Distribution of interstitial cells of Cajal and nerve fibers in rat stomach in streptozotocin-nicotinamide-induced diabetes mellitus
DOI:
https://doi.org/10.2298/ABS230220012VKeywords:
diabetes mellitus type 2, Interstitial cell of Cajal, streptozotocin nicotinamide, stomach (gaster)Abstract
Paper description:
- Regulation of peristalsis is a complex process involving interstitial cells of Cajal (ICCs). There is no data on ICC distribution in the stomach in diabetes mellitus type 2 (DMT2).
- Data provide insight into the role of ICCs in diabetic gastro enteropathy. The research was focused on morphological and numerical changes in different ICC subtypes in the streptozotocin-nicotinamide (STZ-NA)-induced DMT2 rat model.
- Changes in all ICC types without nerve structure disorders were observed in contrast to animal models described in the literature in DMT1.
- These results contribute to the understanding of the mechanism and chronology of gastric motility disorders in diabetes.
Abstract: Diabetic peristalsis disorders are common complications in diabetes mellitus type 2. Disturbance of interstitial cells of Cajal (ICC) caused by metabolic changes in diabetes could explain the symptoms of diabetic gastroenteropathy. Although heterogenous interstitial cell types represent only 5% of the cell population of the muscle layer in the gastrointestinal tract (GIT), they are important for conducting electrical signals and regulating muscle excitability. The aim of this study was to investigate the alterations of the myenteric and intramuscular ICCs in the gaster of rats with diabetes mellitus type 2 (DMT2), as well as determine their distribution in relation to smooth muscle cells and enteric nerve structures. Male Wistar rats were used and DT2 was induced by streptozotocin-nicotinamide (STZ-NA) application. The stomach specimens were exposed to type III transmembrane tyrosine kinase (c-KIT), neurofilament (NF-M) protein and desmin antibodies to investigate the ICC, enteric neurons and smooth muscle cells. Morphological changes of the cells were quantified by the numerical areal density of intramuscular ICC, the ICC score of myenteric ICC and the volume density of nerve fibers. In conclusion, a statistically significant decrease in the number of intramuscular ICC and myenteric ICC without nerve fiber loss were observed in all stomach regions in rats with STZ-NA-induced DMT2.
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References
Khan MAB, Hashim MJ, King JK, Govender RD, Mustafa H, Al Kaabi J. Epidemiology of Type 2 Diabetes - Global Burden of Disease and Forecasted Trends. J Epidemiol Glob Health. 2020;10(1):107-11. https://doi.org/10.2991/jegh.k.191028.001
Fujishiro M, Kushiyama A, Yamazaki H, Kaneko S, Koketsu Y, Yamamotoya T, Kikuchi T, Sakoda H, Suzuki R, Kadowaki T. Gastrointestinal symptom prevalence depends on disease duration and gastrointestinal region in type 2 diabetes mellitus. World J Gastroenterol. 2017;23(36):6694-704. https://doi.org/10.3748/wjg.v23.i36.6694
Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care. 2003;26(5):1553-79. https://doi.org/10.2337/diacare.26.5.1553
Kaplan LM, McCallum RW, Koch KL, Sederman R HB. High prevalence and underdiagnosis of gastroparesis symptoms among patients with type 1 and type 2 diabetes mellitus. Gastroenterology. 2013;144(5):S107. https://doi.org/10.1016/S0016-5085(13)60393-5
Abdelsayed N, Juarez A, Carter M. Severe Gastroparesis Leading to Hypoglycemia and Subsequent Seizures. Cureus. 2022;14(10):e30527. https://doi.org/10.7759/cureus.30527
Kashyap P, Farrugia G. Diabetic gastroparesis: what we have learned and had to unlearn in the past 5 years. Gut. 2010;59(12):1716-26. https://doi.org/10.1136/gut.2009.199703
Sanders KM, Ward SM, Koh SD. Interstitial cells: regulators of smooth muscle function. Physiol Rev. 2014;94(3):859-907. https://doi.org/10.1152/physrev.00037.2013
Maeda H, Yamagata A, Nishikawa S, Yoshinaga K, Kobayashi S, Nishi K, Nishikawa S. Requirement of c-kit for development of intestinal pacemaker system. Development. 1992;116(2):369-75. https://doi.org/10.1242/dev.116.2.369
Komuro T. Structure and organization of interstitial cells of Cajal in the gastrointestinal tract. J Physiol. 2006;576(3):653-8. https://doi.org/10.1113/jphysiol.2006.116624
Komuro T. Atlas of Interstitial Cells of Cajal in the Gastrointestinal Tract. Springer;2012.134 p. https://doi.org/10.1007/978-94-007-2917-9
Faussone-Pellegrini M-S, Cortesini C, Romagnoli P. The ultrastructure of the muscle coat of human gastro-oesophageal junction, with special reference to "interstitial cells of Cajal". Front Neurosci. 2013;7:49. https://doi.org/10.3389/fnins.2013.00049
Al-Shboul OA. The importance of interstitial cells of Cajal in the gastrointestinal tract. Saudi J Gastroenterol. 2013;19(1):3-15. https://doi.org/10.4103/1319-3767.105909
Kito Y. The functional role of intramuscular interstitial cells of Cajal in the stomach. J Smooth Muscle Res. 2011;47(2):47-53. https://doi.org/10.1540/jsmr.47.47
Hwang SJ, Blair PJ, Britton FC, O'Driscoll KE, Hennig G, Bayguinov YR, Rock JR, Harfe BD, Sanders KM, Ward SM. Expression of anoctamin 1/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles. J Physiol. 2009;587(20):4887-904. https://doi.org/10.1113/jphysiol.2009.176198
Huizinga JD, Zarate N, Farrugia G. Physiology, injury, and recovery of interstitial cells of Cajal: basic and clinical science. Gastroenterology. 2009;137(5):1548-56. https://doi.org/10.1053/j.gastro.2009.09.023
Ibba Manneschi L, Pacini S, Corsani L, Bechi P, Faussone-Pellegrini MS. Interstitital cells of Cajal in the human stomach: distribution and relationship with enteric innervation. Histol Histopathol. 2004;19(4):1153-64.
Ward SM, McLaren GJ, Sanders KM. Interstitial cells of Cajal in the deep muscular plexus mediate enteric motor neurotransmission in the mouse small intestine. J Physiol. 2006;573(1):147-59. https://doi.org/10.1113/jphysiol.2006.105189
Powley TL, Wang XY, Fox EA, Phillips RJ, Liu LWC, Huizinga JD. Ultrastructural evidence for communication between intramuscular vagal mechanoreceptors and interstitial cells of Cajal in the rat fundus. Neurogastroenterol Motil. 2008;20(1):69-79.
Huizinga JD, Reed DE, Berezin I, Wang X-Y, Valdez DT, Liu LWC, Diamant NE. Survival dependency of intramuscular ICC on vagal afferent nerves in the cat esophagus. Am J Physiol Regul Integr Comp Physiol. 2008;294(2):R302-10. https://doi.org/10.1152/ajpregu.00398.2007
Beckett EAH, Ro S, Bayguinov YR, Sanders KM, Ward SM. Kit signaling is essential for development and maintenance of interstitial cells of Cajal and electrical rhythmicity in the embryonic gastrointestinal tract. Dev Dyn. 2007;236. https://doi.org/10.1002/dvdy.20929
Vanderwinden JM, Rumessen JJ. Interstitial cells of Cajal in human gut and gastrointestinal disease. Microsc Res Tech. 1999;47(5):344-60. https://doi.org/10.1002/(SICI)1097-0029(19991201)47:5<344::AID-JEMT6>3.0.CO;2-1
Mostafa RM, Moustafa YM, Hamdy H. Interstitial cells of Cajal, the Maestro in health and disease. World J Gastroenterol. 2010;16(26):3239. https://doi.org/10.3748/wjg.v16.i26.3239
Huizinga JD, Hussain A, Chen J-H. Interstitial cells of Cajal and human colon motility in health and disease. Am J Physiol Gastrointest Liver Physiol. 2021;321(5):G552-75. https://doi.org/10.1152/ajpgi.00264.2021
Choi KM, Zhu J, Stoltz GJ, Vernino S, Camilleri M, Szurszewski JH, Gibbons SJ, Farrugia G. Determination of gastric emptying in nonobese diabetic mice. Am J Physiol Liver Physiol. 2007;293(5):G1039-45. https://doi.org/10.1152/ajpgi.00317.2007
Intagliata N, Koch KL. Gastroparesis in type 2 diabetes mellitus: prevalence, etiology, diagnosis, and treatment. Curr Gastroenterol Rep. 2007;9(4):270-9. https://doi.org/10.1007/s11894-007-0030-3
Huang I-H, Schol J, Khatun R, Carbone F, Van den Houte K, Colomier E, Balsiger LM, Törnblom H, Vanuytsel T, Sundelin E, Simrén M, Palsson OS, Bangdiwala SI, Sperber AD, Tack J. Worldwide prevalence and burden of gastroparesis-like symptoms as defined by the United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis. United Eur Gastroenterol J. 2022;10(8):888-97. https://doi.org/10.1002/ueg2.12289
Undeland KA, Hausken T, Aanderud S, Berstad A. Lower postprandial gastric volume response in diabetic patients with vagal neuropathy. Neurogastroenterol Motil. 1997;9(1):19-24. https://doi.org/10.1046/j.1365-2982.1997.d01-3.x
Hasler WL, Soudah HC, Dulai G, Owyang C. Mediation of hyperglycemia-evoked gastric slow-wave dysrhythmias by endogenous prostaglandins. Gastroenterology. 1995;108(3):727-36. https://doi.org/10.1016/0016-5085(95)90445-X
Chen JD, Lin Z, Pan J, McCallum RW. Abnormal gastric myoelectrical activity and delayed gastric emptying in patients with symptoms suggestive of gastroparesis. Dig Dis Sci. 1996;41(8):1538-45. https://doi.org/10.1007/BF02087897
Ordög T, Takayama I, Cheung WK, Ward SM, Sanders KM. Remodeling of networks of interstitial cells of Cajal in a murine model of diabetic gastroparesis. Diabetes. 2000;49(10):1731-9. https://doi.org/10.2337/diabetes.49.10.1731
Wu Y-S, Lu H-L, Huang X, Liu D-H, Meng X-M, Guo X, Kim YC, Xu WX. Diabetes-induced loss of gastric ICC accompanied by up-regulation of natriuretic peptide signaling pathways in STZ-induced diabetic mice. Peptides. 2013;40:104-11. https://doi.org/10.1016/j.peptides.2012.12.024
Wang X-Y, Huizinga JD, Diamond J, Liu LWC. Loss of intramuscular and submuscular interstitial cells of Cajal and associated enteric nerves is related to decreased gastric emptying in streptozotocin-induced diabetes. Neurogastroenterol Motil. 2009;21(10):1095-e92. https://doi.org/10.1111/j.1365-2982.2009.01336.x
Wang Q, Zang J, Huang X, Lu H, Xu W, Chen J. Colonic Dysmotility in Murine Partial Colonic Obstruction Due to Functional Changes in Interstitial Cells. J Neurogastroenterol Motil. 2019;25(4):589-601. https://doi.org/10.5056/jnm19136
Wang H, Zhao K, Shi N, Niu Q, Liu C, Chen Y. Electroacupuncture Regularizes Gastric Contraction and Reduces Apoptosis of Interstitial Cells of Cajal in Diabetic Rats. Front Physiol. 2021;12:560738. https://doi.org/10.3389/fphys.2021.560738
Masiello P, Broca C, Gross R, Roye M, Manteghetti M, Hillaire-Buys D, Novelli M, Ribes G. Experimental NIDDM: development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes. 1998;47(2):224-9. https://doi.org/10.2337/diab.47.2.224
Genuth S, Alberti KGMM, Bennett P, Buse J, Defronzo R, Kahn R, Kitzmiller J, Knowler WC, Lebovitz H, Lernmark A, Nathan D, Palmer J, Rizza R, Saudek C, Shaw J, Steffes M, Stern M, Tuomilehto J, Zimmet P. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care. 2003;26(11):3160-7. https://doi.org/10.2337/diacare.26.11.3160
den Braber-Ymker M, Heijker S, Lammens M, Nagtegaal ID. Practical and reproducible estimation of myenteric interstitial cells of Cajal in the bowel for diagnostic purposes. Neurogastroenterol Motil. 2016;28(8):1261-7. https://doi.org/10.1111/nmo.12831
Szkudelski T. Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med. 2012;237(5):481-90. https://doi.org/10.1258/ebm.2012.011372
Veličkov AI, Djordjević B, Lazarević M, Veličkov AV, Petrović V, Jović M, Denčić T, Radenković G. Distributions of Platelet-Derived Growth Factor Receptor-α Positive Cells and Interstitial Cells of Cajal in the Colon of Rats with Diabetes Mellitus Type 2. Medicina. 2023;59(2):308. https://doi.org/10.3390/medicina59020308
Aronson D. Hyperglycemia and the pathobiology of diabetic complications. Adv Cardiol. 2008;45:1-16. https://doi.org/10.1159/000115118
Díaz A, López-Grueso R, Gambini J, Monleón D, Mas-Bargues C, Abdelaziz KM, Viña J, Borrás C. Sex Differences in Age-Associated Type 2 Diabetes in Rats-Role of Estrogens and Oxidative Stress. Oxid Med Cell Longev. 2019;2019:6734836. https://doi.org/10.1155/2019/6734836
He W-Q, Peng Y-J, Zhang W-C, Lv N, Tang J, Chen C, Zhang CH, Gao S, Chen HQ, Zhi G, Feil R, Kamm KE, Stull JT, Gao X, Zhu MS. Myosin light chain kinase is central to smooth muscle contraction and required for gastrointestinal motility in mice. Gastroenterology. 2008;135(2):610-20. https://doi.org/10.1053/j.gastro.2008.05.032
Touw K, Chakraborty S, Zhang W, Obukhov AG, Tune JD, Gunst SJ, Herring BP. Altered calcium signaling in colonic smooth muscle of type 1 diabetic mice. Am J Physiol Gastrointest Liver Physiol. 2012;302(1):G66-76. https://doi.org/10.1152/ajpgi.00183.2011
Ordög T, Hayashi Y, Gibbons SJ. Cellular pathogenesis of diabetic gastroenteropathy. Minerva Gastroenterol Dietol. 2009;55(3):315-43.
Yarandi SS, Srinivasan S. Diabetic gastrointestinal motility disorders and the role of enteric nervous system: current status and future directions. Neurogastroenterol Motil. 2014;26(5):611-24. https://doi.org/10.1111/nmo.12330
Dixit D, Zarate N, Liu LWC, Boreham DR, Huizinga JD. Interstitial cells of Cajal and adaptive relaxation in the mouse stomach. Am J Physiol Gastrointest Liver Physiol. 2006;291(6):G1129-36. https://doi.org/10.1152/ajpgi.00518.2005
Hirst GDS, Edwards FR. Electrical events underlying organized myogenic contractions of the guinea pig stomach. J Physiol. 2006;576(3):659-65. https://doi.org/10.1113/jphysiol.2006.116491
Farré R, Wang X-Y, Vidal E, Domènech A, Pumarola M, Clave P, Huizinga JD, Jiménez M. Interstitial cells of Cajal and neuromuscular transmission in the rat lower oesophageal sphincter. Neurogastroenterol Motil. 2007;19(6):484-96. https://doi.org/10.1111/j.1365-2982.2007.00901.x
Sanders KM, Ward SM, Friebe A. CrossTalk proposal: Interstitial cells are involved and physiologically important in neuromuscular transmission in the gut. J Physiol. 2016;594(6):1507-9. https://doi.org/10.1113/JP271600
Sanders KM. Spontaneous Electrical Activity and Rhythmicity in Gastrointestinal Smooth Muscles. Adv Exp Med Biol. 2019;1124:3-46. https://doi.org/10.1007/978-981-13-5895-1_1
Iwasaki H, Kajimura M, Osawa S, Kanaoka S, Furuta T, Ikuma M, Hishida A. A deficiency of gastric interstitial cells of Cajal accompanied by decreased expression of neuronal nitric oxide synthase and substance P in patients with type 2 diabetes mellitus. J Gastroenterol. 2006;41(11):1076-87. https://doi.org/10.1007/s00535-006-1909-8
Horváth VJ, Vittal H, Ordög T. Reduced insulin and IGF-I signaling, not hyperglycemia, underlies the diabetes-associated depletion of interstitial cells of Cajal in the murine stomach. Diabetes. 2005;54(5):1528-33. https://doi.org/10.2337/diabetes.54.5.1528
Lin L, Xu LM, Zhang W, Ge YB, Tang YR, Zhang HJ, Li XL, Chen JD. Roles of stem cell factor on the depletion of interstitial cells of Cajal in the colon of diabetic mice. Am J Physiol Gastrointest Liver Physiol. 2010;298(2):G241-7. https://doi.org/10.1152/ajpgi.90706.2008
Huizinga JD, Lammers WJEP. Gut peristalsis is governed by a multitude of cooperating mechanisms. Am J Physiol Gastrointest Liver Physiol. 2009;296(1):G1-8. https://doi.org/10.1152/ajpgi.90380.2008
Velickov A, Mitrovic O, Djordjevic B, Sokolovic D, Zivkovic V, Velickov A, Pantovic V, Urlih NP, Radenkovic G. The effect of bilberries on diabetes-related alterations of interstitial cells of Cajal in the lower oesophageal sphincter in rats. Histol Histopathol. 2017;32(6):639-47. https://doi.org/10.26226/morressier.596dfd5ad462b802923876c1
Vanderwinden JM, Rumessen JJ. Interstitial cells of Cajal in human gut and gastrointestinal disease. Microsc Res Tech. 1999;47(5):344-60. https://doi.org/10.1002/(SICI)1097-0029(19991201)47:5<344::AID-JEMT6>3.0.CO;2-1
Jain D, Moussa K, Tandon M, Culpepper-Morgan J, Proctor DD. Role of interstitial cells of Cajal in motility disorders of the bowel. Am J Gastroenterol. 2003;98(3):618-24. https://doi.org/10.1111/j.1572-0241.2003.07295.x
Farrugia G. Interstitial cells of Cajal in health and disease. Neurogastroenterol Motil. 2008;20(1):54-63. https://doi.org/10.1111/j.1365-2982.2008.01109.x
Singh R, Zogg H, Ghoshal UC, Ro S. Current Treatment Options and Therapeutic Insights for Gastrointestinal Dysmotility and Functional Gastrointestinal Disorders. Front Pharmacol.2022;13:808195. https://doi.org/10.3389/fphar.2022.808195
Quigley EMM. Drug Treatments for Gastroparesis-Why Is the Cupboard So Bare? Gastroenterology. 2023;164(4):522-4. https://doi.org/10.1053/j.gastro.2023.01.029
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