Changes in the percentile value of the HOMA-IR value in adolescents in Korea are yet to be elucidated. This study found that the HOMA-IR peaked at age 12–14 years in boys and age 10–12 years in girls. Further, the age range by which the HOMA-IR value peaked was wider in overweight/obese adolescents than in normal-weight adolescents, and the patterns were similar between 2007–2010 and 2019–2020. Importantly, the percentile value of HOMA-IR significantly increased over time from 2007–2010 to 2019–2020. In the overweight/obesity group, both the mean and percentile values of HOMA-IR were significantly increased. In the normal-weight group, the mean HOMA-IR values were not significantly changed; however, although the subjects had normal weight, the 75th, 95th, and 97th percentile values increased for approximately one decade in both sexes. The increments were more significant during the peak HOMA-IR period. To the best of our knowledge this is the first large-scale study to examine whether the HOMA-IR values remain constant after a decade.
The HOMA-IR value of adolescents has several characteristics. First, it varies according to age, especially during puberty as physiological IR occurs during this stage [23, 31–34]. The physiological IR during puberty is caused by an increase in adiposity [35], and insulin sensitivity is decreased by approximately 25–30% [33] due to increasing sex steroid and GH/IGF-I levels [16, 17, 19, 22]. Moran et al. [34] reported that peak IR was related to the pubertal growth spurt. Second, the HOMA-IR values peak earlier in girls than in boys [13, 23] as puberty begins earlier in girls. Third, the HOMA-IR value of girls is higher than that of boys [13, 22, 24] as girls are more insulin resistant than are boys [34]. Consistent with previous studies [20, 21, 23, 31, 32, 34], the current study showed that the HOMA-IR values peaked at puberty, especially during the growth spurt period, and then decreased towards adulthood. The values reached peak levels earlier and were higher in girls than in boys although blood glucose levels were slightly higher in boys than in girls owing to the higher insulin levels in girls.
In addition, these characteristics of the HOMA-IR in adolescents are consistent in both the 2007–2010 and 2019–2020 datasets. These findings indicated that the normative values of HOMA-IR in adolescents should consider not only pubertal development, but also sex. This study provides sex-specific HOMA-IR values for each age and for three age groups according to HOMA-IR value patterns (10–12 years, 13–15 years, and 16–18 years in girls and 10–11 years, 12–14 years, and 15–18 years in boys). The data will be useful for distinguishing between physiologic IR and non-physiologic IR in adolescents and for properly interpreting HOMA-IR values.
The HOMA-IR is known to be strongly influenced by BMI [23, 24, 36–38], and thus, the modeling of percentile curves of the HOMA-IR values was obtained by separating the subjects into normal-weight and overweight/obese groups in this study. As IR is strongly associated with obesity [23, 36–38], and leptin is correlated with IR [22], HOMA-IR values are naturally higher in overweight/obese individuals than in normal-weight individuals [23]. In this study, the means and distributions of HOMA-IR values were also significantly higher in the overweight/obese group than in normal-weight group across all ages and sexes. In addition, although the age range of peak HOMA-IR value was longer and more fluctuated, physiologic IR was also found in the overweight/obese group.
This might be because of the physiologic IR in the normal-weight and non-physiologic IR in the overweight/obese group. The characteristics of HOMA-IR in obese adolescents have also been reported in previous studies [22, 34, 39]. Physiologic IR during puberty is not correlated with changes in BMI and is also present in obese adolescents [22, 34]. Although the relationship between HOMA-IR and BMI is much weaker in children than in adults [39] and adiposity attenuates sex differences in IR, IR remains more common in girls than in boys [22, 34]. Therefore, the value of HOMA-IR should be interpreted according to pubertal stage and sex not only in normal-weight adolescents, but also in those who are overweight/obese.
However, the percentile value of HOMA-IR changed within one decade in both the normal-weight and overweight/obese groups in the current study. The incidence of obesity is increasing [28, 29]. In this study, the rates of overweight/obesity rates also increased within a 10-year period. In addition, the mean weight, BMI, and BMI z-score were all increased in the overweight/obese group. Therefore, the mean and percentile value of HOMA-IR were also increased. This indicated that not only the overweight/obesity rate, but also the severity of adiposity and the risk of metabolic diseases have increased. Furthermore, even in normal-weight adolescents, the 95th and 97th percentile values of HOMA-IR were increased across the decade despite the mean HOMA-IR values showing no significant change.
In addition, this increment occurred during the physiologic IR period, that is, from the beginning to the end of the growth spurt period. This is because the fasting blood glucose was higher in both sexes, and the mean weight, BMI, and BMI z-score were also higher in in 2019–2020 than in 2007–2010 in boys even in the normal-weight group. Importantly, this indicates that the severity of adiposity and the risk of metabolic diseases have increased even in normal-weight adolescents. Therefore, even normal-weight adolescents need active evaluation and intervention during the growth spurt period as they are particularly vulnerable to IR during this period.
The strength of the present investigation is the large sample size, wide age range, and evaluation within a decade. Given that this study is based on large-scale nationwide data, the results can be generalizable to Korean adolescents, and there is no selection bias. Additionally, unlike previous studies, this study compares HOMA-IR trends over longer period of 10 years.
This study also has some limitations. First, although the KNHANES is a large cross-sectional study that includes a high number of subjects, it is only limited to Koreans, and thus, further studies that include other races are needed. Second, there is a difference in the numbers of subjects between the 2007–2010 dataset and the 2019–2020 dataset, and this can affect the statistical analysis. However, we conducted a weighted statistical method. Third, glucose and insulin measurement methods differed by year. Glucose measurement devices were different in 2007, 2008–2010, and 2019–2020. In addition, insulin concentrations were measured using a 1470 WIZARD gamma-counter in 2007–2010 and using a modular E801 in 2019–2020. Insulin values may have differed according to the measurement method. Finally, the influence of puberty on HOMA-IR values was not accurately measured as the KNHANES did not include individual Tanner stages.
In conclusion, HOMA-IR values vary by age, sex, and BMI categories in Korean adolescents, and thus, these factors should be considered in the clinical interpretation of HOMA-IR values. The mean and percentile value of HOMA-IR have been increasing within the past 10 years with the increase in overweight/obesity. In addition, the 75th, 90th, 95th, and 97th percentile values of HOMA-IR are also increased even in normal-weight adolescents. As such, active intervention for IR is needed during the growth spurt period.