The role of glucose-6-phosphatase in the action of insulin on hepatic glucose production in the rat.
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 x kg-1, euglycemic clamp) suppressed hepatic glucose production virtually completely in both fasted (32.4 +/- 2.4 vs. -6.1 +/- 14 mumol.min-1 x kg-1) and fed (64.6 +/- 6.4 vs. 5.5 +/- 5.2 mumol.min-1 x 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 mumol.min-1 x kg-1 and 80.8 +/- 10.1 vs. -3.6 +/- 12.6 mumol.min-1 x 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Gardner
L B
LB
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut.
Liu
Z
Z
Barrett
E J
EJ
D000818:Animals; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D004435:Eating / Q000502:physiology; D005215:Fasting / Q000502:physiology; D005947:Glucose / Q000032:analysis / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000502:physiology*; D006600:Hexosephosphates / Q000032:analysis / Q000378:metabolism; D006946:Hyperinsulinism / Q000201:enzymology; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000502:physiology / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D014316:Tritium
D006600:Hexosephosphates; D007328:Insulin; D014316:Tritium; D005952:Glucose-6-Phosphatase; D005947:Glucose