Insulin Resistance, Obese Children And Adolescents
MAKALE #1672 © Yazan Prof.Dr.Mehmet Emre ATABEK | Yayın Ekim 2008 | 3,513 Okuyucu
Homeostasis Model Assessment Is More Reliable Than the Fasting
Glucose/Insulin Ratio and Quantitative Insulin Sensitivity Check Index
for Assessing Insulin Resistance Among Obese Children and Adolescents
Mehmet Keskin, MD*; Selim Kurtoglu, MD*; Mustafa Kendirci, MD*; M. Emre Atabek, MD*; and
Cevat Yazici, MD‡
ABSTRACT.
Objective. Simple fasting methods to
measure insulin resistance, such as the homeostasis
model assessment (HOMA), fasting glucose/insulin ratio
(FGIR), and quantitative insulin sensitivity check index
(QUICKI) methods, have been widely promoted for adult
studies but have not been evaluated formally among
children and adolescents. The aim of this study was to
compare the HOMA, FGIR, and QUICKI methods for
measuring insulin resistance, expressed by oral glucose
tolerance test (OGTT) results, among obese children and
adolescents.
Methods.
Fifty-seven pubertal obese children and adolescents
(30 girls and 27 boys; mean age, 12.04
2.90
years; mean BMI: 29.57
5.53) participated in the study.
All participants underwent an OGTT. Blood samples
were obtained 0, 30, 60, 90, and 120 minutes after oral
glucose administration for glucose and insulin measurements,
and 2 separate groups were studied, according to
the presence or absence of insulin resistance. HOMA,
FGIR, and QUICKI methods were studied for validation
of insulin resistance determined with the OGTT for
these groups.
Results.
The groups consisted of 25 obese children
and adolescents with insulin resistance (14 girls and 11
boys; mean age: 12.88
2.88 years; mean BMI: 31.29
5.86) and 32 subjects without insulin resistance (16 girls
and 16 boys; mean age: 11.38
2.79 years; mean BMI:
28.23
4.94). There were significant differences in the
mean HOMA (6.06
4.98 and 3.42 3.14, respectively)
and QUICKI (0.313
0.004 and 0.339 0.004, respectively)
values between the 2 groups. Sensitivity and specificity
calculations based on insulin resistance with receiver
operating characteristic curve analysis indicated
that HOMA had high sensitivity and specificity for measuring
insulin resistance.
Conclusions.
As a measure of insulin resistance
among children and adolescents, HOMA is more reliable
than FGIR and QUICKI. The present HOMA cutoff point
for diagnosis of insulin resistance is 3.16. The HOMA
cutoff point of
>2.5 is valid for adults but not for
adolescents.
Pediatrics 2005;115:e500–e503. URL: www.
pediatrics.org/cgi/doi/10.1542/peds.2004-1921;
insulin resistance,
children, adolescents.
ABBREVIATIONS. HOMA, homeostasis model assessment;
OGTT, oral glucose tolerance test; FGIR, fasting glucose/insulin
ratio; QUICKI, quantitative insulin sensitivity check index; ROC,
receiver operating characteristic.
I
nsulin resistance is the greatest risk factor for the
development of type 2 diabetes and is perhaps
the greatest current health threat to our children.
The prevalence of childhood obesity has more than
doubled in the past 15 years in many regions of the
world.
1–5 The marked increase in pediatric obesity in
the past decade has resulted in unprecedented increases
in the incidence of type 2 diabetes mellitus
among children and adolescents. In these grossly
obese children, both insulin resistance and impaired
insulin secretion contribute to the increase in glucose
levels, and the degree of obesity is related to cardiovascular
risk factors independent of insulin resistance.
2–4
The standard technique for assessment of insulin
sensitivity is the hyperinsulinemic euglycemic clamp; it
is often combined with the hyperglycemic clamp to
determine the adequacy of compensatory
-cell hypersensitivity.
6–9
Although clamp technology has
been applied to the study of insulin sensitivity and
insulin secretion during childhood, it is too invasive
for general epidemiologic studies. Because no intravenous
access is needed, the oral glucose tolerance
test (OGTT) is better suited for assessment of large
populations. Although OGTTs are more difficult to
perform than simple measurements of fasting glucose
and insulin levels, the OGTT is a minimal-risk
procedure that is applicable for large-scale screening
and for repeat studies for individual subjects.
10
In the quest for a noninvasive measurement technique
for insulin sensitivity, several fasting or “homeostatic”
models have been proposed, and each has
correlated reasonably well with clamp techniques.
11–13
The homeostatic model assessment
(HOMA), fasting glucose/insulin ratio (FGIR), and
quantitative insulin sensitivity check index (QUICKI)
methods have been the most frequently used techniques
in clinical investigations. The fact that these
tests require only a single venipuncture in the fasting
state and do not call for concomitant intravenous
access makes them particularly attractive to patients
and clinicians alike.
The HOMA approach has been widely used in
clinical research to assess insulin sensitivity.
9,14
From the *Departments of Pediatrics and ‡Biochemistry, School of Medicine,
Erciyes University, Kayseri, Turkey.
Accepted for publication Nov 8, 2004.
doi:10.1542/peds.2004-1921
No conflict of interest declared.
Address correspondence to Mehmet Keskin, MD, Department of Pediatrics,
School of Medicine, Erciyes University, 38039, Kayseri, Turkey.
PEDIATRICS (ISSN 0031 4005). Copyright © 2005 by the American Academy
of Pediatrics.
e
500
PEDIATRICS Vol. 115 No. 4 April 2005 www.pediatrics.org/cgi/doi/10.1542/peds.2004-1921
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Rather than using fasting insulin levels or FGIR, the
product of the fasting concentrations of glucose (expressed
as milligrams per deciliter) and insulin (expressed
as milliunits per milliliter) is divided by a
constant. The constant 405 should be replaced by 22.5
if the glucose concentration is expressed in Syste`me
International units. Unlike insulin levels and the
FGIR, the HOMA calculation compensates for fasting
hyperglycemia.
13 The HOMA and insulin values
increase for insulin-resistant patients, whereas the
FGIR decreases.
The QUICKI method can be applied to normoglycemic
and hyperglycemic patients. The index is derived
by calculating the inverse of the sum of logarithmically
expressed fasting glucose and insulin
concentrations.
13 As insulin concentrations decrease,
QUICKI values increase.
METHODS
Research Design and Methods
Fifty-seven pubertal obese children and adolescents (30 girls
and 27 boys; mean age: 12.04
2.90 years; mean BMI: 29.57
5.53) participated in the study. All children and adolescents were
recruited from the Department of Pediatric Endocrinology of Erciyes
University Faculty of Medicine. BMI was calculated as
weight (in kilograms) divided by height (in meters) squared. All
subjects had a BMI above the 95th percentile for age and gender
and thus were classified as obese. On the basis of the year 2000
growth charts, this BMI category is referred to as overweight by
the Centers for Disease Control and Prevention. Detailed medical
and family histories were obtained for all subjects, and physical
examinations were performed. All subjects were healthy and had
normal thyroid function. Parents provided informed consent and
children and adolescents provided informed assent before testing
commenced.
We divided the subjects into groups with insulin resistance and
without insulin resistance by using a cutoff point of the sum of
insulin levels during the OGTT of 300 U/mL.
15,16 After a 3-day,
high-carbohydrate diet (300 g/day) and an overnight fast, a standard
OGTT (1.75 g/kg or a maximum of 75 g of glucose) was
performed for all subjects. Blood samples were obtained 0, 30, 60,
90, and 120 minutes after glucose administration, for glucose and
insulin measurements. Plasma glucose levels were measured with
the glucose oxidase method and a modified Trinder color reaction,
catalyzed by the peroxidase enzyme, and insulin levels were
measured with an immunoradiometric assay kit.
Indexes Derived From Fasting Blood Samples
The HOMA index, QUICKI, and FGIR were derived as estimates
of insulin resistance. The HOMA index was calculated as
fasting insulin concentration (U/mL)
fasting glucose concentration
(mmol/L)/22.5, assuming that normal young subjects have
an insulin resistance of 1. The QUICKI was calculated as 1/[log
fasting insulin concentration (U/mL)
log glucose concentration
(mg/dL)].
Statistical Analyses
Analyses were performed with SPSS version 10 software for
Windows (SPSS, Chicago, IL). Data are reported as means
SD
and ranges. We compared groups by using independent-sample
t
tests.
P .05 was considered significant for all data analyses. The
optimal HOMA value for diagnosis of insulin resistance was
established with a receiver operating characteristic (ROC) scatter
plot. An alternative way to establish an optimal cutoff value for a
test is to determine the optimal decision point from an ROC curve,
whereby equal weight is given to the sensitivity and the specificity
of the test. To calculate the sensitivity and specificity of diagnostic
tests, we used this cutoff point. The sensitivity and specificity of
insulin resistance indexes were estimated as true-positive results/
(true-positive results
false-negative results) and true-negative
results/(true-negative results
false-positive results), respectively.
In a ROC curve, the true-positive rate (sensitivity) is plotted
as a function of the false-positive rate (1
specificity) for different
cutoff points. Each point on the ROC plot represents a sensitivity/
specificity pair corresponding to a particular decision threshold. A
test with perfect discrimination has a ROC plot that passes
through the upper left corner (100% sensitivity and 100% specificity).
Therefore, the closer the ROC plot is to the upper left
corner, the greater is the overall accuracy of the test.
17,18
RESULTS
The groups consisted of 25 obese children and
adolescents with insulin resistance (14 girls and 11
boys; mean age: 12.88
2.88 years; mean BMI: 31.29
5.86) and 32 subjects without insulin resistance (16
girls and 16 boys; mean age: 11.38
2.79 years; mean
BMI: 28.23
4.94) (Table 1). The mean fasting glucose
level was 82.67
9.23 mg/dL (range: 65-106
mg/dL), the mean fasting insulin level was 26.98
22.49 U/mL (range: 1.45-109.72 U/mL), and the
mean sum of insulin levels was 447.32
145.22
U/mL (range: 300.24-744.39 U/mL) for the group
with insulin resistance; the mean fasting glucose
level was 80.44
10.51 mg/dL (range: 61-105 mg/
dL), the mean fasting insulin level was 16.65
13.85
U/mL (range: 1.40-51.47 U/mL), and the mean
sum of insulin levels was 154.08
77.78 U/mL
(range: 24.86-275.00 U/mL) for the group without
insulin resistance (Table 1). There were significant
differences in the mean HOMA (6.06
4.98 and 3.42
3.14, P .05) and QUICKI (0.313 0.004 and 0.339
0.004, P .05), but not FGIR, values between the
2 groups (Table 2).
Sensitivity and specificity calculations were based
on insulin resistance with ROC analysis. Each point
on the ROC plot represents a sensitivity/specificity
pair corresponding to a particular decision threshold.
A test with perfect discrimination has a ROC
plot that passes through the upper left corner (100%
sensitivity and 100% specificity). The ROC plot for
TABLE 1.
Physical Characteristics of the Study Population
Obese Subjects With
Insulin Resistance*
Obese Subjects Without
Insulin Resistance
No. 25 32
Age, y 12.88
2.88 11.38 2.79
Gender, M/F 11/14 16/16
BMI, kg/m
2 31.29 5.86 28.23 4.94
Fasting glucose level, mg/dL 82.67
9.23 (65–106) 80.44 10.51 (61–105)
Fasting insulin level, U/mL 26.98
22.49 (1.45–109.72) 16.65 13.85 (1.40–51.47)
Sum of insulin levels, U/mL 447.32
145.22 (300.24–744.39) 154.08 77.78 (24.86–275.00)
Data are expressed as mean
SD (range).
* During OGTT, sum of insulin levels of
300 U/mL.
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HOMA is closer to the upper left corner, indicating
greater overall accuracy of the test (Fig 1). The optimal
HOMA value for diagnosis of insulin resistance
was established on a ROC scatter plot by determining
the optimal decision point from the ROC curve,
whereby equal weight is given to the sensitivity and
the specificity of the test. The sum of the sensitivity
and specificity values is highest at this point. To
calculate the sensitivity and specificity of diagnostic
tests, we used this cutoff point. HOMA had high
sensitivity and specificity for measuring insulin resistance.
The present HOMA cutoff point for diagnosis
of insulin resistance of 3.16 yielded a sensitivity
of 76% and a specificity of 66%.
DISCUSSION
This study demonstrates that HOMA has high sensitivity
and specificity for measuring insulin resistance.
Previous studies evaluated simple indexes for
assessing insulin sensitivity in a wide range of conditions
associated with insulin resistance. This study
was a unique presentation. HOMA, FGIR, and
QUICKI for measuring insulin resistance expressed
by OGTT results among obese children and adolescents
were compared by using sensitivity and specificity
calculations based on insulin resistance with
ROC analysis. ROC curves can be used to compare
the diagnostic performance of
2 laboratory or diagnostic
tests.
19
The FGIR was found to be a highly sensitive and
specific measure of insulin sensitivity.
11,20 The mean
FGIR value was
7 for the study group with insulin
resistance, as we expected, but the difference between
the 2 groups was not statistically significant
and the SD was large. One of the explanations for
interpreting the FGIR might be higher basal insulin
levels among obese pubertal children and adolescents,
and another might be emotional stress at the
time of the blood test.
11 Therefore, we designed statistical
analyses with ROC plots to compare the di
agnostic performance of diagnostic tests, and we
found that HOMA had high sensitivity and specificity
for measuring insulin resistance. We suggested
that misclassification as insulin resistance with the
HOMA was less.
The present study also demonstrated that the
HOMA cutoff point for diagnosis of insulin resistance
was 3.16. Insulin resistance was defined by
Reinehr et al
21 as a HOMA value of 4 for adolescents.
This point was determined to be 2.5 for
adults.
22
Insulin resistance is a state in which normal concentrations
of insulin produce a subnormal biologic
response. There has been considerable interest in the
childhood development of insulin resistance, hyperlipidemia,
ovarian hyperandrogenism, and early
markers of adult diseases such as type 2 diabetes
mellitus, hypertension, and cardiovascular disease.
Patients with insulin resistance have hyperinsulinemia
together with normoglycemia or hyperglycemia.
Insulin resistance is commonly associated with
obesity. The central role of insulin in the clustering of
some cardiovascular risk factors was first suggested
by reports of endogenous hyperinsulinemia and insulin
resistance in essential hypertension. Insulin is
the central regulator of glucose and lipid homeostasis.
Insulin decreased blood glucose concentrations
by reducing hepatic gluconeogenesis and glycogenolysis
and by enhancing glucose uptake into striated
muscles and adipocytes. Insulin also enhances triglyceride
(triacylglycerol) synthesis in liver and adipose
tissues, increases the breakdown of circulating
lipoproteins by stimulating lipoprotein lipase activ-
Fig 1.
ROC curves for indexes of insulin resistance.
TABLE 2.
Indexes of Insulin Resistance
Obese Subjects With
Insulin Resistance
Obese Subjects Without
Insulin Resistance
No. 25 32
FGIR 6.64
11.76 (0.72–59.59) 8.66 8.47 (1.67–47.14)
HOMA 6.06
4.98 (0.30–21.33)* 3.42 3.14 (0.23–12.70)*
QUICKI 0.313
0.004 (0.254–0.475)* 0.339 0.004 (0.270–0.509)*
Data are expressed as mean
SD (range).
* Significant at
P .05.
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502
HOMA RELIABILITY AMONG OBESE CHILDREN
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ity in adipose tissues, and suppresses lipolysis both
in adipose tissues and in muscles.
23,24
CONCLUSIONS
Obesity and type 2 diabetes are globally increasing
health problems for young people, with significant
individual and public health ramifications with respect
to associated morbidity and mortality rates.
1–4
A simpler tool such as HOMA is more appropriate
for large epidemiologic studies and is more reliable
than FGIR and QUICKI as a measure of insulin resistance
among children and adolescents. The use of
HOMA is simpler, cheaper, less labor-intensive, less
time-consuming, and more acceptable to young people
than clamp studies. This study also demonstrates
that the HOMA cutoff point for diagnosis of insulin
resistance is 3.16 for adolescents. The HOMA cutoff
point of
2.5 is valid for adults but not for adolescents.
Additional studies are needed to assess the
HOMA cutoff point for adolescents.
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