Tissue and subcellular distribution of glucokinase in rat liver and their changes during fasting-refeeding

Toyoda, Yusuke; Miwa, Ichitomo; Kamiya, Masahiro; S, Ogiso; Nonogaki, Tsunemasa; Aoki, Shigehisa; Okuda, Jun

doi:10.1007/bf01464473

Cited by 28 publications

(35 citation statements)

References 36 publications

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“…We suggest (Fig. 6) that periportal glycogen is synthesized from G6P derived from cytosolic (active) GK, which is present throughout the lobule in fully refed animals (13) and not from gluconeogenically derived G6P. Several lines of evidence support this contention.…”

Section: Discussionmentioning

confidence: 77%

“…(The half-lives of GK activity and GK mRNA are 30 h and 45 min respectively [30,31].) During fasting, GK is tightly bound to the inhibitory GK regulatory protein (GKRP) (32) in the nucleus (33) (except perivenously [13]). Farrelly et al (34) and Grimsby et al (35) demonstrated that knockout of the GKRP in mice resulted in decreased hepatic GK activity, suggesting that an impor- tant function of nuclear sequestration of GK during starvation might be to delay degradation of GK protein, which is relatively easily inactivated by oxidation in vitro (19).…”

Section: Discussionmentioning

confidence: 99%

“…We have reexamined the pathways of glycogen synthesis during refeeding in starved rats, mapping glucose metabolism (10) and glycogen formation within the hepatic lobule in intact liver. Using this technique, we have previously shown that in starved rats, gluconeogenesis is confined to periportal cells (70 -80% of lobular volume) (10,11), whereas in the perivenous cells, where glucokinase (GK) activity was most concentrated (12,13), uptake of glucose occurs (12,14).…”

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confidence: 99%

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Fetal Programming of Perivenous Glucose Uptake Reveals a Regulatory Mechanism Governing Hepatic Glucose Output During Refeeding

et al. 2003

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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...

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Fetal Programming of Perivenous Glucose Uptake Reveals a Regulatory Mechanism Governing Hepatic Glucose Output During Refeeding

et al. 2003

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“…The liver slices were dehydrated, embedded in paraffin, and sectioned at a thickness of 3 m. The sections were mounted on silanized slides. Immunohistochemical staining was carried out as described previously (16). The total optical density of GK in the nucleus was quantitated and normalized by the total area of nucleus by computerized image analysis using Image-Pro Plus software (Planetron Inc. Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

An Allosteric Activator of Glucokinase Impairs the Interaction of Glucokinase and Glucokinase Regulatory Protein and Regulates Glucose Metabolism

Futamura

Hosaka

Kadotani

et al. 2006

Journal of Biological Chemistry

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Glucokinase (GK) plays a key role in the control of blood glucose homeostasis. We identified a small molecule GK activator, compound A, that increased the glucose affinity and maximal velocity (V max ) of GK. Compound A augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. In rat oral glucose tolerance tests, orally administrated compound A lowered plasma glucose elevation with a concomitant increase in plasma insulin and hepatic glycogen. In liver, GK activity is acutely controlled by its association to the glucokinase regulatory protein (GKRP). In order to decipher the molecular aspects of how GK activator affects the shuttling of GK between nucleus and cytoplasm, the effect of compound A on GK-GKRP interaction was further investigated. Compound A increased the level of cytoplasmic GK in both isolated rat primary hepatocytes and the liver tissues from rats. Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP. On the other hand, compound A did not bind to glucose-unbound GK or GKRPassociated GK. Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP. Given the combined prominent role of GK on insulin secretion and hepatic glucose metabolism where the GK-GKRP mechanism is involved, activation of GK has a new therapeutic potential in the treatment of type 2 diabetes.There are three key aspects of type 2 diabetes pathogenesis, which are the focus of current and future therapies: insulin resistance, defective insulin secretion, and increased hepatic glucose production. Glucokinase (GK) 2 is the predominant glucose phosphorylation enzyme in pancreatic ␤-cells and hepatocytes. GK plays an important role as a glucose sensor for controlling plasma glucose homeostasis by enhancing insulin secretion from pancreatic ␤-cells and glucose metabolism in the liver (1, 2), which provides rational expectations that enhancement of GK activity would be a novel therapeutic strategy for type 2 diabetes. Consistent with this rationale, recently discovered small molecule allosteric activators of GK have been demonstrated to have antidiabetic efficacy in rodents (3, 4).To investigate the mechanism of action of GK activators, the interaction between GK and glucokinase regulatory protein (GKRP) is a key aspect. It is well known that hepatic GK activity is modulated by the endogenous inhibitor, glucokinase regulatory protein (GKRP) (5-8). GK is localized in the nucleus as an inactive complex with GKRP at low glucose concentrations and is dissociated from the GK⅐GKRP complex and translocated to the cytoplasm at high glucose concentrations, which triggers glucose disposal (9). Modulators of the GK-GKRP interaction have been shown to enhance hepatic glucose disposal (7). We recently solved the co-crystal structure of hepatic GK complex with GK activator, in which GK undergoes a large conformational change between the active and inactive forms at diffe...

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“…Fructose 1-phosphate may also contribute to glycogen accumulation by inhibition of glycogen phosphorylase [27]. Since in livers from 48-h starved rats glucokinase activity (and enzyme protein concentration [28]) are markedly concentrated in the most perivenous cells [15], where the accumulation of fructose 1-phosphate is greatest ( Figure 5), glucokinase activation would occur primarily in those cells and present Figure 5 Fractional change in PME during fructose infusion, and the relationship to ∆ATP Top panel : fractional change in PMEs (predominantly fructose 1-phosphate) concentration during fructose infusion (compared with pre-fructose), plotted against FVR. MeanspS.E.M.…”

Section: Figure 3 Hepatic Lactate Uptake Before ($) and During (#) Thmentioning

confidence: 99%

Hepatic intralobular mapping of fructose metabolism in the rat liver

Burns

Murphy

Iles

et al. 2000

Biochemical Journal

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Detailed mapping of glucose and lactate metabolism along the radius of the hepatic lobule was performed in situ in rat livers perfused with 1.5 mM lactate before and during the addition of 5 mM fructose. The majority of fructose uptake occurred in the periportal region ; 45 % of fructose taken up in the periportal half of the lobular volume being converted into glucose. Periportal lactate uptake was markedly decreased by addition of fructose. Basal perivenous lactate output, which was derived from glucose synthesized periportally, was increased in the presence of fructose. During fructose infusion there was a small decrease in cell pH periportally, but acidification of up to 0.5 pH units perivenously. The evidence suggests that in situ the apparent direct conversion of fructose into lactate represents, to a sub-

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Tissue and subcellular distribution of glucokinase in rat liver and their changes during fasting-refeeding

Cited by 28 publications

References 36 publications

Fetal Programming of Perivenous Glucose Uptake Reveals a Regulatory Mechanism Governing Hepatic Glucose Output During Refeeding

Fetal Programming of Perivenous Glucose Uptake Reveals a Regulatory Mechanism Governing Hepatic Glucose Output During Refeeding

An Allosteric Activator of Glucokinase Impairs the Interaction of Glucokinase and Glucokinase Regulatory Protein and Regulates Glucose Metabolism

Hepatic intralobular mapping of fructose metabolism in the rat liver

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