Multi-Tracer Pet Quantitation of Insulin Action
Condition: Diabetes
Study type: Observational

Summary: 
      We are proposing a clinical investigation of the pathogenesis of insulin resistance (IR) in
      skeletal muscle and adipose tissue (AT), focusing specifically on the contributions of
      glucose delivery, transport and phosphorylation. The primary methodology will be dynamic PET
      imaging, using three tracers that respectively portray the kinetics of glucose delivery,
      bi-directional trans-membrane glucose transport and glucose phosphorylation. The three
      tracers are: 1) [15O]-H2O for quantifying tissue perfusion, this portrays the kinetics of
      glucose delivery from plasma to tissue; 2) [11C]-3-O-methyl glucose, a tracer constrained to
      bi-directional trans-membrane glucose transport; and 3) [18F]-fluoro-deoxy glucose, which
      like [11C]-3-OMG is transported, but adds the subsequent metabolic step, that of glucose
      phosphorylation.

      We propose 2 specific aims to apply this methodology to investigate the pathogenesis of IR.
      The 1st aim is to quantitatively assess the kinetics of glucose delivery, transport and
      phosphorylation in skeletal muscle in type 2 DM and as compared to obese and lean
      non-diabetic men and women. We will appraise the contribution of each step to the to the
      pathogenesis of IR. We postulate more severe IR in oxidative muscle, with a dual impairment
      of glucose transport and phosphorylation. The 2nd aim is to implement the triple-tracer
      dynamic PET imaging protocol in adipose tissue (AT), examining normal insulin action in
      non-obese volunteers and testing whether differences in AT insulin action are present in
      obese insulin sensitive volunteers compared to obese IR participants and the relation of AT
      IR to that of muscle and liver.
    

Detailed description: 
      We propose a clinical investigation of the pathogenesis of insulin resistance (IR) in
      skeletal muscle and adipose tissue (AT) in obesity and diabetes mellitus, focusing on the
      separate and interactive roles of glucose delivery, bi-directional trans-membrane glucose
      transport and glucose phosphorylation. The primary methodology will be dynamic PET imaging,
      using three tracers that respectively portray the kinetics of glucose delivery, transport and
      phosphorylation. The three tracers are: 1) [15O]-H2O for quantifying tissue perfusion, this
      parameter together with glucose concentration portrays the kinetics of glucose delivery from
      plasma to tissue interstitial space; 2) [11C]-3-O-methyl glucose, a tracer constrained to
      bi-directional trans-membrane glucose transport; and 3) [18F]-fluoro-deoxy glucose, which
      like [11C]-3-OMG is transported, but adds the subsequent metabolic step, that of glucose
      phosphorylation.

      In our recently completed studies, we implemented this triple-tracer dynamic PET imaging
      protocol to investigate insulin action in lean, healthy individuals 1-3. Rates of glucose
      uptake can be obtained by other methods (e.g. the glucose clamp, arterio-venous limb
      balance). What is uniquely valuable with dynamic PET imaging is acquisition of a temporal
      plot of tracer uptake, one that is obtained within an organ rather than derived from plasma
      determinations. These tissue-time activity curves provide information to assess the velocity
      of metabolic steps. By doing this for each of the three tracers, assessment can be made of
      which among glucose delivery, transport and phosphorylation is rate-controlling, or more
      properly, how rate control is distributed amongst these steps. The triple-tracer procedure
      has provided novel, quantitative insight on the action of insulin to change this distribution
      of control, a re-distribution triggered in healthy individuals by robust activation of
      glucose transport. Robust activation of glucose transport increases permeability of muscle to
      glucose sufficiently that delivery manifests greater rate limitation than during basal
      conditions. Also, we have coupled PET bio-imaging with MRI to study specific muscles 1, 3.
      This approach has yielded provocative and unanticipated new findings. Unlike in lean
      non-diabetics, in whom oxidative muscle is more insulin sensitive (as widely demonstrated in
      animal studies), in type 2 and in type 1 DM, oxidative muscle is more severely IR. We are
      encouraged that this bio-imaging methodology will enable new insight into the pathogenesis of
      IR in skeletal muscle and that the approach can be successfully adapted for in vivo
      investigation of adipose tissue metabolism.

      The 1st specific aim is to quantitatively assess the contribution of glucose delivery,
      transport and phosphorylation to the pathogenesis of skeletal muscle IR in type 2 DM and
      obesity.

      The 2nd specific aim is to implement triple-tracer dynamic PET imaging to study insulin
      action in gluteal-femoral adipose tissue (GF-AT) of non-obese and obese women, investigating
      among the latter group mechanisms of IR of GF-AT, and the role that GF-AT IR may have in
      differentiating obese insulin-sensitive (OB-InS) from obese insulin-resistant (OB-IR) women.

      Experiment Synopsis: During the past year, in pilot studies, we initiated PET imaging
      procedures for AT, using [18F]-FDG. We now propose full development of the triple tracer
      methodology in GF-AT. Non-obese and obese women will be studied, the latter recruited to form
      groups of obese insulin-sensitive (OB-IS) and obese insulin-resistant (OB-IR). Triple-tracer
      PET imaging will be done during basal and insulin stimulated conditions, using an infusion
      rate of 20 mU/min-m2. Complementary assessments will include: a) MRI and DXA to measure the
      quantity of fat-mass (FM), GF-AT, abdominal adipose depots (ABD-SAT and VAT); b) endogenous
      glucose production (EGP) assessed using a primed, constant infusion of [6,6] d2-glucose; c)
      an adipokine profile; and d) a needle biopsy of GF-AT for histological and other analyses.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Normal volunteer sample
      
Biospecimen description: 
      Aliquotted blood samples
    
Keywords: Diabetes