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. 1998 May 15;101(10):2215–2222. doi: 10.1172/JCI2548

Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice.

M Pontoglio 1, S Sreenan 1, M Roe 1, W Pugh 1, D Ostrega 1, A Doyen 1, A J Pick 1, A Baldwin 1, G Velho 1, P Froguel 1, M Levisetti 1, S Bonner-Weir 1, G I Bell 1, M Yaniv 1, K S Polonsky 1
PMCID: PMC508809  PMID: 9593777

Abstract

Mutations in the gene for the transcription factor hepatocyte nuclear factor (HNF) 1alpha cause maturity-onset diabetes of the young (MODY) 3, a form of diabetes that results from defects in insulin secretion. Since the nature of these defects has not been defined, we compared insulin secretory function in heterozygous [HNF-1alpha (+/-)] or homozygous [HNF-1alpha (-/-)] mice with null mutations in the HNF-1alpha gene with their wild-type littermates [HNF-1alpha (+/+)]. Blood glucose concentrations were similar in HNF-1alpha (+/+) and (+/-) mice (7.8+/-0.2 and 7.9+/-0.3 mM), but were significantly higher in the HNF-1alpha (-/-) mice (13.1+/-0.7 mM, P < 0.001). Insulin secretory responses to glucose and arginine in the perfused pancreas and perifused islets from HNF-1alpha (-/-) mice were < 15% of the values in the other two groups and were associated with similar reductions in intracellular Ca2+ responses. These defects were not due to a decrease in glucokinase or insulin gene transcription. beta cell mass adjusted for body weight was not reduced in the (-/-) animals, although pancreatic insulin content adjusted for pancreas weight was slightly lower (0.06+/-0.01 vs. 0.10+/-0.01 microg/mg, P < 0.01) than in the (+/+) animals. In summary, a null mutation in the HNF-1alpha gene in homozygous mice leads to diabetes due to alterations in the pathways that regulate beta cell responses to secretagogues including glucose and arginine. These results provide further evidence in support of a key role for HNF-1alpha in the maintenance of normal beta cell function.

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Selected References

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  1. Bancroft J. D., McDowell S. A., Degen S. J. The human prothrombin gene: transcriptional regulation in HepG2 cells. Biochemistry. 1992 Dec 15;31(49):12469–12476. doi: 10.1021/bi00164a025. [DOI] [PubMed] [Google Scholar]
  2. Bonner-Weir S., Deery D., Leahy J. L., Weir G. C. Compensatory growth of pancreatic beta-cells in adult rats after short-term glucose infusion. Diabetes. 1989 Jan;38(1):49–53. doi: 10.2337/diab.38.1.49. [DOI] [PubMed] [Google Scholar]
  3. Bonner-Weir S. Regulation of pancreatic beta-cell mass in vivo. Recent Prog Horm Res. 1994;49:91–104. doi: 10.1016/b978-0-12-571149-4.50008-8. [DOI] [PubMed] [Google Scholar]
  4. Brooks A. R., Levy-Wilson B. Hepatocyte nuclear factor 1 and C/EBP are essential for the activity of the human apolipoprotein B gene second-intron enhancer. Mol Cell Biol. 1992 Mar;12(3):1134–1148. doi: 10.1128/mcb.12.3.1134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Byrne M. M., Sturis J., Menzel S., Yamagata K., Fajans S. S., Dronsfield M. J., Bain S. C., Hattersley A. T., Velho G., Froguel P. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes. 1996 Nov;45(11):1503–1510. doi: 10.2337/diab.45.11.1503. [DOI] [PubMed] [Google Scholar]
  6. Cereghini S., Raymondjean M., Carranca A. G., Herbomel P., Yaniv M. Factors involved in control of tissue-specific expression of albumin gene. Cell. 1987 Aug 14;50(4):627–638. doi: 10.1016/0092-8674(87)90036-5. [DOI] [PubMed] [Google Scholar]
  7. Courtois G., Morgan J. G., Campbell L. A., Fourel G., Crabtree G. R. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha 1-antitrypsin promoters. Science. 1987 Oct 30;238(4827):688–692. doi: 10.1126/science.3499668. [DOI] [PubMed] [Google Scholar]
  8. Emens L. A., Landers D. W., Moss L. G. Hepatocyte nuclear factor 1 alpha is expressed in a hamster insulinoma line and transactivates the rat insulin I gene. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7300–7304. doi: 10.1073/pnas.89.16.7300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fajans S. S., Bell G. I., Bowden D. W., Halter J. B., Polonsky K. S. Maturity onset diabetes of the young (MODY). Diabet Med. 1996 Sep;13(9 Suppl 6):S90–S95. [PubMed] [Google Scholar]
  10. Froguel P. Glucokinase and MODY: from the gene to the disease. Diabet Med. 1996 Sep;13(9 Suppl 6):S96–S97. [PubMed] [Google Scholar]
  11. Lehto M., Tuomi T., Mahtani M. M., Widén E., Forsblom C., Sarelin L., Gullström M., Isomaa B., Lehtovirta M., Hyrkkö A. Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect. J Clin Invest. 1997 Feb 15;99(4):582–591. doi: 10.1172/JCI119199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Maire P., Wuarin J., Schibler U. The role of cis-acting promoter elements in tissue-specific albumin gene expression. Science. 1989 Apr 21;244(4902):343–346. doi: 10.1126/science.2711183. [DOI] [PubMed] [Google Scholar]
  13. McCulloch D. K., Koerker D. J., Kahn S. E., Bonner-Weir S., Palmer J. P. Correlations of in vivo beta-cell function tests with beta-cell mass and pancreatic insulin content in streptozocin-administered baboons. Diabetes. 1991 Jun;40(6):673–679. doi: 10.2337/diab.40.6.673. [DOI] [PubMed] [Google Scholar]
  14. Montaña E., Bonner-Weir S., Weir G. C. Beta cell mass and growth after syngeneic islet cell transplantation in normal and streptozocin diabetic C57BL/6 mice. J Clin Invest. 1993 Mar;91(3):780–787. doi: 10.1172/JCI116297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Pontoglio M., Barra J., Hadchouel M., Doyen A., Kress C., Bach J. P., Babinet C., Yaniv M. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell. 1996 Feb 23;84(4):575–585. doi: 10.1016/s0092-8674(00)81033-8. [DOI] [PubMed] [Google Scholar]
  16. Pontoglio M., Faust D. M., Doyen A., Yaniv M., Weiss M. C. Hepatocyte nuclear factor 1alpha gene inactivation impairs chromatin remodeling and demethylation of the phenylalanine hydroxylase gene. Mol Cell Biol. 1997 Sep;17(9):4948–4956. doi: 10.1128/mcb.17.9.4948. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Roe M. W., Lancaster M. E., Mertz R. J., Worley J. F., 3rd, Dukes I. D. Voltage-dependent intracellular calcium release from mouse islets stimulated by glucose. J Biol Chem. 1993 May 15;268(14):9953–9956. [PubMed] [Google Scholar]
  18. Sreenan S., Sturis J., Pugh W., Burant C. F., Polonsky K. S. Prevention of hyperglycemia in the Zucker diabetic fatty rat by treatment with metformin or troglitazone. Am J Physiol. 1996 Oct;271(4 Pt 1):E742–E747. doi: 10.1152/ajpendo.1996.271.4.E742. [DOI] [PubMed] [Google Scholar]
  19. Sturis J., Pugh W. L., Tang J., Ostrega D. M., Polonsky J. S., Polonsky K. S. Alterations in pulsatile insulin secretion in the Zucker diabetic fatty rat. Am J Physiol. 1994 Aug;267(2 Pt 1):E250–E259. doi: 10.1152/ajpendo.1994.267.2.E250. [DOI] [PubMed] [Google Scholar]
  20. Tronche F., Ringeisen F., Blumenfeld M., Yaniv M., Pontoglio M. Analysis of the distribution of binding sites for a tissue-specific transcription factor in the vertebrate genome. J Mol Biol. 1997 Feb 21;266(2):231–245. doi: 10.1006/jmbi.1996.0760. [DOI] [PubMed] [Google Scholar]
  21. 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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