The lean, insulin-resistant offspring of patients with type 2 diabetes had severe insulin resistance, as compared with insulin-sensitive control subjects matched for age, height, weight, and activity. The difference could be attributed largely to a reduction of approximately 70 percent in insulin-stimulated nonoxidative muscle glucose metabolism. Using 1
H magnetic resonance spectroscopy to measure intramyocellular lipid content, we found that insulin resistance in muscle was accompanied by an increase of approximately 80 percent in intramyocellular lipid content in the insulin-resistant subjects, as compared with the insulin-sensitive control subjects. These data are consistent with those of previous studies in humans7-9
which have suggested that dysregulated intramuscular fatty acid metabolism has an important causative role in insulin resistance and may have a similar role in fat-induced insulin resistance in the skeletal muscle of the insulin-resistant offspring of patients with type 2 diabetes.
To assess whether the increase in intramyocellular lipid content in the insulin-resistant subjects was due to increased delivery of fatty acids to the muscle, we measured whole-body and localized rates of lipolysis. Rates of whole-body lipolysis were similar in the control subjects and the insulin-resistant subjects during the basal state and were both suppressed to a similar degree during the hyperinsulinemic–euglycemic clamp study. In a manner consistent with this finding, we found that the extent of insulin-induced suppression of the localized rates of lipolysis in subcutaneous fat, as assessed by microdialysis, was also similar in both groups. Taken together, these data suggest that insulin resistance was confined largely to skeletal muscle and that increased basal rates of peripheral lipolysis and defects in insulin-induced suppression of lipolysis do not have a major role in causing the increased intramyocellular lipid content in the insulin-resistant subjects.
To assess whether decreased mitochondrial activity may contribute to the increased intramyocellular lipid content, we also assessed the rates of muscle mitochondrial phosphorylation using 31
P magnetic resonance spectroscopy. We found that the mitochondrial rates of ATP production were reduced by approximately 30 percent in the muscle of the insulin-resistant subjects, as compared with the insulin-sensitive control subjects. Consistent with this finding of altered mitochondrial function, we also found a reduced ratio of inorganic phosphate to phosphocreatine, which may reflect a lower ratio of type I fibers (mostly oxidative) to type II fibers (mostly glycolytic) in the insulin-resistant subjects.29,30
This finding is consistent with those of a biopsy study by Nyholm et al., who found an increased number of type IIb muscle fibers in overweight, insulin-resistant, first-degree relatives of patients with type 2 diabetes.33
Taken together, these data suggest that the insulin-resistant offspring of patients with type 2 diabetes have an inherited reduction in mitochondrial content in muscle, which in turn may be responsible for the reduced rates of mitochondrial oxidative phosphorylation.
Several studies have also implicated a number of novel adipocyte-derived factors in mediating insulin resistance in patients with obesity and in those with type 2 diabetes.17,18,34-37
To address the potential role of resistin, tumor necrosis factor α
, interleukin-6, and adiponectin in mediating insulin resistance in our insulin-resistant subjects, we measured the plasma concentrations of these factors and found no significant differences between the two groups. These data suggest that alterations in plasma concentrations of these adipocyte-derived factors do not have a major role in mediating insulin resistance in these persons.
We assessed systemic and localized rates of lipolysis, plasma concentrations of adipocyte-derived factors, and mitochondrial phosphorylation activity in muscle of healthy, young, lean, normoglycemic, insulin-resistant offspring of patients with type 2 diabetes. Taken together, our results support the hypothesis that insulin resistance in these young people is due to dysregulation of intramyocellular fatty acid metabolism, which may be caused by an inherited defect in mitochondrial oxidative phosphorylation. Such a defect might be due to a reduction in mitochondrial content, which in turn might be attributable to a reduced ratio of type I to type II muscle fibers. These results are similar to those in lean, elderly, insulin-resistant subjects, whose insulin resistance, in contrast to that in insulin-resistant off-spring, is most likely attributable to acquired defects in mitochondrial biogenesis, which lead to reductions in skeletal-muscle mitochondrial content.38
Furthermore, since mitochondria have a critical role in mediating glucose-induced insulin secretion,39
the presence of similar inherited defects in beta-cell mitochondrial function or content, in the setting of peripheral insulin resistance, might explain the increased incidence of diabetes in the insulin-resistant offspring of patients with type 2 diabetes.5
In this regard it is of interest that a common Gly482Ser polymorphism of the peroxisome-proliferator–activated receptor γ
coactivator 1, a transcriptional regulator of genes responsible for mitochondrial biogenesis and fat oxidation,40
has been linked to an increased relative risk of type 2 diabetes in Danish populations41
as well as to altered lipid oxidation and insulin secretion in Pima Indians.42
These data also identify mitochondrial oxidative phosphorylation as a potential target for the prevention and treatment of type 2 diabetes. In addition, two recent studies involving DNA-microarray analysis suggest that there is a coordinated reduction in the expression of genes encoding peroxi-some-proliferator–activated receptor γ
, which are involved in oxidative phosphorylation, in the skeletal muscle of overweight patients with type 2 diabetes,43
obese Mexican-American patients with type 2 diabetes,44
and overweight nondiabetic subjects with a family history of diabetes.44