The Natural Cyclic AMP Antagonist Prostaglandylinositol Cyclic Phosphate (Cyclic PIP) Triggers, Depending on Time, Two Opposing Alpha-Adrenoceptor Effects on Glucose Release from Rat Liver

The synthesis of prostaglandylinositol cyclic phosphate (cyclic PIP) is stimulated by insulin and by adrenaline via its a1- and a2- adrenoceptors. Cyclic PIP inhibits protein kinase A and activates protein ser/thr phosphatase holoenzymes. Consequently, it inhibits glycogen phosphorylase and glucose-release. On extra-corporal rat liver perfusion, 0.1 μM cyclic PIP triggers a rapid glucose-release, comparable to the one generated by the calcium ionophore A23187, confirming reports that phenylephrine stimulates glucose-release via a1-adrenoceptors. 10–9 M glucagon stimulates glucose-release nearly 2-fold in male rat livers. Simultaneous stimulation with glucagon and 2 x 10–9 M insulin causes a 65% reduced glucose-release. 10–6 M adrenaline stimulates a rapid first phase and a second, cyclic AMP-triggered phase of glucose-release. Insulin triggers no rapid glucose- release, though both hormones stimulate the synthesis of cyclic PIP. The synthesis of cyclic PIP peaks 1 min after stimulation with adrenaline, but 3–4 min after stimulation with insulin, and cyclic PIP synthesis increases approximately 6-fold slower on insulin than on adrenaline stimulation. This can explain the too low Ca2+ increase on insulin-stimulation in order to “flash- activate” glycogen phosphorylase. In summary, cyclic PIP first “supports” and thereafter antagonizes the cyclic AMP-triggered glucose-release from liver.