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Melissa A. Linden1,4, Kristi T. Lopez1,2, Justin A. Fletcher1,4, Grace M. Meers1,2, Sameer Siddique1, 2, E. MatthewMorris1,2, M. Harold Laughlin, FACSM5, James R. Sowers1,3, John P. Thyfault, FACSM1,2,4, Jamal A. Ibdah1,2,4,andR. Scott Rector1,2,4; 1Research Service-Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri and Departments of Internal Medicine-2Division of Gastroenterology and Hepatology, Internal Medicine-3Division of Endocrinology, 4Nutrition and Exercise Physiology, and 5Biomedical Sciences, University of Missouri; Columbia, MO

Weight loss remains a cornerstone therapy in the treatment for nonalcoholic fatty liver disease (NAFLD). In addition, limited literature suggests that metformin can effectively lower liver enzymes in type 2 diabetics. However, the efficacy of metformin therapy when taken in combination with weight loss on NAFLD outcomes remains largely unexamined. PURPOSE: Here, we sought to determine the therapeutic effects of metformin, caloric restriction, and the combination on type 2 diabetes and NAFLD outcomes in hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. METHODS: We randomly assigned OLETF rats (age 20 weeks; n=6-8/group) to ad libitum fed (AL), metformin (300 mg/kg/d; Met), daily caloric restriction (70% of AL fed; CR), or combination CR+Met groups for 12 weeks of treatment. RESULTS: Met therapy lowered body weight and body fat compared with AL, but to a lesser extent than CR and CR+Met (p<0.05). All three therapies improved fasting insulin, glucose, and/or HbA1c levels, but only the combination of CR+Met improved post-challenge glucose tolerance. Met, CR, and CR+Met reduced hepatic triglycerides by 40%, 70%, and 60% (p<0.05 between Met and CR/CR+Met groups), respectively compared with AL rats, and although there was no additive effects of CR+Met on lowering hepatic steatosis beyond CR alone, the combination resulted in further attenuation in serum alanine aminotransferase (ALT) levels. Met alone failed to alter hepatic de novo lipogenesis proteins fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC) and stearoyl-CoA desaturase-1 (SCD-1), or hepatic mitochondrial activity assessed with palmitate oxidation and β-hydroxy-acyl-CoA dehydrogenase (β-HAD) activity; whereas, CR alone reduced FAS, ACC and SCD-1 protein content, and increased complete palmitate oxidation and β-HAD activity. Furthermore, the combination therapy resulted in further reductions in ACC and SCD-1 protein content compared with CR alone. CONCLUSIONS: Caloric restriction appears to be a more effective therapy than metformin alone in the treatment of NAFLD in the obese, hyperphagic OLETF rat. However, the combination of caloric restriction + metformin offered greater benefits in improving glycemic control, reducing markers of liver injury, and suppressing markers of hepatic de novo lipogenesis than either therapy alone.

This work was partially supported by NIH grants HL-36088 (MHL), DK-088940 (JPT), HL73101-07 (JRS), HL107910-03 (JRS), and T32 AR-048523 (JAF and EMM) and by VA Grant VHA-CDA2 IK2BX001299-01 (RSR) and VA Merit System 0018 (JRS).

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