Diabetologia

, Volume 36, Issue 12, pp 1258–1265

Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia

  • J. W. M. Höppener
  • J. S. Verbeek
  • E. J. P. de Koning
  • C. Oosterwijk
  • K. L. van Hulst
  • H. J. Visser-Vernooy
  • F. M. A. Hofhuis
  • S. van Gaalen
  • M. J. H. Berends
  • W. H. L. Hackeng
  • H. S. Jansz
  • J. F. Morris
  • A. Clark
  • P. J. A. Capel
  • C. J. M. Lips
Originals

DOI: 10.1007/BF00400803

Cite this article as:
Höppener, J.W.M., Verbeek, J.S., de Koning, E.J.P. et al. Diabetologia (1993) 36: 1258. doi:10.1007/BF00400803

Summary

Type 2 (non-insulin-dependent) diabetes mellitus is characterised by hyperglycaemia, peripheral insulin resistance, impaired insulin secretion and pancreatic islet amyloid formation. The major constituent of islet amyloid is islet amyloid polypeptide (amylin). Islet amyloid polypeptide is synthesized by islet beta cells and co-secreted with insulin. The ability of islet amyloid polypeptide to form amyloid fibrils is related to its species-specific amino acid sequence. Islet amyloid associated with diabetes is only found in man, monkeys, cats and racoons. Pharmacological doses of islet amyloid polypeptide have been shown to inhibit insulin secretion as well as insulin action on peripheral tissues (insulin resistance). To examine the role of islet amyloid polypeptide in the pathogenesis of Type 2 diabetes, we have generated transgenic mice with the gene encoding either human islet amyloid polypeptide (which can form amyloid) or rat islet amyloid polypeptide, under control of an insulin promoter. Transgenic islet amyloid polypeptide mRNA was detected in the pancreas in all transgenic mice. Plasma islet amyloid polypeptide levels were significantly elevated (up to 15-fold) in three out of five transgenic lines, but elevated glucose levels, hyperinsulinaemia and obesity were not observed. This suggests that insulin resistance is not induced by chronic hypersecretion of islet amyloid polypeptide. Islet amyloid polypeptide immunoreactivity was localized to beta-cell secretory granules in all mice. Islet amyloid polypeptide immunoreactivity in beta-cell lysosomes was seen only in mice with the human islet amyloid polypeptide gene, as in human beta cells, and might represent an initial step in intracellular formation of amyloid fibrils. These transgenic mice provide a unique model with which to examine the physiological function of islet amyloid polypeptide and to study intracellular and extracellular handling of human islet amyloid polypeptide in pancreatic islets.

Key words

Islet amyloid polypeptide amylin transgenic mouse islet beta cell islet amyloid glucose metabolism insulin resistance Type 2 (non-insulin-dependent) diabetes mellitus 

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • J. W. M. Höppener
    • 1
    • 2
    • 8
  • J. S. Verbeek
    • 3
  • E. J. P. de Koning
    • 4
    • 5
  • C. Oosterwijk
    • 1
  • K. L. van Hulst
    • 2
  • H. J. Visser-Vernooy
    • 2
  • F. M. A. Hofhuis
    • 3
  • S. van Gaalen
    • 3
  • M. J. H. Berends
    • 6
  • W. H. L. Hackeng
    • 7
  • H. S. Jansz
    • 1
  • J. F. Morris
    • 5
  • A. Clark
    • 4
  • P. J. A. Capel
    • 3
  • C. J. M. Lips
    • 2
  1. 1.Laboratory for Physiological ChemistryUtrecht UniversityThe Netherlands
  2. 2.Department of Internal MedicineUtrecht UniversityThe Netherlands
  3. 3.Department of ImmunologyUtrecht UniversityThe Netherlands
  4. 4.Diabetes Research LaboratoriesRadcliffe InfirmaryOxfordUK
  5. 5.Department of Human AnatomyUniversity of OxfordUK
  6. 6.Department of PathologyWesteinde HospitalThe HagueThe Netherlands
  7. 7.Practice for Laboratory DiagnosisGeervlietThe Netherlands
  8. 8.Institute of Molecular Biology and Medical BiotechnologyUtrecht UniversityCH UtrechtThe Netherlands

Personalised recommendations