Potential of single cationic amino acid molecule “Arginine” for stimulating oral absorption of insulin

We have reported that cell-penetrating peptides, such as oligoarginine, act as powerful absorption enhancers for the development of oral insulin delivery systems. However, the minimal essential sequence of oligoarginine that stimulates intestinal insulin absorption remains unclear. Therefore, the present study was conducted to clarify this minimum sequence of oligoarginine and to examine the effect of single cationic amino acid arginine on the intestinal and oral absorption of insulin. The results demonstrated that a remarkable enhancement of intestinal insulin absorption was observed after coadministration of insulin with L-arginine. The efficacy of D-forms of oligoarginine/arginine tended to decrease with a decreasing number of amino acid residues, whereas the effect of L-arginine was the strongest of any of the L-forms of oligoarginine/arginine. Interestingly, the effect of L-arginine was stronger than that of D-arginine at various concentrations, and the effect of other cationic amino acids such as lysine and histidine was relatively lower than that of arginine. In addition, no leakage of lactate dehydrogenase from the intestinal epithelium and no change in the transepithelial electrical resistance of a Caco-2 cell monolayer were detected after administration of L-arginine as the single amino acid, which suggests that there were no undesirable effects of arginine on the integrity of cell membranes and paracellular tight junctions. Oral administration study in mice demonstrated that the stronger hypoglycemic effects were observed after coadministration of insulin with L-arginine. In this study, we found that arginine is a key cationic amino acid for delivering insulin across intestinal epithelial barriers and hopefully accelerating the clinical development of oral insulin delivery systems.