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Exendin 4 Up-Regulates Expression of PDX 1 and Hastens Differentiation and Maturation of Human Fetal Pancreatic Cells

Whittier Institute and Department of Pediatrics (J.M., G.M.B., A.D.L., A.H.), University of California, San Diego, La Jolla, California 92037; and Laboratoire de Physiopathologie de la Nutrition (J.M.), Centre National de la Recherche Scientifique UMR 7059, 75251 Paris, France

Address all correspondence and requests for reprints to: Alberto Hayek, M.D., Islet Research Laboratory, Department of Pediatrics, University of California, San Diego Medical School, 9894 Genesee Avenue, La Jolla, California 92037.

Abstract

In addition to stimulating insulin secretion, glucagon-like peptide and its long-acting analog exendin 4 have been reported to increase ß-cell mass by both differentiation/neogenesis of precursor cells and enhanced replication of existing ß-cells. Here, we investigated the effect of exendin 4 in the growth and differentiation of ß-cells from undifferentiated precursors in islet-like cell clusters (ICCs) derived from human fetal pancreases. Our results show that the addition of exendin 4 to the culture media stimulates PDX 1 expression in ICCs as shown by immunofluorescence staining. The up-regulation of PDX 1 was not accompanied by changes in insulin expression because we did not find a significant difference in the number of insulin-positive cells in the exendin 4-treated ICCs, compared with controls. We also tested the effects of exendin 4 in the glucose-induced insulin secretion of human ICCs transplanted under the kidney capsule of athymic rats. In the exendin 4-treated rats (given ip during 10 d) 8 wk after the beginning of the treatment, insulin was released in response to glucose as detected by the measurement of circulating human C-peptide. In control (saline-treated) rats, the basal levels of human C-peptide did not change significantly after glucose stimulation. Thus, exendin 4 induces functional maturation of fetal ß-cells in response to glucose. In these rats, serial sections of the kidney-bearing grafts were examined histologically for insulin containing cells. We found a significant increase in ß-cell number, compared with the control rats. Overall, these results show that in vivo exendin 4 causes growth and differentiation of human fetal ß-cells from undifferentiated precursor cells. It also accelerates the functional maturation of fetal ß-cells as evidenced by their glucose-stimulated insulin secretion.

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