Multi-Tracer Pet Quantitation of Insulin Action

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.