Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats

Endocrinology. 2002 Nov;143(11):4397-408. doi: 10.1210/en.2002-220405.

Abstract

A constant remodeling of islet cell mass mediated by proliferative and apoptotic stimuli ensures a dynamic response to a changing demand for insulin. In this study, we investigated the effect of glucagon-like peptide-1 (GLP-1) in Zucker diabetic rats, an animal model in which the onset of diabetes occurs when the proliferative potential and the rate of beta-cell apoptosis no longer compensate for the increased demand for insulin. We subjected diabetic rats to a 2-d infusion of GLP-1 and tested their response to an ip glucose tolerance test. GLP-1 produced a significant increase of insulin secretion, which was paralleled by a decrease in plasma glucose levels (P < 0.001 and P < 0.01, respectively). Four days after the removal of the infusion pumps, rats were killed and the pancreas harvested to study the mechanism by which GLP-1 ameliorated glucose tolerance. Ex vivo immunostaining with the marker of cell proliferation, Ki-67, showed that the metabolic changes observed in rats treated with GLP-1 were associated with an increase in cell proliferation of the endocrine and exocrine component of the pancreas. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling staining, a marker of cellular apoptosis, indicated a reduction of apoptotic cells within the islet as well in the exocrine pancreas in GLP-1-treated rats. Double immunostaining for the apoptotic marker caspase-3 and for insulin showed a significant reduction of caspase-3 expression and an increase in insulin content in GLP-1-treated animals. Finally, staining of pancreatic sections with the nuclear dye 4,6-Diaminidino-2-phenyl-dihydrochloride demonstrated a marked reduction of fragmented nuclei in the islet cells of rats treated with GLP-1. Our findings provide evidence that the beneficial effects of GLP-1 in Zucker diabetic rats is mediated by an increase in islet cell proliferation and a decrease of cellular apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Blood Glucose / metabolism
  • Caspase 3
  • Caspases / analysis
  • Cell Division / drug effects*
  • Diabetes Mellitus / pathology*
  • Glucagon / blood
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • In Situ Nick-End Labeling
  • Insulin / blood
  • Insulin / metabolism
  • Insulin Secretion
  • Islets of Langerhans / pathology*
  • Ki-67 Antigen / analysis
  • Kinetics
  • Male
  • Peptide Fragments / blood
  • Peptide Fragments / pharmacology*
  • Protein Precursors / blood
  • Protein Precursors / pharmacology*
  • Rats
  • Rats, Zucker

Substances

  • Blood Glucose
  • Insulin
  • Ki-67 Antigen
  • Peptide Fragments
  • Protein Precursors
  • Glucagon-Like Peptide 1
  • Glucagon
  • Casp3 protein, rat
  • Caspase 3
  • Caspases