Metformin protects against lipoapoptosis and enhances GLP-1 secretion from GLP-1-producing cells

J Gastroenterol. 2013 Mar;48(3):322-32. doi: 10.1007/s00535-012-0637-5. Epub 2012 Aug 2.

Abstract

Background: Metformin is the most frequently prescribed drug for treatment of type 2 diabetes. It improves insulin resistance and glycemia by reducing hepatic gluconeogenesis. In addition, diabetic patients on metformin therapy have elevated levels of the insulinotropic hormone glucagon-like peptide-1 (GLP-1) and metformin has been shown to regulate the expression of the GLP-1R in the pancreas.

Methods: We have studied the direct long-term effects of metformin on apoptosis, and function of GLP-1-secreting L cells in vitro, using the murine GLUTag cell line as a model. The apoptosis of GLUTag cells was detected by DNA-fragment assay and caspase-3 activity determination. GLP-1 secretion was determined using ELISA and the expression of proglucagon mRNA was assessed by reverse transcription polymerase chain reaction. The activation of intracellular messengers was determined using western blotting.

Results: Metformin significantly decreased lipotoxicity-induced apoptosis in conjunction with increased phosphorylated AMPK. Metformin also countered the JNK2 activation evoked by lipotoxicity. In addition, long-term metformin treatment stimulated GLP-1 secretion.

Conclusion: This study demonstrates that metformin protects against lipoapoptosis (possibly by blocking JNK2 activation), and enhances GLP-1 secretion from GLP-1-producing cells in vitro. These direct effects of the drug might explain the elevated plasma GLP-1 levels seen in diabetic patients on chronic metformin therapy. The findings may also be harnessed to therapeutic advantage in efforts aiming at enhancing endogenous GLP-1 secretion in type 2 diabetic patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cytoprotection / physiology
  • Enteroendocrine Cells / drug effects*
  • Enteroendocrine Cells / metabolism
  • Glucagon-Like Peptide 1 / biosynthesis*
  • Glucagon-Like Peptide 1 / metabolism
  • Hypoglycemic Agents / pharmacology*
  • MAP Kinase Kinase 4 / metabolism
  • Metformin / pharmacology*
  • Mice
  • Palmitic Acid / antagonists & inhibitors
  • Palmitic Acid / pharmacology
  • Phosphorylation / drug effects
  • Protein Kinases / metabolism
  • Ribonucleotides / pharmacology
  • Tumor Cells, Cultured

Substances

  • Hypoglycemic Agents
  • Ribonucleotides
  • Palmitic Acid
  • Aminoimidazole Carboxamide
  • Glucagon-Like Peptide 1
  • Metformin
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • MAP Kinase Kinase 4
  • Caspase 3
  • AICA ribonucleotide