The fundamental goal of the laboratory is to investigate mechanisms of metabolic regulation and fuel homeostasis in mammalian systems. Major projects include: 1) Mechanisms involved in regulation of insulin secretion from pancreatic islet β-cells by glucose and other metabolic fuels; 2) Pathways that control islet cell replication and survival; 3) Studies on the role of branched-chain amino acids in pathogenesis of cardiometabolic diseases.
Our work on the mechanisms of glucose-stimulated insulin secretion (GSIS) has used differentially glucose-responsive insulinoma cell lines created in our laboratory (1), in which we applied NMR-based metabolic flux analysis to demonstrate that GSIS is tightly correlated to pyruvate anaplerosis and cycling activity rather than pyruvate oxidation (2). We subsequently used mass spectrometry-based metabolomics tools resident at DMPI to demonstrate that a pyruvate/isocitrate/glutathione pathway is a potent regulator of GSIS, and that intermediates in this novel pathway are able to rescue function in glucose unresponsive islets from humans with type 2 diabetes (3, 4). In addition, DMPI metabolomics tools were used to identify a novel insulin secretagogue (S-AMP) derived from glucose-induced purine biosynthesis, which also rescues function in islets from humans with type 2 diabetes (5). We have also integrated our static and dynamic metabolic profiling tools to demonstrate an important role of reductive TCA cycle flux in glucose- and glutamine-stimulated insulin secretion (6). Several potential therapeutic targets have emerged from these studies, as recently reviewed (7).
Our work on pathways that control islet β-cell replication and survival is co-led by our DMPI faculty colleague Dr. Hans Hohmeier, and details are provided at Dr. Hohmeier’s web page.
Finally, the DMPI has built once of the most collaborative metabolomics core laboratories in the world, and our lab has used these tools for defining mechanisms of metabolic dysregulation underlying pandemic cardiometabolic diseases. For example, we discovered that a cluster of metabolites from the branched-chain amino acid (BCAA) catabolic pathway is more strongly associated with insulin resistance than other metabolite clusters, including lipid-related clusters, in humans, and in animal studies, BCAA supplementation exacerbates insulin resistance, whereas BCAA restriction improves insulin action (8,9,10). The BCAA-related metabolite cluster is predictive of diabetes intervention outcomes at baseline, and strongly responsive to such interventions (4,10). The association between BCAA levels and cardiometabolic diseases is explained at least in part by regulation of the lipogenic enzyme ATP-citrate lyase by the same kinase and phosphatase that regulate the key BCAA metabolic enzyme, branched-chain ketoacid dehydrogenase (11). Moreover, the BCAA-related signature is influenced by the gut microbiome (12) and may also contribute to obesity-associated behavioral abnormalities (13). This work has been funded by the NIH for 15 years.