Inhibition by Somatostatin of Glucagon-Induced Glucose Release from the Isolated Perfused Rat Liver

Livers from fed rats (140–160 g) were perfused in situ with a non-recycled, semi-synthetic, erythrocyte-containing medium to determine whether synthetic cyclic somatostatin directly inhibited glucagon-stimulated glucose release into the effluent. Hepatic glucose release was measured by the increase (or in some instances, the decrease) between steady-state basal and steady-state stimulated effluent glucose concentrations. While somatostatin (L.4 × 10−7M in the influent) had no effect on basal glucose release, it significantly inhibited (81%, P < 0.001) simultaneous glucagon (1.2 × 10−10M)-induced hepatic glucose output, but not concurrent cAMP increments in the effluent. Somatostatin (1.4 × 10−8M) also inhibited (38%, P < 0.05) glucagon (1.2 × 10−10M)-induced glucose release. Inhibition by somatostatin (1.4 × 10−7M) was overcome by a high concentration of glucagon (1.2 × 10−8M) which was saturating for glucose but not cAMP production. In further experiments, somatostatin (1.4 × 10−7M) blunted glucose mobilization by cAMP (1 × 10−3M) infusion and suppressed theophylline (2.5 × 10−3M)- potentiated, glucagon (6 × 10−11M)-induced glucose output. However, it had no effect on glucose output stimulated by theophylline (2.5 × 10−3M) alone and did not lower, over 6 to 10 min, glucose release into the effluent when added to a glucagon (1.2 × l0−l0M) infusion once steady-state glucose mobilization had been attained. In conclusion, somatostatin directly suppresses glucagon-stimulated glucose release from rat liver in vitro in a dose-dependent manner, probably by a mechanism affecting cAMP action rather than its formation.