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Open AccessArticle

Pancreatic Transdifferentiation and Glucose-Regulated Production of Human Insulin in the H4IIE Rat Liver Cell Line

1
School of Life Sciences and Centre for Health Technologies, University of Technology Sydney, P.O. Box 123, Broadway, 2007 Sydney, NSW, Australia
2
School of Medical Sciences (Anatomy & Histology) and Bosch Institute, University of Sydney, 2006 Sydney, NSW, Australia
*
Author to whom correspondence should be addressed.
Academic Editor: Toshiro Arai
Int. J. Mol. Sci. 2016, 17(4), 534; https://doi.org/10.3390/ijms17040534
Received: 3 March 2016 / Revised: 24 March 2016 / Accepted: 1 April 2016 / Published: 8 April 2016
(This article belongs to the Special Issue Molecular Research on Obesity and Diabetes)
Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat NeuroD1 gene alone, or the human insulin gene and rat NeuroD1 genes together, to the rat liver cell line, H4IIE, to determine if storage of insulin and pancreatic transdifferentiation occurred. Stable clones were selected and expanded into cell lines: H4IIEins (insulin gene alone), H4IIE/ND (NeuroD1 gene alone), and H4IIEins/ND (insulin and NeuroD1 genes). The H4IIEins cells did not store insulin; however, H4IIE/ND and H4IIEins/ND cells stored 65.5 ± 5.6 and 1475.4 ± 171.8 pmol/insulin/5 × 106 cells, respectively. Additionally, several β cell transcription factors and pancreatic hormones were expressed in both H4IIE/ND and H4IIEins/ND cells. Electron microscopy revealed insulin storage vesicles in the H4IIE/ND and H4IIEins/ND cell lines. Regulated secretion of insulin to glucose (0–20 mmol/L) was seen in the H4IIEins/ND cell line. The H4IIEins/ND cells were transplanted into diabetic immunoincompetent mice, resulting in normalization of blood glucose. This data shows that the expression of NeuroD1 and insulin in liver cells may be a useful strategy for inducing islet neogenesis and reversing diabetes. View Full-Text
Keywords: diabetes; gene therapy; H4IIE cells; regulated insulin secretion; insulin storage; secretory granules; liver cells; β cell transcription factors; furin-cleavable human insulin diabetes; gene therapy; H4IIE cells; regulated insulin secretion; insulin storage; secretory granules; liver cells; β cell transcription factors; furin-cleavable human insulin
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Ren, B.; Tao, C.; Swan, M.A.; Joachim, N.; Martiniello-Wilks, R.; Nassif, N.T.; O’Brien, B.A.; Simpson, A.M. Pancreatic Transdifferentiation and Glucose-Regulated Production of Human Insulin in the H4IIE Rat Liver Cell Line. Int. J. Mol. Sci. 2016, 17, 534.

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