A flowchart summarizing the literature search and screening results is shown in
Figure 1. A total of 1360 abstracts were screened for inclusion in the study. Of these abstracts, 424 were excluded because they were not in the pediatric population or did not use HOMA to assess insulin resistance. The remaining 936 full-text articles were obtained and assessed for eligibility. Of these articles, 298 met the criteria for inclusion in the final analysis. Thirty-four studies were excluded at the full-text screening stage because they included patients older than 18 years, 5 were excluded because they were review articles or letters to the editor, and 9 were excluded because they used HOMA to classify patients as having metabolic syndrome. The remaining 590 articles were excluded because they measured HOMA in children but did not use a cutoff to define insulin resistance. Examples included comparing HOMA in different populations, tracking changes in response to an intervention, and correlating HOMA to other factors, such as body mass index.
24-26
Among the 298 studies included in this review, 51 different HOMA cutoff values ranging from 0.77 to 6.3 were used to classify patients as having insulin resistance (
Figure 2). The most frequently used values were 3.16 and 2.5. Forty-three studies (14.4%) used a percentile cutoff specific to the study population. Of the 255 studies (85.6%) that used a predetermined fixed cutoff to define insulin resistance, 72 (28.2%) provided a reference that supported the use of that cutoff in the population. Forty-eight studies (18.8%) provided no reference for their cutoff values, and 62 (24.3%) cited a study that was irrelevant (did not discuss HOMA). Twenty-three articles (9%) cited a study that used the same cutoff value but did not validate it. In addition, 50 studies (19.6%) cited a reference for the HOMA cutoff that clearly did not support the use of that cutoff in their study population (
Figure 3). For example, several studies cited the 1985 study by Matthews et al
6 to support the 2.5 cutoff for defining insulin resistance. This study
6 had a small population size, receiver operating characteristic (ROC) curves were not generated, and the authors did not propose 2.5 as a cutoff for diagnosing insulin resistance. That number seems to reflect the study's finding that the median HOMA score for an overnight basal sample was 2.5 in the 6 adult diabetic participants compared with 1.3 in the 6 nondiabetic participants.
6
The most commonly cited reference for the 3.16 cutoff was Keskin et al.
13 This study compared HOMA to OGTT in 57 pubertal obese children and adolescents. The ROC analysis completed in that study identified 3.16 as the most appropriate cutoff in this population. However, numerous studies cited this article as support for using 3.16 in prepubertal populations despite the fact that insulin resistance is known to increase naturally during puberty.
10,11 The most commonly cited references for the 2.5 cutoff were Valerio et al
27 in 2006, Madeira et al
28 in 2008, and Matthews et al.
6 As described above, the study by Matthews et al
6 did not validate the use of 2.5 as a cutoff value in either adult or pediatric populations. The study by Valerio et al
27 reported the prevalence of insulin resistance in a population of obese children and adolescents in southern Italy. In that study, 2.5 was used as a cutoff for defining insulin resistance in children, and 4.0 was used as a cutoff for adolescents, citing a 2004 study by D'Annunzio et al.
29 Although the authors were contacted, we have been unable to obtain this article. However, an abstract
30 presentation and a later article by the same group
31 reveal the likelihood that these numbers were based on percentiles of HOMA according to Tanner stage in a population of about 100 healthy children. The study by Madeira et al
28 used data from overweight prepubertal children to identify HOMA cutoff values for predicting metabolic syndrome. Although metabolic syndrome and insulin resistance are related, they are not equivalent. Using this study to validate the 2.5 cutoff for diagnosing insulin resistance is not appropriate. Other studies that attempted to establish HOMA cutoffs for identifying metabolic syndrome or assessing cardiovascular risk were also cited by some groups as evidence to support their use in diagnosing insulin resistance.
32,33