Journal Article

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

Equipe NuTox (LNC - U1231) (NUTOX) ; Lipides - Nutrition - Cancer [Dijon - U1231] (LNC) ; Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Institut de rythmologie et modélisation cardiaque (Bordeaux) (LIRYC), Université des Sciences et de la Technologie Houari Boumediene = University of Sciences and Technology Houari Boumediene [Alger] (USTHB), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN) ; Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL) ; Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon) ; Université de Lyon-Institut

2017

Overview

IntroductionWhile 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).Materials and methodsP. 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).ResultsIn 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.ConclusionsMET prevents the progression of insulin resistance in diabetes-prone P. obesus, possibly through a tight control of gluconeogenesis and fatty acid beta-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.

• Publisher: CCSD,Public Library of Science,Public Library of Science (PLoS)
• Subject: Alanine / Animals / Antidiabetics / Biology and Life Sciences / Blood glucose / Desert environments / Deserts / Diabetes / Diabetes mellitus / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - metabolism / Disease Models, Animal / Dosage and administration / Drug therapy / Electron transport / Energy balance / Fatty acids / Gerbillinae / Gerbils / Gluconeogenesis / Glucose / Glycolysis / Hemoglobin / Hepatocytes / Homeostasis / Hypoglycemic Agents - therapeutic use / Impact damage / Insulin / Insulin Resistance / Intestinal microflora / Ketogenesis / Kinases / Lactic acid / Life Sciences / Liver / Liver - drug effects / Liver - metabolism / Male / Medicine and Health Sciences / Metformin / Metformin - therapeutic use / Microbiota / Mitochondria / Mitochondria, Liver - drug effects / Mitochondria, Liver - metabolism / Obesity / Oxidation / Oxidation-Reduction - drug effects / Physical Sciences / Physiological aspects / Psammomys obesus / Pyruvic acid / Redox properties / Rodents / Substrates / Type 2 diabetes