Development of Novel Therapies for NIDDM
Condition: Metabolism
Study type: Interventional

Summary: 
      The overarching goal of this program project grant is 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.

      Project 4 of the grant, led by Dr. Craig Malloy at UTSW, will develop and apply new
      technology in MRI to test core hypotheses about the development of insulin resistance in
      people. The long-term goal is to develop technology to monitor metabolism in skeletal muscle,
      brain and the liver using magnetic resonance imaging (MRI) and magnetic resonance
      spectroscopy (MRS) in a 3 Tesla and 7 Tesla MRI scanners. These advanced imaging methods
      allow researchers to take pictures of the inside of the body and to measure metabolism as it
      occurs in the MRI scanner. Standard clinical MRI for medical diagnosis and treatment is
      performed in a 1 Tesla or 3 Tesla MRI scanner.

      A primary goal of the 7 Tesla research program is to develop a group of protocols for
      investigating specific metabolic pathways in adipose (fat) tissue, skeletal muscle and the
      liver. This study is being done to improve methods of imaging and measuring molecules in a 3
      Tesla or 7 Tesla scanners.
    

Detailed description: 
      The overarching goal of this program project grant is 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 research will be led by an
      Administrative Core team (Core C) under the direction of Dr. Newgard at the Sarah W. Stedman
      Nutrition and Metabolism Center at Duke to ensure the integration of all analyses in the
      Projects and Cores. Research within the PPG will be supported by two established scientific
      core laboratories including the mass spectrometry (MS)-based metabolic profiling core (Core
      B) of Duke Stedman Center Metabolomics Core Laboratory directed by James Bain, Ph.D. and the
      Metabolomic flux/Imaging Core (Core A) at the Advanced Imaging Research Center (AIRC) of the
      University of Texas Southwestern Medical Center under the direction of Dean Sherry, Ph.D.

      Projects 1-3 of the current program continue the animal model work of the previous research
      and Project 4, to be conducted at UTSWMC, adds a human studies component as well as
      additional animal studies. The goal of Project 1 (led by Dr. Newgard/Duke) is to collaborate
      with the other projects and cores to fully understand the metabolic and molecular changes
      that lead to perturbed branched-chain amino acid (BCAA) homeostasis and loss of insulin
      sensitivity in animal models, thereby leading to better understanding of possible
      cause/effect relationships between BCAA and metabolic disease. The goal of Project 2 (led by
      Dr. Muoio/Duke), also working with the other components of the program, is to test the
      hypothesis that excessive mitochondrial catabolism of lipid and BCAA plays a central role in
      triggering mitochondrial stress, insulin resistance and eventual metabolic failure in
      skeletal muscle during the pathological progression of diet-induced obesity. Project 3 (led
      by Dr. Burgess/UTSWMC) uses the tools in Cores A and B to help define the temporal sequence
      of changes in mitochondrial metabolism in liver during development of hepatic insulin
      resistance, and also dissects the contribution of key signaling events (insulin receptor
      engagement, mTOR activation) and nutrients (BCAA, lipids) in this process. Project 4 (led by
      Dr. Malloy at UTSWMC) will develop and apply novel high-field 7T NMR spectroscopy/metabolic
      flux analysis technologies to help test three core hypotheses about the development of
      insulin resistance emanating from Projects 1-3 (animal studies) in human subjects.

      For project 4, the current request is to establish a protocol to vary the site of 13C
      labeling in several physiological molecules: glucose, lactate, acetate, pyruvate, and
      octanoate. All of these molecules can undergo oxidation in the citric acid cycle and all can
      be safely administered to human subjects. The intent is to study a particular 13C labeling
      pattern and molecule in 70 subjects to determine if downstream products (such as 13C
      bicarbonate or 13C glutamate) due to oxidation in the mitochondria can be detected in
      skeletal muscle or in blood by NMR analysis.

      Additional work will include using 31P imaging to probe mitochondrial function by measuring
      phosphorus-containing metabolites, as well as pH and metabolic flux activities
      non-invasively.

      Aim 3 of this project to commence in September of 2014 is a cross-sectional study in
      overweight humans with measurements of branched-chain amino acids (BCAA) to test
      mitochondrial function in skeletal muscle using 7T 31P imaging and an insulin clamp (infusion
      of a glucose tracer). Subjects for the Aim 3 phase of the study will be 25 to 60 years of
      age.

      These new high-field MR technologies will be integrated with those largely in hand for
      understanding mitochondrial function in liver and skeletal muscle in a project that
      translates the biological/mechanistic findings of all these grant projects to human studies.

      This protocol is primarily for technology development. Most of the subjects will undergo a 7T
      MR exam as optimal information is expected from the stronger field strength. The 3T MR
      scanner will be used once a protocol has been established for comparison.
    

Intervention name(s): 3 Tesla; 7 Tesla
Intervention type(s): Other; Other
Intervention description(s): 3 Tesla scanning with intravenous infusion of tracers; 7 Tesla scanning with intravenous infusion of tracers
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: MRI; metabolism; healthy; 7 Tesla