Multi-Tracer PET Quantitation of Skeletal Muscle Insulin Resistance in Type 2 Diabetes Mellitus
Condition: Diabetes; Obesity
Study type: Observational

Summary: 
      The purpose of this research is to use a recently developed triple-tracer positron emission
      tomography (PET) method to study skeletal muscle insulin resistance. Insulin is the hormone
      made by your body to control the blood sugar level. "Resistance' to insulin could cause poor
      blood glucose control (blood sugar levels that are higher than normal). We want to use this
      new method 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.

      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 three radioactive tracers (markers), to study
      skeletal muscle glucose transport in individuals with type 2 diabetes mellitus (type 2 DM)
      and in non-diabetic individuals who are either normal weight or overweight/obese
    

Detailed description: 
      The goal of this proposal is to use a recently developed triple-tracer positron emission
      tomography (PET) method to study skeletal muscle insulin resistance (IR) in research
      volunteers with type 2 diabetes mellitus (type 2 DM) and in comparison to age and
      gender-matched, normal weight non-diabetic volunteers, and in comparison to age, gender, and
      weight-matched overweight or obese non-diabetic volunteers. We will use the three tracers to
      obtain data on the respective insulin actions upon tissue perfusion, glucose transport and
      glucose phosphorylation in order to test the hypothesis that insulin resistance (IR) in type
      2 DM is caused by an aggregation of impairments at these steps, thus challenging the
      prevalent concept that IR derives from a solitary impairment in trans-membrane transport.

      Proximal steps of glucose transport and phosphorylation are considered to contribute strongly
      to the pathogenesis of IR in obesity and type 2 DM (1-5). These scientific considerations
      might have potential therapeutic implications. The overall goal of this project is to provide
      clarity in separating the respective roles of these proximal steps of glucose metabolism.
      Glucose transport will be assessed using 11C-3-O-methyl glucose (half-life ~ 20 min; also
      referred to as 3-0-MG), an analog that is transported but not phosphorylated.
      18F-2-deoxy-2-fluoro-glucose (half-life ~ 109 min; also referred to as FDG), will be used to
      assess glucose transport and glucose phosphorylation. The third tracer that will be used,
      15O-H2O, will provide information on tissue perfusion. The challenge with the use of FDG to
      study insulin action in muscle has been to derive data on two biochemical steps from the
      tissue activity pattern of a single tracer; this has placed a higher reliance upon the
      modeling of the data. However, in this project, because of the use of three tracers and the
      differences in the metabolism of the two glucose analogs, we will be able to address with
      clear resolution the respective roles of transport and phosphorylation in the pathogenesis of
      IR in obesity and type 2 DM.
    

Time perspective: Prospective
Keywords: Skeletal muscle; Triple-tracer PET imaging