Mohammad Yassin1, Zuzanna Sadowska1, Katerina Tritsaris1, Hannelouise Kissow2, Camilla H F Hansen3, Julie L Forman4, Gerhard Rogler5, Jesper T Troelsen6, Anders E Pedersen7, Jørgen Olsen1. 1. Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark. 2. Department of Biomedical Sciences and NNF Center of Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark. 3. Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 4. Section of Biostatistics, Department of Public Health, Faculty of Health Sciences, University of Copenhagen, Copenhagen K, Denmark. 5. Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland. 6. Department of Science and Environment, Roskilde University, Roskilde, Denmark. 7. Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
Abstract
BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Tiansheng Wang; Jeff Y Yang; John B Buse; Virginia Pate; Huilin Tang; Edward L Barnes; Robert S Sandler; Til Stürmer Journal: Diabetes Care Date: 2019-08-30 Impact factor: 19.112
Authors: A L Ostermann; C M Wunderlich; L Schneiders; M C Vogt; M A Woeste; B F Belgardt; C M Niessen; B Martiny; A C Schauss; P Frommolt; A Nikolaev; N Hövelmeyer; R C Sears; P J Koch; D Günzel; J C Brüning; F T Wunderlich Journal: Nat Metab Date: 2019-03-04