Morphofunctional changes underlying intestinal dysmotility in diabetic RIP-I/hIFNβ transgenic mice
Anna Domènech
Department of Animal Medicine and Surgery, Universitat Autònoma de Barcelona, Bellaterra, Spain
Search for more papers by this authorGianandrea Pasquinelli
Department of Radiological and Histocytopathological Sciences, Ospedale St.Orsola-Malpighi, Università di Bologna, Bologna, Italy
Search for more papers by this authorRoberto De Giorgio
Department of Clinical Medicine, Ospedale St.Orsola-Malpighi, Università di Bologna, Bologna, Italy
Search for more papers by this authorAlessandra Gori
Department of Clinical Medicine, Ospedale St.Orsola-Malpighi, Università di Bologna, Bologna, Italy
Search for more papers by this authorFàtima Bosch
Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
Search for more papers by this authorMartí Pumarola
Department of Animal Medicine and Surgery, Universitat Autònoma de Barcelona, Bellaterra, Spain
Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
Search for more papers by this authorMarcel Jiménez
Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Barcelona, Spain
Search for more papers by this authorAnna Domènech
Department of Animal Medicine and Surgery, Universitat Autònoma de Barcelona, Bellaterra, Spain
Search for more papers by this authorGianandrea Pasquinelli
Department of Radiological and Histocytopathological Sciences, Ospedale St.Orsola-Malpighi, Università di Bologna, Bologna, Italy
Search for more papers by this authorRoberto De Giorgio
Department of Clinical Medicine, Ospedale St.Orsola-Malpighi, Università di Bologna, Bologna, Italy
Search for more papers by this authorAlessandra Gori
Department of Clinical Medicine, Ospedale St.Orsola-Malpighi, Università di Bologna, Bologna, Italy
Search for more papers by this authorFàtima Bosch
Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
Search for more papers by this authorMartí Pumarola
Department of Animal Medicine and Surgery, Universitat Autònoma de Barcelona, Bellaterra, Spain
Center of Animal Biotechnology and Gene Therapy, Universitat Autònoma de Barcelona, Bellaterra, Spain
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona, Spain
Search for more papers by this authorMarcel Jiménez
Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Barcelona, Spain
Search for more papers by this authorSummary
The pathogenetic mechanisms underlying gastrointestinal dysmotility in diabetic patients remain poorly understood, although enteric neuropathy, damage to interstitial cells of Cajal (ICC) and smooth muscle cell injury are believed to play a role. The aim of this study was to investigate the morphological and functional changes underlying intestinal dysmotility in RIP-I/hIFNβ transgenic mice treated with multiple very low doses of streptozotocin (20 mg/kg, i.p., 5 days). Compared with vehicle-treated mice, streptozotocin-treated animals developed type 1 diabetes mellitus, with sustained hyperglycaemia for 3.5 months, polyphagia, polydipsia and increased faecal output without changes in faecal water content (metabolic cages). Diabetic mice had a longer intestine, longer ileal villi and wider colonic crypts (conventional microscopy) and displayed faster gastric emptying and intestinal transit. Contractility studies showed selective impaired neurotransmission in the ileum and mid-colon of diabetic mice. Compared with controls, the ileal and colonic myenteric plexus of diabetic mice revealed ultrastructural features of neuronal degeneration and HuD immunohistochemistry on whole-mount preparations showed 15% reduction in neuronal numbers. However, no immunohistochemical changes in apoptosis-related markers were noted. Lower absolute numbers of neuronal nitric oxide synthase- and choline acetyltransferase-immunopositive neurons and enhanced vasoactive intestinal polypeptide and substance P immunopositivity were observed. Ultrastructural and immunohistochemical analyses did not reveal changes in the enteric glial or ICC networks. In conclusion, this model of diabetic enteropathy shows enhanced intestinal transit associated with intestinal remodelling, including neuroplastic changes, and overt myenteric neuropathy. Such abnormalities are likely to reflect neuroadaptive and neuropathological changes occurring in this diabetic model.
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