforehand the individuals at risk of not reaching a hypoglycemic state during IHT. In these cases, either alternative tests or a higher dose of insulin should be considered.

The homeostasis model assessment (HOMA) has proved to be a robust method for assessing insulin resistance in epidemiological studies. The sampling is simple, and the result is available without complex computing as soon as fasting glucose and insulin values are available. In addition, estimates of insulin resistance from HOMA correlate well with estimates from euglycemic clamp (20). On this basis, we hypothesized that the higher the HOMA, the higher the rate of hypoglycemic failure. To explore this hypothesis we prospectively measured insulin resistance by means of HOMA in a cohort of patients undergoing IHT to determine its usefulness as a predictor of hypoglycemia.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
A total of 32 consecutive patients of Caucasian origin in whom a IHT was performed at the Endocrine Testing Laboratory between February 2001 and November 2002 were included in the study. Subjects who had been receiving a supraphysiological dose of glucocorticoids and diabetic patients were excluded. The study group consisted of 16 women and 16 men (mean age, 44 ± 16 yr) in whom organic hypothalamic-pituitary disease was diagnosed: pituitary tumors before (n = 16) and after pituitary surgery (n = 2), suprasellar meningiomas (n = 3), craniopharyngiomas (n = 3), empty sella (n = 3), central hypothyroidism (n = 2), lymphocytic hypophysitis (n = 1), and isolated ACTH deficiency (n = 1).

The IHT was performed in the morning between 0800–0900 h after an overnight fast. The patients remained recumbent during the test. Hypoglycemia was induced by a bolus injection of 0.15 IU/kg body weight human regular insulin (Actrapid, Novo Nordisk, Copenhagen, Denmark) though an indwelling cannula that had been inserted into a forearm vein 30 min previously. Blood samples were taken before (time zero) and 30, 60, and 90 min after insulin injection. Blood samples for plasma ACTH assay were collected in ice-chilled siliconized glass tubes with EDTA and immediately centrifuged at 4 C, and the plasma was frozen and stored at –20 C until it was assayed. Blood glucose levels were measured by the hexokinase method (Hitachi 917, Roche, Indianapolis, IN). We used a glucose nadir below 45 mg/dl (2.5 mmol/liter) as a criterion for sufficient hypoglycemia (19). Cortisol, ACTH, and GH were determined by an immunochemiluminescence assay using commercial kits (cortisol: Bayer Diagnostics, Dublin, Ireland; ACTH: Nichols Institute Diagnostics, Paris, France; GH: Diagnostic Products Corp., Llanberis, UK).

To estimate insulin resistance, the HOMA index was calculated by the formula: fasting plasma insulin (microinternational units per milliliter) x fasting plasma glucose (millimoles per liter)/22.5 (21, 22). Plasma insulin levels were measured by immunoradiometric assay using a commercially available kit (DiaSorin, Inc., Reutlinger, Germany).

The study was conducted in accordance with the guidelines laid down in The Helsinki Declaration and was approved by a local ethics committee. All patients gave their informed consent to participate in the study.

Statistics

Results are expressed as the mean ± SD. Receiver operating characteristics (ROC) curves were constructed to determine the efficacy of the insulin serum concentration and the HOMA index to correctly identify subjects who would not achieve hypoglycemia during IHT. The optimal cut-off point (for the predictor) coincided with the point on the ROC curve at which the sum of sensitivity and specificity was maximal. An area under the curve of 0.7 or higher signified that the diagnostic test was better than chance (23). All statistical analyses were performed using the software package SPSS.10 for Windows (SPSS, Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
All subjects tolerated the testing procedure well and no test complications occurred. Eight patients (25%) did not reach adequate hypoglycemia (blood glucose level, >45 mg/dl). ROC curve analyses were performed to assess the sensitivity and specificity of both insulinemia and HOMA depending on the cut-off point selected. The cut-off point of a serum insulin concentration of 17.7 µIU/ml provided the best sensitivity (S)/specificity (E) pair (S 0.82/E 0.86; Fig. 1Go). Equally, the cut-off point of 4.38 of the HOMA index provided a similar sensitivity/specificity pair (S 0.82/E 0.9; Fig. 2Go). The areas under the curve were very similar for the two tests evaluated (0.823 ± 0.94 for insulinemia and 0.853 ± 0.92 for the HOMA index). A serum insulin concentration above 17.7 µIU/ml or a HOMA value above 4.38 identified those subjects who would not reach adequate hypoglycemia during the IHT with a probability of 75%. On the other hand, when the levels of either insulinemia or HOMA were lower than the cut-off points mentioned above, the probability that individuals would reach sufficient hypoglycemia was 89.5%. As the limit of 40 mg/dl (2.2 mmol/liter) is also often used as a criterion of adequate hypoglycemia, we have calculated by means of ROC curves the sensitivity and specificity of both insulinemia and HOMA depending on this cut-off value. The HOMA index and insulin cut-off points that allow us to identify those patients in whom an adequate hypoglycemia will not be achieved (n = 9; 28.1%) were 4.38 (S 0.8/E 0.87) and 18 µIU/ml (S 0.8/E 0.82), respectively. These results are very similar to those previously obtained using the threshold of 45 mg/dl (2.5 mmol/liter).



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  		FIG. 1. An ROC curve constructed to determine the efficacy of the serum insulin concentration to correctly identify individuals who will not attain hypoglycemia during the IHT.

 


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  		FIG. 2. An ROC curve constructed to determine the efficacy of the HOMA index to correctly identify individuals who will not attain hypoglycemia during the IHT.

 
The results of all IHTs performed according to the HOMA index selected (4.38) are summarized in Tables 1Go and 2Go. Those patients in whom ACTH or GH deficits were detected presented a HOMA index of 4.38 or less. By contrast, baseline hormone values showed that patients with a HOMA index above 4.38 were free of hypothalamic-pituitary-adrenocortical deficit, and two of them presented active acromegaly. Finally, significant differences in body mass index were not observed between patients with a HOMA index greater than 4.38 compared with patients with a HOMA index of 4.38 or less (30.6 ± 7.44 vs. 27.9 ± 5.71; P = nonsignificant).


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  		TABLE 1. IHT results corresponding to those patients with HOMA index of 4.38 or less

 

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  		TABLE 2. IHT results corresponding to those patients with HOMA index greater than 4.38

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The specific threshold level of plasma glucose that can be considered as sufficient hypoglycemia for activation of the HPA axis when an IHT is performed has been the subject of intense debate (1, 7, 8, 13, 14, 15, 16, 17, 18, 19, 24, 25). Studies employing hyperinsulinemic hypoglycemic clamp methods, in which plasma glucose levels are reduced and maintained at selected incremental levels below basal for 45–60 min, have identified specific glycemic thresholds for the onset of the counterregulatory hormone response and symptoms of hypoglycemia (26). These glycemic thresholds are dynamic and may shift to higher or lower levels depending on antecedent glucose concentrations. Streeten et al. (19) have shown that plasma cortisol concentrations do not increase until the plasma glucose concentration has fallen below 70 mg/dl (3.8 mmol/liter) and are maximally stimulated at a plasma glucose level of 45 mg/dl (2.5 mmol/liter) or less. Based on these data and using a glucose nadir below 45 mg/dl (2.5 mmol/liter) as a criterion for sufficient hypoglycemia, we have found a high prevalence (25%) of hypoglycemia failure. When a threshold of less than 40 mg/dl (2.2 mmol/liter) was used for defining an adequate hypoglycemia, the prevalence of hypoglycemia failure was 28.1%. Although this is a well recognized problem with IHT, the specific prevalence of hypoglycemia failure has not been previously detailed in most of the studies specifically designed to assess the HPA axis response to hypoglycemia. However, it must be taken into account, because it is desirable in both physiological and economical terms.

In the present study we provide the first evidence that either the plasma insulin concentration or HOMA could be useful in identifying those subjects who will not achieve adequate hypoglycemia during the IHT. Thus, taking a glucose nadir below 45 mg/dl (2.5 mmol/liter) as a criterion of adequate hypoglycemia, a basal insulin concentration above 17.7 µIU/ml or a HOMA index above 4.38 can serve as reliable predictors of hypoglycemia failure. These results were almost identical when the threshold for defining adequate hypoglycemia was less than 40 mg/dl (2.2 mmol/liter).

Survey data from the National Cholesterol Education Program Adult Treatment Panel III suggest that the insulin resistance syndrome is very common, affecting about 24% of U.S. adults over 20 yr of age (27). Given the similar prevalence of hypoglycemic failure reported here, it could be speculated that most patients in whom hypoglycemia is not achieved have the insulin resistance syndrome. However, it should be noted that most of the patients undergoing IHT have specific pituitary diseases that significantly influence the degree of insulin resistance. Therefore, in these patients the HOMA index could be considered an integration of counterregulatory hormones rather than a reliable reflection of the metabolic syndrome. In fact, we did not observe a relationship between body mass index and HOMA in these patients. In addition, most of the patients with pituitary deficits presented a HOMA index lower than 4.38, whereas those patients with a HOMA index greater than 4.38 were either free of pituitary deficits or had acromegaly, a disease clearly associated with insulin resistance.

From a clinical point of view it would seem reasonable to assess insulin resistance by means of either fasting insulin concentration or a HOMA index before performing an IHT because of their low costs and the ease with which they can be performed. If basal insulin concentrations or HOMA levels are higher than the cut-off point mentioned above, we believe that other alternative tests, such as the low dose ACTH (1 µg) test or the glucagon stimulation test, may be applied to assess the integrity of the HPA axis. Alternatively, the insulin dose could be increased. However, our study was not designed to determine the exact dose of insulin that would be effective in such a group of patients; therefore, future studies are required to elucidate this issue.

The hyperinsulinemic hypoglycemic clamp method provides a more controlled setting in which to assess hypothalamic-pituitary function than the standard IHT performed by iv bolus insulin injection (28, 29, 30, 31, 32). In addition, the counterregulatory response of the HPA axis could be induced with less profound hypoglycemia, thus limiting the risk of cardiac dysrhytmia, seizure, or coma. For these reasons, the hypoglycemic clamp may be pertinent when assessing pituitary function in the elderly. In addition, the clamp method permits an optimal insulin dosage adjustment to the individual sensitivity, thus avoiding failure to achieve adequate hypoglycemia. However, it is labor-intensive, costly, and requires the presence of a physician or a well trained nurse throughout the procedure. For this reason it is desirable to carefully identify those patients, besides older adults, in which this method might be more cost-effective. In this regard, on the basis of our study it is suggested that priority be given to those patients in whom HOMA is higher than 4.38.

In summary, the rate of hypoglycemia failure during an IHT using the standard dose of insulin is far from insignificant. Thus, quantitative estimates of insulin resistance by a HOMA index could be an easy way of identifying those subjects who will not achieve sufficient hypoglycemia, with consequent saving of medical resources.


   Footnotes
 
This work was supported by grants from Instituto Carlos III (G03/212, C03/08) and Novo Nordisk Pharma S.A. (01/0066).

Abbreviations: HOMA, Homeostasis model assessment; HPA, hypothalamic-pituitary-adrenocortical; IHT, insulin hypoglycemia test; ROC, receiver operating characteristics curve.

Received October 31, 2003.

Accepted March 29, 2004.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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