Rat insulinoma cells, which grow in culture and secrete insulin, were used to study the mechanism of stimulation of insulin release by glucagon. The parent cell line (RIN-m) and a clone that secretes high levels of insulin (5F) had been shown to possess specific receptors for glucagon. Glucagon (1 μM) stimulated a rapid increase in cyclic adenosine 3'5'-monophosphate (cAMP) that was followed by an increase in insulin secretion in both cell lines. The concentration of glucagon necessary for half-maximal stimulation of cAMP was 50 μM in parent and approximately 0.5 μM in 5F, whereas the concentration required to inhibit binding by 50% was 0.5 nM and 30 nM, respectively. In 5F, the dose-response relationships for cAMP and insulin secretion were superimposable. The glucagon effects on insulin secretion and cAMP did not require either glucose or amino acids in the incubation media. No refractoriness to glucagon stimulation of cAMP or insulin was noted.

It may be concluded that (1) there are significant differences between glucagon binding and glucagon responses in parent cells and clone 5F, (2) there are glucagon receptors that are not coupled to adenylate cyclase, and (3) cAMP mediates glucagon-stimulated insulin release.

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