Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes

N Engl J Med. 2004 Feb 12;350(7):664-71. doi: 10.1056/NEJMoa031314.


Background: Insulin resistance appears to be the best predictor of the development of diabetes in the children of patients with type 2 diabetes, but the mechanism responsible is unknown.

Methods: We performed hyperinsulinemic-euglycemic clamp studies in combination with infusions of [6,6-(2)H(2)]glucose in healthy, young, lean, insulin-resistant offspring of patients with type 2 diabetes and insulin-sensitive control subjects matched for age, height, weight, and physical activity to assess the sensitivity of liver and muscle to insulin. Proton ((1)H) magnetic resonance spectroscopy studies were performed to measure intramyocellular lipid and intrahepatic triglyceride content. Rates of whole-body and subcutaneous fat lipolysis were assessed by measuring the rates of [(2)H(5)]glycerol turnover in combination with microdialysis measurements of glycerol release from subcutaneous fat. We performed (31)P magnetic resonance spectroscopy studies to assess the rates of mitochondrial oxidative-phosphorylation activity in muscle.

Results: The insulin-stimulated rate of glucose uptake by muscle was approximately 60 percent lower in the insulin-resistant subjects than in the insulin-sensitive control subjects (P<0.001) and was associated with an increase of approximately 80 percent in the intramyocellular lipid content (P=0.005). This increase in intramyocellular lipid content was most likely attributable to mitochondrial dysfunction, as reflected by a reduction of approximately 30 percent in mitochondrial phosphorylation (P=0.01 for the comparison with controls), since there were no significant differences in systemic or localized rates of lipolysis or plasma concentrations of tumor necrosis factor alpha, interleukin-6, resistin, or adiponectin.

Conclusions: These data support the hypothesis that insulin resistance in the skeletal muscle of insulin-resistant offspring of patients with type 2 diabetes is associated with dysregulation of intramyocellular fatty acid metabolism, possibly because of an inherited defect in mitochondrial oxidative phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / biosynthesis
  • Adipose Tissue / metabolism
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / genetics*
  • Fatty Acids / metabolism*
  • Female
  • Glucose / biosynthesis
  • Glucose / metabolism
  • Glucose Clamp Technique
  • Glucose Tolerance Test
  • Glycerol / metabolism
  • Humans
  • Insulin / pharmacology
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Lipolysis / physiology*
  • Magnetic Resonance Spectroscopy
  • Male
  • Mitochondria / metabolism*
  • Muscle, Skeletal / metabolism*
  • Oxidative Phosphorylation*
  • Triglycerides / analysis


  • Blood Glucose
  • Fatty Acids
  • Insulin
  • Triglycerides
  • Adenosine Triphosphate
  • Glucose
  • Glycerol