title: Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats.
abstract: Weight loss is recommended for patients with nonalcoholic fatty liver disease (NAFLD), while metformin may lower liver enzymes in type 2 diabetics. Yet, the efficacy of the combination of weight loss and metformin in the treatment of NAFLD is unclear. We assessed the effects of metformin, caloric restriction, and their combination on NAFLD in diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Male OLETF rats (age 20 weeks; n = 6-8 per group) were fed ad libitum (AL), given metformin (300 mg·kg(-1)·day(-1); Met), calorically restricted (70% of AL; CR), or calorically restricted and given metformin (CR+Met) for 12 weeks. Met lowered adiposity compared with AL but not to the same magnitude as CR or CR+Met (p < 0.05). Although only CR improved fasting insulin and glucose, the combination of CR+Met was needed to improve post-challenge glucose tolerance. All treatments lowered hepatic triglycerides, but further improvements were observed in the CR groups (p < 0.05, Met vs. CR or CR+Met) and a further reduction in serum alanine aminotransferases was observed in CR+Met rats. CR lowered markers of hepatic de novo lipogenesis (fatty acid synthase, acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD-1)) and increased hepatic mitochondrial activity (palmitate oxidation and β-hydroxyacyl CoA dehydrogenase (β-HAD) activity). Changes were enhanced in the CR+Met group for ACC, SCD-1, β-HAD, and the mitophagy marker BNIP3. Met decreased total hepatic mTOR content and inhibited mTOR complex 1, which may have contributed to Met-induced reductions in de novo lipogenesis. These findings in the OLETF rat suggest that the combination of caloric restriction and metformin may provide a more optimal approach than either treatment alone in the management of type 2 diabetes and NAFLD.
authors.affiliation: a Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.|b Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Linden
authors.affiliation: a Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.|c Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Kristi T
authors.initials: KT
authors.lastname: Lopez
authors.affiliation: a Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.|b Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: a Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.|c Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: E Matthew
authors.initials: EM
authors.lastname: Morris
authors.affiliation: a Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.|c Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Meers
authors.affiliation: a Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.|c Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Sameer
authors.initials: S
authors.lastname: Siddique
authors.affiliation: e Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.
authors.forename: M Harold
authors.initials: MH
authors.lastname: Laughlin
authors.affiliation: a Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.|d Department of Medicine, Division of Endocrinology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
authors.affiliation: a Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.|b Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA.|c Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Thyfault
authors.affiliation: a Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.|b Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA.|c Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Jamal A
authors.initials: JA
authors.lastname: Ibdah
authors.affiliation: a Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO 65201, USA.|b Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA.|c Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Rector
mesh_terms: D000818:Animals; D015153:Blotting, Western; D031204:Caloric Restriction; D003921:Diabetes Mellitus, Experimental; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D009765:Obesity / Q000150:complications / Q000378:metabolism / Q000628:therapy*; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin
keywords: caloric restriction; de novo lipogenesis; fonction mitochondriale; hepatic steatosis; lipogenèse de novo; metformin; metformine; mitochondrial function; nonalcoholic fatty liver disease; restriction calorique; stéatose hépatique; stéatose hépatique non alcoolique