Insulinotropic Hormone Glucagon-Like peptide-1 Differentiation of Human Pancreatic Islet-Derived Progenitor Cells Into Insulin-Producing Cells

Endocrinology. 2002 Aug;143(8):3152-61. doi: 10.1210/endo.143.8.8973.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Calcium / metabolism
  • Cell Differentiation / drug effects
  • Glucagon / genetics
  • Glucagon / metabolism
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor
  • Homeodomain Proteins*
  • Humans
  • Insulin / biosynthesis*
  • Intermediate Filament Proteins / analysis
  • Islets of Langerhans / cytology*
  • Nerve Tissue Proteins*
  • Nestin
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*
  • Proglucagon
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Protein Precursors / pharmacology*
  • Receptors, Glucagon / analysis
  • Receptors, Glucagon / physiology
  • Stem Cells / physiology*
  • Trans-Activators / physiology
  • Transfection

Substances

  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Homeodomain Proteins
  • Insulin
  • Intermediate Filament Proteins
  • NES protein, human
  • Nerve Tissue Proteins
  • Nestin
  • Peptide Fragments
  • Protein Precursors
  • Receptors, Glucagon
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Proglucagon
  • Glucagon-Like Peptide 1
  • Glucagon
  • Calcium