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Fetal programming of perivenous glucose uptake reveals a regulatory mechanism governing hepatic glucose output during refeeding

Murphy, Helena C., Regan, Gemma, Bogdarina, Irina G., Clark, Adrian J.L., Iles, Richard A., Cohen, Robert D., Hitman, Graham A., Berry, Colin L., Coade, Zoe, Petry, Clive J. and Burns, Shamus P. (2003) Fetal programming of perivenous glucose uptake reveals a regulatory mechanism governing hepatic glucose output during refeeding. Diabetes, 52 (6). pp. 1326-1332. ISSN 0012-1797

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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 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.

Item Type: Article
Additional Information: © 2003 by the American Diabetes Association, Inc.
Uncontrolled Keywords: hepatic gluconeogenesis glycemia glucose diabetes
Subjects: Q Science > Q Science (General)
Q Science > QP Physiology
Q Science > QR Microbiology
Schools: School of Applied Sciences

1. Rossetti L, Giaccari A, Barzilai N, Howard K, Sebel G, Hu M: Mechanism by
which hyperglycemia inhibits hepatic glucose production in conscious
rats. J Clin Invest 92:1126–1134, 1993
2. McGarry JD, Kuwajima M, Newgard CB, Foster DW: From dietary glucose
to liver glycogen: the full circle round. Ann Rev Nutr 7:51–73, 1987
3. Newgard CB, Hirsch LJ, Foster DW, McGarry JD: Studies on the mechanism
by which exogenous glucose is converted into liver glycogen in the
rat. J Biol Chem 258:8046–8052, 1983
4. Newgard CB, Moore SV, Foster DW, McGarry JD: Efficient hepatic
glycogen synthesis in refeeding rats requires continued flow through the
gluconeogenic pathway. J Biol Chem 259:6958–6963, 1984
5. Ludvik B, Nolan JJ, Roberts J, Baloga M, Joyce J, Bell J, Olefsky JM:
Evidence for decreased splanchnic glucose uptake after glucose administration
in non-insulin dependent diabetes mellitus. J Clin Invest 100:2354–
2361, 1997
6. Liljenquist J, Meuller G, Cherrington A, Perry J, Rabinowitz D: Hyperglycaemia
per se can inhibit glucose production in man. J Clin Endocrinol
Metab 48:171–175, 1979
7. Basu A, Caumo A, Bettini F, Gelisio A, Alzaid A, Cobelli C, Rizza RA:
Impaired basal glucose effectiveness in NIDDM. Contribution of defects in
glucose disappearance and production, measured using an optimized
minimal model independent protocol. Diabetes 46:421–432, 1997
8. Mevorach M, Giacca A, Aharon Y, Hawkins M, Shamoon H, Rossetti L:
Regulation of endogenous glucose production by glucose per se is impaired
in type 2 diabetes mellitus. J Clin Invest 102:744–753, 1998
9. Minassian C, Daniele N, Bordet JC, Zitoun C, Mithieux G: Liver glucose-6-
phosphatase activity is inhibited by refeeding in rats. J Nutr 125:2727–
2732, 1995
10. Burns SP, Cohen RD, Iles RA, Germain JP, Going TCH, Evans SJW,
Royston P: A method for the determination in situ of variations within the
hepatic lobule of hepatocyte function and metabolite concentrations.
Biochem J 319:377–383, 1996
11. Jungermann K, Katz N: Functional specialization of different hepatocyte
populations. Physiol Rev 69:708–764, 1989
12. Burns SP, Desai M, Cohen RD, Hales CN, Iles RA, Germain JP, Going TCH,
Bailey RA: Gluconeogenesis, glucose handling, and structural changes in
livers of the adult offspring of rats partially deprived of protein during
pregnancy and lactation. J Clin Invest 100:1768–1774, 1997
13. Toyoda Y, Miwa I, Kamiya M, Ogiso S, Nonogaki N, Aoki S, Okuda J: Tissue
and subcellular distribution of glucokinase in rat liver and their changes
during fasting-refeeding. Histochemistry 103:31–38, 1995
14. Burns SP, Murphy HC, Iles RA, Bailey RA, Cohen RD: Hepatic intralobular
mapping of fructose metabolism in the rat liver. Biochem J 349:539–545,
15. Hales CN, Barker DJP: Type 2 (non-insulin-dependent) diabetes mellitus:
the thrifty phenotype hypothesis. Diabetologia 35:595–601, 1992
16. Hales CN, Desai M, Ozanne SE, Crowther NJ: Fishing in the stream of
diabetes: from measuring insulin to the control of fetal organogenesis.
Biochem Soc Trans 24:341–350, 1996
17. Cohen RD, Iles RA Barnett D, Howell MEO, Strunin J: The effect of change
in lactate uptake on the intracellular pH of the perfused rat liver. Clin Sci
41:159–170, 1971
18. Krebs HA, Henseleit K: Untersuchungen u¨ ber die Harnstoffbildung im
Tierko¨ rper. Hoppe-Seylers Zeitschr Physiol Chem 210:33–36, 1932
19. Davidson AL, Arion WJ: Factors underlying significant underestimations of
glucokinase activity in crude liver extracts: physiological implications of
higher cellular activity. Arch Biochem Biophys 253:156–167, 1987
20. Babcock MB, Cardell RR: Hepatic glycogen patterns in fasted and fed rats.
Am J Anat 140:299–338, 1974
21. Moorman AF, de Boer PA, Charles R, Lamers WH: Pericentral expression
pattern of glucokinase RNA in the rat liver lobulus. FEBS Lett 287:47–52,
22. Rossetti L, Chen W, Hu M, Hawkins M, Barzilai N, Efrat S: Abnormal
regulation of HGP by hyperglycemia in mice with a disrupted glucokinase
allele. Am J Physiol 273: E743–E750, 1997
23. Matschinsky FM: Glucokinase as glucose sensor and metabolic signal
generator in pancreatic beta-cells and hepatocytes. Diabetes 39:647–652,
24. Kurland IJ, Pilkis SJ: Indirect versus direct routes of hepatic glycogen
synthesis. FASEB J 3:2277–2281, 1989
25. Kuwajima M, Golden S, Katz J, Unger RH, Foster DW, McGarry JD: Active
hepatic glycogen synthesis from gluconeogenic precursors despite high
tissue levels of fructose 2,6-bisphosphate. J Biol Chem 261:2632–2637,
26. Seoane J, Gomez-Foix AM, O’Doherty R, Gomez-Ara C, Newgard CB,
Guinovart JJ: Glucose 6-phosphate produced by glucokinase, but not
hexokinase 1, promotes the activation of hepatic glycogen synthase. J Biol
Chem 271:23756–23760, 1996
27. Gomis RR, Cid E, Garcia-Rocha M, Ferrer JC Guinovart JJ: Liver glycogen
synthase but not the muscle isoform differentiates between glucose
6-phosphate produced by glucokinase or hexokinase. J Biol Chem 277:
23246–23252, 2002
28. Agius L, Peak M, Newgard CB, Gomez-Foix AM, Guinovart JJ: Evidence for
a role of glucose-induced translocation of glucokinase in the control of
hepatic glycogen synthesis. J Biol Chem 271:30479–30486, 1996
29. Gomis RR, Ferrer JC Guinovart JJ: Shared control of hepatic glycogen
synthesis by glycogen synthase and glucokinase. Biochem J 351:811–816,
30. Iynedjian PB, Gjinovci A, Renold AE: Stimulation by insulin of glucokinase
gene transcription in liver of diabetic rats. J Biol Chem 263:740–744, 1988
31. Iynedjian PB, Jotterand D, Nouspikel T, Asfari M, Pilot P-R: Transcriptional
induction of glucokinase gene by insulin in cultured liver cells and its
repression by the glucagon-cAMP system. J Biol Chem 264:21824–21829,
32. Vandercammen A, Van Schaftingen E: Species and tissue distribution of
the regulatory protein of glucokinase. Biochem J 294:551–556, 1993
33. Fernandez-Novell JM, Castel S, Bellido D, Ferrer JC, Vilaro S, Guinovart JJ:
Intracellular distribution of hepatic glucokinase and glucokinase regulatory
protein during the fasted to refed transition in rats. FEBS Lett
459:211–214, 1999
34. Farrelly D, Brown KS, Tieman A, Ren J, Lira SA, Hagan D, Gregg R,
Mookhtiar KA, Hariharan N: Mice mutant for GK regulatory protein exhibit
decreased liver GK: a sequestration mechanism in metabolic regulation.
Proc Natl Acad Sci U S A 96:14511–14516, 1999
35. Grimsby J, Coffey JW, Dvorozniak MT, Magram J, Li G, Matschinsky FM,
Shiota C, Kaur S, Magnuson MA, Grippo JF: Characterization of glucokinase
regulatory protein-deficient mice. J Biol Chem 275:7826–7831, 2000
36. Cohen RD: Roles of the liver and kidney in acid-base regulation and its
disorders. Br J Anaesth 67:154–164, 1991
37. Magnusson R, Rothman DL, Katz LD, Shulman RG, Shulman GI: Increased
rate of gluconeogenesis in type II diabetes mellitus: a 13C nuclear magnetic
resonance study. J Clin Invest 90:1323–1327, 1992

Depositing User: Sara Taylor
Date Deposited: 20 Dec 2007
Last Modified: 04 Nov 2015 16:25


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