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 mechanisms involved in obesity-related impairment of insulin secretion and action leading to diabetes.
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 mass isotopomer analysis to demonstrate that GSIS is tightly correlated to pyruvate anaplerosis and cycling activity rather than pyruvate oxidation (2). We subsequently demonstrated that the pyruvate-isocitrate cycle is the primary pyruvate cycling pathway regulating GSIS (3, 4), and have provided insights into molecular partners that are activated by the cycle (5). Our work in this area has been continuously funded by an NIH grant (DK-046492-22) for 22 years, and this grant achieved “Merit” status from 2001-2011. More recently, we have been investigating the potential utility of pyruvate-isocitrate cycling intermediates for rescuing impaired secretory function in islets isolated from humans with type 2 diabetes.
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. Briefly, we have been focusing on pathways controlled by the homeobox transcription factors Nkx6.1 and Pdx-1. Nkx6.1 and Pdx-1 stimulate islet cell replication by distinct and additive pathways, such that the combined overexpression of the two factors stimulates islet cell replication by more than 20-fold (6). Overexpression of Nkx6.1 in pancreatic islets simultaneously enhances GSIS and β-cell replication (7,8). Nkx6.1 enhances GSIS by induction of a prohormone, VGF, which is processed to yield multiple peptides, including TLQP-21, which is insulinotropic, protective against apoptotic agents, and able to attenuate onset of hyperglycemia in the diabetic rats (9). Nkx6.1 stimulates β-cell proliferation via upregulation of the orphan nuclear receptors Nr4a1 and Nr4a3 to activate E2F1 and cyclin E1, and to degrade the cell cycle inhibitor p21 (10). The knowledge gained in this work allowed us to design and execute a cell-based screen for small molecular activators of the Nkx6.1/VGF pathway. Our work on novel Nkx6.1- and Pdx-1-mediated pathways has been funded continuously by the Juvenile Diabetes Research Foundation since 2007.
Over the past 10 years, the Stedman Center and DMPI have developed one of the most active and collaborative metabolomics core laboratories in the world, and have used these tools for defining mechanisms underlying pandemic metabolic disorders such as obesity, diabetes, and cardiovascular diseases. For example, collaboration of our laboratory with the DMPI metabolomics core laboratory led to the finding 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. Our group went on to show in animal studies that BCAA supplementation exacerbates insulin resistance (11). The BCAA-related metabolite cluster is predictive of diabetes intervention outcomes at baseline, and strongly responsive to such interventions (12, 13, 14). Moreover, the BCAA-related and other metabolic signatures of insulin resistance are influenced by the gut microbiome (15) and may also contribute to obesity-associated behavioral abnormalities (16). Our work in this area has been continuously funded by the NIH for 13 years, and its translational implications are being investigated via a sponsored research agreement with Pfizer.