Protective role of gut insulin action in the development of nonalcoholic steatohepatitis and hepatocellular carcinoma associated with diabetes in mice

Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treated STAM (STelic Animal Model) mice, which develop diabetes, NASH and HCC associated with dysbiosis upon low-dose streptozotocin and high-fat diet (HFD), with insulin or phlorizin. Although both treatments ameliorated hyperglycemia and NASH, insulin treatment alone led to suppression of HCC accompanied by improvement of dysbiosis through restoration of antimicrobial peptide production. Similar changes in microflora are observed in insulin-treated patients comorbid with diabetes and NASH. Insulin treatment, however, failed to suppress HCC in the STAM mice lacking insulin receptor specifically in intestinal epithelial cells (ieIRKO), which showed dysbiosis and impaired gut barrier function. Furthermore, ieIRKO mice were prone to develop HCC merely on HFD. These data suggest that impaired gut insulin signaling increases the risk of HCC which can be countered by restoration of insulin action in diabetes. Gene expression in liver of six STAM mice or three normal mice was measured at 20 weeks of age. Three of STAM mice were treated with insulin, and the other STAM mice were non-treated control.