Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents

J Clin Invest. 2005 Dec;115(12):3587-93. doi: 10.1172/JCI25151. Epub 2005 Nov 10.


To further explore the nature of the mitochondrial dysfunction and insulin resistance that occur in the muscle of young, lean, normoglycemic, insulin-resistant offspring of parents with type 2 diabetes (IR offspring), we measured mitochondrial content by electron microscopy and insulin signaling in muscle biopsy samples obtained from these individuals before and during a hyperinsulinemic-euglycemic clamp. The rate of insulin-stimulated muscle glucose uptake was approximately 60% lower in the IR offspring than the control subjects and was associated with an approximately 60% increase in the intramyocellular lipid content as assessed by H magnetic resonance spectroscopy. Muscle mitochondrial density was 38% lower in the IR offspring. These changes were associated with a 50% increase in IRS-1 Ser312 and IRS-1 Ser636 phosphorylation and an approximately 60% reduction in insulin-stimulated Akt activation in the IR offspring. These data provide new insights into the earliest defects that may be responsible for the development of type 2 diabetes and support the hypothesis that reductions in mitochondrial content result in decreased mitochondrial function, which predisposes IR offspring to intramyocellular lipid accumulation, which in turn activates a serine kinase cascade that leads to defects in insulin signaling and action in muscle.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biopsy
  • Blood Glucose / metabolism
  • Blotting, Western
  • Body Mass Index
  • Body Weight
  • DNA, Mitochondrial / metabolism
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism*
  • Family Health
  • Female
  • Gene Expression Regulation
  • Glucose Clamp Technique
  • Glucose Tolerance Test
  • Humans
  • Hyperinsulinism
  • Immunoprecipitation
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance*
  • Lipids / chemistry
  • Male
  • Microscopy, Electron
  • Microscopy, Electron, Transmission
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Muscles / pathology
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serine / chemistry*
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic
  • Triglycerides / metabolism


  • Blood Glucose
  • DNA, Mitochondrial
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Lipids
  • Phosphoproteins
  • RNA, Messenger
  • Triglycerides
  • Serine
  • Protein-Serine-Threonine Kinases