title: Interaction of sympathomimetics and insulin with hepatic glucose production by isolated perfused rat livers: effects of continuous versus pulsatile infusion.
abstract: To elucidate the efficacy of continuous vs. intermittent exposure to epinephrine, phenylephrine, and insulin, hepatic glucose production was monitored in isolated perfused rat livers (means +/- SE, n = 6 each). To this end livers of fed rats were perfused with 5 mM glucose Krebs-Ringer buffer in a nonrecirculating system. Using this model it was shown that intermittent exposure (3 min on/off period, dose reduction -50%) to epinephrine (0.4 microM, alpha + beta-agonist) and phenylephrine (5 microM, alpha-agonist) elicited an almost identical rise in hepatic glucose production [epinephrine: 0.72 +/- 0.08 mmol/(86 min X 100 g BW); phenylephrine: 0.68 +/- 0.07 mmol/(86 min X 100 g BW) as their continuous administration (epinephrine: 0.78 +/- 0.06 mmol/(86 min X 100 g BW); phenylephrine: 0.74 +/- 0.09 mmol/(86 min X 100 g BW)]. Inhibition by insulin (100 mU/liter) given either continuously or intermittently (3 min on/off intervals; dose reduction -50%) was equipotent for epinephrine- and phenylephrine-stimulated hepatic glucose production. When the off period was doubled to 6 min, thereby reducing the total insulin dose to 33%, no significant suppression of epinephrine- and phenylephrine-stimulated hepatic glucose production was observed. From this we conclude that 1) the effect on hepatic glucose production of pulsatile (3 min on/off, dose reduction 50%) and continuous administration is equipotent for the respective action of epinephrine, phenylephrine as well as of insulin; and 2) insulin is more effective (P less than 0.02) in inhibiting hepatic glucose production stimulated by an alpha-agonist (phenylephrine; 5.0 microM) than in counteracting alpha + beta-agonist action (epinephrine; 0.4 microM). The characteristics of hepatic glucose release as stimulated by alpha- and/or beta-adrenergic agonists and its inhibition by continuously or intermittently infused insulin were simulated and described by a computer model. Thereby, no qualitative difference could be demonstrated in alpha- vs. beta-adrenergic agonists action on stimulated hepatic glucose production.
mesh_terms: D000818:Animals; D004837:Epinephrine / Q000494:pharmacology*; D005947:Glucose / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D061389:Insulin, Regular, Pork; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010477:Perfusion; D010643:Phenoxybenzamine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D013997:Time Factors
chemical_list: D007328:Insulin; D061389:Insulin, Regular, Pork; D010643:Phenoxybenzamine; D010656:Phenylephrine; C000006:insulin, neutral; D005947:Glucose; D004837:Epinephrine