Effect of β-Casomorphins and Analogs on Insulin Release in Dogs*

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Abstract
Opioid-active substances have been isolated from bovine β-casein peptone (β-casomorphin). Since the ingestion of β-casomorphin-containing foodstuff elicits an increase inpostprandial insulin release, the present study was designed todetermine the effects of iv infused β-casomorphins on insulinrelease. The infusion of β-casomorphin-7, -5, -4, and -3 did notalter basal insulin secretion. During prestimulation of insulin release with amino acids and glucose the infusion of β-casomorphin-7, -5, -4, and -3 at a dose of 1 nmol/kg· augmented insulin release, whereas at a concentration of 100 nmol/kg·h no further stimulatory effect was observed except for the infusion of β- casomorphin-4. In comparison, the infusion of morphine elicited a potentiation of insulin release at the lower dose, whereas noffect was observed at the higher infusion rate. Leucine-enkephalin ad no effect at the lower dose but elicited an inhibitory effect at the higher rate. The infusion of opiate-active and nactive analogs of β-casomorphin-4 resulted in a loss of its stimulatory effect, indicating that the full tetrapeptide structure of the molecule is important for its stimulatory activity on β- cell secretion. All stimulatory and inhibitory effects of the opioid-active substances were blocked by the specific opiatereceptor antagonist naloxone. Additionally, the present data support the concept that β-cell secretion is stimulated by μ-receptor activation and inhibited by Δ5-receptor activation. The K-receptor antagonist ethyl-ketocyclazocine did not alter insulin secretion. The fact that iv administered β-casomorphins stimulate insulin release raises the possibility that ingested food-derived opioid-active substances modulate pancreatic endocrine function also after their absorption, provided the doses employed in the present study reflect physiological concentrations of circulating β-casomorphins.