title: First-degree relatives of type 2 diabetic patients have reduced expression of genes involved in fatty acid metabolism in skeletal muscle.
abstract: BACKGROUND
  First-degree relatives of patients with type 2 diabetes (FH+) have been shown to have decreased energy expenditure and decreased expression of mitochondrial genes in skeletal muscle. In previous studies, it has been difficult to distinguish whether mitochondrial dysfunction and differential regulation of genes are primary (genetic) or due to reduced physical activity, obesity, or other correlated factors.
  
  
  OBJECTIVE
  The aim of this study was to investigate whether mitochondrial dysfunction is a primary defect or results from an altered metabolic state.
  
  
  METHODS
  We compared gene expression in skeletal muscle from 24 male subjects with FH and 26 without FH matched for age, glucose tolerance, VO(2peak) (peak oxygen uptake), and body mass index using microarrays. Additionally, type fiber composition, mitochondrial DNA content, and citrate synthase activity were measured. The results were followed up in an additional cohort with measurements of in vivo metabolism.
  
  
  RESULTS
  FH+ vs. FH- subjects showed reduced expression of mitochondrial genes (P = 2.75 × 10(-6)), particularly genes involved in fatty acid metabolism (P = 4.08 × 10(-7)), despite similar mitochondrial DNA content. Strikingly, a 70% reduced expression of the monoamine oxidase A (MAOA) gene was found in FH+ vs. FH- individuals (P = 0.0009). Down-regulation of the genes involved in fat metabolism was associated with decreased in vivo fat oxidation and increased glucose oxidation examined in an additional cohort of elderly men.
  
  
  CONCLUSIONS
  These results suggest that genetically altered fatty acid metabolism predisposes to type 2 diabetes and propose a role for catecholamine-metabolizing enzymes like MAOA in the regulation of energy metabolism.
authors.affiliation: Department of Clinical Sciences, Clinical Research Center, Malmö University Hospital, Lund University, 20502 Malmö, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Elgzyri
authors.forename: H
authors.initials: H
authors.lastname: Parikh
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Dekker Nitert
authors.forename: T
authors.initials: T
authors.lastname: Rönn
authors.forename: Å B
authors.initials: ÅB
authors.lastname: Segerström
authors.forename: C
authors.initials: C
authors.lastname: Ling
authors.forename: P W
authors.initials: PW
authors.lastname: Franks
authors.forename: P
authors.initials: P
authors.lastname: Wollmer
authors.forename: K F
authors.initials: KF
authors.lastname: Eriksson
authors.forename: L
authors.initials: L
authors.lastname: Groop
authors.forename: O
authors.initials: O
authors.lastname: Hansson
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D005190:Family; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D005796:Genes / Q000502:physiology; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology
chemical_list: D005227:Fatty Acids