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Horm Metab Res 2002; 34(6): 288-292
DOI: 10.1055/s-2002-33256
Original Basic
© Georg Thieme Verlag Stuttgart · New York

Up-Regulation of Liver Glucose-6-Phosphatase in X-Linked Hypophosphatemic Mice

W.  Xie 1 , M.-C.  Méchin 1 , S.  G.  Dubois 2 , D.  Lajeunesse 2 , G.  van de Werve 1
  • 1Laboratoire d’Endocrinologie Métabolique, Departments of Nutrition and Biochemistry, Centre de Recherche du CHUM, University of Montreal, Montreal, Canada
  • 2Osteoarthritis Research Unit, Centre de Recherche du CHUM, University of Montreal, Montreal, Canada
Further Information

Publication History

Received 18 September 2001

Accepted after Revision 6 March 2002

Publication Date:
12 August 2002 (online)

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Abstract

We previously showed that a phosphate-deficient diet resulting in hypophosphatemia upregulated the catalytic subunit p36 of rat liver glucose-6-phosphatase, which is responsible for hepatic glucose production. A possible association between phosphate and glucose homeostasis was now further evaluated in the Hyp mouse, a murine homologue of human X-linked hypophosphatemia. We found that in the Hyp mouse as in the dietary Pi deficiency model, serum insulin was reduced while glycemia was increased, and that liver glucose-6-phosphatase activity was enhanced as a consequence of increased mRNA and protein levels of p36. In contrast, the Hyp model had decreased mRNA and protein levels of the putative glucose-6-phosphate translocase p46 and liver cyclic AMP was not increased as in the phosphate-deficient diet rats. It is concluded that in genetic as in dietary hypophosphatemia, elevated glucose-6-phosphatase activity could be partially responsible for the impaired glucose metabolism albeit through distinct mechanisms.

Key words

Glucose Intolerance - Phosphate Homeostasis - Mouse Liver

References

  • 1 Foster J DF, Pederson B A, Nordlie R C. Glucose-6-phosphatase structure, regulation, and function: an update.  Proc Soc Exp Biol Med. 1997;  215 314-332
    PubMedSearch in Google Scholar
  • 2 Lei K J, Shelly L L, Pan C J, Sidbury J B, Chou J Y. Mutations in the glucose-6-phosphatase gene that cause glycogen storage disease type 1a.  Science. 1993;  262 580-583
    PubMedSearch in Google Scholar
  • 3 Gerin I, Veiga-da-Cunha M, Achouri Y, Collet J F, van Schaftingen E. Sequence of a putative glucose-6-phosphate translocase, mutation in glycogen storage disease type Ib.  FEBS Lett. 1997;  419 235-238
    CrossrefPubMedSearch in Google Scholar
  • 4 van de Werve G, Lange A, Newgard C, Méchin M C, Li Y, Berteloot A. New lessons in the regulation of glucose metabolism taught by the glucose 6-phosphatase system.  Eur J Biochem. 2000;  267 1533-1549
    CrossrefPubMedSearch in Google Scholar
  • 5 Li Y, Méchin M C, van de Werve G. Diabetes affects similarly the catalytic subunit and putative glucose-6-phosphate translocase of glucose-6-phosphatase.  J Biol Chem. 1999;  274 33 866-33 868
    PubMedSearch in Google Scholar
  • 6 Li Y, van de Werve G. Distinct hormone stimulation and counteraction by insulin of the expression of the two components of glucose 6-phosphatase in HepG2 cells.  Biochem Biophys Res Commun. 2000;  272 41-44
    CrossrefPubMedSearch in Google Scholar
  • 7 Trinh K Y, O’Doherty R M, Anderson P, Lange A J, Newgard C B. Perturbation of fuel homeostasis caused by over-expression of the glucose-6-phosphatase catalytic subunit in liver of normal rats.  J Biol Chem. 1998;  273 31 615-31 620
    PubMedSearch in Google Scholar
  • 8 Econs M J. New insights into the pathogenesis of inherited phosphate wasting disorders.  Bone. 1999;  25 131-135
    CrossrefPubMedSearch in Google Scholar
  • 9 Lajeunesse D, Meyer Jr. R A, Hamel L. Direct demonstration of a humorally-mediated inhibition of renal phosphate transport in the Hyp mouse.  Kidney Int. 1996;  50 1531-1538
    PubMedSearch in Google Scholar
  • 10 The HYP Consortium . A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets.  Nature Genet. 1995;  11 130-136
    CrossrefPubMedSearch in Google Scholar
  • 11 Du L, Desbarats M, Viel J, Glorieux F H, Cawthorn C, Ecarot B. cDNA cloning of the murine Pex gene implicated in X-linked hypophosphatemia and evidence for expression in bone.  Genomics. 1996;  36 22-28
    CrossrefPubMedSearch in Google Scholar
  • 12 Guo R, Quarles L D. Cloning and sequencing of human PEX from a bone cDNA library: evidence for its developmental stage-specific regulation in osteoblasts.  J Bone Miner Res. 1997;  12 1009-1017
    PubMedSearch in Google Scholar
  • 13 DeFronzo R A, Lang R. Hypophosphatemia and glucose intolerance: evidence for tissue insensitivity to insulin.  N Engl J Med. 1980;  303 1259-1263
    CrossrefPubMedSearch in Google Scholar
  • 14 Paula F J, Plens A E, Foss M C. Effects of hypophosphatemia on glucose tolerance and insulin secretion.  Horm Metab Res. 1998;  30 281-284
    PubMedSearch in Google Scholar
  • 15 Xie W S, Li Y, Méchin M C, van de Werve G. Upregulation of liver glucose-6-phosphatase in rats fed with a Pi-deficient diet.  Biochem J. 1999;  343 393-396
    CrossrefPubMedSearch in Google Scholar
  • 16 Xie W S, Tran T L, Finegood D T, van de Werve G. Dietary phosphate deprivation in rats affects liver cyclic AMP, glycogen, key steps of gluconeogenesis and glucose production.  Biochem J. 2000;  352 227-232
    CrossrefPubMedSearch in Google Scholar
  • 17 Méchin M C, Annabi B, Pegorier J P, van de Werve G. Ontogeny of the catalytic subunit and putative glucose-6-phosphate transporter proteins of the rat microsomal liver glucose-6-phosphatase system.  Metabolism. 2000;  49 1200-1203
    CrossrefPubMedSearch in Google Scholar
  • 18 Tenenhouse H S. X-linked hypophosphatemia: a homologous disorder in humans and mice.  Nephrol Dial Transplant. 1999;  14 333-341
    CrossrefPubMedSearch in Google Scholar
  • 19 Kido S, Miyamoto K, Mizobuchi H, Taketani Y, Ohkido I, Ogawa N, Kaneko Y, Harashima S, Takeda E. Identification of regulatory sequences and binding proteins in the type II sodium/phosphate cotransporter NPT2 gene responsive to dietary phosphate.  J Biol Chem. 1999;  274 28 256-28 263
    PubMedSearch in Google Scholar
  • 20 Cowgill L D, Goldfarb S, Lau K, Slatopolsky E. Evidence for an intrinsic renal tubular defect in mice with genetic hypophosphatemic rickets.  J Clin Invest. 1979;  63 1203-1210
    PubMedSearch in Google Scholar
  • 21 Kiebzak G M, Roos B A, Meyer Jr. R A. Secondary hyperparathyroidism in X-linked hypophosphatemic mice.  Endocrinol. 1982;  111 650-652
    PubMedSearch in Google Scholar
  • 22 Zhou X J, Fadda G Z, Perna A F, Massry S G. Phosphate depletion impairs insulin secretion by pancreatic islets.  Kidney Int. 1991;  39 120-128
    PubMedSearch in Google Scholar
  • 23 Moore E E, Kuestner R E, Conklin D C, Whitmore T E, Downey W, Buddle M M, Adams R L, Bell L A, Thompson D L, Wolf A, Chen L, Stamm M R, Grant F J, Lok S, Ren H, de Jongh K S. Stanniocalcin 2: characterization of the protein and its localization to human pancreatic alpha cells.  Horm Metab Res. 1999;  31 406-414
    PubMedSearch in Google Scholar
  • 24 Drezner M K. PHEX gene and hypophosphatemia.  Kidney Int. 2000;  57 9-18
    CrossrefPubMedSearch in Google Scholar
  • 25 Shimada T, Mizutani S, Muto T, Vonega T, Hino R, Takeda S, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T. Cloning and characterization of FGF-23 as a causative factor of tumor-induced osteomalacia.  Proc Natl Acad Sci. 2001;  98 6500-6505
    CrossrefPubMedSearch in Google Scholar
  • 26 Bowe A E, Finnegan R, Jan de Beur S M, Cho J, Levine M A, Kumar R, Schiavi S C. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate.  Biochem Biophysical Res Comm. 2001;  284 977-981
    PubMedSearch in Google Scholar
  • 27 Rowe P S, de Zoysa P A, Dong R, Wang H R, White K E, Econs M J, Oudet C L. MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia.  Genomics. 2000;  67 54-68
    CrossrefPubMedSearch in Google Scholar
  • 28 Argiro L, Desbarats M, Glorieux F H, Ecarot B. MEPE, the gene encoding a tumor-secreted protein in oncogenic hypophosphatemic osteomalacia, is expressed in bone.  Genomics. 2001;  74 342-351
    CrossrefPubMedSearch in Google Scholar

G. van de Werve, Ph.D.

Département de Nutrition · Centre de Recherche du CHUM · Hôpital Notre-Dame ·

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