Modulation by adenosine of hepatic responsiveness to insulin was investigated in vivo in 10 healthy mongrel dogs of both sexes by determining net hepatic glucose output (NHGO) in response to insulin during the presence or absence of exogenous adenosine infusion. In addition, two separate series of experiments were performed to study the effect of adenosine (n = 7) or glucagon (n = 5) on NHGO. Basal NHGO, quantitated via the Fick principle, was significantly decreased by insulin infusion (4 U/min; 4.8 ± 0.6 vs. −1.7 ± 2.6 mg · kg−1 · min−1, P < 0.05). The addition of an intrahepatic arterial infusion of adenosine (10 μmol/min) during insulin infusion caused glucose output to return to basal levels (insulin, −1.7 ± 2.6 mg · kg−1 · min−1; insulin + adenosine, 3.8 ± 1.6 mg · kg−1 · min−1, P < 0.05). The addition of intrahepatic arterial saline (control) during insulin infusion had no effect on insulin's action (insulin, −1.0 ± 1.9 mg · kg−1 · min−1; insulin + saline, −1.2 ± 1.6 mg · kg−1 · min−1, P > 0.05). Hepatic glucose, lactate, and oxygen deliveries were not affected during either insulin or insulin plus adenosine infusion. Intrahepatic arterial infusion of adenosine alone had no effect on NHGO, whereas intrahepatic arterial infusion of glucagon alone stimulated glucose output approximately fivefold (basal, 2.7 ± 0.4 mg · kg−1 · min−1; glucagon, 15.5 ± 1.2 mg · kg−1 · min−1, P < 0.01). These results show that adenosine completely reversed the inhibition by insulin of NHGO. These data suggest that adenosine may act as a modulator of insulin action on the liver.

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