Engineering physiologically regulated insulin secretion in non-beta cells by expressing glucagon-like peptide 1 receptor.

Wu L, Nicholson W, Wu CY, Xu M, McGaha A, Shiota M, Powers AC
Gene Ther. 2003 10 (19): 1712-20

PMID: 12923570 · DOI:10.1038/sj.gt.3302055

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 beta cells. To develop non-beta 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 beta 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-beta cells.

MeSH Terms (23)

Adenoviridae Animals Cells, Cultured Diabetes Mellitus, Type 1 Gene Expression Genetic Therapy Genetic Vectors Glucagon-Like Peptide-1 Receptor Glucose Humans Insulin Insulin Secretion Male Mice Mice, Inbred NOD Mice, SCID Pituitary Gland Pituitary Hormones Rats Rats, Sprague-Dawley Receptors, Glucagon Stimulation, Chemical Transduction, Genetic

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