title: Effects of metformin on oxidative stress, adenine nucleotides balance, and glucose-induced insulin release impaired by chronic free fatty acids exposure in rat pancreatic islets.
abstract: BACKGROUND
  In rat pancreatic islets, chronic exposure to high free fatty acid (FFA) levels impairs insulin secretion and β cell mass. The mechanisms underlying this defect are not completely understood. Since islets have intrinsically low anti-oxidant enzyme defense, oxidative stress might be responsible for β cell damage.
  
  
  OBJECTIVE
  In this study, we investigated if FFA could induce oxidative stress in rat pancreatic islets and if metformin might reverse adverse effects.
  
  
  METHODS
  We cultured rat pancreatic islets in the presence or absence of FFA (oleate/palmitate 2:1, 2 mM) for 72 h. In some experiments, we used metformin (2.5 μg/ml) during the last 24 h.
  
  
  RESULTS
  In our model, glucosestimu lated insulin release was markedly reduced (p<0.005) after chronic FFA exposure, and the ATP/ADP ratio was altered (p<0.05). We observed a significant increase of reactive oxygen species (ROS) (p<0.001), malondialdehyde a lipid peroxidation product (p<0.01) and nitric oxide (NO) levels in the culture media (p<0.001). Inducible NO synthase (iNOS) and heat shock protein-70 (HSP-70) protein expression were also increased (p<0.001 and p<0.01, respectively). When metformin was present during the last 24 h of culture, insulin secretion was restored, and the ATP/ADP ratio was normalized. ROS production, NO production, lipid peroxidation, iNOS and HSP-70 protein expression levels had decreased.
  
  
  CONCLUSIONS
  These data indicate that, in rat pancreatic islets, chronic exposure to high FFA induces oxidative stress and that metformin, by reducing this effect, may have a direct beneficial effect on insulin secretion impaired by lipotoxicity.
authors.affiliation: Department of Clinical and Molecular Biomedicine, Laboratory of Molecular Medicine, University of Catania, Garibaldi-Nesima Hospital, Via Palermo 636-95122, Catania, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Piro
authors.forename: A M
authors.initials: AM
authors.lastname: Rabuazzo
authors.forename: M
authors.initials: M
authors.lastname: Renis
authors.forename: F
authors.initials: F
authors.lastname: Purrello
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000009:adverse effects*; D005947:Glucose / Q000494:pharmacology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D005230:Fatty Acids, Nonesterified; D018840:HSP70 Heat-Shock Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D009573:Nitrites; D008315:Malondialdehyde; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D008687:Metformin; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D005947:Glucose