TRANSENDOTHELIAL INSULIN TRANSPORT IS NOT SATURABLE IN-VIVO - NO EVIDENCE FOR A RECEPTOR-MEDIATED PROCESS

In vitro, insulin transport across endothelial cells has been reported to be saturable, suggesting that the transport process is receptor me diated. In the present study, the transport of insulin across capillar y endothelial cells was investigated in vivo. Euglycemic glucose clamp s were performed in anesthetized dogs (n = 16) in which insulin was in fused to achieve concentrations in the physiological range (1.0 mU/kg per min + 5 mU/kg priming bolus; n = 8) or pharmacologic range (18 mU/ kg per min + 325 mU/kg priming bolus; n = 8). Insulin concentrations w ere measured in plasma and hindlimb lymph derived from interstitial fl uid (ISF) surrounding muscle. Basal plasma insulin concentrations were twice the basal ISF insulin concentrations and were not different bet ween the physiologic and pharmacologic infusion groups (plasma/ISF rat io 2.05+/-0.22 vs 2.05+/-0.23; P = 0.0003). The plasma/ISF gradient wa s, however, significantly reduced at steady-state pharmacologic insuli n concentrations (1.37+/-0.25 vs 1.98+/-0.21; P = 0.0003). The reduced gradient is opposite to that expected if transendothelial insulin tra nsport were saturable. Insulin transport into muscle ISF tended to inc rease with pharmacologic compared with physiologic changes in insulin concentration (41% increase; 1.37+/-0.18 10(-2) to 1.93+/-10.24 10(-2) min(-1); P = 0.088), while at the same time insulin clearance out of the muscle ISF compartment was unaltered (2.53+/-0.26 10(-2) vs 2.34+/ -0.28 10(-2) min(-1); P = 0.62). Thus, the reduced plasmal ISF gradien t at pharmacologic insulin was due to enhanced transendothelial insuli n transport rather than changes in ISF insulin clearance. We conclude that insulin transport is not saturable in vivo and thus not receptor mediated. The increase in transport efficiency with saturating insulin is likely due to an increase in diffusionary capacity resulting from capillary dilation or recruitment.