Over 20 million people in the US have diabetes mellitus (DM). Of patients with DM, type II accounts for 90-95% of all diagnosed cases. Many diabetic patients develop significant gastrointestinal symptoms, with up to 60% of longstanding diabetics suffering from delayed gastrointestinal transit, diarrhea or constipation. Chronic constipation associated with type II DM, in addition to diarrhea and incontinence, is increasingly regarded as having serious effects on patient quality of life. Current treatments of Gl complications have considerable side-effects and therefore a greater understanding of the disease would provide novel targets for treatment and possible cure. The current dogma is that Gl disorders associated with type II DM is a consequence of an enteric neuropathy. In the present proposal we have investigated the mechanisms underlying Gl disorders in type II DM. Rather than an enteric neuropathy, we provide evidence that interstitial cells of Cajal that generate pacemaker activity and are critical for enteric motor neurotransmission are disrupted in type II DM. The finding that ICC are affected by type II DM introduces a novel hypothesis that Gl dysmotility and neuromuscular dysfunction associated with this disease could, in part, be due to changes in ICC pacemaker activity and the 'in-series'relationship that exists between enteric motor nerves and intramuscular ICC. The loss of Kit-labeling of ICC associated with DM in humans and animal models has been attributed to cell death though the apoptotic signaling pathway or transdifferentiation. We investigated whether ICC homeodynamics are affected by increased apoptosis or decreased cell division. The mechanism(s) of cell growth and expansion of ICC populations will be investigated in type II DM tissues allotransplanted with ICC. In summary, this proposal will provide important information about the defects in ICC networks (which are involved in pacemaker activity and in enteric neuromuscular transmission witin the Gl tract) that occur in the Gl tracts of patients with type II DM. New information will be obtained about the processes underlying the disruption of neuromuscular function in the Gl tracts of animal models with DM, that may be causative in delayed intestinal transit, constipation or diarrhea in human patients.
Relevance to gastrointestinal motility disorders associated with type II diabetes.
|Durnin, Leonie; Kwok, Benjamin; Kukadia, Priya et al. (2018) An ex vivo bladder model with detrusor smooth muscle removed to analyse biologically active mediators released from the suburothelium. J Physiol :|
|Shi, Junchao; Ko, Eun-A; Sanders, Kenton M et al. (2018) SPORTS1.0: A Tool for Annotating and Profiling Non-coding RNAs Optimized for rRNA- and tRNA-derived Small RNAs. Genomics Proteomics Bioinformatics 16:144-151|
|Drumm, Bernard T; Sung, Tae S; Zheng, Haifeng et al. (2018) The effects of mitochondrial inhibitors on Ca2+ signalling and electrical conductances required for pacemaking in interstitial cells of Cajal in the mouse small intestine. Cell Calcium 72:1-17|
|Baker, Salah A; Drumm, Bernard T; Skowronek, Karolina E et al. (2018) Excitatory Neuronal Responses of Ca2+ Transients in Interstitial Cells of Cajal in the Small Intestine. eNeuro 5:|
|Drumm, Bernard T; Hennig, Grant W; Battersby, Matthew J et al. (2017) Clustering of Ca2+ transients in interstitial cells of Cajal defines slow wave duration. J Gen Physiol 149:703-725|
|Smith, Terence Keith; Koh, Sang Don (2017) A model of the enteric neural circuitry underlying the generation of rhythmic motor patterns in the colon: the role of serotonin. Am J Physiol Gastrointest Liver Physiol 312:G1-G14|
|Beckett, Elizabeth A H; Sanders, Kenton M; Ward, Sean M (2017) Inhibitory responses mediated by vagal nerve stimulation are diminished in stomachs of mice with reduced intramuscular interstitial cells of Cajal. Sci Rep 7:44759|
|Durnin, Leonie; Lees, Andrea; Manzoor, Sheerien et al. (2017) Loss of nitric oxide-mediated inhibition of purine neurotransmitter release in the colon in the absence of interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol 313:G419-G433|
|Cobine, C A; Hannah, E E; Zhu, M H et al. (2017) ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter. J Physiol 595:2021-2041|
|Lee, Moon Young; Park, Chanjae; Ha, Se Eun et al. (2017) Serum response factor regulates smooth muscle contractility via myotonic dystrophy protein kinases and L-type calcium channels. PLoS One 12:e0171262|
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