Abstract
Background:
As a result of the rising prevalence of childhood obesity, there is an increasing interest in the type 2 diabetes mellitus precursor insulin resistance (IR). The aim of this study is to review definitions (methods and cutoff values) to define IR in children and to apply these definitions to a previously described obese pediatric population.
Methods:
A systematic literature review on prevalence and/or incidence rates in children was performed. The extracted definitions were applied to an obese pediatric population.
Results:
In the 103 identified articles, 146 IR definitions were reported based on 14 different methods. Fasted definitions were used 137 times, whereas oral/intravenous glucose tolerance test-derived methods were used nine times. The homeostasis model for the assessment of insulin resistance (HOMA-IR) and fasted plasma insulin (FPI) were the most frequently used fasted methods (83 and 37 times, respectively). A wide range in cutoff values to define IR was observed, resulting in prevalence rates in the predefined obese pediatric population between 5.5% (FPI>30 mU/L) and 72.3% (insulin sensitivity indexMatsuda≤7.2).
Conclusions:
To compare IR incidence and prevalence rates in pediatric populations, a uniform definition of IR should be defined.
Introduction
As the prevalence of childhood obesity and consequently type 2 diabetes mellitus (T2DM) is rising [1], [2], [3], there is an increasing interest in insulin resistance (IR) as a well-known precursor and risk factor for T2DM [4], [5], [6], [7]. The recognition of IR in (obese) children and adolescents at risk for T2DM is important in order to implement preventive measures for T2DM, since T2DM causes major health care costs and burden for the patient [8], [9], [10], [11]. Early prevention by recognizing IR is therefore important.
The gold standard to determine IR is the euglycemic–hyperinsulinemic clamp study [12], [13]. The euglycemic–hyperinsulinemic clamp study measures the glucose uptake, while the subject receives exogenous insulin, resulting in a hyperinsulinemic state. Subjects who are sensitive for insulin will require higher amount of glucose infusion than subjects who are less sensitive for insulin (insulin resistant) to remain euglycemic. This technique requires infusion of both insulin and glucose and frequent blood sampling to control the hyperinsulinemic and euglycemic state, which is a large burden for the patients. Moreover, expertise in managing the glucose and insulin infusions is essential in order to guarantee patients safety and reliable test results. Because of this invasive and time-consuming character, the euglycemic–hyperinsulinemic clamp study is not standard of care in pediatric patients [13].
As alternatives, many less invasive methods have been developed to establish IR in daily clinical practice [14], [15], [16], [17]. These methods vary in terms of parameters that are needed to calculate IR and in invasiveness. Some methods are based on measurements in fasted blood samples, whereas others require measurements derived from an oral glucose tolerance test (OGTT), which is used in daily practice or a (frequently sampled) intravenous glucose tolerance test [(FS)IVGTT], which is not suitable for daily practice. Most frequently used methods based on fasted blood samples are the homeostasis model for the assessment of insulin resistance (HOMA-IR), the quantitative insulin-sensitivity check index (QUICKI), and the fasted glucose/insulin ratio (FGIR). The use of fasted plasma insulin (FPI) as measure for IR has been described frequently as well [18]. Most often used methods based on OGTT or (FS)IVGTT are the Insulin sensitivity indexes of Cederholm, Belfiore, or Stumvoll (based on OGTT) or the minimal model analysis of frequently sampled intravenous glucose tolerance test [13], [19].
However, there seems no consensus yet on which method and cutoff value is the preferable one [12], [18], [20]. Therefore, all methods are being used concurrently, which impedes comparison of incidence and prevalence rates of IR between populations and countries and to study these rates over time. Therefore, the aim of this study is to review the different methods and definitions of IR as used to estimate prevalence rates of IR in pediatric populations. First, we present an overview of the definitions and cutoff values used to determine IR in publications describing the prevalence of IR in children and adolescents. Secondly, to illustrate the impact of the definition on the prevalence of IR, we calculated the prevalence of IR using the different definitions in a previously described population of obese children and adolescents from a pediatric obesity outpatient clinic [21].
Materials and methods
Systematic review of definitions of IR
A systematic review of available literature in The Cochrane library, PubMed, and Embase was performed in December 2014. The search strategy is displayed in Appendix 1. After importing the results into Refworks (www.refworks.com) and removing duplicates, abstracts were screened for title and abstract. The exclusion criteria were language (other than English, French, German, Spanish, or Dutch); review articles; study population >19 years of age; and the lack of reporting on the prevalence of IR in the aim or results part of the abstract. Publications were checked for full text availability. Conference abstracts without a full text publication were excluded, as well as articles not clearly describing a definition for IR. From the articles that fulfilled the criteria, methods defining IR (including mathematical formula), parameters used in the method and the used cutoff values were extracted.
Application of reported definitions to a previously described population of obese children
The definitions reported in the above-described publications were applied to a previously reported population of 311 obese children and adolescents from a pediatric obesity outpatient clinic [21]. As part of standard of care, all these children underwent an OGTT. Data were collected retrospectively. Collected data were anthropometric measurements, fasted plasma glucose (FPG), FPI, and 2-h plasma glucose measured during an OGTT. A detailed description of the data collection is provided in a previously published study [21]. The characteristics of the population of obese children are displayed in Table 1.
Characteristics of the population of obese children visiting a pediatric obesity outpatient clinic between January 2006 and December 2009 (n=311) [21].
| Mean | Range | |
|---|---|---|
| Age | 10.83 (3.20) | 2.4–17.7 |
| Male, % | 50.5 | – |
| Height, cm | 149.4 (18.5) | 90.5–185.8 |
| Weight, kg | 66.7 (25.9) | 20.7–153.9 |
| BMI, kg/m2 | 28.71 (5.23) | 20.24–47.83 |
| BMI-SDS | 2.93 (0.49) | 2.31–5.52 |
| FPG, mmol/L | 5.0 (0.5) | 3.4–8.6 |
| FPI, μU/L | 12.7 (10.0) | 2–61 |
| 2 h-PG, mmol/L | 6.4 (1.5) | 3.3–20.3 |
| T2DM, n, % | 5 (1.6) | – |
BMI, body mass index; BMI-SDS, body mass index standard deviation score.
If the same cutoff values were reported in different studies as less or greater than (< or >) and less or greater than or equal to (≤ or ≥), we only calculated the prevalence of IR with the definition using less or greater than (< or >).
Data analysis
IBM-SPSS version 21.0 was used to calculate IR according to the different definitions and to calculate the percentage of the population being insulin resistant according to the different definitions.
Results
Searching the three databases yielded 4.596 unique results. Screening of title and abstract led to exclusion of 4430 articles. Of the remaining 166 articles, 103 articles could be included for data extraction (Figure 1). Study characteristics of all included studies are summarized in Supplemental Data, Table 1.
Flowchart of literature search.
Methods to determine IR
Table 2 gives an overview of the reported methods to determine IR extracted from the 103 articles. These articles were reporting on 146 definitions. Fasted definitions were used 137 times, whereas OGTT/IVGTT-derived methods were used nine times.
Overview of reported methods and range of used cutoff values to determine IR in children.
| Method | Parameters | Formula | Range of used cutoff values | Number of studies using methoda |
|---|---|---|---|---|
| Based on fasted samples | ||||
| HOMA-IR | FPG, FPI | (FPG (mmol/L)*FPI (mU/L))/22.5 | >1.14–5.56 | 83 |
| FPI | FPI | NA | 7.34–30 mU/L | 37 |
| QUICKI | FPG, FPI | 1/[log (FPI (mU/mL))+log (FPG (mg/dL))] | 0.300–0.360 | 9 |
| FGIR | FPG, FPI | (FPG [mg/dL]/FPI [mIU/L]) | <6–7 | 4 |
| HOMA2 | FPG, FPI | Computer model: HOMA2-calculator: http://www.dtu.ox.ac.uk/homa | >1.53–2 | 2 |
| McAuley-index | FPI, triglycerides | (2.63−0.28 ln[FPI]−0.31 ln[fasted triglycerides]) | ≤6.3 | 1 |
| C-peptide | C-peptide | NA | ≥4.4 ng/mL | 1 |
| Based OGTT/IVGTT derived samples | ||||
| Insulin during OGTT | Insulin at 120′ | NA | >45-75 mU/L | 2 |
| OGIS | Glucose at 0′, 90′, and 120′ Insulin at 0′ and 90′ | Webcalculator: http://webmet.pd.cnr.it/ogis/ogis.php | <400–436 | 2 |
| Maximum insulin during OGTT | Insulin max | NA | >150 mU/L | 1 |
| ISIMatsuda | FPG, FPI, glucose and insulin during OGTT at 30′, 60′, 90′, and 120′ | 10.000/√((FPG (mg/dL)×FPI (µU/mL)×(Mean OGTT glucose (mg/dL)×Mean OGTT insulin (mU/L)) | ≤7.2 | 1 |
| Si(IVGTT) | Glucose and insulin during IVGTT at −5′, −1′, 2′, 4′, 8′, 10′, 19′, 22′, 30′, 40′, 50′, 60′, 70′, 90′, 180′ and 240′ | Computerized model, using the program MINMOD [22] | 4.5×104 μU/mL/min | 1 |
| IRIBelfiore [17] | Glucose and insulin during OGTT at 0′, 60′ and 120′ | 2/[[1/(GLYpxINSp)]+1] | >1.27 | 1 |
| ∑ insulin during OGTT | Insulin during OGTT at 0′, 30′, 60′, 90′, and 120′ | Insulin0+insulin30+insulin60+insulin90+insulin120 | >300 μU/mL | 1 |
aSome studies used more than one definition. FGIR, fasted glucose to insulin ratio; FPG, fasted plasma glucose; FPI, fasted plasma insulin; HOMA(-IR), homeostasis model assessment (for insulin resistance); IRI, insulin resistance index; ISI, insulin sensitivity index; NA, not applicable; OGIS, oral glucose insulin sensitivity; OGTT, oral glucose tolerance test; Si(IVGTT), insulin sensitivity from intravenous glucose tolerance test; and QUICKI, quantitative insulin-sensitivity check index.
Overall, we identified 14 methods to determine IR. Seven (50%) methods are based on parameters derived exclusively from fasted blood samples, the other seven use parameters of fasted blood samples combined with parameters obtained from an OGTT or IVGTT. Out of the fasted methods, HOMA-IR and FPI were the most frequently used methods to determine IR: these were reported 83 and 37 times, respectively. The other five fasted methods were each used one to nine times, and the seven OGTT/IVGTT-based methods were used one or two times.
FPI was used as parameter in 11 out of 14 methods. In two methods, the insulin concentration derived from the OGTT was used; one definition defined IR based on the insulin value after 120 min and the other method used the maximum concentration during the OGTT. The only method not using insulin was the definition based on C-peptide (Table 2).
Cutoff values
Table 2 provides for each of the methods to determine IR, the range in reported cutoff values. For the fasted methods, typically wide ranges in cutoff values were observed: for the commonly used method HOMA-IR, cutoff values ranged from 1.14 to 5.56. The same was observed for FPI with cutoff values ranging from 7.34 to 30 mU/L. In the less frequently used OGTT-derived methods, a wide range in cutoff values was reported as well: for insulin at 120 min during the OGTT this range varied between 45 and 75 mU/L (Table 2).
In addition, some studies used separate cutoff values for boys and girls, for example for HOMA-IR 2.28 and 2.67, respectively, and for prepubertal and pubertal children, for example QUICKI <0.33 for prepubertal and <0.36 for pubertal children.
Application of definitions for IR to a population of obese children and adolescents
Figure 2 shows the results of the application of the different definitions to the available clinical data of a population of 311 obese children and adolescents from our pediatric obesity outpatient clinic [21].
Prevalence of IR in a pediatric population visiting an obesity outpatient clinic (n=311) using different methods and cutoff values of IR.
FGIR, fasted glucose to insulin ratio; FPI, fasted plasma insulin; HOMA(-IR), homeostasis model assessment (for insulin resistance); ISI, insulin sensitivity index; OGIS, oral glucose insulin sensitivity; OGTT, oral glucose tolerance test; QUICKI, quantitative insulin-sensitivity check index. *Age-specific cutoff values for HOA-IR: 2–5 year >1.14; 5.1–10 year >1.67; 10.1–15 year >2.53; 15.1–19 year >2.52.
All fasted methods except C-peptide could be applied as well as prevalence rates based on different cutoff values per pubertal stage. For the OGTT/IVGTT-based methods, results of Si(IVGTT)and IRIBelfiore could not be presented from the available data.
Comparing the prevalence rates of definitions based on fasted blood samples only, the lowest prevalence was 5.5% (FPI>30 mU/L) and the highest prevalence was 64.0% (FPI>7.34 mU/L). For the definitions based on OGTT/IVGTT-derived values, the lowest prevalence was 18.8%, based on oralglucoseinsulin sensitivity (OGIS)<400, and the highest prevalence was 72.3% (ISIMatsuda≤7.2).
For the HOMA-IR and the QUICKI, the range in prevalence due to the variation in cutoff values was 10.0%–62.0% and 10.9%–65%, respectively. For FPI, this range was even wider: 5.5%–64.0%. For the OGTT-derived definition based on insulin at 120′, the prevalence rates were 34.5%–63.2%.
Discussion
The current review of the pediatric literature shows that many different methods and cutoff values are used to determine IR in children and adolescents. The impact of these different definitions on prevalence rates is demonstrated by applying the various definitions to a given dataset of obese children and adolescents, which resulted in a wide range of prevalence rates (i.e. 5.5%–72.3%). This finding emphasizes the need for a standard definition to be able to compare incidence and prevalence rates of IR between populations and countries and particularly to study these rates over time.
The gold standard test for IR is the euglycemic–hyperinsulinemic clamp. However, this test is not useful for screening purposes in clinical practice because of the expertise needed to perform the test on one hand, and the invasive and time-consuming character of the test, resulting in high burden for the patient on the other hand. As a result, the euglycemic–hyperinsulinemic clamp is only used in experimental settings. Due to the invasive character of the gold standard test for IR, many surrogate methods have been developed. Different studies have been performed to determine the correlations of the methods with the euglycemic–hyperinsulinemic clamp. However, most of these studies were performed in adults, and few of them in pediatric populations. In pediatric populations, the methods based on fasted blood samples, i.e. HOMA-IR, QUICKI, and FGIR, have moderate to strong correlations with IR assessed with the euglycemic–hyperinsulinemic clamp, respectively, 0.51–0.81, 0.43–0.91, and 0.25–0.92 [6], [12], [13], [23], [24], [25]. For the OGTT-derived methods, the ISIMatsuda index has a moderate to good correlation as well (0.74–0.78). No data are available for the correlation between the euglycemic–hyperinsulinenic clamp and the IRIBelfioreindex in pediatric populations [13]. Since all indices have moderate to good correlations, this criterion does not distinguish in which method would be the best to use.
The optimal test to define IR in children and adolescents should be in our opinion minimally invasive and pose a minimal burden to the child, in order to be widely applicable in the growing population of obese children and adolescents. Therefore, methods based on fasted blood samples have an advantage over methods using blood samples obtained during an OGTT or IVGTT. Although an OGTT or IVGTT is less invasive than the euglycemic–hyperinsulinemic clamp, repetitive vena punctures or a venous cannula over 120 min are necessary for collecting blood samples, while fasted methods only require one vena puncture to collect the blood sample.
Another criterion for the preferred method is the reproducibility. The test has to be reliable in repeated measurements, as it will be used for the follow-up of children with IR. As described previously, many studies in pediatric populations focus on the correlation of surrogate methods with a gold standard test; unfortunately, they do not describe the reproducibility. The available data for reproducibility for the methods to determine IR are from adult studies. Henriquez et al. studied in 78 adults without T2DM the reproducibility of HOMA-IR, QUICKI, and FPI. Fasted blood samples were taken twice from each participant within 30 min on the same day. This resulted in a coefficient of variation (CV) for HOMA-IR of 11.8% (7.8–11.9), for QUICKI 1.8% (1.1–2.9), and for FPI 13.4% (8.8–21.9) [26]. The low CV reported for the QUICKI was however debated by Antuna et al. because this measure is composed of log transformed values of FPG and FPI [27]. When the CV of log transformed, HOMA-IR values are compared to the CV of the QUICKI, similar, low CV’s were found for both measures. Since all of these formulas are based on the same measurements of glucose and insulin, the CV is not discriminating between HOMA-IR and QUICKI either.
Finally, the method should preferably be easy to use in daily clinical practice. HOMA-IR is easier to calculate than QUICKI because the QUICKI uses log-transformed glucose and insulin values (Table 2), even though in this era of apps this may be debated. While there seems not much difference between the HOMA-IR and the QUICKI, we propose to use the HOMA-IR because its ease of use and because our study shows that HOMA-IR is already the most frequently used method to determine IR in pediatric study populations.
In addition to the different methods described, we observed a wide range in cutoff values within the different methods. This wide range of cutoff values leads to a large variation in the prevalence of IR even when one method (e.g. HOMA-IR) is used (Figure 2). The definition of a cutoff value for IR with clinical relevance to identify children and adolescents at risk for T2DM will help the clinician to select the patients who require lifestyle intervention to prevent or delay the onset of T2DM.
In this study, more than 25 cutoff values for HOMA-IR have been described, and still it is not clear which cutoff value is the best to define IR. To date, studies are available on the use of HOMA-IR as screening measure to identify children and adolescents with impaired glucose tolerance and T2DM during an OGTT. To identify T2DM in a population of obese children and adolescents, Shah et al. reported a HOMA-IR value of 7.9 as the best critical value with a sensitivity of 62% and specificity of 70%. Unfortunately, they did not report on the best value to identify impaired glucose tolerance in their study population [28]. The study of Brar et al. who studied the optimal threshold for impaired glucose tolerance or T2DM, identified a cutoff value of 3.4 in a population of obese pediatric patients [29]. This cutoff value resulted in a sensitivity of 72.2% (46.4–89.3) and a specificity of 60.7% (50.8%–69.9%) for impaired glucose tolerance or T2DM during an OGTT. Other cutoff values studied were 2.7, 3.1, and 4.0, resulting in lower sensitivity and specificity [29]. In a study from our own group in overweight and obese children, screening with FPG and HOMA-IR of 3.4 identified all cases of T2DM and up to 64% of cases of impaired glucose tolerance [21]. The use of HOMA-IR with cutoff value of 3.4 resulted in sensitivity of 70% and specificity 72.6%, with a positive predictive value of 21.4% and a negative predictive value of 95.7%. However, to properly define the cutoff value for the HOMA-IR and use it as a screening measure in obese children to predict impaired glucose tolerance and T2DM in the future, longitudinal epidemiological studies of a cohort of obese children and adolescents should be performed, with regular checks of their insulin sensitivity state and glucose metabolism including an eventual diagnosis of T2DM. Future studies should also focus on the need for age, sex, and pubertal stage-specific cutoff values, since studies providing data on HOMA-IR in large study populations, found differences in IR values for different age, sex, and Tanner stages [30], [31]. In our opinion, until further evidence becomes available, the lowest reported HOMA-IR value from the above-reported studies (i.e. 3.4) improving detection of T2DM in obese children and adolescents could be used as additional screening measure. This screening should be used in addition to the ADA recommended 3-yearly screening with FPG [32].
To our best knowledge, our report is the first to show the large variety in prevalence rates of IR in a given obese pediatric population caused by the heterogeneity of the different definitions. A strength of our study is the availability of data from a previously described population of 311 obese children and adolescents, who underwent an OGTT for clinical reasons. We were able to calculate all fasted methods except C-peptide. As C-peptide has been described to be a measure of insulin secretion and is produced in equal amounts along with insulin, it is possible to use it as a measure for endogenous insulin production. Especially in patients using exogenous insulin, C-peptide was reported useful to establish endogenous insulin production [33]. In order to define IR in a nondiabetic population, we think that C-peptide does not have any advantage over insulin. Moreover, from the OGTT/IVGTT based methods, we were not able to calculate Si(IVGTT) and IRIBelfiore. Finally, a comparison with the gold standard method was not possible, as we do not use the euglycemic–hyperinsulinemic clamptest as part of standard of care in our clinic.
Conclusions
In conclusion, we reported in this study all published methods and cut offvalues used to define IR in pediatric populations. When these definitions were applied to a known population of 311 obese children and adolescents, a large variety of prevalence rates of IR was found. As a result, we conclude that a uniform definition for IR is needed to allow comparison between studies and populations and to be able to follow trends in incidence and prevalence rates over time. Longitudinal, epidemiological studies are necessary to investigate which level of IR is clinically relevant and will help the clinician to select the patients who require lifestyle intervention to prevent or delay the development of T2DM.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. M.A. performed the literature review and data analysis and wrote a first version of the manuscript. All authors discussed study design, data, and interpreted the results. C.K., A.B., and M.V. reviewed and edited the manuscript. All authors take full responsibility for the contents of the manuscript, M.V. is the guarantor of this work.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
Appendix
Search strategies of literature search.
| Database | Search strategy |
|---|---|
| Pubmed | ((“Insulin Resistance”[Mesh] OR insulin resistan*[tiab] OR insulin sensitivity[tiab] OR (resistan*[tiab] AND insulin*[tiab]) OR metabolic syndr*[tiab]) AND (“Prevalence”[Mesh] OR prevalence*[tiab] OR “Incidence”[Mesh] OR incidence*[tiab]) AND (“Child”[Mesh:noexp] OR “Adolescent”[Mesh] OR “Puberty”[Mesh:noexp] OR “Minors”[Mesh] OR Pediatrics[MeSH:noexp] OR child[tiab] OR children[tiab] OR child care[tiab] OR childhood[tiab] OR child*[tiab] OR childc*[tiab] or childr*[tiab] OR childh*[tiab] OR adoles*[tiab] OR boy[tiab] OR boys[tiab] OR boyhood[tiab] OR girl[tiab] OR girls[tiab] OR girlhood[tiab] OR junior*[tiab] OR juvenile*[tiab] OR kid[tiab] OR kids[tiab] OR minors*[tiab] OR paediatr*[tiab] OR pediatr*[tiab] OR prepubert*[tiab] OR pre-pubert*[tiab] OR prepubesc*[tiab] OR pubert*[tiab] OR pubesc*[tiab] OR school age*[tiab] OR schoolchild*[tiab] OR teen[tiab] OR teens[tiab] OR teenage*[tiab] OR youngster*[tiab] OR youth[tiab] OR youths* OR Primary school*[tiab] OR Secondary school*[tiab] OR Elementary school*[tiab] OR High school*[tiab] OR Highschool*[tiab]) |
| Embase | (prevalence/ or incidence/ or (prevalence* or incidence*).ti,ab.) AND (insulin resistance/ or insulin sensitivity/ or metabolic syndrome X/ or (resistan* and insulin*).ti,ab. or insulin sensitivity.ti,ab. or metabolic syndr*.ti,ab.) AND (child/ or boy/ or girl/ or hospitalized child/ or school child/ or exp adolescent/ or adolescence/ or puberty/ or pediatrics/ or (child or children or child care or childhood or child* or childc* or childr* or childh* or adoles* or boy or boys or boyhood or girl or girls or girlhood or junior* or juvenile* or kid or kids or minors* or paediatr* or pediatr* or prepubert* or pre-pubert* or prepubesc* or pubert* or pubesc* or school age* or schoolchild* or teen or teens or teenage* or youngster* or youth).ti,ab. or youths*.ti,ab. or Primary school*.ti,ab. or Secondary school*.ti,ab. or Elementary school*.ti,ab. or High school*.ti,ab. or Highschool*.ti,ab.) |
| Cochrane | ((prevalence* or incidence*) and ((resistan* and insulin*) or insulin sensitivity or metabolic syndr*) and (child or children or child care or childhood or child* or childc* or childr* or childh* or adoles* or boy or boys or boyhood or girl or girls or girlhood or junior* or juvenile* or kid or kids or minors* or paediatr* or pediatr* or prepubert* or pre-pubert* or prepubesc* or pubert* or pubesc* or school age* or schoolchild* or teen or teens or teenage* or youngster* or youth or youths* or Primary school* or Secondary school* or Elementary school* or High school* or Highschool*)).ti,ab. |
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