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Post-translational protein modifications in type 1 diabetes: a role for the repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase?

Wagner, A. M.; Cloos, P.; Bergholdt, R.; Boissy, P.; Andersen, T. L.; Henriksen, D. B.; Christiansen, C.; Christgau, S.; Pociot, Flemming LU and Nerup, Jörn LU (2007) In Diabetologia 50(3). p.676-681
Abstract
Aims/hypothesis Post-translational modifications, such as isomerisation of native proteins, may create new antigenic epitopes and play a role in the development of the autoimmune response. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), encoded by the gene PCMT1, is an enzyme that recognises and repairs isomerised Asn and Asp residues in proteins. The aim of this study was to assess the role of PIMT in the development of type 1 diabetes. Materials and methods Immunohistochemical analysis of 59 normal human tissues was performed with a monoclonal PIMT antibody. CGP3466B, which induces expression of Pcmt1, was tested on MIN6 and INS1 cells, to assess its effect on Pcmt1 mRNA and PIMT levels (RT-PCR and western blot) and... (More)
Aims/hypothesis Post-translational modifications, such as isomerisation of native proteins, may create new antigenic epitopes and play a role in the development of the autoimmune response. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), encoded by the gene PCMT1, is an enzyme that recognises and repairs isomerised Asn and Asp residues in proteins. The aim of this study was to assess the role of PIMT in the development of type 1 diabetes. Materials and methods Immunohistochemical analysis of 59 normal human tissues was performed with a monoclonal PIMT antibody. CGP3466B, which induces expression of Pcmt1, was tested on MIN6 and INS1 cells, to assess its effect on Pcmt1 mRNA and PIMT levels (RT-PCR and western blot) and apoptosis. Forty-five diabetes-prone BioBreeding (BB) Ottawa Karlsburg (OK) rats were randomised to receive 0, 14 or 500 mu g/kg (denoted as the control, low-dose and high-dose group, respectively) of CGP3466B from week 5 to week 20. Results A high level of PIMT protein was detected in beta cells. CGP3466B induced a two- to threefold increase in Pcmt1 mRNA levels and reduced apoptosis by 10% in MIN6 cells. No significant effect was seen on cytokine-induced apoptosis or PIMT protein levels in INS1 cells. The onset of diabetes in the BB/OK rats was significantly delayed (85.6 +/- 9.0 vs 84.3 +/- 6.8 vs 106.6 +/- 13.5 days, respectively; p < 0.01 for high-dose vs low-dose and control groups), the severity of the disease was reduced (glucose 22.2 +/- 3.2 vs 16.9 +/- 2.6 vs 15.8 +/- 2.7 mmol; p < 0.01 for high- and low-dose groups vs control group) and residual beta cells were more frequently identified (43% vs 71% vs 86%; p < 0.05 for high-dose vs control group) in the treated animals. Conclusions/interpretation The results support a role for post-translational modifications and PIMT in the development of type 1 diabetes in the diabetes-prone BB rat, and perhaps also in humans. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
prevention, MIN6 cells, BB rat, INS1 cells
in
Diabetologia
volume
50
issue
3
pages
676 - 681
publisher
Springer Verlag
external identifiers
  • wos:000244025500025
  • scopus:33846826589
ISSN
1432-0428
DOI
10.1007/s00125-006-0556-1
language
English
LU publication?
yes
id
1df78d0d-e678-46a0-b0e5-372e7ea0e5e7 (old id 675248)
date added to LUP
2007-12-19 13:44:07
date last changed
2017-01-01 04:54:44
@article{1df78d0d-e678-46a0-b0e5-372e7ea0e5e7,
  abstract     = {Aims/hypothesis Post-translational modifications, such as isomerisation of native proteins, may create new antigenic epitopes and play a role in the development of the autoimmune response. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT), encoded by the gene PCMT1, is an enzyme that recognises and repairs isomerised Asn and Asp residues in proteins. The aim of this study was to assess the role of PIMT in the development of type 1 diabetes. Materials and methods Immunohistochemical analysis of 59 normal human tissues was performed with a monoclonal PIMT antibody. CGP3466B, which induces expression of Pcmt1, was tested on MIN6 and INS1 cells, to assess its effect on Pcmt1 mRNA and PIMT levels (RT-PCR and western blot) and apoptosis. Forty-five diabetes-prone BioBreeding (BB) Ottawa Karlsburg (OK) rats were randomised to receive 0, 14 or 500 mu g/kg (denoted as the control, low-dose and high-dose group, respectively) of CGP3466B from week 5 to week 20. Results A high level of PIMT protein was detected in beta cells. CGP3466B induced a two- to threefold increase in Pcmt1 mRNA levels and reduced apoptosis by 10% in MIN6 cells. No significant effect was seen on cytokine-induced apoptosis or PIMT protein levels in INS1 cells. The onset of diabetes in the BB/OK rats was significantly delayed (85.6 +/- 9.0 vs 84.3 +/- 6.8 vs 106.6 +/- 13.5 days, respectively; p &lt; 0.01 for high-dose vs low-dose and control groups), the severity of the disease was reduced (glucose 22.2 +/- 3.2 vs 16.9 +/- 2.6 vs 15.8 +/- 2.7 mmol; p &lt; 0.01 for high- and low-dose groups vs control group) and residual beta cells were more frequently identified (43% vs 71% vs 86%; p &lt; 0.05 for high-dose vs control group) in the treated animals. Conclusions/interpretation The results support a role for post-translational modifications and PIMT in the development of type 1 diabetes in the diabetes-prone BB rat, and perhaps also in humans.},
  author       = {Wagner, A. M. and Cloos, P. and Bergholdt, R. and Boissy, P. and Andersen, T. L. and Henriksen, D. B. and Christiansen, C. and Christgau, S. and Pociot, Flemming and Nerup, Jörn},
  issn         = {1432-0428},
  keyword      = {prevention,MIN6 cells,BB rat,INS1 cells},
  language     = {eng},
  number       = {3},
  pages        = {676--681},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  title        = {Post-translational protein modifications in type 1 diabetes: a role for the repair enzyme protein-L-isoaspartate (D-aspartate) O-methyltransferase?},
  url          = {http://dx.doi.org/10.1007/s00125-006-0556-1},
  volume       = {50},
  year         = {2007},
}