The human glucagon-like peptide-1 analogue liraglutide regulates pancreatic beta-cell proliferation and apoptosis via an AMPK/mTOR/P70S6K signaling pathway

Peptides. 2013 Jan:39:71-9. doi: 10.1016/j.peptides.2012.10.006. Epub 2012 Oct 30.

Abstract

Glucagon-like peptide-1 (GLP-1), an effective therapeutic agent for the treatment of diabetes, has been proven to protect pancreatic beta cells through many pathways. Recent evidence demonstrates that AMP-activated protein kinase (AMPK), as a metabolic regulator, coordinates beta-cell protein synthesis through regulation of the mammalian target of rapamycin (mTOR) signaling pathway. The purpose of the present study was to explore whether liraglutide, a human GLP-1 analogue, protects beta cells via AMPK/mTOR signaling. We evaluated INS-1 beta-cell line proliferation using the Cell Counting Kit-8, and examined the effect of GLP-1 on cellular ATP levels using an ATP assay kit. mTOR pathway protein expression levels were tested by Western blotting and glucolipotoxicity-induced cell apoptosis was evaluated by flow cytometry. Liraglutide increased beta-cell viability at an optimum concentration of 100 nmol/L in the presence of 11.1 or 30 mmol/L glucose. Liraglutide (100 nmol/L) activated mTOR and its downstream effectors, 70-kDa ribosomal protein S6 kinase and eIF4E-binding protein-1, in INS-1 cells. This effect was abated by pathway blockers: the AMPK activator AICAR and the mTOR inhibitor rapamycin. Furthermore, the effect of liraglutide on beta-cell proliferation was inhibited by AICAR and rapamycin. Liraglutide increased cellular ATP levels. In addition, liraglutide protected beta cells from glucolipotoxicity-induced apoptosis. This response was also prevented by rapamycin treatment. These results suggest that the enhancement of beta-cell proliferation by that GLP-1 receptor agonist liraglutide is mediated, at least in part, by AMPK/mTOR signaling. Liraglutide also prevents beta-cell glucolipotoxicity by activating mTOR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adenosine Triphosphate / metabolism
  • Adenylate Kinase / metabolism
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Cell Cycle Proteins
  • Cell Line
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / pharmacology
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / physiology*
  • Liraglutide
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Ribonucleotides / pharmacology
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Hypoglycemic Agents
  • Phosphoproteins
  • Ribonucleotides
  • Aminoimidazole Carboxamide
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Adenosine Triphosphate
  • MTOR protein, human
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases
  • Adenylate Kinase
  • AICA ribonucleotide
  • Sirolimus