Project Number: 5306-51530-016-09
Project Type: Reimbursable

Start Date: Jan 01, 2008
End Date: Dec 31, 2012

Objective:
Poor muscle fat combustion is a hallmark of reduced insulin sensitivity, pre-diabetes, and propensity toward development of type 2 diabetes mellitus. Identifying persons who display this phenotype, however, has been difficult and requires in-depth specialized and costly clinical evaluation (i.e., muscle biopsies, analysis of blood parameters across the muscle bed using dual catheterization). The lack of a facile, inexpensive technique to characterize muscle fat utilization hinders strategies to optimally apply nutritional and physical activity regimens to thwart insulin resistance and diabetes, since markers are unavailable to identify at-risk persons who may benefit most from said interventions, and to use in order to track efficacy of the interventions. Our objective is to identify blood metabolites or metabolite signatures reflective of skeletal muscle fat combustion, and to test whether said patterns shift in response to a diet and exercise regimen in overweight to obese persons.

Approach:
We will use unique organelle (mitochondria), cell, and animal models which display altered muscle fat utilization to derive biofluids that will be tested using state-of-the-art metabolomics technologies--these studies will identify specific metabolites or metabolite signatures reflective of fat combustion in this tissue. In addition, we will analyze the plasma of human subjects who display a disruptive genetic polymorphism in a muscle protein involved in mitochondrial fatty acid metabolism (UCP3) to assess whether metabolomic patterns differ from people without the polymorphism. Finally, we will evaluate whether overweight to obese persons with insulin resistance have plasma metabolite patterns reflective of poor muscle fat burning, and test whether a diet and exercise intervention strategy normalizes these patterns concurrent with improvements in insulin action. Documents Reimbursable with National Institute of Health. Log 34154.