Splanchnic Glucose Uptake (SGU) accounts for the disposal of approximately 1/3 of an oral glucose load. To investigate the effect of an elevated plasma free fatty acid concentration on SGU, we measured SGU in 9 healthy non-diabetic subjects (age 44±4 y, BMI=27.4±1.2kg/m²,FPG=5.2±0.1mmol/L)during an Intralipid/heparin (LIP) infusion and during a saline (SAL)infusion.SGU was estimated by the ORAL GLUCOSE LOAD(OGL)-INSULIN CLAMP method: subjects received a 7h euglycemic 100 mU/m²per minute insulin clamp and a 75g oral glucose load(OGL)was ingested 3h after starting the insulin clamp.After glucose ingestion, the steady state glucose infusion rate(GIR)during the insulin clamp was decreased appropriately to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in GIR during the 4h period after glucose ingestion from the ingested glucose load. 3-[ ³H] glucose was infused during the initial 3h of the insulin clamp prior to glucose ingestion to determine the rate of endogenous glucose production (EGP) and glucose disappearance rates (Rd). The plasma FFA concentration was higher during the LIP vs. SAL infusion study (2.40±0.3 vs. 0.14±0.01mM, p<0.001). During the 3h euglycemic insulin clamp prior to glucose ingestion, the rate of glucose disposal (Rd) was decreased (8.8±0.5 vs. 7.6±0.5 mg/kg-min, p<0.01) and suppression of EGP was impaired(0.2±0.04 vs. 0.07±0.03 mg/kg-min,p<0.01). During the 4h period after glucose ingestion, SGU was significantly increased during the LIP vs. SAL infusion study (30±2% vs. 20±%,p<0.005).In conclusion, an elevation in plasma FFA concentration impairs whole body glucose disposal and insulin-mediated suppression of EGP in healthy subjects, but augments SGU.These results provide evidence for "cross talk" (that is independent of hyperglycemia) between peripheral tissues (muscle) and liver in the maintainance of normal glucose homeostasis.