title: Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids.
abstract: Hyperandrogenic syndrome (HAS) is associated with insulin resistance (IR) and type 2 diabetes. Muscle IR in type 2 diabetes is linked with defects in mitochondrial oxidative capacity. In vivo muscle mitochondrial function has not been studied in HAS, especially in youth, who are early in the disease process. Our goal was to measure muscle mitochondrial oxidative function and peripheral IR in obese youth with HAS. Obese girls without HAS [n = 22, age 15(13,17) yr, BMI Z-score 2.05 ± 0.37] and with HAS [n = 35, age 15(14,16) yr, BMI Z-score 2.18 ± 0.30] were enrolled. Mitochondrial function was assessed with (31)phosphorus MR spectroscopy before, during, and after near-maximal isometric calf exercise, and peripheral IR was assessed with an 80 mU·m(-2)·min(-1) hyperinsulinemic euglycemic clamp. Girls with HAS had higher androgens [free androgen index 7.9(6.6,15.5) vs. 3.5(3.0,4.0), P < 0.01] and more IR [glucose infusion rate 9.4(7.0, 12,2) vs. 14.5(13.2,15.8) mg·kg lean(-1)·min(-1), P < 0.01]. HAS girls also had increased markers of inflammation including CRP, platelets, and white blood cell count and higher serum free fatty acids during hyperinsulinemia. Mitochondrial oxidative phosphorylation was lower in HAS [0.11(0.06,0.19) vs. 0.18(0.12,0.23) mmol/s, P < 0.05], although other spectroscopy markers of mitochondrial function were similar between groups. In multivariate analysis of the entire cohort, IR related to androgens, oxidative phosphorylation, and free fatty acid concentrations during hyperinsulinemia. These relationships were present in just the HAS cohort as well. Obese girls with HAS have significant peripheral IR, which is related to elevated androgens and free fatty acids and decreased mitochondrial oxidative phosphorylation. These may provide future options as targets for therapeutic intervention.
authors.affiliation: Division of Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Center for Women's Health Research, Anschutz Medical Campus, Aurora, Colorado; Melanie.Green@childrenscolorado.org.
authors.forename: Melanie
authors.initials: M
authors.lastname: Cree-Green
authors.affiliation: Department of Clinical and Diagnostic Sciences, University of Alabama at Birmingham, Birmingham, Alabama;
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Newcomer
authors.affiliation: Division of Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Gregory
authors.initials: G
authors.lastname: Coe
authors.affiliation: Division of Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Lindsey
authors.initials: L
authors.lastname: Newnes
authors.affiliation: Division of Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Amy
authors.initials: A
authors.lastname: Baumgartner
authors.affiliation: Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Mark S
authors.initials: MS
authors.lastname: Brown
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, and Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado;
authors.forename: Laura
authors.initials: L
authors.lastname: Pyle
authors.affiliation: Division of Endocrinology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Department of Veteran Affairs, Denver, Colorado.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Reusch
authors.affiliation: Division of Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado; Center for Women's Health Research, Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Kristen J
authors.initials: KJ
authors.lastname: Nadeau
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003430:Cross-Sectional Studies; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D017588:Hyperandrogenism / Q000150:complications / Q000378:metabolism*; D006946:Hyperinsulinism / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D010085:Oxidative Phosphorylation; D063766:Pediatric Obesity / Q000150:complications / Q000378:metabolism*; D011085:Polycystic Ovary Syndrome / Q000150:complications / Q000378:metabolism*; D055815:Young Adult
chemical_list: D005230:Fatty Acids, Nonesterified
keywords: hyperandrogenic syndrome; hyperandrogenism; insulin resistance; mitochondria; obesity