title: Mitochondrial dysfunction in patients with primary congenital insulin resistance.
abstract: Mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes. It has thus been suggested that primary and/or genetic abnormalities in mitochondrial function may lead to accumulation of toxic lipid species in muscle and elsewhere, impairing insulin action on glucose metabolism. Alternatively, however, defects in insulin signaling may be primary events that result in mitochondrial dysfunction, or there may be a bidirectional relationship between these phenomena. To investigate this, we examined mitochondrial function in patients with genetic defects in insulin receptor (INSR) signaling. We found that phosphocreatine recovery after exercise, a measure of skeletal muscle mitochondrial function in vivo, was significantly slowed in patients with INSR mutations compared with that in healthy age-, fitness-, and BMI-matched controls. These findings suggest that defective insulin signaling may promote mitochondrial dysfunction. Furthermore, consistent with previous studies of mouse models of mitochondrial dysfunction, basal and sleeping metabolic rates were both significantly increased in genetically insulin-resistant patients, perhaps because mitochondrial dysfunction necessitates increased nutrient oxidation in order to maintain cellular energy levels.
authors.affiliation: Wolfson Brain Imaging Centre, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Alison
authors.initials: A
authors.lastname: Sleigh
authors.forename: Philippa
authors.initials: P
authors.lastname: Raymond-Barker
authors.forename: Kerrie
authors.initials: K
authors.lastname: Thackray
authors.forename: David
authors.initials: D
authors.lastname: Porter
authors.forename: Mensud
authors.initials: M
authors.lastname: Hatunic
authors.forename: Alessandra
authors.initials: A
authors.lastname: Vottero
authors.forename: Christine
authors.initials: C
authors.lastname: Burren
authors.forename: Catherine
authors.initials: C
authors.lastname: Mitchell
authors.forename: Martin
authors.initials: M
authors.lastname: McIntyre
authors.forename: Soren
authors.initials: S
authors.lastname: Brage
authors.forename: T Adrian
authors.initials: TA
authors.lastname: Carpenter
authors.forename: Peter R
authors.initials: PR
authors.lastname: Murgatroyd
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Brindle
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Kemp
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Robert K
authors.initials: RK
authors.lastname: Semple
authors.forename: David B
authors.initials: DB
authors.lastname: Savage
mesh_terms: D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000473:pathology; D000328:Adult; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001481:Basal Metabolism / Q000502:physiology*; D016022:Case-Control Studies; D005080:Exercise Test; D005215:Fasting / Q000097:blood; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D006946:Hyperinsulinism / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008931:Mitochondria, Muscle / Q000502:physiology*; D020125:Mutation, Missense; D010101:Oxygen Consumption; D010725:Phosphocreatine / Q000378:metabolism; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D057185:Sedentary Behavior; D012890:Sleep / Q000502:physiology
chemical_list: D052242:Adiponectin; D015703:Antigens, CD; D006442:Glycated Hemoglobin; D007328:Insulin; D010725:Phosphocreatine; D011972:Receptor, Insulin; C499918:ADIPOQ protein, human; C435941:INSR protein, human