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 fluxgenerating. 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. Diabetes 52:1326 -1332, 2003 T he precise mechanism(s) by which the liver normally switches rapidly from glucose production during fasting to glucose uptake and glycogen synthesis after refeeding or a glucose load remain unclear. Net hepatic glycogenolysis is promptly curtailed during glucose infusion, but gluconeogenesis is not decreased (1). These and other observations (2) have contributed to the view that glycogen is mainly synthesized via an "indirect" pathway during the early postprandial phase, in which gluconeogenic glucose-6-phosphate (G6P) is diverted to glycogen (3,4), rather than via the "direct" pathway from glucose to glycogen. Experiments in humans and in rats have demonstrated that if insulin is maintained at constant levels but glycemia is increased by glucose administration, then hepatic glucose output is rapidly suppressed and hepatic glucose uptake rises (1,5-8); postprandial hyperglycemia in type 2 diabetes is partly caused by failure of this mechanism. Hyperglycemia per se has no significant effect on hepatic gluconeogenic flux (1), and refeeding does not suppress rat liver G6P (9) in the time frame in which glucose production is switched off in individuals without diabetes (6,7). These observations raise the problem of how the balance between glycogen synthesis, gluconeogenesis, and glucose output is regulated from a generally assumed common pool of G6P.However, none of these studies takes account of metabolic heterogeneity along the radius of the hepatic lobule. If glucose output and uptake occurred in different hepatocytes, then a relatively simple explan...

We demonstrate that MRI imaging at sub-millimetre resolution can distinguish between periportal and perivenous zones of the rat liver lobule. This made it possible to measure the hepatic lobular radius in ex-vivo perfused fixed livers using MRI. Comparisons of histomorphometric and MRI measurements of lobular radius were in good agreement, although MRI measurements were significantly smaller (P`0.001). Male rats whose mothers were fed 40% of the protein of controls during gestation and lactation, had a significantly larger hepatic lobular radius than that of controls [449 AE 11 mm vs 373 AE 9 mm (mean AE SEM), respectively, p`0.001, n = 12; histomorphometry data]. The proton T 2 in periportal and perivenous zones was mapped both before and after antegrade or retrograde perfusion of 10 ml of digitonin (4 mg ml À1 ). Only the T 2 of the hypointense regions increased significantly following antegrade perfusion of digitonin and conversely only that of the intense regions following retrograde perfusion. Digitonin causes permeabilization of cells in specific hepatic zones, determined by the direction of perfusion. The intense and hypointense regions of the hepatic MR images thus arise from the perivenous and periportal zones of the hepatic lobule, respectively.

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