title: The desert gerbil Psammomys obesus as a model for metformin-sensitive nutritional type 2 diabetes to protect hepatocellular metabolic damage: Impact of mitochondrial redox state.
abstract: BACKGROUND
  While metformin (MET) is the most widely prescribed antidiabetic drug worldwide, its beneficial effects in Psammomys obesus (P. obesus), a rodent model that mimics most of the metabolic features of human diabetes, have not been explored thoroughly. Here, we sought to investigate whether MET might improve insulin sensitivity, glucose homeostasis, lipid profile as well as cellular redox and energy balance in P. obesus maintained on a high energy diet (HED).
  
  
  METHODS
  P. obesus gerbils were randomly assigned to receive either a natural diet (ND) consisting of halophytic plants (control group) or a HED (diabetic group) for a period of 24 weeks. MET (50 mg/kg per os) was administered in both animal groups after 12 weeks of feeding, i.e., the time required for the manifestation of insulin resistance in P. obesus fed a HED. Parallel in vitro experiments were conducted on isolated hepatocytes that were shortly incubated (30 min) with MET and energetic substrates (lactate + pyruvate or alanine, in the presence of octanoate).
  
  
  RESULTS
  In vivo, MET lowered glycemia, glycosylated haemoglobin, circulating insulin and fatty acid levels in diabetic P. obesus. It also largely reversed HED-induced hepatic lipid alterations. In vitro, MET increased glycolysis but decreased both gluconeogenesis and ketogenesis in the presence of glucogenic precursors and medium-chain fatty acid. Importantly, these changes were associated with an increase in cytosolic and mitochondrial redox states along with a decline in respiration capacity.
  
  
  CONCLUSIONS
  MET prevents the progression of insulin resistance in diabetes-prone P. obesus, possibly through a tight control of gluconeogenesis and fatty acid β-oxidation depending upon mitochondrial function. While the latter is increasingly becoming a therapeutic issue in diabetes, the gut microbiota is another promising target that would need to be considered as well.
authors.affiliation: Bioenergetics and Intermediary Metabolism team, Laboratory of Biology and Organism Physiology, Biological Sciences Institute, University of Sciences and Technology Houari Boumediene, BP 32, ElAlia, Algiers, Algeria.
authors.forename: Inès
authors.initials: I
authors.lastname: Gouaref
authors.affiliation: Université de Bordeaux, Rhythmology and Heart Modeling Institute, Bordeaux, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Detaille
authors.affiliation: CarMeN Laboratory, INSERM U1060, Villeurbanne, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wiernsperger
authors.affiliation: Physiologie de la Nutrition & Toxicologie, INSERM U1236, Université de Bourgogne Franche-Comté (UBFC), Dijon, France.
authors.forename: Naim Akhtar
authors.initials: NA
authors.lastname: Khan
authors.affiliation: University Grenoble Alpes, Laboratoire de Bioénergétique Fondamentale et Appliquée (LBFA), INSERM, U1055, Grenoble, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Leverve
authors.affiliation: Bioenergetics and Intermediary Metabolism team, Laboratory of Biology and Organism Physiology, Biological Sciences Institute, University of Sciences and Technology Houari Boumediene, BP 32, ElAlia, Algiers, Algeria.
authors.forename: Elhadj-Ahmed
authors.initials: EA
authors.lastname: Koceir
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005849:Gerbillinae; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin