Exendin 4 up-regulates expression of PDX 1 and hastens differentiation and maturation of human fetal pancreatic cells.
In addition to stimulating insulin secretion, glucagon-like peptide and its long-acting analog exendin 4 have been reported to increase beta-cell mass by both differentiation/neogenesis of precursor cells and enhanced replication of existing beta-cells. Here, we investigated the effect of exendin 4 in the growth and differentiation of beta-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 beta-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 beta-cell number, compared with the control rats. Overall, these results show that in vivo exendin 4 causes growth and differentiation of human fetal beta-cells from undifferentiated precursor cells. It also accelerates the functional maturation of fetal beta-cells as evidenced by their glucose-stimulated insulin secretion.
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D002096:C-Peptide / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D003470:Culture Media; D000077270:Exenatide; D005786:Gene Expression Regulation / Q000187:drug effects*; D005865:Gestational Age; D018398:Homeodomain Proteins; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000032:analysis; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology* / Q000502:physiology; D016381:Islets of Langerhans Transplantation; D007668:Kidney; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D011923:Rats, Nude; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics*; D014183:Transplantation, Heterologous; D014688:Venoms
D001786:Blood Glucose; D002096:C-Peptide; D003470:Culture Media; D018398:Homeodomain Proteins; D007328:Insulin; D010455:Peptides; D015534:Trans-Activators; D014688:Venoms; C084010:pancreatic and duodenal homeobox 1 protein; D000077270:Exenatide