Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis.

Published

Journal Article

Glucagon-like peptide-1 (GLP-1) controls glucose homeostasis by regulating secretion of insulin and glucagon through a single GLP-1 receptor (GLP-1R). GLP-1R agonists also increase pancreatic weight in some preclinical studies through poorly understood mechanisms. Here we demonstrate that the increase in pancreatic weight following activation of GLP-1R signaling in mice reflects an increase in acinar cell mass, without changes in ductal compartments or β-cell mass. GLP-1R agonists did not increase pancreatic DNA content or the number of Ki67(+) cells in the exocrine compartment; however, pancreatic protein content was increased in mice treated with exendin-4 or liraglutide. The increased pancreatic mass and protein content was independent of cholecystokinin receptors, associated with a rapid increase in S6 phosphorylation, and mediated through the GLP-1R. Rapamycin abrogated the GLP-1R-dependent increase in pancreatic mass but had no effect on the robust induction of Reg3α and Reg3β gene expression. Mass spectrometry analysis identified GLP-1R-dependent upregulation of Reg family members, as well as proteins important for translation and export, including Fam129a, eIF4a1, Wars, and Dmbt1. Hence, pharmacological GLP-1R activation induces protein synthesis, leading to increased pancreatic mass, independent of changes in DNA content or cell proliferation in mice.

Full Text

Duke Authors

Cited Authors

  • Koehler, JA; Baggio, LL; Cao, X; Abdulla, T; Campbell, JE; Secher, T; Jelsing, J; Larsen, B; Drucker, DJ

Published Date

  • March 2015

Published In

Volume / Issue

  • 64 / 3

Start / End Page

  • 1046 - 1056

PubMed ID

  • 25277394

Pubmed Central ID

  • 25277394

Electronic International Standard Serial Number (EISSN)

  • 1939-327X

Digital Object Identifier (DOI)

  • 10.2337/db14-0883

Language

  • eng

Conference Location

  • United States