Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes
Kitt Falk Petersen1, Sylvie Dufour, Douglas Befroy
1Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
Insights
Insulin resistance in offspring of type 2 diabetes patients is linked to impaired muscle glucose uptake and increased muscle fat. This may stem from inherited mitochondrial defects affecting energy production.
Area of Science:
- Metabolic research
- Genetics of diabetes
- Mitochondrial function
Background:
- Insulin resistance predicts type 2 diabetes in offspring.
- The underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the mechanisms of insulin resistance in lean, young offspring of type 2 diabetes patients.
- To compare insulin sensitivity in liver and muscle between insulin-resistant offspring and controls.
Main Methods:
- Hyperinsulinemic-euglycemic clamp studies with isotopic tracers.
- Proton (1H) and Phosphorus-31 (31P) magnetic resonance spectroscopy.
- Assessment of lipolysis and mitochondrial oxidative phosphorylation.
Main Results:
- Insulin-resistant offspring had 60% lower muscle glucose uptake and 80% higher intramyocellular lipids.
- Mitochondrial dysfunction was indicated by a 30% reduction in mitochondrial phosphorylation.
- No significant differences in lipolysis or key inflammatory markers were observed.
Conclusions:
- Insulin resistance in skeletal muscle of offspring is associated with impaired fatty acid metabolism.
- An inherited defect in mitochondrial oxidative phosphorylation is a likely cause.
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.
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