BackgroundOptimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model.Methodology/Principal FindingsEight-week-old C57BL/6 mice were fed a methionine- and choline-deficient plus high fat (MCD+HF) diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH.Conclusions/SignificanceThese histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance.

Chronic endoplasmic reticulum (ER) stress is a major contributor to obesity-induced insulin resistance in the liver. However, the molecular link between obesity and ER stress remains to be identified. Proteasomes are important multicatalytic enzyme complexes that degrade misfolded and oxidized proteins. Here, we report that both mouse models of obesity and diabetes and proteasome activator (PA)28-null mice showed 30–40% reduction in proteasome activity and accumulation of polyubiquitinated proteins in the liver. PA28-null mice also showed hepatic steatosis, decreased hepatic insulin signaling, and increased hepatic glucose production. The link between proteasome dysfunction and hepatic insulin resistance involves ER stress leading to hyperactivation of c-Jun NH2-terminal kinase in the liver. Administration of a chemical chaperone, phenylbutyric acid (PBA), partially rescued the phenotypes of PA28-null mice. To confirm part of the results obtained from in vivo experiments, we pretreated rat hepatoma-derived H4IIEC3 cells with bortezomib, a selective inhibitor of the 26S proteasome. Bortezomib causes ER stress and insulin resistance in vitro—responses that are partly blocked by PBA. Taken together, our data suggest that proteasome dysfunction mediates obesity-induced ER stress, leading to insulin resistance in the liver.

IntroductionA step-up strategy for dipeptidyl peptidase (DPP)-4 inhibitor-based regimens has not yet been established. In addition, similarities and differences between DPP-4 inhibitors and glucagon-like peptide (GLP)-1 receptor agonists remain to be elucidated in humans. We investigated the pleiotropic effects of vildagliptin vs liraglutide in patients with type 2 diabetes on sitagliptin-based regimens in an open-label, randomized, clinical trial.Materials and MethodsA total of 122 patients with type 2 diabetes that was inadequately controlled by sitagliptin-based regimens were randomly assigned to either vildagliptin (50 mg, twice daily) or liraglutide treatment (0.9 mg, once daily) for 12 weeks. The primary outcomes were glycated hemoglobin and body mass index.ResultsBoth vildagliptin and liraglutide significantly lowered glycated hemoglobin within 12 weeks after switching from sitagliptin, but liraglutide produced a greater reduction (−0.67 ± 0.12% vs −0.36 ± 0.53%). Liraglutide lowered body mass index, whereas vildagliptin did not affect body mass index. Vildagliptin lowered fasting C-peptide immunoreactivity, but liraglutide did not. Vildagliptin increased serum levels of adiponectin, arachidonic acid, eicosapentaenoic acid and docosahexaenoic acid, whereas liraglutide had no effect on these levels. Quality of life, assessed using the diabetes treatment satisfaction questionnaire, was not impaired in either group. The most common adverse events were gastrointestinal symptoms, which occurred with similar frequencies in both groups.ConclusionsVildagliptin-mediated improvements in glycemic control did not correlate with indices for insulin secretion and insulin sensitivity. Switching from sitagliptin to liraglutide is useful in managing hyperglycemia and weight. Each agent exerts unique pleiotropic effects. This trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (no. 000004953).