Functional Maturation of Fetal Porcine Beta-Cells by Glucagon-Like Peptide 1 and Cholecystokinin

Endocrinology. 2002 Sep;143(9):3505-14. doi: 10.1210/en.2001-211344.

Abstract

Fetal beta-cells are immature in their responsiveness to glucose, and maturation occurs after oral feeding commences at birth. The incretin hormones glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are known to be released from the gut in response to oral feeding and enhance insulin secretion from pancreatic beta-cells. We hypothesized that these fetal beta-cells would mature in their glucose responsiveness if they were previously exposed to incretins. We exposed fetal pig islet-like cell clusters (ICCs) to 100 nM GLP-1, 5 micro M CCK, or 10 mM nicotinamide (NIC; a positive control) for 6 h and demonstrated 3- and 1.7-fold increases in glucose-induced insulin secretion for GLP-1 and CCK, respectively. This effect did not reach statistical significance if the ICCs were exposed to the incretins for 3 d. However, exposure for 4 d enhanced formation of beta-cells from undifferentiated cells, from 8 +/- 1% (controls) to 17 +/- 3% for GLP-1, 20 +/- 4% for CCK, and 15 +/- 1 for NIC (P < 0.001). ICCs exposed to GLP-1 for 3 d also showed a 1.9-fold increase in the intensity of PDX-1(+) cells, as assessed by semiquantitative fluorescent immunocytochemistry. Exposure of ICCs to incretins for 3 d did not show any increase in size of the islet clusters. ICCs exposed to either incretin as well as controls were transplanted into severe combined immunodeficient mice and examined at 1 and 2 months. We found a significant increase in the number of beta-cells in the GLP-1- and NIC-treated groups compared with the untreated controls or CCK. Perfusion of these grafts at 2 months showed that ICCs previously exposed to GLP-1, CCK, and NIC (but not controls), were functional and mature. In conclusion, GLP-1 and CCK have a dual effect on fetal pig ICCs, causing maturation of glucose-induced insulin secretion from beta-cells as well as enhancement of differentiation from undifferentiated precursors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Division
  • Cell Size
  • Cholecystokinin / pharmacology*
  • Culture Techniques
  • Fluorescent Antibody Technique
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Glucose / pharmacology
  • Insulin / analysis
  • Islets of Langerhans / chemistry
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / embryology*
  • Islets of Langerhans Transplantation
  • Niacinamide / pharmacology
  • Peptide Fragments / pharmacology*
  • Protein Precursors / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Swine
  • Time Factors

Substances

  • Insulin
  • Peptide Fragments
  • Protein Precursors
  • Niacinamide
  • Glucagon-Like Peptide 1
  • Glucagon
  • Cholecystokinin
  • Glucose