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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
5P01DK058398-13
Application #
8692742
Study Section
Special Emphasis Panel (ZDK1-GRB-N (J2))
Program Officer
Castle, Arthur
Project Start
2000-09-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
13
Fiscal Year
2014
Total Cost
$1,966,913
Indirect Cost
$359,543
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2017) Band inversion amplifies 31 P-31 P nuclear overhauser effects: Relaxation mechanism and dynamic behavior of ATP in the human brain by 31 P MRS at 7 T. Magn Reson Med 77:1409-1418
Newgard, Christopher B (2017) Metabolomics and Metabolic Diseases: Where Do We Stand? Cell Metab 25:43-56
Stöckli, Jacqueline; Fisher-Wellman, Kelsey H; Chaudhuri, Rima et al. (2017) Metabolomic analysis of insulin resistance across different mouse strains and diets. J Biol Chem 292:19135-19145
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2016) A simple approach to evaluate the kinetic rate constant for ATP synthesis in resting human skeletal muscle at 7 T. NMR Biomed 29:1240-8
Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49
Kucejova, Blanka; Duarte, Joao; Satapati, Santhosh et al. (2016) Hepatic mTORC1 Opposes Impaired Insulin Action to Control Mitochondrial Metabolism in Obesity. Cell Rep 16:508-519
Zhang, Wenwei; Bu, So Young; Mashek, Mara T et al. (2016) Integrated Regulation of Hepatic Lipid and Glucose Metabolism by Adipose Triacylglycerol Lipase and FoxO Proteins. Cell Rep 15:349-59
Jin, Eunsook S; Sherry, A Dean; Malloy, Craig R (2016) An Oral Load of [13C3]Glycerol and Blood NMR Analysis Detect Fatty Acid Esterification, Pentose Phosphate Pathway, and Glycerol Metabolism through the Tricarboxylic Acid Cycle in Human Liver. J Biol Chem 291:19031-41
Davies, Michael N; Kjalarsdottir, Lilja; Thompson, J Will et al. (2016) The Acetyl Group Buffering Action of Carnitine Acetyltransferase Offsets Macronutrient-Induced Lysine Acetylation of Mitochondrial Proteins. Cell Rep 14:243-54
Ren, Jimin; Sherry, A Dean; Malloy, Craig R (2016) Efficient (31) P band inversion transfer approach for measuring creatine kinase activity, ATP synthesis, and molecular dynamics in the human brain at 7 T. Magn Reson Med :

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