Glucose 6-phosphate hydrolysis is activated by glucagon in a low temperature-sensitive manner.
Glucagon affects liver glucose metabolism mainly by activating glycogen breakdown and by inhibiting pyruvate kinase, whereas a possible effect on glucose-6-phosphatase has also been suggested. Although such a target is of physiological importance for liver glucose production it was never proven. By using a model of liver cells, perifused with dihydroxyacetone, we show here that the acute stimulation of gluconeogenesis by glucagon (10(-7) m) was not related to the significant inhibition of pyruvate kinase but to a dramatic activation of the hydrolysis of glucose 6-phosphate. We failed to find an acute change in glucose-6-phosphatase activity by glucagon, but the increase in glucose 6-phosphate hydrolysis was abolished at 21 degrees C; conversely the effect on pyruvate kinase was not affected by temperature. The activation of glucose 6-phosphate hydrolysis by glucagon was confirmed in vivo, in postabsorptive rats receiving a constant infusion of glucagon, by the combination of a 2-fold increase in hepatic glucose production and a 60% decrease in liver glucose 6-phosphate concentration. Besides the description of a novel effect of glucagon on glucose 6-phosphate hydrolysis by a temperature-sensitive mechanism, this finding could represent an important breakthrough in the understanding of type II diabetes, because glucose 6-phosphate is proposed to be a key molecule in the transcriptional effect of glucose.
Ichai
C
C
Laboratoire de Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier, Grenoble 38041, France.
Guignot
L
L
El-Mir
M Y
MY
Nogueira
V
V
Guigas
B
B
Chauvin
C
C
Fontaine
E
E
Mithieux
G
G
Leverve
X M
XM
D000495:Allosteric Site; D000818:Animals; D004098:Dihydroxyacetone / Q000494:pharmacology; D004099:Dihydroxyacetone Phosphate / Q000494:pharmacology; D004789:Enzyme Activation; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006868:Hydrolysis; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D011770:Pyruvate Kinase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013696:Temperature; D013997:Time Factors; D014158:Transcription, Genetic
D019298:Glucose-6-Phosphate; D004099:Dihydroxyacetone Phosphate; D005934:Glucagon; D011770:Pyruvate Kinase; D005952:Glucose-6-Phosphatase; D005947:Glucose; D004098:Dihydroxyacetone