title: Differential Response to High Glucose in Skin Fibroblasts of Monozygotic Twins Discordant for Type 1 Diabetes.
abstract: BACKGROUND
  Most epigenetic studies in diabetes compare normal cells in "high glucose" (HG) to cells in "normal glucose" (NG) and cells returned from HG to NG. Here we challenge this approach.
  
  
  OBJECTIVE
  The objective was to determine whether there were differences in gene expression in skin fibroblasts of monozygotic twins (MZT) discordant for type 1 diabetes (T1D).
  
  
  METHODS
  Skin fibroblasts were grown in NG (5.5 mmol/L) and HG (25 mmol/L) for multiple passages.
  
  
  METHODS
  This study was conducted at the University of Minnesota.
  
  
  METHODS
  Patients were nine MZT pairs discordant for T1D.
  
  
  METHODS
  Gene expression was assessed by mRNA-Seq, using the Illumina HiSeq 2000 instrument. Pathway analysis tested directionally consistent group differences within the Kyoto Encyclopedia of Genes and Genomes pathways.
  
  
  RESULTS
  A total of 3308 genes were differentially expressed between NG and HG in T1D MZT vs 889 in non-T1D twins. DNA replication, proteasome, cell cycle, base excision repair, homologous recombination, pyrimidine metabolism, and spliceosome pathways had overrepresented genes with increased expression in T1D twins with P values ranging from 7.21 × 10(-10) to 1.39 × 10(-4). In a companion article, we demonstrate that these pathway changes are related to diabetic nephropathy risk. There were no pathways statistically significant differently expressed in nondiabetic twins in HG vs NG.
  
  
  CONCLUSIONS
  In vivo exposure to diabetes alters cells in a manner that markedly changes their in vitro responses to HG. These results highlight the importance of using cells directly derived from diabetic patients for studies examining the effects of HG in diabetes.
authors.affiliation: Departments of Medicine and Pediatrics (M.L.C., M.M.) and Pediatrics and Laboratory Medicine and Pathology (Y.K.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Diabetes Complications, Obesity and Metabolism (R.N.), Beckman Research Institute, City of Hope, Duarte, California 91010; Department of Genetics (J.H.M.), Dartmouth College, Hanover, New Hampshire 03755; Departments of Public Health Sciences (S.S.R.) and Bioinformatics and Genetics (J.C.M.), University of Virginia, Charlottesville, Virginia 22908; and Department of Genetics, Cell Biology and Development (R.K., D.K.), University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: M Luiza
authors.initials: ML
authors.lastname: Caramori
authors.affiliation: Departments of Medicine and Pediatrics (M.L.C., M.M.) and Pediatrics and Laboratory Medicine and Pathology (Y.K.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Diabetes Complications, Obesity and Metabolism (R.N.), Beckman Research Institute, City of Hope, Duarte, California 91010; Department of Genetics (J.H.M.), Dartmouth College, Hanover, New Hampshire 03755; Departments of Public Health Sciences (S.S.R.) and Bioinformatics and Genetics (J.C.M.), University of Virginia, Charlottesville, Virginia 22908; and Department of Genetics, Cell Biology and Development (R.K., D.K.), University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Youngki
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Departments of Medicine and Pediatrics (M.L.C., M.M.) and Pediatrics and Laboratory Medicine and Pathology (Y.K.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Diabetes Complications, Obesity and Metabolism (R.N.), Beckman Research Institute, City of Hope, Duarte, California 91010; Department of Genetics (J.H.M.), Dartmouth College, Hanover, New Hampshire 03755; Departments of Public Health Sciences (S.S.R.) and Bioinformatics and Genetics (J.C.M.), University of Virginia, Charlottesville, Virginia 22908; and Department of Genetics, Cell Biology and Development (R.K., D.K.), University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
authors.affiliation: Departments of Medicine and Pediatrics (M.L.C., M.M.) and Pediatrics and Laboratory Medicine and Pathology (Y.K.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Diabetes Complications, Obesity and Metabolism (R.N.), Beckman Research Institute, City of Hope, Duarte, California 91010; Department of Genetics (J.H.M.), Dartmouth College, Hanover, New Hampshire 03755; Departments of Public Health Sciences (S.S.R.) and Bioinformatics and Genetics (J.C.M.), University of Virginia, Charlottesville, Virginia 22908; and Department of Genetics, Cell Biology and Development (R.K., D.K.), University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Moore
authors.affiliation: Departments of Medicine and Pediatrics (M.L.C., M.M.) and Pediatrics and Laboratory Medicine and Pathology (Y.K.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Diabetes Complications, Obesity and Metabolism (R.N.), Beckman Research Institute, City of Hope, Duarte, California 91010; Department of Genetics (J.H.M.), Dartmouth College, Hanover, New Hampshire 03755; Departments of Public Health Sciences (S.S.R.) and Bioinformatics and Genetics (J.C.M.), University of Virginia, Charlottesville, Virginia 22908; and Department of Genetics, Cell Biology and Development (R.K., D.K.), University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Departments of Medicine and Pediatrics (M.L.C., M.M.) and Pediatrics and Laboratory Medicine and Pathology (Y.K.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Diabetes Complications, Obesity and Metabolism (R.N.), Beckman Research Institute, City of Hope, Duarte, California 91010; Department of Genetics (J.H.M.), Dartmouth College, Hanover, New Hampshire 03755; Departments of Public Health Sciences (S.S.R.) and Bioinformatics and Genetics (J.C.M.), University of Virginia, Charlottesville, Virginia 22908; and Department of Genetics, Cell Biology and Development (R.K., D.K.), University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.affiliation: Departments of Medicine and Pediatrics (M.L.C., M.M.) and Pediatrics and Laboratory Medicine and Pathology (Y.K.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Diabetes Complications, Obesity and Metabolism (R.N.), Beckman Research Institute, City of Hope, Duarte, California 91010; Department of Genetics (J.H.M.), Dartmouth College, Hanover, New Hampshire 03755; Departments of Public Health Sciences (S.S.R.) and Bioinformatics and Genetics (J.C.M.), University of Virginia, Charlottesville, Virginia 22908; and Department of Genetics, Cell Biology and Development (R.K., D.K.), University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Kuriyama
authors.affiliation: Departments of Medicine and Pediatrics (M.L.C., M.M.) and Pediatrics and Laboratory Medicine and Pathology (Y.K.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Diabetes Complications, Obesity and Metabolism (R.N.), Beckman Research Institute, City of Hope, Duarte, California 91010; Department of Genetics (J.H.M.), Dartmouth College, Hanover, New Hampshire 03755; Departments of Public Health Sciences (S.S.R.) and Bioinformatics and Genetics (J.C.M.), University of Virginia, Charlottesville, Virginia 22908; and Department of Genetics, Cell Biology and Development (R.K., D.K.), University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: David
authors.initials: D
authors.lastname: Kirkpatrick
authors.affiliation: Departments of Medicine and Pediatrics (M.L.C., M.M.) and Pediatrics and Laboratory Medicine and Pathology (Y.K.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Diabetes Complications, Obesity and Metabolism (R.N.), Beckman Research Institute, City of Hope, Duarte, California 91010; Department of Genetics (J.H.M.), Dartmouth College, Hanover, New Hampshire 03755; Departments of Public Health Sciences (S.S.R.) and Bioinformatics and Genetics (J.C.M.), University of Virginia, Charlottesville, Virginia 22908; and Department of Genetics, Cell Biology and Development (R.K., D.K.), University of Minnesota, Minneapolis, Minnesota 55455.
authors.forename: Michael
authors.initials: M
authors.lastname: Mauer
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000235:genetics*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D008875:Middle Aged; D061251:Primary Cell Culture; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D014430:Twins, Monozygotic
chemical_list: D001786:Blood Glucose