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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Oct 1;100(7):1768–1774. doi: 10.1172/JCI119703

Gluconeogenesis, glucose handling, and structural changes in livers of the adult offspring of rats partially deprived of protein during pregnancy and lactation.

S P Burns 1, M Desai 1, R D Cohen 1, C N Hales 1, R A Iles 1, J P Germain 1, T C Going 1, R A Bailey 1
PMCID: PMC508361  PMID: 9312176

Abstract

Maternal protein restriction is a model of fetal programming of adult glucose intolerance. Perfused livers of 48-h- starved adult offspring of rat dams fed 8% protein diets during pregnancy and lactation produced more glucose from 6 mM lactate than did control livers from rats whose dams were fed 20% protein. In control livers, a mean of 24% of the glucose formed from lactate in the periportal region of the lobule was taken up by the most distal perivenous cells; this distal perivenous uptake was greatly diminished in maternal low protein (MLP) livers, accounting for a major fraction of the increased glucose output of MLP livers. In control livers, the distal perivenous cells contained 40% of the total glucokinase of the liver; this perivenous concentration of glucokinase was greatly reduced in MLP livers. Intralobular distribution of phosphenolpyruvate carboxykinase was unaltered, though overall increased activity could have contributed to the elevated glucose output. Hepatic lobular volume in MLP livers was twice that in control livers, indicating that MLP livers had half the normal number of lobules. Fetal programming of adult glucose metabolism may operate partly through structural alterations and changes in glucokinase expression in the immediate perivenous region.

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Selected References

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  1. Almond M. K., Smith A., Cohen R. D., Iles R. A., Flynn G. Substrate and pH effects on glutamine synthesis in rat liver. Consequences for acid-base regulation. Biochem J. 1991 Sep 15;278(Pt 3):709–714. doi: 10.1042/bj2780709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bali D., Svetlanov A., Lee H. W., Fusco-DeMane D., Leiser M., Li B., Barzilai N., Surana M., Hou H., Fleischer N. Animal model for maturity-onset diabetes of the young generated by disruption of the mouse glucokinase gene. J Biol Chem. 1995 Sep 15;270(37):21464–21467. doi: 10.1074/jbc.270.37.21464. [DOI] [PubMed] [Google Scholar]
  3. Ballard F. J., Hanson R. W. Phosphoenolpyruvate carboxykinase and pyruvate carboxylase in developing rat liver. Biochem J. 1967 Sep;104(3):866–871. doi: 10.1042/bj1040866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burns S. P., Cohen R. D., Iles R. A., Germain J. P., Going T. C., Evans S. J., Royston P. A method for determination in situ of variations within the hepatic lobule of hepatocyte function and metabolite concentrations. Biochem J. 1996 Oct 15;319(Pt 2):377–383. doi: 10.1042/bj3190377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Caro J. F., Triester S., Patel V. K., Tapscott E. B., Frazier N. L., Dohm G. L. Liver glucokinase: decreased activity in patients with type II diabetes. Horm Metab Res. 1995 Jan;27(1):19–22. doi: 10.1055/s-2007-979899. [DOI] [PubMed] [Google Scholar]
  6. Clément K., Pueyo M. E., Vaxillaire M., Rakotoambinina B., Thuillier F., Passa P., Froguel P., Robert J. J., Velho G. Assessment of insulin sensitivity in glucokinase-deficient subjects. Diabetologia. 1996 Jan;39(1):82–90. doi: 10.1007/BF00400417. [DOI] [PubMed] [Google Scholar]
  7. Cohen R. D., Iles R. A., Barnett D., Howell M. E., Strunin J. The effect of changes in lactate uptake on the intracellular pH of the perfused rat liver. Clin Sci. 1971 Aug;41(2):159–170. doi: 10.1042/cs0410159. [DOI] [PubMed] [Google Scholar]
  8. Davidson A. L., Arion W. J. Factors underlying significant underestimations of glucokinase activity in crude liver extracts: physiological implications of higher cellular activity. Arch Biochem Biophys. 1987 Feb 15;253(1):156–167. doi: 10.1016/0003-9861(87)90648-5. [DOI] [PubMed] [Google Scholar]
  9. Desai M., Byrne C. D., Zhang J., Petry C. J., Lucas A., Hales C. N. Programming of hepatic insulin-sensitive enzymes in offspring of rat dams fed a protein-restricted diet. Am J Physiol. 1997 May;272(5 Pt 1):G1083–G1090. doi: 10.1152/ajpgi.1997.272.5.G1083. [DOI] [PubMed] [Google Scholar]
  10. Desai M., Crowther N. J., Lucas A., Hales C. N. Organ-selective growth in the offspring of protein-restricted mothers. Br J Nutr. 1996 Oct;76(4):591–603. doi: 10.1079/bjn19960065. [DOI] [PubMed] [Google Scholar]
  11. Desai M., Crowther N. J., Ozanne S. E., Lucas A., Hales C. N. Adult glucose and lipid metabolism may be programmed during fetal life. Biochem Soc Trans. 1995 May;23(2):331–335. doi: 10.1042/bst0230331. [DOI] [PubMed] [Google Scholar]
  12. Exton J. H., Park C. R. Control of gluconeogenesis in liver. I. General features of gluconeogenesis in the perfused livers of rats. J Biol Chem. 1967 Jun 10;242(11):2622–2636. [PubMed] [Google Scholar]
  13. Guder W. G., Schmidt U. Liver cell heterogeneity. The distribution of pyruvate kinase and phosphoenolpyruvate carboxykinase (GTP) in the liver lobule of fed and starved rats. Hoppe Seylers Z Physiol Chem. 1976 Dec;357(12):1793–1800. doi: 10.1515/bchm2.1976.357.2.1793. [DOI] [PubMed] [Google Scholar]
  14. Hales C. N., Barker D. J. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia. 1992 Jul;35(7):595–601. doi: 10.1007/BF00400248. [DOI] [PubMed] [Google Scholar]
  15. Hales C. N., Desai M., Ozanne S. E., Crowther N. J. Fishing in the stream of diabetes: from measuring insulin to the control of fetal organogenesis. Biochem Soc Trans. 1996 May;24(2):341–350. doi: 10.1042/bst0240341. [DOI] [PubMed] [Google Scholar]
  16. Häussinger D., Sies H., Gerok W. Functional hepatocyte heterogeneity in ammonia metabolism. The intercellular glutamine cycle. J Hepatol. 1985;1(1):3–14. doi: 10.1016/s0168-8278(85)80063-5. [DOI] [PubMed] [Google Scholar]
  17. Jungermann K. Dynamics of zonal hepatocyte heterogeneity. Perinatal development and adaptive alterations during regeneration after partial hepatectomy, starvation and diabetes. Acta Histochem Suppl. 1986;32:89–98. [PubMed] [Google Scholar]
  18. Martin-Pont B., Tamboise E. Etude cytologique et histologique quantitative de quelques aspects de l'hépatocyte maternel et du lobule au 18e jour de la gestation chez le rat "Wistar". Bull Assoc Anat (Nancy) 1984 Dec;68(203):23–40. [PubMed] [Google Scholar]
  19. Quistorff B., Grunnet N., Cornell N. W. Digitonin perfusion of rat liver. A new approach in the study of intra-acinar and intracellular compartmentation in the liver. Biochem J. 1985 Feb 15;226(1):289–297. doi: 10.1042/bj2260289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Racine L., Scoazec J. Y., Moreau A., Bernuau D., Feldmann G. Effects of digitonin on the intracellular content of rat hepatocytes: implications for its use in the study of intralobular heterogeneity. J Histochem Cytochem. 1993 Jul;41(7):991–1001. doi: 10.1177/41.7.8515054. [DOI] [PubMed] [Google Scholar]
  21. Snoeck A., Remacle C., Reusens B., Hoet J. J. Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. Biol Neonate. 1990;57(2):107–118. doi: 10.1159/000243170. [DOI] [PubMed] [Google Scholar]
  22. Tal M., Schneider D. L., Thorens B., Lodish H. F. Restricted expression of the erythroid/brain glucose transporter isoform to perivenous hepatocytes in rats. Modulation by glucose. J Clin Invest. 1990 Sep;86(3):986–992. doi: 10.1172/JCI114801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Toyoda Y., Miwa I., Kamiya M., Ogiso S., Okuda J., Nonogaki T. Changes in subcellular and zonal distribution of glucokinase in rat liver during postnatal development. FEBS Lett. 1995 Feb 6;359(1):81–84. doi: 10.1016/0014-5793(94)01452-7. [DOI] [PubMed] [Google Scholar]
  24. Trinder P. Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol. 1969 Mar;22(2):158–161. doi: 10.1136/jcp.22.2.158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Valera A., Bosch F. Glucokinase expression in rat hepatoma cells induces glucose uptake and is rate limiting in glucose utilization. Eur J Biochem. 1994 Jun 1;222(2):533–539. doi: 10.1111/j.1432-1033.1994.tb18895.x. [DOI] [PubMed] [Google Scholar]
  26. Vandercammen A., Van Schaftingen E. Species and tissue distribution of the regulatory protein of glucokinase. Biochem J. 1993 Sep 1;294(Pt 2):551–556. doi: 10.1042/bj2940551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Vionnet N., Stoffel M., Takeda J., Yasuda K., Bell G. I., Zouali H., Lesage S., Velho G., Iris F., Passa P. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature. 1992 Apr 23;356(6371):721–722. doi: 10.1038/356721a0. [DOI] [PubMed] [Google Scholar]
  28. Wagenaar G. T., Chamuleau R. A., Pool C. W., de Haan J. G., Maas M. A., Korfage H. A., Lamers W. H. Distribution and activity of glutamine synthase and carbamoylphosphate synthase upon enlargement of the liver lobule by repeated partial hepatectomies. J Hepatol. 1993 Mar;17(3):397–407. doi: 10.1016/s0168-8278(05)80224-7. [DOI] [PubMed] [Google Scholar]
  29. Yamagata K., Furuta H., Oda N., Kaisaki P. J., Menzel S., Cox N. J., Fajans S. S., Signorini S., Stoffel M., Bell G. I. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature. 1996 Dec 5;384(6608):458–460. doi: 10.1038/384458a0. [DOI] [PubMed] [Google Scholar]
  30. Yamagata K., Oda N., Kaisaki P. J., Menzel S., Furuta H., Vaxillaire M., Southam L., Cox R. D., Lathrop G. M., Boriraj V. V. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature. 1996 Dec 5;384(6608):455–458. doi: 10.1038/384455a0. [DOI] [PubMed] [Google Scholar]

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