title: The interaction between the adenylate cyclase system and insulin-stimulated glucose transport. Evidence for the importance of both cyclic-AMP-dependent and -independent mechanisms.
abstract: The counter-regulatory effect of adenosine, isoprenaline and selected cyclic AMP analogues on insulin-stimulated 3-O-methylglucose transport and insulin binding were studied in rat fat-cells. Isoprenaline alone had no consistent effect on glucose transport in the presence of maximally effective insulin concentrations. However, it decreased insulin binding by approx. 20% and increased EC50 (concn. giving 50% of maximal stimulation) for insulin from 8 +/- 1 to 17 +/- 2 mu units/ml. Adenosine deaminase (ADA) alone only exerted a slight effect, whereas isoprenaline and ADA in combination consistently decreased the maximal effect of insulin on glucose transport, decreased insulin binding by approx. 30% and markedly decreased insulin-sensitivity (EC50 61 +/- 8 mu units/ml). In cells from pertussis-toxin-treated animals, isoprenaline alone decreased the insulin response by approx. 75%, decreased insulin binding by approx. 45% and caused a marked rightward shift in the dose-response curve for insulin (EC50 103 +/- 34 mu units/ml). The importance of cyclic AMP for these effects was evaluated with the analogue N6-monobutyryl cyclic AMP, which is resistant to hydrolysis by the phosphodiesterase. The importance of phosphodiesterase activation by insulin was studied with 8-bromo cyclic AMP, which is an excellent substrate for this enzyme. N6-Monobutyryl cyclic AMP, in contrast with 8-bromo cyclic AMP, markedly impaired insulin-sensitivity (EC50 approx. 100 mu units/ml). However, the maximal effect of insulin was only slightly attenuated.
  
  
  CONCLUSIONS
  (1) beta-adrenergic stimulation and cyclic AMP markedly alter insulin-sensitivity, but not responsiveness, mainly through post-receptor perturbations; (2) when cyclic AMP is increased phosphodiesterase activation by insulin is a critical step to elicit insulin action; (3) adenosine modulates the insulin-antagonistic effect of beta-adrenergic stimulation via Ni (inhibitory nucleotide-binding protein) through both cyclic-AMP-dependent and -independent mechanisms.
authors.affiliation: Department of Medicine II, Sahlgren's Hospital, Gothenburg, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Lönnroth
authors.forename: J I
authors.initials: JI
authors.lastname: Davies
authors.forename: I
authors.initials: I
authors.lastname: Lönnroth
authors.forename: U
authors.initials: U
authors.lastname: Smith
mesh_terms: D019325:3-O-Methylglucose; D000243:Adenosine Deaminase / Q000494:pharmacology; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D000242:Cyclic AMP / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008757:Methylglucosides / Q000378:metabolism; D037342:Pertussis Toxin; D051381:Rats; D011919:Rats, Inbred Strains; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D007328:Insulin; D008757:Methylglucosides; D010566:Virulence Factors, Bordetella; D019325:3-O-Methylglucose; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000243:Adenosine Deaminase; D000262:Adenylyl Cyclases; D005947:Glucose; D007545:Isoproterenol