Actions of the novel antidiabetic agent englitazone in rat hepatocytes.

We examined effects of a novel antidiabetic agent, racemic englitazone (CP 68,722, Pfizer), on normal rat hepatocytes in vitro. For optimal effects, CP 68,722 must be preincubated for approximately 20 minutes. CP 68,722 inhibited the actions of glucagon on glycogenolysis (measured by monitoring cyclic adenosine monophosphate [cAMP] levels, phosphorylase activation, and glucose output) and gluconeogenesis (from 14C-lactate). Since CP 68,722 was able to attenuate the ability of glucagon to increase cAMP levels, this may account for part of its inhibitory actions on glycogenolysis and gluconeogenesis. The observation that CP 68,722 also inhibits the ability of the cAMP analog, 8-(4-chlorophenylthio)-adenosine 3':5'-cyclic monophosphate (8 CPT cAMP), to stimulate phosphorylase a is consistent with an effect of CP 68,722 to activate cAMP-dependent phosphodiesterase. The ability of vasopressin (an agonist known to stimulate glycogenolysis via a Ca(2+)-dependent mechanism) to stimulate phosphorylase a was slightly inhibited by CP 68,722. Another site of action of CP 68,722 was to inhibit hormonal-mediated Ca2+ influx, an effect that would decrease intracellular free calcium ([Ca2+]i), thereby inhibiting the actions of the Ca(2+)-dependent hormones such as alpha 1-adrenergic agonists and vasopressin, agents known to promote glucose output from the liver. In summary, CP 68,722 inhibits glucagon-stimulated glycogenolysis and gluconeogenesis in hepatocytes by a mechanism that may include activation of cAMP phosphodiesterase and inhibition of Ca2+ influx.