Effect of phosphate depletion on gluconeogenesis in isolated rat hepatocytes.
In isolated hepatocytes of rats with advanced phosphate depletion (serum Pi in controls: 8.79 +/- 0.16 mg/dl; Pi depletion: 2.79 +/- 0.18 mg/dl), diminished gluconeogenesis is observed [controls: 247 +/- 21 nmol X (mg protein)-1 X (30 min)-1; Pi depletion: 174 +/- 15]. In vitro stimulation with glucagon (28 nmol/l) caused a significant rise of glucose production, fall in lactate production, and increase in cAMP content in controls, but did not change glucose or lactate production in Pi depletion despite significant stimulation of cAMP content. This defect was not corrected by pretreating Pi-depleted animals with somatostatin. Impaired basal and glucagon-stimulated glucose production by hepatocytes of Pi-depleted animals was not reversed by incubation in a medium with high Pi content. Insulin (17 nmol/l) did not influence glucose or lactate production in hepatocytes of control or Pi-depleted animals. Epinephrine (10(-6) M) caused a significant stimulation of glucose production in control animals which was inhibited both by phenoxybenzamine (10(-4) M) and propranolol (10(-3) M). Epinephrine-mediated increase of glucose production with pyruvate (10 mM) as substrate was reduced but still demonstrable in hepatocytes of phosphate-depleted animals in parallel with a significant rise of hepatocellular cAMP concentration. Various concentrations of bovine PTH1-34 failed to affect cAMP concentration, glucose or lactate production in Pi-depleted animals and glucose or lactate production in controls. Impaired basal and stimulated (glucagon and epinephrine) glucose production despite adequate cellular cAMP generation points to steps distal to adenylate cyclase as the cause of disturbed hepatic gluconeogenesis in phosphate depletion.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004837:Epinephrine / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology; D005943:Gluconeogenesis; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D007773:Lactates / Q000096:biosynthesis; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010643:Phenoxybenzamine / Q000494:pharmacology; D010710:Phosphates / Q000097:blood / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology; D011773:Pyruvates / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013004:Somatostatin / Q000494:pharmacology
D007328:Insulin; D007773:Lactates; D010710:Phosphates; D011773:Pyruvates; D010643:Phenoxybenzamine; D013004:Somatostatin; D005934:Glucagon; D011433:Propranolol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D004837:Epinephrine