Increased hepatic gluconeogenesis maintains glycemia during fasting and has been considered responsible for elevated hepatic
glucose output in
type 2 diabetes.
Glucose derived periportally via gluconeogenesis is partially taken up perivenously in perfused liver but not in adult rats whose mothers were
protein-restricted during gestation (MLP rats)-an environmental model of fetal programming of adult
glucose intolerance exhibiting diminished perivenous
glucokinase (GK) activity. We now show that perivenous
glucose uptake rises with increasing
glucose concentration (0-8 mmol/l) in control but not MLP liver, indicating that GK is flux-generating. The data demonstrate that acute control of hepatic
glucose output is principally achieved by increasing perivenous
glucose uptake, with rising
glucose concentration during refeeding, rather than by downregulation of gluconeogenesis, which occurs in different hepatocytes. Consistent with these observations,
glycogen synthesis in vivo commenced in the perivenous cells during refeeding, MLP livers accumulating less
glycogen than controls. GK gene transcription was unchanged in MLP liver, the data supporting a recently proposed posttranscriptional model of GK regulation involving nuclear-cytoplasmic transport. The results are pertinent to impaired regulation of hepatic
glucose output in
type 2 diabetes, which could arise from diminished GK-mediated
glucose uptake rather than increased gluconeogenesis.