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Department of Pediatrics, Division of Pediatric Endocrinology, Albert Einstein College of Medicine/Children’s Hospital, Montefiore Medical Center, Bronx, New York 10467
Address all correspondence and requests for reprints to: Joan DiMartino-Nardi, M.D., Division of Pediatric Endocrinology, Albert Einstein College of Medicine/Children’s Hospital, Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10467. E-mail: jdimartinonardi{at}aol.com
Abstract
The purpose of this study was to determine whether the fasting glucose/insulin ratio is a useful screening test for insulin resistance in prepubertal girls with premature adrenarche. The glucose/insulin ratio was compared with the insulin sensitivity index calculated from the frequently sampled iv glucose tolerance test with tolbutamide using the minimal model computer program. Thirty-three prepubertal girls (22 Caribbean Hispanic and 11 African American; mean age, 6.8 yr; bone age, 8 yr) were studied. All underwent a 60-min ACTH stimulation test. The fasting glucose/insulin ratio was also compared with IGF-binding protein-1 and ACTH-stimulated androgen levels. Insulin sensitivity correlated significantly with the glucose/insulin ratio (0.76; P < 0.001), fasting insulin (0.75; P < 0.001), and IGF-binding protein-1 (0.59; P < 0.005). Stepwise regression analysis with the insulin sensitivity index as the dependent variable showed that the fasting glucose/insulin ratio was significantly predictive of the insulin sensitivity index (P < 0.002). When viewed as a screening test, setting a value of the fasting glucose/insulin ratio of less than 7 as abnormal and of less than 5.7 x 10-4 min/µU·ml for the insulin sensitivity index as evidence of insulin resistance (normal prepubertal insulin sensitivity index, >5.7 x 10-4 min/ µU·ml), the sensitivity of the fasting glucose/insulin ratio was 87%, and the specificity was 89%. Furthermore, those girls with a low glucose/insulin ratio (<7) had higher body mass index, fasting insulin, free T, and ACTH-stimulated 17-hydroxypregnenolone and lower fasting IGF-binding protein-1 and SHBG than those girls with a glucose/insulin ratio greater than 7. The fasting glucose/insulin ratio is a useful screening test for insulin resistance in prepubertal Caribbean Hispanic and African American girls with premature adrenarche.
THE TERM INSULIN resistance refers to an impaired biological response to either exogenous or endogenous insulin (1). The euglycemic insulin clamp and the frequently sampled iv glucose tolerance test (FSIVGTT) are the standard methods of assessing insulin sensitivity (SI) (2, 3). These tests are time, labor, and cost intensive and are not practical for large scale studies, screening, or routine assessment.
It is well established that polycystic ovarian syndrome (PCOS) is frequently characterized by insulin resistance (4). Recently, Legro et al. (5) compared the fasting glucose/insulin (G:I) ratio to insulin sensitivity measured by the FSIVGTT in obese non-Hispanic white women with PCOS. The fasting G:I ratio was found to be a highly sensitive and specific measurement of insulin sensitivity. When viewed as a screening test for insulin resistance, a fasting G:I ratio of less than 4.5 in obese Caucasian women was considered abnormal, with 95% sensitivity and 84% specificity.
We previously reported that approximately 50% of Caribbean Hispanic and African American prepubertal girls with premature adrenarche also have insulin resistance when measured by the FSIVGTT. Furthermore, the hyperandrogenism in these girls correlated inversely with their insulin sensitivity (6, 7). That is, the more insulin-resistant girls had the higher ACTH-stimulated androgen levels. In addition to insulin resistance, many girls with premature adrenarche have many of the clinical and laboratory features of syndrome X (8). These include a strong family history of type 2 diabetes mellitus, acanthosis nigricans, obesity, and alterations in their lipid profiles. Currently, studies are being conducted to determine which girls with premature adrenarche are at risk for developing the long-term complications of insulin resistance.
As the FSIVGTT is not practical for large scale screening, the purpose of this study was to determine whether the fasting G:I ratio could identify insulin resistance in prepubertal girls with premature adrenarche, as it does in adult women with PCOS.
Subjects and Methods
Thirty-three prepubertal girls (22 Caribbean Hispanic and 11 African American) between 4 and 9 yr of age with premature adrenarche were recruited from the pediatric endocrine clinics at Montefiore Medical Center and Bronx Municipal Hospital Center. The results of ACTH testing and insulin sensitivity assessed using the FSIVGTT were previously reported (3, 6). All studies were approved by the institutional review board of Montefiore Medical Center, and written informed consent was obtained from one legal guardian of each patient before the study. The criteria for entry included the appearance of Tanner stage II–III pubic hair in prepubertal girls before the age of 8 yr. Excluded were girls with breast development, malignancy, or an enzymatic defect of adrenal steroidogenesis (9). Body mass index (BMI) was calculated using the formula weight (kilograms)/height (meters)2 (10). Obesity was defined as a BMI greater than the 95th percentile for chronological age and sex (10). Twenty-three children had at least one first or second degree relative with type 2 diabetes mellitus. Ethnicity was determined by self-reporting. Caribbean Hispanic girls had both parents from either Puerto Rico or the Dominican Republic, and African American girls had both parents of non-Caribbean, non-Latin American descent.
Study protocol
All children underwent a standard ACTH stimulation test, with the following steroids measured before and 60 min after an iv bolus of Cortrosyn (0.25 mg; Organon, East Orange, NJ): cortisol, 17hydroxypregnenolone (17-OH Preg), 17-hydroxyprogesterone (17-OH Prog), 11-deoxycortisol, deoxycorticosterone, dehydroepiandroesterone (DHEA), androstenedione (AS), and T. All children underwent an LH-releasing hormone test to confirm their prepubertal status, with LH and FSH measured before and 20, 40, and 60 min after an iv injection of Factrel (100 mg gonadorelin hydrochloride; Ayerst Laboratories, Inc., Philadelphia, PA). All children had a peak LH response of less than 5 mIU/liter. Baseline fasting serum samples were obtained for IGF-binding protein-1 (IGFBP-1), SHBG, and free T. The FSIVGTT was performed with tolbutamide on the morning after an overnight fast of 10–12 h. A 21-gauge needle was placed into each arm, and the child was allowed to rest for 30 min. Baseline samples were drawn at -30, -15, and 0 min. At zero time, 0.3 g/kg 25% dextrose was injected over 1 min. Samples were drawn from the contralateral arm at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 19, 22, 23, 24, 25, 27, 30 35, 40, 50, 60, 70, 80, and 90 min. A tolbutamide bolus (5 mg/kg) diluted in 20 cc sterile water was infused at 20 min over a period of 30 sec.
Insulin and glucose levels were measured in all of the above samples. In addition, blood sugar levels were checked with a bedside blood sugar-measuring device to monitor for hypoglycemia, and a physician was present throughout the study. Subjects were supine throughout the study. No patient suffered any ill effects during the procedure. The G:I ratio was calculated using the baseline insulin and glucose level at 0 min. The insulin sensitivity index (SI) was calculated using the Minimod computer program version NUDEMMI as reported by Bergman (10) and validated for children by Cutfield (11, 12).
Laboratory
Assays for 17-OH Preg, 17-OH Prog, AS, cortisol, T, DHEA, deoxycorticosterone, 11-deoxycortisol, FSH, LH, SHBG, and free T were performed as previously reported (6). Glucose levels were measured using the glucose oxidase method (Hitachi Scientific Instruments, Inc., Tokyo, Japan).
The Abbott Imx insulin assay (Dainabot, Abbott Laboratories, Tokyo, Japan) is a microparticle enzyme immunoassay for the quantitative measurement of human insulin in human serum and plasma. This assay shows no cross-reactivity with proinsulin (<0.005%). The coefficients of variation within the assay at mean values of 8.3 and 121.7 µU/ml are 4% and 2.5%, respectively. The coefficients of variation between assays at mean values of 8.3 and 121.7 µU/ml are 4.5% and 3.6%, respectively.
IGFBP-1 levels were measured using the DSL active immunoradiometric assay (Diagnostics Systems Laboratories, Inc., Webster, TX). The intra- and interassay coefficients of variation were 4.6% at 50 ng/ml and 6% at 47 ng/ml, respectively.
Statistics
All statistical analyses were performed using SPSS (SPSS, Inc., Chicago, IL). Results were expressed as the mean ± SD/SE. Correlations between variables were analyzed using the Spearman correlation coefficient (correlation of ranks). Stepwise regression analysis was performed with SI as the dependent variable and several independent variables (basal insulin, fasting glucose, IGFBP-1, G:I ratio, etc.). Sensitivity and specificity were calculated using a G:I ratio of 7 as a fixed cut-off point. The girls were divided into two groups based on their SI. Those girls with a low insulin sensitivity (low SI) had an SI more than 2 SD below the mean of the SI reported for normal prepubertal girls (12). The ACTH-stimulated hormonal data and the lipid profiles of the girls with normal SI were compared with those of girls with reduced SI. Also, the 60 min ACTH hormonal data and lipid profiles of the girls with a G:I ratio below 7 were also compared with those girls with a G:I above 7. The comparisons between groups were performed using t test, and P < 0.05 was considered to be statistically significant.
Results
Clinical and biochemical features of minority group girls with premature adrenarche
For the entire group, the mean chronological age was 6.8 ±
1.0 yr. Fourteen patients were obese, and 19 had acanthosis
nigricans. None of these patients was hirsute or had any other
sign of hyperandrogenism. All patients had normal fasting blood sugar
(<6.1 mmol/liter) and lipid levels. The mean fasting insulin level was
14.5 ± 11.5 µIU/ml (104 ± 82.5 pmol/liter; range, 5–30
µIU/ml) (36–216 pmol/liter). The mean SI for
the entire group of prepubertal girls with premature adrenarche was
6.8 ± 5.2 x 10-4 min/µU·ml. As
reported by Cutfield (12), the normal
SI for prepubertal children is 6.57 ±
0.54 x 10-4 min/µU·ml, and that for
pubertal children is 2.92 ± 0.45 x
10-4 min/µU·ml. The mean
SI for the African-American patients was 6.4
x 10-4 min/µU·ml, and the
SI for the Caribbean Hispanic patients was
6.2 x 10-4 min/µU·ml (Table 1
). There was no statistical difference
in these parameters between the Caribbean Hispanic and African-American
girls.
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SI was highly correlated with the fasting
G:I ratio (r = 0.76; P < 0.001) and IGFBP-1
(r = 0.59; P < 0.005). Stepwise regression
analysis with SI as the dependent variable and
the G:I ratio showed that the fasting G:I ratio was significantly
predictive of SI in the model (P
= 0.002). When we added other independent variables to the regression
equation to improve the prediction of the independent variable, the
impact of the colinearity between the variables decreased the
predictive value. The ideal screening test is one that approaches or
reaches 100% sensitivity and specificity. A fasting G:I ratio below 7
provides the best combination of sensitivity (87%), specificity
(89%), positive predictive value (87%), and negative predictive value
(89%) for identifying those girls with an SI
more than 2 SD below the mean for normal
prepubertal girls. Fifteen of the 33 girls had a G:I ratio below 7. A
G:I ratio below 7 identified 13 of the 15 girls with insulin
resistance, and a G:I ratio above 7 identified 16 of the 18 girls with
normal insulin sensitivity (Table 1
).
Chemical and biochemical features of patients with premature adrenarche according to SI and G:I ratio
Fifteen prepubertal girls with premature adrenarche had an
SI that was more than 2 SD below the
mean for normal prepubertal girls. Fifteen girls had a G:I less than 7.
The BMI, fasting insulin, fasting IGFBP-1, free T, SHBG,
ACTH-stimulated 17-OH Preg, DHEA, 17-OH Prog, AS, and
lipid levels are shown in Table 2 and are
plotted according to their SI and G:I ratio. The
girls with a low G:I ratio (<7) had higher BMI, fasting insulin level,
ACTH-stimulated 17-OH Preg, DHEA, AS, and free T and lower
fasting SI, IGFBP-1, and SHBG than girls with a
G:I above 7. These findings have been previously reported to occur in
girls with a low SI (6, 7).
Furthermore, those girls with a lower G:I ratio and lower
SI also had the lower fasting HDL. Therefore,
although obesity is a significant cause of insulin resistance in both
lean and obese girls, the G:I ratio correlated with insulin
sensitivity, as determined by the FSIVGTT with tolbutamide.
Furthermore, those girls with a low G:I ratio were the girls with the
higher ACTH-stimulated androgen and lower high density lipoprotein
cholesterol levels.
|
Discussion
Premature adrenarche refers to the early appearance of pubic hair in girls before the age of 8 yr and is characterized by modest hyperandrogenism in the range seen in early pubertal girls (13). However, we reported that many prepubertal African American and Caribbean Hispanic girls with premature adrenarche have ACTH-stimulated androgen levels more than 2 SD above the mean for early pubertal girls (14). Furthermore, many prepubertal girls with premature adrenarche have been shown to have insulin resistance. Recently, we reported that insulin-resistant girls with premature adrenarche had significantly higher ACTH-stimulated androgens than their peers with normal SI (6). Perhaps insulin has an important role in normal adrenarche. Hence, the hyperinsulinism and insulin resistance in young obese girls are associated with exaggerated premature adrenarche.
As the findings of obesity, insulin resistance, hyperandrogenism, decreased SHBG, and increased free T in these insulin-resistant prepubertal girls with premature adrenarche are very similar to those reported in women with PCOS, these girls may represent an early phase in the evolution of PCOS. In support of this hypothesis are recent reports indicating that the pubertal outcome for many girls with premature adrenarche is frequently not benign, and many girls with premature adrenarche develop functional ovarian hyperandrogenism (15, 16). Accurately confirming the presence of alterations in SI requires cost- and labor-intensive protocols, such as the euglycemic clamp or the FSIVGTT. Recently, Legro et al. (5) reported that the fasting G:I ratio is an easily obtained, highly sensitive, and specific measure of SI in obese non-Hispanic white PCOS women, with excellent positive and negative predictive values. These researchers defined insulin resistance as the lower 10th percentile of SI for an age-, weight-, and ethnicity-matched control group. In those patients, a G:I ratio less than 4.5 was the best screening measure for detecting insulin resistance.
We defined insulin resistance as an SI more than 2 SD below the mean reported for normal prepubertal girls (12). SI determined by the FSIVGTT has been shown to be highly correlated with insulin action determined by the euglycemic glucose clamp techniques (r = 0.84) (3). A fasting G:I ratio less than 7 was found to be a highly sensitive and specific test for insulin resistance in prepubertal girls with premature adrenarche. Furthermore, the G:I ratio correlated better with SI than did the fasting insulin level. The difference in the ratio reported by Legro et al. (5) may reflect the differences in pubertal status and insulin levels between the two groups.
The clinical and biochemical features of girls with a low G:I ratio (<7) are virtually identical to those of girls with a markedly reduced SI, i.e. they tend to be obese and have higher fasting insulin levels, lower fasting IGFBP-1 levels, higher ACTH-stimulated 17-OH Preg, higher free T, and lower SHBG and high density lipoprotein cholesterol levels.
Our results indicate that a fasting G:I ratio is an easily obtainable, highly sensitive, and specific measure of SI in prepubertal African-American and Caribbean Hispanic girls with premature adrenarche. Further studies will be needed to validate this measure in other pediatric populations and across ethnic groups. These studies would be important in the early identification of insulin resistance in children, so that early intervention can occur before more serious complications such as dyslipidemia, type 2 diabetes mellitus, and PCOS.
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We thank Ms. Zaida Fajardo for her expert secretarial assistance with the preparation of this manuscript, and Dr. Wisnivesky for his assistance with the statistical analysis.
Footnotes
This work was supported by a grant from the Genentech Foundation for Growth and Development. This work was presented in part at the Annual Meeting of the Society for Pediatric Research, San Francisco, California, May 1–4, 1999 (Pediatr Res 45–99A, 1999) and the 38th Annual Meeting of the European Society for Pediatric Endocrinology, Warsaw, Poland, 1999.
Abbreviations: AS, Androstenedione; BMI, body mass index; DHEA, dehydroepiandroesterone; FSIVGTT, frequently sampled iv glucose tolerance test; G:I ratio, glucose/insulin ratio; IGFBP, IGF-binding protein; 17-OH Preg, 17-hydroxypregnenolone; 17-OH Prog, 17-hydroxyprogesterone; PCOS, polycystic ovarian syndrome; SI, insulin sensitivity.
Received July 18, 2000.
Accepted July 13, 2001.
References
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