Steroid Metabolomic Signature of Insulin Resistance in Childhood Obesity Diabetes Care 2020;43:405–410 | https://doi.org/10.2337/dc19-1189 OBJECTIVE On the basis of urinary steroidal gas chromatography-mass spectrometry (GC-MS), we previously defined a novel concept of a disease-specific “steroid metabolomic signature” and reclassified childhood obesity into five groups with distinctive signatures. The objective of the current study was to delineate the steroidal signature of insulin resistance (IR) in obese children. RESEARCH DESIGN AND METHODS Urinary samples of 87 children (44 girls) aged 8.5–17.9 years with obesity (BMI >97th percentile) were quantified for 31 steroid metabolites by GC-MS. Defined as HOMA- IR >95th percentile and fasting glucose-to-insulin ratio >0.3, IR was diagnosed in 20 (of 87 [23%]) of the examined patients. The steroidal fingerprints of subjects with IR were compared with those of obese children without IR (non-IR). The steroidal signature of IR was created from the product of IR 2 non-IR for each of the 31 steroids. RESULTS IR and non-IR groups of children had comparable mean age (13.7 6 1.9 and 14.6 6 2.4 years, respectively) and z score BMI (2.7 6 0.5 and 2.7 6 0.5, respectively). The steroidal signature of IR was characterized by high adrenal androgens, glucocorti- coids, and mineralocorticoid metabolites; higher 5a-reductase (An/Et) (P 5 0.007) and 21-hydroxylase [(THE 1 THF 1aTHF)/PT] activity (P 5 0.006); and lower 11bHSD1 [(THF 1aTHF)/THE] activity (P 5 0.012). CONCLUSIONS The steroidal metabolomic signature of IR in obese children is characterized by enhanced secretion of steroids from all three adrenal pathways. As only the fasciculata and reticularis are stimulated by ACTH, these findings suggest that IR directly affects the adrenals. We suggest a vicious cycle model, whereby gluco- corticoids induce IR, which could further stimulate steroidogenesis, even directly. We do not know whether obese children with IR and the new signature may benefit from amelioration of their hyperadrenalism. Nonsyndromic childhood obesity is associated with “insulin resistance (IR),” which denotes a decreased metabolic response to insulin at the cellular level or, at the whole-organism level, a diminished lowering effect of insulin on blood glucose (1). However, many individuals with obesity, mostly those with subcutaneous rather than visceral adipose tissue, seem to be protected from IR and adverse metabolic responses (2). Indeed, human omental adipocytes display an approximately twofold higher 1 Department of Pediatrics and Pediatric Endo- crinology, School of Medicine in Katowice, Med- ical University of Silesia, Upper Silesia Children’s Care Health Centre, Katowice, Poland 2 Bioinformatics Knowledge Unit, Lorry I. Lokey Interdisciplinary Center for Life Sciences and Engineering, Technion–Israel Institute of Tech- nology, Haifa, Israel 3 Steroid Research and Mass Spectrometry Unit, Division of Pediatric Endocrinology and Diabe- tology, Center of Child and Adolescent Medi- cine, Justus Liebig University Giessen, Giessen, Germany 4 Faculty of Medicine, Technion–Israel Institute of Technology, Haifa, Israel Corresponding author: Aneta M. Gawlik, agawlik@ mp.pl Received 16 June 2019 and accepted 24 October 2019 © 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More infor- mation is available at http://www.diabetesjournals .org/content/license. Aneta M. Gawlik, 1 Michael Shmoish, 2 Michaela F. Hartmann, 3 Stefan A. Wudy, 3 and Ze’ev Hochberg 4 Diabetes Care Volume 43, February 2020 405 PATHOPHYSIOLOGY/COMPLICATIONS Downloaded from http://diabetesjournals.org/care/article-pdf/43/2/405/531480/dc191189.pdf by guest on 07 September 2022