Morphofunctional changes underlying intestinal dysmotility in diabetic RIP-I/hIFNβ transgenic mice

Abstract

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.

Circulating IGF-I and IGFBP3 Levels Control Human Colonic Stem Cell Function and Are Disrupted in Diabetic Enteropathy

“…Our results demonstrate that individuals with long-standing T1D experienced severe intestinal disorders and that these clinical conditions are associated with alterations of the intestinal mucosa, with reduced proliferation of intestinal epithelial cells and with signs of neural degeneration. Similar features have also been reported in rodent models of T1D and DE(Domenech et al, 2011). Our data link DE to a defect in CoSCs and implicate IGFBP3 as having an important role in the maintenance of intestinal epithelium homeostasis.…”

“…The presence of these gastrointestinal symptoms, known as diabetic enteropathy (DE), significantly reduces the quality of life(1993; Atkinson et al, 2013; Camilleri, 2007; Talley et al, 2001) and has a largely unknown pathogenesis(Feldman and Schiller, 1983). Preclinical studies showed significant derangement of the intestinal mucosa morphology in diabetic rodents(Domenech et al, 2011; Zhao et al, 2003), suggesting that in T1D intestinal homeostasis may be altered; however, little data are available in humans. The intestinal epithelium is maintained by intestinal stem cells and their niche, which respond to physiological stress and to environmental injury(Barker, 2014; Medema and Vermeulen, 2011).…”

Purinergic signalling and diabetes

“…It was suggested that reduction in NO synthase activity was associated with the impairment of NANC relaxation. Impairment of both purinergic and nitrergic components of NANC inhibitory neurotransmission was claimed in the gastrointestinal tract of T1D diabetic RIP-I/hIFNβ transgenic mice [22]. Electrophysiological responses to NA, but not to acetylcholine or ATP, were potentiated in the caecum of 8 week STZ-diabetic rats, perhaps resulting from supersensitivity of α-adrenoceptors after sympathetic nerve damage [202].…”

“…Streptozotocin (STZ)-induced diabetes in rats has been widely used [17], but has been questioned as a valuable model for some aspects of diabetes in man. Other animal models include alloxan-induced diabetes [18, 19], Bio Breeder diabetic rats (BBD) [20], non-obese diabetic (NOD) mice [21] and the murine model of T1D, the RIP-I/hIFNβ transgenic mouse treated with very low doses of STZ [22]. For T2D diabetes, leptin-deficient or leptin-resistant mice (ob/ob and db/db) and Zucker diabetic fatty rats (ZDF) [23] are the most common models.…”

Diabetes Mellitus and the Colon

“…The well-described changes of the vagus nerve including segmental demylelination, axonal degeneration, and a reduction in motor as well as sensory ganglions are also presumed to involve the autonomic nerves of the colon as well [9]. Indeed, DM-related changes to the myenteric plexus of the colon have been repeatedly demonstrated in rat models to include neuronal degeneration and neuronal reduction [10–12]. A case series of seven patients with diabetes has also revealed a reduction in density of interstial cells of Cajal (ICCs) in the colon [13].…”