Over ninety percent of diabetics fall into the category of type 2 diabetes and while the primary factors causing this disease are unknown it is clear that insulin resistance plays a major role in its development. Furthermore insulin resistance is the best predictor for the later development of diabetes. Recent preliminary studies by our group have implicated increases in intramyocellular lipid content due to mitochondrial dysfunction as a major factor in causing insulin resistance in skeletal muscle of offspring of parents with type 2 diabetes (IR offspring). The overall goal of this project is to determine the rote of mitochondrial dysfunction in the pathogenesis of insulin resistance in IR offspring. This will be done using state-of-the-art magnetiq resonance spectroscopy in combination with GC-MS and LC/MS/MS techniques.
The specific aims that will be addressed in this patient oriented project are to: 1) Assess mitochondrial function by 13C/31P MRS in skeletal muscle of young lean insulin resistant offspring of parents with type 2 diabetic subjects and ageweight-activity-matched control subjects, 2) Assess mitochondrial density, insulin signaling, IRS-1 serine phosphorylation status, protein kinase Cbeta activation, IKKbeta activation, JNK1 activation, fatty acyl CoA concentrations in muscle biopsy samples obtained from young lean insulin resistant offspring of parents with type 2 diabetic subjects and age-weight-activity-matched control subjects, 3) Assess mitochondrial function by 13C/31P MRS in liver of young lean insulin resistant offspring of parents with type 2 diabetic subjects and age-weight-activity-matched control subjects, 4) Assess mitochondrial function by 13C/31P MRS in skeletal muscle of patients with hypertension and hyperlipidemia due to a novel homoplasmic mitochondrial tRNA/ile mutation (identified by R. Lifton) and age-weight-activity matched control subjects. It is anticipated that the results of these studies will yield new and important insights into the role of mitochondrial dysfunction and resultant dysregulation of intramyocellular fatty acid metabolism in the pathogenesis of insulin resistance in offspring of parents with type 2 diabetes. This information will enable the rational development of novel therapeutic agents to prevent or reverse this pathologic condition.
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