Nonalcoholic fatty liver disease (NAFLD) is now the most common liver disorder in the USA, affecting 90% of morbidly obese individuals and often clustering with prediabetes or overt type 2 diabetes mellitus. While its exact pathogenesis remains unclear, insulin resistance and obesity are considered contributing and risk factors, suggesting effective blood glucose control as a means of preventing and managing NAFLD. To assess this treatment avenue, C57b1/6J mice maintained on a high-fat diet (HFD) for 13 weeks, were treated daily with insulin (INS; 3.6 mg/kg), delivered via a feeding tube, or sham-saline treatment for three consecutive weeks. Peripheral blood and liver samples were collected to analyze inflammatory and fibrosis markers and to histologically assess NAFLD activity score (NAS). Following the treatment period, INS HFD mice demonstrated lower body weight (8.6±1.8 g vs. 7.5±4.1 g) and significantly lower NAS (0.11 vs. 3.7; p<0.005) as compared to sham HFD mice. Further, the mean baseline alanine aminotransferase (ALT) levels of 212±223.6 U/L dropped to 38.3±34.5 U/L and 88.4±85.3 U/L in sham and INS animals, respectively. However, post-treatment aspartate aminotransferase (AST) levels were unchanged in sham HFD animals (202.8±83.7 U/L), but were two-fold lower in INS mice (123.2±80.4 U/L; p=0.03). Mean AST/ALT ratios, a reliable indicator of liver disease, were significantly lower among INS, as compared to sham mice (2.6±1.3 vs. 4.7±2.9; p=0.04). Change from baseline alpha smooth muscle actin (αSMA) RNA levels, a hallmark of fibrosis, was lowest among INS (0.31±0.23-fold increase) as compared to saline-treated HFD mice (0.58±0.14). In parallel, a consistently higher percentage of active, antifibrotic (NKP46+) CD3+ natural killer cells were observed among INS vs. sham and untreated NFD mice. These preliminary findings provide a proof of concept for the potentially therapeutic effect of enteral insulin on fibrotic and inflammatory processes in the liver.
R. Safadi: None. A. Salhab: None. J. Amer: None. D.J. Weiss: None. D. Blumenfeld: None. Y. Mintz: None. N. Kunicher: None. M. Kidron: Employee; Self; Oramed Pharmaceuticals, Inc..