ArticleJournal of autoimmune diseases2004
Insulin expressing hepatocytes not destroyed in transgenic NOD mice.
Article in Journal of autoimmune diseases, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 23 citations in OpenAlex.
- Pancreatic Transdifferentiation Using β-Cell Transcription Factors for Type 1 Diabetes Treatment.Cells · 2022Review
- Gene therapy with neurogenin3, betacellulin and SOCS1 reverses diabetes in NOD mice.Gene therapy · 2015Article
- Glucose-regulated insulin production in the liver improves glycemic control in type 1 diabetic mice.Molecular metabolism · 2015Article
- Article
- Remission of diabetes by insulin gene therapy using a hepatocyte-specific and glucose-responsive synthetic promoter.Molecular therapy : the journal of the American Society of Gene Therapy · 2011Article
- Nonvirally modified autologous primary hepatocytes correct diabetes and prevent target organ injury in a large preclinical model.PloS one · 2008Article
- Failure to achieve normal metabolic response in non-obese diabetic mice and streptozotocin-induced diabetic mice after transplantation of primary murine hepatocytes electroporated with the human proinsulin gene (p3MTChins).Transplantation proceedingsArticle
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe 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 beta 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.
methodsTo 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).
resultsThe 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.
conclusionsThese 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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Registered trials
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