2011 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.
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 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 of an NIH-NIDDK grant. In addition, the laboratory of an ARS scientist at Davis, CA, has established a metabolite screen of >50 oxylipid and endocannabinoid molecules, which have recently been applied to the plasma samples just discussed and a manuscript is currently being prepared. An additional paper related to global metabolite patterns in these subjects was published in FY2011 in PLoS One, with UC Davis collaborators. Recruitment and testing of pre-diabetic women at the WHNRC (13 to date) has taken place for studies of plasma metabolite signatures associated with exercise and improvements in fitness and insulin sensitivity and the clinical aspects of the studies are considered complete.