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Validation of Surrogate Models to Assess Tissue and Whole-Body Insulin Resistance in High-Risk Adolescent Girls
Danielle Xie1, 2, Anne-Marie Carreau2, Yesenia Garcia-Reyes2, Haseeb Rahat2, Kai Bartlette3, Cecilia D. Behn2, 3, Laura Pyle2, 4, K.J. Nadeau2, 5, Melanie Cree-Green2, 5. 1Biochemistry and Molecular Biology, Bryn Mawr College, Bryn Mawr, Pennsylvania, United States, 2Pediatric Endocrinology, CU Anschutz Medical Campus, Aurora, Colorado, United States, 3Applied Mathematics and Statistics, Colorado School of Mines, Golden, Colorado, United States, 4Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado, United States, 5Center for Women's Health Research, Aurora, Colorado, United States

Purpose of Study Multiple-tissue insulin resistance (IR) is common in adolescents with polycystic ovarian syndrome (PCOS), and a reliable means to quantify IR in this population is critical for new therapy development.The hyper-insulinemic euglycemic clamp is the gold-standard but is too intensive for use in routine research. We aimed to validate surrogate indices (oral minimal model (OMM) whole-body index and Abdul-Ghani muscle and liver indices) against their respective clamp measurements in high-IR-risk adolescent girls.
Methods Used 45 adolescent girls (14.6 ± 1.7 yrs; BMI %ile 23-98%) underwent a standard 2-hr oral glucose tolerance test (OGTT) (75g glucose) and a multi-phase hyper-insulinemic euglycemic clamp (10,16 and 80 mU/m2/min) with a glucose isotope tracer. OMM total Si was computed using SAAM II software, using 0, 15, 30, 60, 90, 120 min time points and the assumption that glucose appearance rate (Ra) decays exponentially after 120 min. Abdul-Ghani muscle and liver IR indices (IRIs) were calculated: liver IRI= AUC0-30minGlucose x AUC0-30minInsulin; muscle IRI= (dG/dt) / (mean insulin0-120min). Correlation analyses were performed using Spearman's or Pearson's correlation, as appropriate.
Summary of Results OMM total Si correlated with clamp-measured insulin sensitivity (glucose infusion rate, r=0.65; p<0.0001), whereas muscle IRI did not (p=0.45). Liver IRI correlated moderately with clamp-derived hepatic insulin sensitivity (insulin concentration required to suppress 50% of basal endogenous glucose production; r=0.35; p=0.03).
Conclusions In adolescent girls at high risk of IR, OMM offers an effective, OGTT-based methodology to be used in research studies for characterizing whole-body IR that is less resource-intensive compared to the clamp. Future work is needed to determine if the sensitivity of this model can be further improved with a longer-duration OGTT as obese youth can have an exaggerated and prolonged response to an OGTT.


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