Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
Department of Biomedical Sciences and NNF Center of Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
J Crohns Colitis. 2018 Nov 28;12(12):1459-1474. doi: 10.1093/ecco-jcc/jjy112.
Epithelial expression of the insulin receptor in the colon has previously been reported to correlate with extent of colonic inflammation. However, the impact of insulin signalling in the intestinal mucosa is still unknown. Here, we investigated the effects of inactivating the epithelial insulin receptor in the intestinal tract, in an experimental model of inflammation-induced colorectal cancer.
The mice were generated by utilizing the intestinal- and epithelial-specific villin promoter and the Cre-Lox technology. All mice included in the cohorts were generated by crossing [vil-Cre-INSR+/-] × [INSRfl/fl] to obtain [vil-Cre-INSR-/-], and their floxed littermates [INSRfl/fl] served as the control group. For the intervention study, phosphate-buffered saline with or without insulin was instilled rectally in anaesthetized wild-type mice with chemically induced colitis.
We found higher endoscopic colitis scores together with potentiated colonic tumorigenesis in the knockout mice. Furthermore, we showed that topically administered insulin in inflamed colons of wild-type mice reduced inflammation-induced weight loss and improved remission in a dose-dependent manner. Mice receiving rectal insulin enemas exhibited lower colitis endoscopic scores and reduced cyclooxygenase 2 mRNA expression, and developed significantly fewer and smaller tumours compared with the control group receiving phosphate-buffered saline only.
Rectal insulin therapy could potentially be a novel treatment, targeting the epithelial layer to enhance mucosal healing in ulcerated areas. Our findings open up new possibilities for combination treatments to synergize with the existing anti-inflammatory therapies.
先前已有报道称，结肠上皮细胞胰岛素受体的表达与结肠炎症的严重程度相关。然而，肠道黏膜中胰岛素信号的作用仍不清楚。在此，我们在炎症诱导的结直肠癌实验模型中，研究了破坏肠道上皮细胞胰岛素受体的影响。
利用肠道和上皮特异性的微管蛋白启动子和 Cre-Lox 技术来生成这些小鼠。所有纳入研究的小鼠都是通过将 [vil-Cre-INSR+/-] × [INSRfl/fl] 杂交以获得 [vil-Cre-INSR-/-] ，并将其 floxed 同窝仔鼠 [INSRfl/fl] 作为对照组。对于干预研究，我们在接受化学诱导结肠炎的野生型小鼠中，通过直肠内给予胰岛素或磷酸盐缓冲液。
我们发现，在敲除小鼠中，内镜下结肠炎评分更高，且结肠肿瘤发生也更严重。此外，我们发现，在野生型小鼠发炎的结肠中局部给予胰岛素可减轻炎症引起的体重减轻，并以剂量依赖的方式改善缓解。与仅接受磷酸盐缓冲液的对照组相比，接受直肠胰岛素灌肠的小鼠的结肠炎内镜评分更低，环氧合酶 2 mRNA 表达减少，且肿瘤数量更少、体积更小。
直肠胰岛素治疗可能是一种新型治疗方法，靶向上皮层以增强溃疡性区域的黏膜愈合。我们的研究结果为联合治疗提供了新的可能性，以与现有的抗炎治疗协同作用。
