title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Clinical Science and Education, Unit for Diabetes Research, Karolinska Institutet, Södersjukhuset, 118 83, Stockholm, Sweden. camilla.kappe@ki.se
authors.forename: Camilla
authors.initials: C
authors.lastname: Kappe
authors.forename: Cesare
authors.initials: C
authors.lastname: Patrone
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ake
authors.initials: A
authors.lastname: Sjöholm
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D019610:Cytoprotection / Q000502:physiology; D019858:Enteroendocrine Cells / Q000187:drug effects* / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000096:biosynthesis* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D019308:Palmitic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D007004:Hypoglycemic Agents; D012265:Ribonucleotides; D019308:Palmitic Acid; D000620:Aminoimidazole Carboxamide; D052216:Glucagon-Like Peptide 1; D008687:Metformin; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; C031143:AICA ribonucleotide