During Thursday morning’s plenary session, Christopher B. Newgard, PhD, demonstrated how the study of metabolomics could translate into therapies for conditions such as diabetes.
His talk, “Metabolomics for the Clinician: Implications for the Treatment of Metabolic Diseases,” showed attendees how exploring data from multiple disciplines, including genomics, epigenetics, and proteomics can shed light on the biological mechanisms of disease.
Dr. Newgard, who is Director of the Duke Molecular Physiology Institute at Duke University Medical Center, Durham, North Carolina, said his goal for his lecture mirrored the goal of the institute, which is to use integrated “multi-omics” and physiologic profiles of chronic human diseases to develop disease detection strategies, novel therapies, and insights into disease mechanisms.
He likened the study of metabolomics to the end of a funnel — it is the point where all data from upstream can be found.
After describing how his lab uses such tools as mass spectrometry to collect data, Dr. Newgard reviewed a number of studies — giving particular focus to branched-chain amino acids and their related metabolites.
Starting in 2007, Dr. Newgard and Laura Svetkey, MD, MHS, conducted a study comparing data from obese subjects to lean controls.
“As we looked at the results, we realized what we saw was a signature of the pathway of branched-chain amino acid catabolism…” Dr. Newgard said. “The surprising thing was that among the principal components that we identified in this study, it was not the fatty acid-related principal components that were most strongly associated with insulin sensitivity, but rather the branched-chain amino acids and related metabolites.”
This led to a series of clinical studies during the next several years.
In addition to showing that branched-chain amino acids and their related metabolites are strongly associated with insulin resistance and type 2 diabetes, research has also shown they are prognostic for the development of type 2 diabetes as well as interventional outcomes, he said.
Further studies have subsequently shown branched-chain amino acids and their related metabolites are causally linked to insulin resistance and respond well to the most efficacious intervention methods, including gastric bypass surgery, Dr. Newgard said.
He reviewed results from a 2016 study in Molecular Metabolism that looked at the effects of restricting branched-chain amino acids in Zucker obese rats.
“I can say that BCAA restriction enhances insulin sensitivity, and it enhances glucose disposal,” Dr. Newgard said. “So to this issue of cause and effect, there does seem to be a cause-and-effect relationship between the branched-chain amino acids, insulin sensitivity, and glucose disposal.”
In addition, the study showed BCAA restriction also relieved accumulation of excess acyl-CoAs in skeletal muscle, normalized muscle glycine levels, increased excretion of acylglycine metabolites in urine, and increased fat oxidation.