Abstract | AIMS/HYPOTHESIS: 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 microg/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.
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Authors | A M Wägner, P Cloos, R Bergholdt, P Boissy, T L Andersen, D B Henriksen, C Christiansen, S Christgau, F Pociot, J Nerup |
Journal | Diabetologia
(Diabetologia)
Vol. 50
Issue 3
Pg. 676-81
(Mar 2007)
ISSN: 0012-186X [Print] Germany |
PMID | 17216280
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Oxepins
- dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine
- Protein D-Aspartate-L-Isoaspartate Methyltransferase
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Topics |
- Animals
- Diabetes Mellitus, Type 1
(metabolism)
- Gene Expression Regulation, Enzymologic
(drug effects, genetics)
- Humans
- Immunohistochemistry
- Oligonucleotide Array Sequence Analysis
- Oxepins
(pharmacology, therapeutic use)
- Pancreas
(cytology, enzymology)
- Protein D-Aspartate-L-Isoaspartate Methyltransferase
(genetics, metabolism)
- Protein Processing, Post-Translational
- Rats
- Rats, Inbred BB
- Reference Values
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