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

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.

• Authors: Camilla Kappe, Cesare Patrone, Jens J Holst, Qimin Zhang, Ake Sjöholm
• Journal: Journal of gastroenterology (J Gastroenterol) Vol. 48 Issue 3 Pg. 322-32 (Mar 2013) ISSN: 1435-5922 [Electronic] Japan
• PMID: 22850868 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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