Paracellular and transcellular pathways facilitate insulin permeability in rat gut

The aim of this study was to conduct a systematic investigation of the absorption of insulin in the rat intestine in the presence of permeation enhancers and protease inhibitors. An in-situ perfused rat gut model was used for the co-perfusion of insulin and PEG 4000 in the presence or absence of bile salts, bile salt:fatty acid surfactant systems and protease inhibitors. Perfusion experiments were conducted for 180 min with perfusate and blood collection at regular intervals. Permeability coefficients for insulin were calculated from plasma insulin and PEG 4000 permeability coefficients were calculated from lumenal disappearance data. In the absence of enzyme inhibitors, insulin permeability was consistently lower than PEG 4000, but increased in proportion to PEG 4000 permeability. Large increases in insulin permeability were obtained for mixed micellar systems and protease inhibitors. In the presence of protease inhibitors and simple micelle systems, PEG 4000 permeability was three-fold greater than insulin permeability. In the presence of absorption enhancers, PEG 4000 permeability increased up to a maximum value of 3.63 x 10(-6)cm s(-1), a value five-fold less than that of the estimated aqueous boundary layer permeability for PEG 4000. This suggests that PEG 4000 permeability is primarily membrane controlled. Insulin permeability is enhanced to a maximum value of 9.17 x 10(-6)cm s(-1), suggesting that paracellular transport routes do not account exclusively for insulin permeation across the intestinal epithelium. The results add support to suggestions that routes other than the paracellular route may contribute to insulin absorption in rat gut.