Promoting Effect of the Chymotrypsin Inhibitor FK-448 on the Intestinal Absorption of Insulin in Rats

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Abstract
The role of the chymotrypsin inhibitor, 4-(4-isopropylpiperazinocarbonyl)phenyl 1,2,3,4-tetrahydro-1-naphthoate methanesulfonate (FK-448) in the promoting effect on the intestinal absorption of insulin was studied. After administration of insulin (63 U/kg) into the intestinal loop of the rat, the immunoreactive insulin (IRI) level in the portal plasma reached 49 .+-. 2 .mu.U/ml, but the blood glucose level remained unchaned. When insulin was administered at the same dose with FK-448 (20 mg/kg), the IRI level increased to 331 .+-. 91 .mu.U/ml and the blood glucose level was decreased by 40% as compared with that before administration. The percentage of insulin absorption was estimated to be about 0.7 (7 times over control) by using the area under the plasma IRI concentration-time curve (AUC) after intramesenteric venous administration of known amounts of insulin. When insulin alone was administered into the intestinal loop after washing for 30 min with Krebs-Henseleit solution, the AUC was not significantly different from that without washing. This means that insulin administered into the intestine is degraded by digestive enzymes adsorbed onto the mucosal glycocalyx or those in the mucous membrane. To clarify the role of FK-448 in its promoting effect on the intestinal absorption of insulin, the influence on the permeability of intestinal mucosa was examined by measuring the extent of exsorption of sulfanilic acid into the small intestine. FK-448 exhibits no enhanced permeability of the intestinal mucosa which accounts for the observed promoting effect on the intestinal absorption of insulin. Therefore, the promoting effect of FK-448 on the intestinal absorption of insulin was considered to be based on the inhibition of proteolytic enzyme(s), but the results above mentioned could not reveal where insulin administered into the intestinal tract was mainly degraded.