Gut insulin action protects from hepatocarcinogenesis in diabetic mice comorbid with nonalcoholic steatohepatitis.
Kotaro SoedaTakayoshi SasakoKenichiro EnookuNaoto KubotaNaoki KobayashiYoshiko Matsumoto IkushimaMotoharu AwazawaRyotaro BouchiGotaro TodaTomoharu YamadaTakuma NakatsukaRyosuke TateishiMiwako KakiuchiShogo YamamotoKenji TatsunoKoji AtarashiWataru SudaKenya HondaHiroyuki AburataniToshimasa YamauchiMitsuhiro FujishiroTetsuo NodaKazuhiko KoikeTakashi KadowakiKohjiro UekiPublished in: Nature communications (2023)
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.
Keyphrases
- type diabetes
- glycemic control
- high fat diet
- insulin resistance
- low dose
- cardiovascular disease
- adipose tissue
- high fat diet induced
- end stage renal disease
- newly diagnosed
- chronic kidney disease
- skeletal muscle
- machine learning
- high dose
- ejection fraction
- metabolic syndrome
- oxidative stress
- patient reported outcomes
- artificial intelligence
- diabetic rats
- binding protein
- diabetic nephropathy