2009 Annual Report
1a.Objectives (from AD-416)
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.
1b.Approach (from AD-416)
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.
Significant progress has been made toward several of the objectives in this project, which examines broad metabolite patterns reflective of metabolic status in muscle in order to identify biomarkers of muscle fat combustion. This overarching aim is driven by the fact that poor insulin sensitivity and frank type 2 diabetes typically occur in the setting of reduced or inefficient muscle long chain fatty acid (LCFA) catabolism in mitochondria. In FY2009, the research team has published a significant paper outlining the finding that metabolite by-products of inefficient LCFA combustion (chain-shortened acylcarnitine moieties) are elevated in the plasma of type 2 diabetic African-American women. Most remarkably, follow-up studies have revealed that these acylcarnitines act as triggers for pro-inflammatory pathways implicated in driving insulin resistance. The work has led to successful grant funding for proof-of-principle work in this area, and a well-scored NIH grant application currently under review. In addition, a team member has established a metabolite screen of >50 oxylipid and endocannabinoid molecules, which have recently been applied to the plasma samples just discussed, and a collaborator has analyzed >200 metabolites in the samples. These results are currently being interpreted and prepared for publication. Next, clinical studies to test for the effects of muscle exercise and fitness on metabolite profiles (metabolomics) have been designed, standard operating procedures finalized, and diet design completed. These efforts poise the team to begin recruiting human subjects in FY2010. Finally, studies have been completed to determine unique metabolites effluxed from and changing within mitochondrial during active LCFA combustion. Those studies are under consideration at a peer-reviewed journal.