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Insulin expressing hepatocytes not destroyed in transgenic NOD mice
BACKGROUND: The liver has been suggested as a suitable target organ for gene therapy of Type 1 diabetes. However, the fundamental issue whether insulin-secreting hepatocytes in vivo will be destroyed by the autoimmune processes that kill pancreatic β cells has not been fully addressed. It is possibl...
Autores principales: | , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2004
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC544947/ https://www.ncbi.nlm.nih.gov/pubmed/15679918 http://dx.doi.org/10.1186/1740-2557-1-3 |
Sumario: | BACKGROUND: The liver has been suggested as a suitable target organ for gene therapy of Type 1 diabetes. However, the fundamental issue whether insulin-secreting hepatocytes in vivo will be destroyed by the autoimmune processes that kill pancreatic β cells has not been fully addressed. It is possible that the insulin secreting liver cells will be destroyed by the immune system because hepatocytes express major histocompatibility complex (MHC) class I molecules and exhibit constitutive Fas expression; moreover the liver has antigen presenting activity. Together with previous reports that proinsulin is a possible autoantigen in the development of Type 1 diabetes, the autoimmune destruction of insulin producing liver cells is a distinct possibility. METHODS: To address this question, transgenic Non-Obese Diabetic (NOD) mice which express insulin in the liver were made using the Phosphoenolpyruvate Carboxykinase (PEPCK) promoter to drive the mouse insulin I gene (Ins). RESULTS: The liver cells were found to possess preproinsulin mRNA, translate (pro)insulin in vivo and release it when exposed to 100 nmol/l glucagon in vitro. The amount of insulin produced was however significantly lower than that produced by the pancreas. The transgenic PEPCK-Ins NOD mice became diabetic at 20–25 weeks of age, with blood glucose levels of 24.1 ± 1.7 mmol/l. Haematoxylin and eosin staining of liver sections from these transgenic NOD PEPCK-Ins mice revealed the absence of an infiltrate of immune cells, a feature that characterised the pancreatic islets of these mice. CONCLUSIONS: These data show that hepatocytes induced to produce (pro)insulin in NOD mice are not destroyed by an ongoing autoimmune response; furthermore the expression of (pro)insulin in hepatocytes is insufficient to prevent development of diabetes in NOD mice. These results support the use of liver cells as a potential therapy for type 1 diabetes. However it is possible that a certain threshold level of (pro)insulin production might have to be reached to trigger the autoimmune response. |
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