Mitochondrial dysfunction in patients with primary congenital insulin resistance

Alison Sleigh, Philippa Raymond-Barker, Kerrie Thackray, David Porter, Mensud Hatunic, Alessandra Vottero, Christine Burren, Catherine Mitchell, Martin McIntyre, Soren Brage, T Adrian Carpenter, Peter R Murgatroyd, Kevin M Brindle, Graham J Kemp, Stephen O'Rahilly, Robert K Semple, David B Savage

Research output: Contribution to journalArticle (Academic Journal)peer-review

72 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2457-61
Number of pages5
JournalJournal of Clinical Investigation
Volume121
Issue number6
DOIs
Publication statusPublished - Jun 2011

Keywords

  • Adiponectin
  • Adipose Tissue
  • Adult
  • Antigens, CD
  • Basal Metabolism
  • Case-Control Studies
  • Exercise Test
  • Fasting
  • Female
  • Hemoglobin A, Glycosylated
  • Humans
  • Hyperinsulinism
  • Insulin
  • Insulin Resistance
  • Male
  • Mitochondria, Muscle
  • Mutation, Missense
  • Oxygen Consumption
  • Phosphocreatine
  • Point Mutation
  • Protein Structure, Tertiary
  • Receptor, Insulin
  • Sedentary Lifestyle
  • Sleep
  • Journal Article
  • Research Support, Non-U.S. Gov't

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