Effects of adenosine, 2-deoxyadenosine and N6-phenylisopropyladenosine on rat islet function and metabolism.
Adenosine (1.0-100 mum). N(6)-phenylisopropyladenosine (0.1-10 mum) and 2-deoxyadenosine (10 mm) all produced a dose-dependent inhibition of glucose-stimulated insulin release. The inhibition of glucose-stimulated insulin release by adenosine and N(6)-phenylisopropyladenosine was abolished by 3-isobutyl-1-methylxanthine (0.1 mm), whereas 2-deoxyadenosine inhibited insulin release even in the presence of 3-isobutyl-1-methylxanthine. These adenosine nucleosides also inhibited the release of insulin induced by 4-methyl-2-oxopentanoate (20 mm), dl-glyceraldehyde (30 mm) and l-leucine (20 mm). Adenosine (10 mum). N(6)-phenylisopropyladenosine (10 mum) and 2-deoxyadenosine (10 mm) did not inhibit insulin biosynthesis or [U-(14)C]glucose oxidation at concentrations of the nucleosides that gave maximal inhibition of insulin release. However, adenosine, 2-deoxyadenosine and N(6)-phenylisopropyladenosine produced marked inhibition of the glucose-stimulated increases seen in islet cyclic AMP accumulation. Similar to its effects on insulin release, 3-isobutyl-1-methylxanthine (0.1 mm) antagonized the inhibitory effects of cyclic AMP accumulation produced by adenosine and N(6)-phenylisopropyladenosine, but had no effect on the inhibition of cyclic AMP accumulation seen with 2-deoxyadenosine. These results show that adenosine and its specifically modified analogues, 2-deoxyadenosine and N(6)-phenylisopropyladenosine, are strong inhibitors of insulin release from rat islets, a function that appears to be the consequence of their ability to inhibit the accumulation of cyclic AMP. It is proposed that the B cells, in common with many other tissues, may possess two different sites at which adenosine nucleosides interact to produce their biological effects; these are the so-called ;P' and ;R' sites first described by Londos & Wolff [(1977) Proc. Natl. Acad. Sci. U.S.A.74, 5482-5486].
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D003839:Deoxyadenosines / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010660:Phenylisopropyladenosine / Q000494:pharmacology*; D011384:Proinsulin / Q000378:metabolism; D014176:Protein Biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013268:Stimulation, Chemical
D003839:Deoxyadenosines; D007328:Insulin; D010660:Phenylisopropyladenosine; D011384:Proinsulin; D000242:Cyclic AMP; D005947:Glucose; D000241:Adenosine