Treating fatty liver and insulin resistance

Americans by the year 2050 and is a leading cause of blindness, end stage renal failure and loss of limb with associated costs exceeding $180 billion/year. Insulin resistance in liver and skeletal muscle are major factors in the pathogenesis of T2D, with a strong relationship between ectopic lipid content in liver and skeletal muscle with insulin resistance and T2D in both humans and rodent models of NAFLD and T2D (Shulman, J. Evidence in support of the key role of ectopic lipid in the pathogenesis of hepatic insulin resistance and T2D in humans comes from studies where we (Petersen et al. have shown that modest weight loss (~8 kg) resulted in large (~80%) reductions in liver triglyceride content, which were associated with normalization of fasting plasma glucose concentrations, hepatic glucose production and hepatic insulin sensitivity. Thus we hypothesized that reversal of non-alcoholic fatty liver disease (NAFLD), by promoting mild mitochondrial uncoupling would reverse insulin resistance and diabetes in rat models of NAFLD and T2D. Previous studies by our group had found that treating high fat fed rats with 2,4-dinitrophenol (DNP), a well established mitochondrial protonophore, would lead to mitochondrial energy uncoupling leading to reductions in liver triacylglycerol (TAG) and DAG content, decreased PKCε activation and decreased hepatic insulin resistance (Samuel et al., DNP uncouples mitochondrial glucose and fat oxidation from ATP production by shuttling protons across the mito-chondrial membrane resulting in increased mitochondrial energy consumption, but can be fatally toxic due to its on-target side effect of hyperthermia. We hypothesized that we could markedly increase the therapeutic window of DNP by targeting it to the liver. We therefore generated several derivatives of DNP, which would be preferentially metabolized by the cytochrome P-450 system in the liver to the active protonophore, DNP, and screened them in isolated hepatocytes for their ability to promote increased oxygen consumption. From this screen we identified DNP-methyl ether (DNPME), which raised oxygen Editorial consumption rates with similar potencies to DNP. As predicted, the ratio of toxic to effective dose was 50-fold greater for DNPME than DNP, without any evidence of hyperthermia or renal or hepatic toxicity in rats treated for 6 weeks with DNPME. This therapeutic index also compares favorably with other drugs that are in common use such as acetaminophen, which has a LD 50 /ED 50 of 13. Given the markedly increased therapeutic window for DNPME versus DNP we then examined whether DNPME would reverse …