It has been suggested that regulation of glucose-6-phosphatase by insulin plays a role in the suppression of hepatic glucose production during feeding. We used hepatic glucose production (measured with the D-[3-3H]glucose infusion method) as an indicator of substrate flux through glucose-6-phosphatase in vivo. Compared with saline controls, insulin (7 mU · min−1 · kg−1, euglycemic clamp) suppressed hepatic glucose production virtually completely in both fasted (32.4 ± 2.4 vs. –6.1 ± 14 μmol · min−1 · kg−1) and fed (64.6 ± 6.4 vs. 5.5 ± 5.2 μmol · min−1 · kg−1) rats. Whereas hepatic glucose production was totally suppressed, [glucose-6-phosphate] in liver cytosol declined by only 27 and 35% in fasted and fed rats, respectively. Addition of hyperglycemia (10 mM) to the insulin infusion likewise fully suppressed hepatic glucose production (26.9 ± 1.4 vs. −9 ± 10 μmol · min−1 · kg−1 and 80.8 ± 10.1 vs. −3.6 ± 12.6 μmol · min−1 · kg−1 in fasted and fed rats, respectively), but [glucose-6-phosphate] again declined only modestly (21 and 27% in fasted and fed rats, respectively). This disproportionate suppression of hepatic glucose production could not be explained by cooperative substrate effects inasmuch as microsomal glucose-6-phosphatase isolated from saline- and insulin-treated rats followed Michaelis-Menten kinetics (Hill coefficient approximated 1). Acute insulin treatment of fasted rats in vivo did not reproducibly inhibit glucose-6-phosphatase activity assayed subsequently in isolated microsomes incubated in the absence of insulin. However, addition of insulin (0.6–600 nM) to either crude liver homogenates or to isolated, concentrated hepatic membranes (containing both microsomes and plasma membranes) inhibited glucose-6-phosphatase (P < 0.005 for each preparation). These findings indicate that inhibition of glucose-6-phosphatase is involved in the action of insulin to control hepatic glucose production.

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