Abstract
Glucagon-like peptide 1 (GLP-1) is released from neuroendocrine cells in the intestine in the postprandial state and augments glucose-stimulated insulin secretion from pancreatic β cells. To develop non-β cells that exhibit physiologically regulated insulin secretion, we coexpressed the GLP-1 receptor and human insulin in primary rat pituitary cells using adenovirus-mediated gene transfer. The transduced cells were analyzed in a perifusion system and after transplantation into mice. Normal pituitary cells do not express the GLP-1 receptor as shown by the absence of GLP-1 receptor mRNA and the inability of GLP-1 to stimulate pituitary hormone secretion. Following transduction with an adenovirus carrying the GLP-1 receptor cDNA, the pituitary cells expressed functional GLP-1 receptors as reflected by the ability of GLP-1 to stimulate secretion of pituitary hormones. When both the GLP-1 receptor and human insulin were introduced, GLP-1 stimulated cosecretion of human insulin and endogenous pituitary hormones. GLP-1 was similar in potency to the hypothalamic-releasing hormones and stimulated hormone secretion in a dose-dependent fashion. In contrast to pancreatic β cells, the hormone-releasing effect of GLP-1 on transduced pituitary cells was not dependent on the concentration of extracellular glucose. After transplantation of pituitary cells coexpressing human insulin and GLP-1 receptor into mice, enteral glucose stimulated insulin secretion. These results demonstrate a new approach to engineer physiologically regulated insulin secretion by non-β cells.
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Acknowledgements
This study was supported by a postdoctoral training grant from the Juvenile Diabetes Research Foundation International, a Merit Review Award from the VA Research Service, a research grant from the National Institutes of Health (DK55233), research grants from the American Diabetes Association and the Juvenile Diabetes Research Foundation International, and the Vanderbilt Diabetes Research and Training Center (NIH DK20593). The GLP-1 receptor cDNA was kindly provided by Dr Svetlana Mojsov at The Rockefeller University. The proinsulin assay was graciously performed at the Diabetes Research and Training Center at the University of Chicago (NIH DK20595) by Diane Ostrega and Dr Kenneth Polonsky.
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Wu, L., Nicholson, W., Wu, CY. et al. Engineering physiologically regulated insulin secretion in non-β cells by expressing glucagon-like peptide 1 receptor. Gene Ther 10, 1712–1720 (2003). https://doi.org/10.1038/sj.gt.3302055
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DOI: https://doi.org/10.1038/sj.gt.3302055
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