Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Nat Commun. 2023 Oct 18;14(1):6584. doi: 10.1038/s41467-023-42334-y.
Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treat male 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 ameliorate hyperglycemia and NASH, insulin treatment alone lead to suppression of HCC accompanied by improvement of dysbiosis and restoration of antimicrobial peptide production. There are some similarities in changes of microflora from insulin-treated patients comorbid with diabetes and NASH. Insulin treatment, however, fails to suppress HCC in the male STAM mice lacking insulin receptor specifically in intestinal epithelial cells (ieIRKO), which show dysbiosis and impaired gut barrier function. Furthermore, male ieIRKO mice are 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.
糖尿病已知会增加非酒精性脂肪性肝炎（NASH）和肝细胞癌（HCC）的风险。在这里，我们治疗雄性 STAM（STelic 动物模型）小鼠，这些小鼠在低剂量链脲佐菌素和高脂肪饮食（HFD）下会发展出糖尿病、NASH 和与肠道菌群失调相关的 HCC，并用胰岛素或根皮苷进行治疗。虽然这两种治疗方法都能改善高血糖和 NASH，但单独使用胰岛素治疗会导致 HCC 受到抑制，同时改善肠道菌群失调并恢复抗菌肽的产生。从合并糖尿病和 NASH 的胰岛素治疗患者的微生物群变化中可以看出一些相似之处。然而，胰岛素治疗并不能抑制雄性 STAM 小鼠中特异性缺乏肠道上皮细胞胰岛素受体（即 ieIRKO）的 HCC，这些小鼠表现出肠道菌群失调和肠道屏障功能受损。此外，雄性 ieIRKO 小鼠仅在 HFD 上就容易发生 HCC。这些数据表明，肠道胰岛素信号受损会增加 HCC 的风险，而在糖尿病中恢复胰岛素作用可以对抗这种风险。
