Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells.
Glucagon-like peptide-1 (GLP-1) is an intestinal incretin hormone, derived from the processing of proglucagon, that exerts insulinotropic actions on insulin-producing pancreatic islet beta-cells. Recently GLP-1 was shown to stimulate the growth and differentiation (neogenesis) of beta-cells and appears to do so by inducing the expression of the homeodomain protein IDX-1 (islet duodenum homeobox-1; also known as PDX-1, pancreatic and duodenal homeobox gene; and as IPF-1, insulin promoter factor), which is required for pancreas development and the expression of beta-cell-specific genes. Earlier we identified multipotential progenitor cells in the islet and ducts of the pancreas, termed nestin-positive islet-derived progenitor cells (NIPs). Here we report the expression of functional GLP-1 receptors on NIPs and that GLP-1 stimulates the differentiation of NIPs into insulin-producing cells. Furthermore, confluent NIP cultures express the proglucagon gene and secrete GLP-1. These findings suggest a model of islet development in which pancreatic progenitor cells express both GLP-1 receptors and proglucagon with the formation of GLP-1. Locally produced GLP-1 may act as an autocrine/paracrine developmental morphogen on receptors on NIPs, resulting in the activation of IDX-1 and the expression of the proinsulin gene conferring a beta-cell phenotype. GLP-1 may be an important morphogen both for the embryonic development of the pancreas and for the neogenesis of beta-cells in the islets of the adult pancreas.
Abraham
Elizabeth J
EJ
Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
Leech
Colin A
CA
Lin
Julia C
JC
Zulewski
Henryk
H
Habener
Joel F
JF
D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D005934:Glucagon / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins; D006801:Humans; D007328:Insulin / Q000096:biosynthesis*; D007381:Intermediate Filament Proteins / Q000032:analysis; D007515:Islets of Langerhans / Q000166:cytology*; D009419:Nerve Tissue Proteins; D064231:Nestin; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D052336:Proglucagon; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D018027:Receptors, Glucagon / Q000032:analysis / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology; D014162:Transfection
C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins; D007328:Insulin; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; D064231:Nestin; D010446:Peptide Fragments; D011498:Protein Precursors; D018027:Receptors, Glucagon; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D052336:Proglucagon; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D002118:Calcium