Skip to main content
SpringerLink
Log in
Book cover

Contributions of Physiology to the Understanding of Diabetes pp 43–53Cite as

Expression of the Insulin Gene and Its Regulation

  • Chapter

Abstract

Maintenance of the blood glucose concentration within a narrow range requires a delicate balance between glucose production and utilization; this can only be realized through the interplay of two major hormones, insulin and glucagon. Insulin is synthesized by the β;-cells of the pancreatic islets of Langerhans whereas glucagon is produced by the α;-cells. Biosynthesis and secretion of these two hormones must be tightly regulated to match fuel production and delivery to metabolic demands. Insulin is secreted in response to nutrients (glucose and amino acids) to promote energy storage in target organs (liver, muscle and adipose tissue); glucagon secretion is then inhibited. In the fasted state, insulin secretion falls and glucagon release is stimulated; this results in an activation of glycogenolysis and gluconeogenesis and, despite the lack of exogenous glucose, in the maintenance of a stable blood glucose concentration.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   39.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Steiner DF, Chan SJ, Welsh MJ, Kwok SCM (1985) Structure and evolution of the insulin gene. Annu Rev Genet 19: 463–484

    Article  PubMed  CAS  Google Scholar 

  2. Chan SJ, Episkopon V, Zeitlin S, Karathanasis SK, McKrell A, Steiner DF, Efstratiadis A (1984) Guinea pig preproinsulin gene: an evolutionary compromise? Proc Natl Acad Sci USA 81: 5046–5050

    Article  PubMed  CAS  Google Scholar 

  3. Seino S, Welsh M, Bell GI, Chan SJ, Steiner DF (1986) Mutations in the guinea pig preproglucagon gene are restricted to a specific portion of the prohormone sequence. FEBS Lett 203: 25–30

    Article  PubMed  CAS  Google Scholar 

  4. Soares MB, Schon E, Henderson A, Karathanasis SK, Cate R, Zeitlin S, Chirgwin J, Efstratiadis A (1985) RNA-mediated gene duplication: the rat preproinsulin I gene is a functional retroposon. Mol Cell Biol 5: 2090–2103

    PubMed  CAS  Google Scholar 

  5. Owerbach D, Bell GI, Rutter WJ, Shows TB (1980) The insulin gene is located on chromosome 11 in humans. Nature 286: 82–84

    Article  PubMed  CAS  Google Scholar 

  6. Deltour L, Leduque P, Blume N, Madsen O, Dubois P, Jami J, Bucchini D (1993) Differential expression of the nonallelic proinsulin genes in the developing mouse embryo. Proc Natl Acad Sci USA 90: 527–531

    Article  PubMed  CAS  Google Scholar 

  7. Muglia L, Locker J (1984) Extrapancreatic insulin gene expression in the fetal rat. Proc Natl Acad Sci USA 81: 3635–3639

    Article  PubMed  CAS  Google Scholar 

  8. Giddings SJ, Carnaghi LR (1990) Selective expression and developmental regulation of the ancestral rat insulin II gene in fetal liver. Mol Endocrinol 4: 1363–1369

    Article  PubMed  CAS  Google Scholar 

  9. Herrera PL, Huarte J, Zufferey R, Nichols A, Mermillod B, Philippe J, Muniesa P, Sanvito F, Orci L, Vassali JD (1994) Ablation of islet endocrine cells by targeted expression of hormone- promoter-driven toxigenes. Proc Natl Acad Sci USA 91: 12999–13003

    Article  PubMed  CAS  Google Scholar 

  10. Selden RF, Skoskiewics MJ, Burke Howie K, Russel PS, Goodman HS (1986) Regulation of human insulin gene expression in transgenic mice. Nature 321: 525–528

    Article  PubMed  CAS  Google Scholar 

  11. Bucchini D, Ripoche MA, Stinnakre MG, Desbois P, Lores P, Monthioux E, Absil J, Lepesant J A, Pictet R, Jami J (1986) Pancreatic expression of human insulin in transgenic mice. Proc Natl Acad Sci USA 83: 2511–2515

    Article  PubMed  CAS  Google Scholar 

  12. Walker MD, Edlund T, Boulet AM, Rutter WJ (1983) Cell-specific expression controlled by the 5’-fianking region of insulin and chymotrypsin genes. Nature 306: 557–561

    Article  PubMed  CAS  Google Scholar 

  13. Edlund T, Walker MD, Barr PJ, Rutter WJ (1985) Cell-specific expression of the rat insulin gene: evidence for role of two distinct 5’-flanking elements. Science 230: 912–916

    Article  PubMed  CAS  Google Scholar 

  14. Dandroy-Dron F, Monthioux E, Jami J, Bucchini D (1991) Regulatory regions of rat insulin I gene necessary for expression in transgenic mice. Nucleic Acids Res 19: 4925–4930

    Article  Google Scholar 

  15. German MS, Wang J, Chadwick RB, Rutter WJ (1992) Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein: building a functional insulin mini-enhancer complex. Genes Dev 6: 2165–2176

    Article  PubMed  CAS  Google Scholar 

  16. German MS, Moss LG, Wang J, Rutter WJ (1992) The insulin and islet amyloid polypeptide genes contain similar cell-specific promoter elements that bind identical beta cell nuclear complexes. Mol Cell Biol 12: 1777–1788

    PubMed  CAS  Google Scholar 

  17. Kadesch T (1992) Helix-loop-helix proteins in the regulation of immunoglobulin gene transcription. Immunol Today 13: 31–37

    Article  PubMed  CAS  Google Scholar 

  18. Wright WE (1992) Muscle basic helix-loop-helix proteins and the regulation of myogenesis. Curr Opin Genet Dev 2: 243–248

    Article  PubMed  CAS  Google Scholar 

  19. Therrien M, Drouin J (1993) Cell-specific helix-loop-helix factor required for pituitary expression of the proopiomelanocortin gene. Mol Cell Biol 13: 2342–2353

    PubMed  CAS  Google Scholar 

  20. Murre C, Schonleber McCow P, Baltimore D (1989) A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell 56: 777–783

    Article  PubMed  CAS  Google Scholar 

  21. Aronheim A, Ohlsson H, Park CW, Edlund T, Walker MD (1991) Distribution and characterization of helix-loop-helix enhancer-binding proteins from pancreatic beta cells and lymphocytes. Nucleic Acids Res 19: 3893–3899

    Article  PubMed  CAS  Google Scholar 

  22. Park CW, Walker MD (1992) Subunit structure of cell-specific E box-binding proteins analyzed by quantitation of electrophoretic mobility shift. J Biol Chem 267: 15642–15649

    PubMed  CAS  Google Scholar 

  23. Ohlsson H, Thor S, Edlund T (1991) Novel insulin promoter- and enhancer-binding proteins that discriminate between alpha and beta cells. Mol Endocrinol 5: 897–904

    Article  PubMed  CAS  Google Scholar 

  24. Wang TC, Brand SJ (1990) Islet cell-specific regulatory domain in the gastrin promoter contains adjacent positive and negative elements. J Biol Chem 265: 8908–8914

    PubMed  CAS  Google Scholar 

  25. Wheeler MB, Nishitani J, Buchan AM J, Kopin AS, Chey WY, Chang TM, Leiter AB (1992) Identification of a transcriptional enhancer important for entero-endocrine and pancreatic islet cell- specific expression of the secretin gene. Mol Cell Biol 12: 3531–3539

    PubMed  CAS  Google Scholar 

  26. Cordier-Bussat M, Morel C, Philippe J (1995) Homologous DNA sequences and cellular factors are implicated in the control of glucagon and insulin gene expression. Mol Cell Biol 15: 3904–3916

    PubMed  CAS  Google Scholar 

  27. Ohlsson H, Karlsson K, Edlund T (1993) IPF1, a homeo-domain-containing transactivator of the insulin gene. EMBO J 12: 4251–4259

    PubMed  CAS  Google Scholar 

  28. Leonard J, Peers B, Johnson T, Ferreri K, Lee S, Montminy M (1993) Characterization of somatostatin transactivating factor-1, a novel homeobox factor which stimulates somatostatin expression in pancreatic islet cells. Mol Endocrinol 7: 1275–1283

    Article  PubMed  CAS  Google Scholar 

  29. Peers B, Leonard J, Sharma S, Teitelman G, Montminy MR (1994) Insulin expression in pancreatic islet cells relies on cooperative interactions. Mol Endocrinol 8: 1798–1806

    Article  PubMed  CAS  Google Scholar 

  30. Miller C, McGehee R, Habener J (1994) IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. EMBO J 13: 1145–1156

    PubMed  CAS  Google Scholar 

  31. Peshavaria M, Gamer L, Henderson E, Teitelman G, Wright C, Stein R (1994) XIHbox 8, an endoderm-specific Xenopus homeo domain protein, is closely related to a mammalian insulin gene transcription factor. Mol Endocrinol 8: 806–816

    Article  PubMed  CAS  Google Scholar 

  32. Jonsson J, Carlsson L, Edlund T, Edlund H (1994) Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371: 606–609

    Article  PubMed  CAS  Google Scholar 

  33. Shieh SY, Tsai MJ (1991) Cell-specific and ubiquitous factors are responsible for the enhancer activity of the rat insulin II gene. J Biol Chem 266: 16708–16714

    PubMed  CAS  Google Scholar 

  34. Stellrecht CM, Finegold MJ, DeMayo MJ, Tsai MJ (1993) Tissue-specific activity of the rat insulin II gene enhancer, RIPE3, in transgenic mice. Proceedings of the 75th Annual Meeting of The Endocrine Society, Las Vegas, pp 373 (abstract)

    Google Scholar 

  35. Permutt MA (1974) Insulin biosynthesis IV Effect of glucose on initiation and elongation rates in isolated rat pancreatic islets J Biol Chem 249: 2738–2742

    CAS  Google Scholar 

  36. Nielsen DA, Welsh M, Casadaban MJ, Steiner DF (1985) Control of insulin gene expression in pancreatic beta cells and in an insulin-producing cell line, RIN 5F cells. Effects of glucose and cAMP on the transcription of insulin mRNA. J Biol Chem 260: 13585–13589

    PubMed  CAS  Google Scholar 

  37. Welsh M, Nielsen DA, MacKrell AJ, Steiner DF (1985) Control of insulin gene expression in pancreatic beta cells and in an insulin-producing cell line, RIN 5F cells. II. Regulation of insulin mRNA stability. J Biol Chem 260: 13590–13594

    PubMed  CAS  Google Scholar 

  38. German MS, Moss LG, Rutter WJ (1990) Regulation of insulin gene expression by glucose and calcium in transfected primary islet cultures. J Biol Chem 265: 22063–22066

    PubMed  CAS  Google Scholar 

  39. Melloul D, Ben-Neriah Y, Cerasi E (1993) Glucose modulates the binding of an islet-specific factor to a conserved sequence within the rat I and the human insulin promoters. Proc Natl Acad Sci USA 90: 3865–3869

    Article  PubMed  CAS  Google Scholar 

  40. MacFarlane W, Read M, Gilligan M, Bujalska I, Docherty K (1994) Glucose modulates the binding activity of the beta-cell transcription factor IUF1 in a phosphorylation-dependent manner. Biochem J 303: 625–631

    PubMed  CAS  Google Scholar 

  41. German MS, Wang J (1994) The insulin gene contains multiple transcriptional elements that respond to glucose. Mol Cell Biol 14: 4067–4075

    PubMed  CAS  Google Scholar 

  42. Petersen H, Serup P, Leonard J, Michelsen BK, Madsen OD (1994) Transcriptional regulation of the human insulin gene is dependent on the homeodomain protein STF1/IPE1 acting through the CT boxes. Proc Natl Acad Sci USA 91: 10465–10469

    Article  PubMed  CAS  Google Scholar 

  43. Sharma A, Stein R (1994) Glucose-induced transcription of the insulin gene is mediated by factors required for beta-cell-type-specific expression. Mol Cell Biol 14: 871–879

    PubMed  CAS  Google Scholar 

  44. Philippe J, Missotten M (1990) Functional characterization of a cAMP-responsive element of the rat insulin I gene. J Biol Chem 265: 1465–1469

    PubMed  CAS  Google Scholar 

  45. Oetjen E, Diedrich T, Eggers A, Eckert B, Knepel W (1994) Distinct properties of the cAMP- responsive element of the rat insulin I gene. J Biol Chem 269: 27036–27044

    PubMed  CAS  Google Scholar 

  46. Gonzalez GA, Montminy MR (1989) Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59: 675–680

    Article  PubMed  CAS  Google Scholar 

  47. Inagaki N, Maekawa T, Sudo T, Ishii T, Seino S, Imura H (1992) C-jun represses the human insulin promoter activity that depends on multiple cAMP response elements. Proc Natl Acad Sci USA 89: 1045–1049

    Article  PubMed  CAS  Google Scholar 

  48. Fehmann HC, Habener JF (1992) Galanin inhibits proinsulin gene expression stimulated by the insulinotropic hormone glucagon-like peptide I (7–37) in mouse insulinoma BTC-1 cells. Endocrinoogy 130: 159–166

    Article  CAS  Google Scholar 

  49. Zhang IJ, Redmon JB, Andresen JM, Robertson RP (1991) Somatostatin and epinephrine decrease insulin messenger ribonucleic acid in HIT cells through a pertussis toxin-sensitive mechanism. Endocrinology 129: 2409–2414

    Article  PubMed  CAS  Google Scholar 

  50. Philippe J (1993) Somatostatin inhibits insulin gene expression through a posttranscriptional mechanism in a hamster islet cell line. Diabetes 42: 244–249

    Article  PubMed  CAS  Google Scholar 

  51. German M, Ashcroft S, Docherty K et al. (1995) The insulin gene promoter: a simplified nomenclature. Diabetes 44: 1002–1009

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. J. Philippe
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Fondation pour Recherches Médicales Faculté de Médecine, Université de Genève, 64, Avenue dela Roseraie, 1211, Genève 4, Switzerland

    Gaston R. Zahnd

  2. Division de Biochimie clinique et de Diabétologie expérimentale, Centre Médical Universitaire, 1211, Genève 4, Switzerland

    Claes B. Wollheim

Rights and permissions

Reprints and permissions

Copyright information

© 1997 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Philippe, J. (1997). Expression of the Insulin Gene and Its Regulation. In: Zahnd, G.R., Wollheim, C.B. (eds) Contributions of Physiology to the Understanding of Diabetes. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-60475-1_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-60475-1_4

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-64422-1

  • Online ISBN: 978-3-642-60475-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation