Multi-Tracer PET Quantitation of Insulin Action in Muscle (Phase 1, Phase 2, Phase 3, Phase 4)
Condition: Diabetes; Obesity
Study type: Observational

Summary: 
      The purpose of this research is to develop a new method to study insulin action using
      positron emission tomography (PET). Insulin is the hormone made by your body to control the
      blood sugar level. We want to develop a way to image (look at) the following three things: 1)
      how insulin affects blood flow in skeletal muscle 2) how insulin affects glucose (sugar)
      transport (movement) into muscle, and 3) how insulin affects glucose metabolism (breakdown)
      in skeletal muscle of healthy individuals. The long term goal will be to later apply this
      method to the study of metabolic diseases, especially type 2 diabetes mellitus and obesity.

      PET imaging is a relatively non-invasive way to obtain a "metabolic picture" of body organs,
      and has been used successfully to study brain, heart and more recently skeletal muscle. In
      this research study, we will use PET with as many as four radioactive tracers (markers) to
      study skeletal muscle glucose transport in healthy volunteers.
    

Detailed description: 
      The goal of this proposal is to develop a novel triple-tracer positron emission tomography
      (PET) method to image in vivo insulin-stimulated tissue perfusion, glucose transport and
      glucose phosphorylation in skeletal muscle in healthy individuals. The long term goal will be
      to later apply this model to the study of metabolic diseases, notably type 2 diabetes
      mellitus (Type 2 DM) and obesity (Ob). While it is often suggested that glucose transport is
      the rate-controlling step for insulin action, we will test the hypothesis that the control
      insulin exerts on the uptake of glucose into skeletal muscle is distributed across flow and
      tissue perfusion, trans-membrane transport and intra-cellular phosphorylation of glucose.

      Specific Aim 1. The first specific aim is to develop the triple-tracer PET method for
      quantitative determinations of tissue perfusion, glucose transport and glucose
      phosphorylation in skeletal muscle. To measure blood flow and tissue perfusion, we will use
      15O-H2O (half-life ~ 2 min; also referred to as 15O-water). To measure glucose transport, we
      will use 11C-3-O-methyl glucose (half-life ~ 20 min; also referred to as 3-0-MG), an analog
      that is transported but not phosphorylated or otherwise metabolized.
      18F-2-deoxy-2-fluoro-glucose (half-life ~ 109 min; also referred to as FDG), will be used to
      examine glucose transport and glucose phosphorylation. Because of the differences in
      half-life of the three positrons (15O, 11C, and 18F), it is feasible to use each of these
      tracers, in sequence, in the same individual.

      Specific Aim 2. The second specific aim is to rigorously test mathematical models to extract
      quantitative physiological information from dynamic PET imaging. We will test a novel model
      that specifically addresses the kinetics of substrate delivery within the interstitial space
      of skeletal muscle (i.e. a 5 rate constant, 4 compartment model with respect to FDG. Model
      testing will entail use of non-compartmental models e.g. spectral analysis).
    

Time perspective: Prospective
Keywords: PET imaging; Skeletal muscle; In vivo insulin-stimulated tissue perfusion; Glucose transport; Glucose phosphorylation