The overarching goal of this competing renewal application (P01-DK58398-11) continues to be the development of technologies that lead to new methods for studying, detecting, and treating type 2 diabetes, and their integration with hypothesis-driven diabetes research projects. The program involves collaboration of two major metabolic research centers at Duke University Medical Center and the University of Texas Southwestern Medical Center, Dallas. In the past funding cycle, our team's most compelling advances in technology development have centered on comprehensive tools for metabolic analysis, including NMR-based methods for measurement of metabolic flux and mass spectrometry-based methods for static profiling of intermediary metabolites. A key goal of the program in moving forward is to apply these tools in an integrated fashion to a diverse array of animal models and human subjects to gain a more comprehensive view of metabolic perturbations associated with development of type 2 diabetes than has heretofore been possible. The four projects and three cores of the program are organized around three core hypotheses: 1) Major complications of over-nutrition such as insulin resistance and glucose intolerance are the result of overload of normally functioning mitochondrial pathways rather than intrinsic deficiencies in mitochondrial metabolism;2) In addition to lipids, branched-chain amino acids and related metabolites play an important role in causation of mitochondrial dysfunction and loss of insulin sensitivity;3) Mitochondrial flexibility in oxidative and anaplerotic pathways is impaired in insuin resistant liver via constitutive activation of mTORCI and substrate overload. A distinguishing feature of the application is the translation of new understanding and hypotheses developed in cell and animal models in Projects 1, 2, and 3 to human subjects via the studies proposed in Project 4. Through this work, we hope to derive the most complete understanding to date of changes in metabolism within major organs and tissues during development of insulin resistance, type 2 diabetes, and related disorders, leading to novel therapeutic targets and new diagnostic tests for metabolic diseases that cripple modern society.

Public Health Relevance

This program seeks to integrate novel technologies for metabolic flux analysis and static metabolic profiling to gain a unique understanding of changes in peripheral metabolism during development of insulin resistance and type 2 diabetes. These new insights could lead to new diagnostic tests and novel therapies for this crippling disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-N (J2))
Program Officer
Castle, Arthur
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
Ren, Jimin; Yang, Baolian; Sherry, A Dean et al. (2015) Exchange kinetics by inversion transfer: integrated analysis of the phosphorus metabolite kinetic exchanges in resting human skeletal muscle at 7 T. Magn Reson Med 73:1359-69
Bartz, Sarah; Mody, Aaloke; Hornik, Christoph et al. (2014) Severe acute malnutrition in childhood: hormonal and metabolic status at presentation, response to treatment, and predictors of mortality. J Clin Endocrinol Metab 99:2128-37
Fabbrini, Elisa; Serafini, Mauro; Colic Baric, Irena et al. (2014) Effect of plasma uric acid on antioxidant capacity, oxidative stress, and insulin sensitivity in obese subjects. Diabetes 63:976-81
Purmal, Colin; Kucejova, Blanka; Sherry, A Dean et al. (2014) Propionate stimulates pyruvate oxidation in the presence of acetate. Am J Physiol Heart Circ Physiol 307:H1134-41
Mody, Aaloke; Bartz, Sarah; Hornik, Christoph P et al. (2014) Effects of HIV infection on the metabolic and hormonal status of children with severe acute malnutrition. PLoS One 9:e102233
Sinha, Rohit A; Farah, Benjamin L; Singh, Brijesh K et al. (2014) Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. Hepatology 59:1366-80
Thalacker-Mercer, Anna E; Ingram, Katherine H; Guo, Fangjian et al. (2014) BMI, RQ, diabetes, and sex affect the relationships between amino acids and clamp measures of insulin action in humans. Diabetes 63:791-800
Heinicke, Katja; Dimitrov, Ivan E; Romain, Nadine et al. (2014) Reproducibility and absolute quantification of muscle glycogen in patients with glycogen storage disease by 13C NMR spectroscopy at 7 Tesla. PLoS One 9:e108706
Khoo, Chin Meng; Muehlbauer, Michael J; Stevens, Robert D et al. (2014) Postprandial metabolite profiles reveal differential nutrient handling after bariatric surgery compared with matched caloric restriction. Ann Surg 259:687-93
Seiler, Sarah E; Martin, Ola J; Noland, Robert C et al. (2014) Obesity and lipid stress inhibit carnitine acetyltransferase activity. J Lipid Res 55:635-44

Showing the most recent 10 out of 121 publications