In conclusion, we have for the first time assessed in vivo fluxes and metabolic fate of both glucose and FFA at the whole body and individual tissue levels as well as the control of these fluxes by insulin in the obese Zucker rat. The results reveal that defective insulin regulation of metabolism extends beyond glucose control to include profound impairments in control of tissue FFA fluxes in this animal model. In addition it was determined that the improvement in whole body insulin mediated glucose control afforded by the PPARα/γ agonist tesaglitazar was due to restoration of insulin's ability to suppress hepatic glucose production and stimulate glucose uptake in skeletal muscle. Beyond glucose control, however, tesaglitazar restored insulin's ability to suppress fatty acid availability and the flux of FFA from plasma into muscles and liver which together with the effects on glucose metabolism resulted in a remarkable improvement in insulin mediated switching of fuel utilization.
