To the Editor:
We appreciate the commentary by Arisaka et al and agree that there is a need to clarify relationships between insulin resistance and body mass index (BMI) in “early maturers.” Although Arisaka et al mention the importance of clarifying these relationships specifically in terms of sex differences, we believe it is equally important to consider race/ethnicity differences as well. Indeed, numerous studies have shown that insulin resistance differs by race/ethnicity. For example, Haffner et al found that nondiabetic non-Hispanic Blacks (NHBs) and Hispanics have increased insulin resistance and higher acute insulin response compared with nondiabetic non-Hispanic whites (NHWs).1 Danielson et al similarly showed that among youth with type 1 diabetes, age-adjusted estimated glucose disposal rate (eGDR; lower eGDR indicates greater insulin resistance) was significantly lower among NHBs and Hispanics compared with NHWs.2 Therefore, in addition to further clarifying these relationships in terms of sex differences, race/ethnicity differences also must be accounted for in such analyses.3,4
Arisaka et al also draw attention to important studies showing that insulin resistance increases from pubertal onset to midpuberty in both sexes,5,6 concluding that “early maturers” have increased insulin resistance, even in those without overweight or obesity based on BMI-adjusted pubertal maturation. However, we believe that this still requires further exploration. In the cross-sectional study by Moran et al of youth from all stages of puberty (Tanner stage 1–5) who underwent euglycemic clamps as a marker for insulin resistance, it was found that insulin resistance significantly increases at Tanner stages 2–4 (with a peak at stage 3) and then decreases to near prepubertal levels by Tanner stage 5. However, in this study, Tanner stage in boys was determined by pubic hair development, which could falsely elevate pubertal status in children with premature adrenarche, and only NHBs and NHWs were evaluated.5,7 A longitudinal study by Hannon et al of normal-weight youth who underwent the euglycemic hyperinsulinemic clamp technique at 2 different timepoints (prepuberty and puberty) found that insulin resistance increased by 50% during puberty compared with prepubertal measures, and that this change was independent of changes in percent body fat.6 However, that study comprised only 9 youths (8 NHWs and 1 NHB), and follow-up clamp was only performed once at various pubertal stages (girls, between Tanner stages 4 and 5; boys, between Tanner stages 3 and 5).
Importantly, although the above studies show that insulin resistance increases during puberty and appears to differ by pubertal stage, they do not specifically show that “early maturers” have increased insulin resistance, nor do they show how important “early maturity” is to the development of insulin resistance compared with the contribution from overweight/obesity and/or adiposity. Consider, for example, an 8-year-old normal-weight “early maturing” female with Tanner stage 2 pubertal development. Given that insulin resistance rises during puberty, it could be expected that this individual would have increased insulin resistance compared with a normal-weight “on-time maturing” 8-year-old Tanner 1 female. Indeed, Sorensen et al found higher insulin levels in girls with central precocious puberty compared with healthy controls after adjusting for age, bone age, and breast development.8 However, our 8-year-old female undergoing early puberty is also expected to complete puberty earlier compared with an “on-time maturer.” Thus, it is possible that by age 12 years, the “early maturer” may have already completed puberty and have decreased insulin resistance compared with the 12-year-old “on-time maturer” who is still in puberty.
Furthermore, using the foregoing example, we do not yet know how a normal-weight 8-year-old undergoing “early maturity” will compare to an 8-year-old “on-time maturer” with overweight/obesity in terms of insulin resistance. Studies have shown that the relationship between early pubertal development and insulin resistance is mediated via adiposity and weight status.9–11 In addition, body composition also may impact the age of pubertal onset, at least in girls, and also must be considered.12
To begin answering the above questions, future larger-scale studies examining insulin resistance measures in youth of various races/ethnicities over a spectrum of pubertal stages (as measured by Marshall–Tanner criteria examining breast and pubic hair development for girls and genitalia and pubic hair for boys13,14), body composition, and weight status (including underweight, normal weight, and overweight/obesity) are needed. This would allow for the determination of associations between pubertal development and insulin resistance while adjusting for BMI, which could help determine the degree to which “early maturation” contributes to insulin resistance compared with overweight/obesity status.
Acknowledgments
E.B. is a site principal investigator for Novo Nordisk. B.M. is a consultant for AbbVie, Ascendis, BioMarin, Bluebird Bio, Endo Pharmaceuticals, Novo Nordisk, Pfizer, Sandoz, Sanofi Genzyme, Tolmar, and Vertice and has received research support from Alexion, AbbVie, Amgen, Ascendis, BioMarin, Novo Nordisk, Opko, Protalix, Sandoz, Sangamo, Sanofi Genzyme, and Takeda. K.S. receives research support from the Federal Food and Drug Administration, National Cancer Institute, National Science Foundation, Spruce Biosciences, Alexion, and Neurocrine.
Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award K23DK125668. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Contributor Information
Eric Morris Bomberg, Center for Pediatric Obesity Medicine, Department of Pediatrics, University of Minnesota Medical School; Division of Endocrinology, Department of Pediatrics, University of Minnesota Masonic Children’s Hospital, Minneapolis, Minnesota.
Oppong Yaw Addo, Department of Global Health, Rollins School of Emory University, Atlanta, Georgia.
Kyriakie Sarafoglou, Division of Endocrinology, Department of Pediatrics, University of Minnesota Masonic Children’s Hospital; Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy, Minneapolis, Minnesota.
Bradley Scott Miller, Division of Endocrinology, Department of Pediatrics, University of Minnesota Masonic Children’s Hospital, Minneapolis, Minnesota.
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