Improved efficacy of metformin therapy when combined with caloric restriction in the treatment of type 2 diabetes and NAFLD in OLETF rats (LB743)

Abstract

Weight loss is recommended for nonalcoholic fatty liver disease (NAFLD) patients while metformin may lower liver enzymes in type 2 diabetics. Yet, the efficacy of the combination of treatments on NAFLD is unclear. We sought to assess the effects of metformin, caloric restriction, and the combination on NAFLD in diabetic Otsuka Long‐Evans Tokushima Fatty (OLETF) rats. OLETF rats were (age 20 weeks; n=6‐8/group) fed ad libitum (AL), given metformin (300 mg/kg/d; Met), caloric restricted (70% of AL fed; CR), or CR+Met for 12 weeks. Met lowered body weight and adiposity compared with AL, but was less effective than CR and CR+Met (p<0.05). All therapies improved fasting insulin, glucose, and/or HbA1c, but only CR+Met improved post‐challenge glucose tolerance. Met, CR, and CR+Met reduced hepatic triglycerides by 40%, 70%, and 60% (p<0.05 Met vs. CR/CR+Met groups), respectively compared to AL rats; however, CR+Met further attenuated serum alanine aminotransferase levels. Only CR altered hepatic de novo lipogenesis proteins fatty acid synthase (FAS), acetyl‐CoA carboxylase (ACC), and stearoyl‐CoA desaturase‐1 (SCD‐1) and hepatic mitochondrial activity (palmitate oxidation and β‐hydroxy‐acyl‐CoA dehydrogenase (β‐HAD) activity). ACC and SCD‐1 protein content were further reduced with CR+Met. The combination of caloric restriction + metformin further benefited glycemic control, liver injury, and markers of hepatic de novo lipogenesis compared with either therapy alone in the diabetic OLETF rat. *co‐first authorship.Grant Funding Source: Supported by: NIH HL‐36088, DK‐088940, HL73101‐07, HL107910‐03, and T32 AR‐048523 and VA Merit System 0018 and CDA2‐1299.