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…
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