title: Adiposity in Children Born Small for Gestational Age Is Associated With β-Cell Function, Genetic Variants for Insulin Resistance, and Response to Growth Hormone Treatment.
abstract: BACKGROUND
  Genetic susceptibility to insulin resistance is associated with lower adiposity in adults. Insulin resistance, and therefore adiposity, may alter sensitivity to GH. We aimed to determine the relationship between adiposity, genetic susceptibility to insulin resistance or insulin secretion, and response to GH treatment in short children born small for gestational age (SGA).
  
  
  METHODS
  In 89 short prepubertal SGA children (age, 6.2 ± 1.6 y; 55 boys) treated with GH for 1 year in a multicenter study, body fat percentage was estimated at baseline and 1 year using dual-energy x-ray absorptiometry. The main outcome measures were treatment-related changes in height, IGF-1 standard deviation score, insulin sensitivity, insulin secretion, and disposition index. Combined multiallele gene scores based on single nucleotide polymorphisms with known associations with lower insulin sensitivity (gene scores for insulin resistance [GS-InRes]) and insulin secretion (gene scores for insulin secretion [GS-InSec]) were analyzed for their relationships with adiposity.
  
  
  RESULTS
  Mean percentage body fat at baseline was low compared to normative data (P = .045) and decreased even further on GH treatment (baseline vs 1-year z-scores, -0.26 ± 1.2 vs -1.23 ± 1.54; P < .0001). Baseline percentage body fat was positively associated with IGF-1 responses (p-trends = .042), first-year height gains (B [95% confidence interval], 0.61 cm/y [0.28,0.95]; P < .0001), insulin secretion at baseline (p-trends = .020) and 1 year (p-trends = .004), and disposition index at 1 year (p-trends = .024). GS-InRes was inversely associated with body mass index (-0.13 SD score per allele [-0.26, -0.01]; P = .040), body fat (-0.49% per allele [-0.97, -0.007]; P = .047), and limb fat (-0.81% per allele [-1.62, 0.00]; P = .049) at baseline. During GH treatment, GS-InRes was related to a lesser decline in trunk fat (0.38% per allele [0.16, 0.59]; P = .001) and a higher trunk-limb fat ratio at 1 year (0.04 per allele [0.01, 0.08]; P = .008). GS-InSec was positively associated with truncal fat (0.36% per allele [0.09, 0.63]; P = .009).
  
  
  CONCLUSIONS
  Adiposity in SGA children has favorable effects on GH sensitivity and glucose metabolism. The associations with multiallele scores support a causal role of insulin resistance in linking lesser body fat to reduced sensitivity to exogenous GH.
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Ajay
authors.initials: A
authors.lastname: Thankamony
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Rikke Beck
authors.initials: RB
authors.lastname: Jensen
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Susan M
authors.initials: SM
authors.lastname: O'Connell
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Felix
authors.initials: F
authors.lastname: Day
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Kirk
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Donaldson
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Sten A
authors.initials: SA
authors.lastname: Ivarsson
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Olle
authors.initials: O
authors.lastname: Söder
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Edna
authors.initials: E
authors.lastname: Roche
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Hilary
authors.initials: H
authors.lastname: Hoey
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Ken K
authors.initials: KK
authors.lastname: Ong
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: David B
authors.initials: DB
authors.lastname: Dunger
authors.affiliation: Department of Growth and Reproduction (A.T., R.B.J., A.J.), Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark; Department of Pediatrics (A.T., D.B.D.), and Medical Research Council Epidemiology Unit, Institute of Metabolic Science (F.D., K.K.O.), University of Cambridge, Cambridge CB2 0QQ, United Kingdom; Department of Endocrinology (J.K.), Birmingham Children's Hospital, Birmingham B4 6NH, United Kingdom; Department of Endocrinology (M.D.), Royal Hospital for Sick Children, Glasgow G51 4TF, United Kingdom; Department of Clinical Sciences (S.A.I.), Endocrine and Diabetes Unit, University of Lund, SE-205 02 Malmö, Sweden; Pediatric Endocrinology Unit (O.S.), Department of Women's and Children's Health, Karolinska Institutet and University Hospital, Stockholm 17177, Sweden; Department of Pediatrics (S.M.O., E.R., H.H.), The National Children's Hospital, University of Dublin, Trinity College, Dublin 2, Ireland.
authors.forename: Anders
authors.initials: A
authors.lastname: Juul
mesh_terms: D015502:Absorptiometry, Photon; D050154:Adiposity / Q000235:genetics*; D001823:Body Composition / Q000235:genetics; D001827:Body Height; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D019382:Human Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D050417:Insulin-Secreting Cells; D008297:Male; D010186:Pancreatic Function Tests; D011994:Recombinant Proteins / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D007328:Insulin; D011994:Recombinant Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D005947:Glucose