Diabetic gastrointestinal motility disorders and the role of enteric nervous system: Current status and future directions

Neurogastroenterology and Motility

Volumn 26, Issue 5, 2014, Pages 611-624

  Yarandi, S S ^a,b   Srinivasan, S ^a,b  

^a EMORY UNIVERSITY   (United States)

^b ATLANTA VA MEDICAL CENTER   (United States)

Author keywords

Diabetes; Enteric nervous system; Enteric neurons; Interstitial cells of Cajal; Oxidative stress; Smooth muscle

Indexed keywords

DIABETIC NEUROPATHY; GASTROINTESTINAL DISEASE; GASTROINTESTINAL MOTILITY; GASTROINTESTINAL TRACT; HUMAN; INTESTINE INNERVATION; PATHOPHYSIOLOGY; PHYSIOLOGY; SMOOTH MUSCLE;

DIABETIC NEUROPATHIES; ENTERIC NERVOUS SYSTEM; GASTROINTESTINAL DISEASES; GASTROINTESTINAL MOTILITY; GASTROINTESTINAL TRACT; HUMANS; MUSCLE, SMOOTH;

EID: 84898801659     PISSN: 13501925     EISSN: 13652982     Source Type: Journal    
DOI: 10.1111/nmo.12330     Document Type: Review

References (140)

1. Costa M, Brookes SJ. The enteric nervous system. Am J Gastroenterol 1994; 89: S129-37.
2. Goyal RK, Hirano I. The enteric nervous system. N Engl J Med 1996; 334: 1106-15.
3. Surendran S. Upregulation of N-acetylaspartic acid alters inflammation, transcription and contractile associated protein levels in the stomach and smooth muscle contractility. Mol Biol Rep 2009; 36: 201-6.
4. Lundgren O, Svanvik J, Jivegard L. Enteric nervous system. I. Physiology and pathophysiology of the intestinal tract. Dig Dis Sci 1989; 34: 264-83.
5. Farrugia G. Interstitial cells of Cajal in health and disease. Neurogastroenterol Motil 2008; 20(Suppl. 1): 54-63.
6. Sanders KM, Koh SD, Ward SM. Interstitial cells of cajal as pacemakers in the gastrointestinal tract. Annu Rev Physiol 2006; 68: 307-43.
7. Thuneberg L. Interstitial cells of Cajal: intestinal pacemaker cells? Adv Anat Embryol Cell Biol 1982; 71: 1-130.
8. Ward SM, Beckett EA, Wang X, Baker F, Khoyi M, Sanders KM. Interstitial cells of Cajal mediate cholinergic neurotransmission from enteric motor neurons. J Neurosci 2000; 20: 1393-403.
9. 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: 147-59.
10. Bytzer P, Talley NJ, Leemon M, Young LJ, Jones MP, Horowitz M. Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15, 000 adults. Arch Intern Med 2001; 161: 1989-96.
11. Maleki D, Locke GR 3rd, Camilleri M, Zinsmeister AR, Yawn BP, Leibson C, Melton LJ 3rd. Gastrointestinal tract symptoms among persons with diabetes mellitus in the community. Arch Intern Med 2000; 160: 2808-16.
12. Ordog T, Hayashi Y, Gibbons SJ. Cellular pathogenesis of diabetic gastroenteropathy. Minerva Gastroenterol Dietol 2009; 55: 315-43.
13. Sellin JH, Chang EB. Therapy Insight: gastrointestinal complications of diabetes-pathophysiology and management. Nat Clin Pract Gastroenterol Hepatol 2008; 5: 162-71.
14. Nishida T, Tsuji S, Tsujii M, Arimitsu S, Sato T, Haruna Y, Miyamoto T, Kanda T et al. Gastroesophageal reflux disease related to diabetes: analysis of 241 cases with type 2 diabetes mellitus. J Gastroenterol Hepatol 2004; 19: 258-65.
15. Kinekawa F, Kubo F, Matsuda K, Fujita Y, Tomita T, Uchida Y, Nishioka M. Relationship between esophageal dysfunction and neuropathy in diabetic patients. Am J Gastroenterol 2001; 96: 2026-32.
16. Talley NJ. Diabetic gastropathy and prokinetics. Am J Gastroenterol 2003; 98: 264-71.
17. Camilleri M. Clinical practice. Diabetic gastroparesis. N Engl J Med 2007; 356: 820-9.
18. 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 Gastrointest Liver Physiol 2007; 293: G1039-45.
19. Intagliata N, Koch KL. Gastroparesis in type 2 diabetes mellitus: prevalence, etiology, diagnosis, and treatment. Curr Gastroenterol Rep 2007; 9: 270-9.
20. Samsom M, Roelofs JM, Akkermans LM, van Berge Henegouwen GP, Smout AJ. Proximal gastric motor activity in response to a liquid meal in type I diabetes mellitus with autonomic neuropathy. Dig Dis Sci 1998; 43: 491-6.
21. Undeland KA, Hausken T, Aanderud S, Berstad A. Lower postprandial gastric volume response in diabetic patients with vagal neuropathy. Neurogastroenterol Motil 1997; 9: 19-24.
22. 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: 1538-45.
23. Hasler WL, Soudah HC, Dulai G, Owyang C. Mediation of hyperglycemia-evoked gastric slow-wave dysrhythmias by endogenous prostaglandins. Gastroenterology 1995; 108: 727-36.
24. Jebbink RJ, Samsom M, Bruijs PP, Bravenboer B, Akkermans LM, Vanberge Henegouwen GP, Smout AJ. Hyperglycemia induces abnormalities of gastric myoelectrical activity in patients with type I diabetes mellitus. Gastroenterology 1994; 107: 1390-7.
25. Sellin JH, Hart R. Glucose malabsorption associated with rapid intestinal transit. Am J Gastroenterol 1992; 87: 584-9.
26. Rosa-e-Silva L, Troncon LE, Oliveira RB, Foss MC, Braga FJ, Gallo Júnior L. Rapid distal small bowel transit associated with sympathetic denervation in type I diabetes mellitus. Gut 1996; 39: 748-56.
27. Imaeda K, Takano H, Koshita M, Yamamoto Y, Joh T, Suzuki H. Electrical properties of colonic smooth muscle in spontaneously non-insulin-dependent diabetic rats. J Smooth Muscle Res 1998; 34: 1-11.
28. Islam MS. Animal models of diabetic neuropathy: progress since 1960s. J Diabetes Res 2013; 2013: 149452.
29. Schmidt RE, Dorsey DA, Beaudet LN, Frederick KE, Parvin CA, Plurad SB, Levisetti MG. Non-obese diabetic mice rapidly develop dramatic sympathetic neuritic dystrophy: a new experimental model of diabetic autonomic neuropathy. Am J Pathol 2003; 163: 2077-91.
30. Homs J, Ariza L, Pagès G, Verdú E, Casals L, Udina E, Chillón M, Bosch A et al. Comparative study of peripheral neuropathy and nerve regeneration in NOD and ICR diabetic mice. J Peripher Nerv Syst 2011; 16: 213-27.
31. Jakobsen J, Lundbaek K. Neuropathy in experimental diabetes: an animal model. Br Med J 1976; 2: 278-9.
32. Obrosova IG, Ilnytska O, Lyzogubov VV, Pavlov IA, Mashtalir N, Nadler JL, Drel VR. High-fat diet induced neuropathy of pre-diabetes and obesity: effects of "healthy" diet and aldose reductase inhibition. Diabetes 2007; 56: 2598-608.
33. Davidson E, Coppey L, Lu B, Arballo V, Calcutt NA, Gerard C, Yorek M. The roles of streptozotocin neurotoxicity and neutral endopeptidase in murine experimental diabetic neuropathy. Exp Diabetes Res 2009; 2009: 431980.
34. Murakami T, Iwanaga T, Ogawa Y, Fujita Y, Sato E, Yoshitomi H, Sunada Y, Nakamura A. Development of sensory neuropathy in streptozotocin-induced diabetic mice. Brain Behav 2013; 3: 35-41.
35. Yagihashi S, Wada R, Kamijo M, Nagai K. Peripheral neuropathy in the WBN/Kob rat with chronic pancreatitis and spontaneous diabetes. Lab Invest 1993; 68: 296-307.
36. Drel VR, Mashtalir N, Ilnytska O, Shin J, Li F, Lyzogubov VV, Obrosova IG. The leptin-deficient (ob/ob) mouse: a new animal model of peripheral neuropathy of type 2 diabetes and obesity. Diabetes 2006; 55: 3335-43.
37. Guy RJ, Dawson JL, Garrett JR, Laws JW, Thomas PK, Sharma AK, Watkins PJ. Diabetic gastroparesis from autonomic neuropathy: surgical considerations and changes in vagus nerve morphology. J Neurol Neurosurg Psychiatry 1984; 47: 686-91.
38. Smith B. Neuropathology of the oesophagus in diabetes mellitus. J Neurol Neurosurg Psychiatry 1974; 37: 1151-4.
39. Yagihashi S, Sima AA. Diabetic autonomic neuropathy in BB rat. Ultrastructural and morphometric changes in parasympathetic nerves. Diabetes 1986; 35: 733-43.
40. Carroll SL, Byer SJ, Dorsey DA, Watson MA, Schmidt RE. Ganglion-specific patterns of diabetes-modulated gene expression are established in prevertebral and paravertebral sympathetic ganglia prior to the development of neuroaxonal dystrophy. J Neuropathol Exp Neurol 2004; 63: 1144-54.
41. Guo C, Quobatari A, Shangguan Y, Hong S, Wiley JW. Diabetic autonomic neuropathy: evidence for apoptosis in situ in the rat. Neurogastroenterol Motil 2004; 16: 335-45.
42. Tay SS, Wong WC. Short- and long-term effects of streptozotocin-induced diabetes on the dorsal motor nucleus of the vagus nerve in the rat. Acta Anat (Basel) 1994; 150: 274-81.
43. Clouse RE, Lustman PJ. Gastrointestinal symptoms in diabetic patients: lack of association with neuropathy. Am J Gastroenterol 1989; 84: 868-72.
44. Yoshida MM, Schuffler MD, Sumi SM. There are no morphologic abnormalities of the gastric wall or abdominal vagus in patients with diabetic gastroparesis. Gastroenterology 1988; 94: 907-14.
45. Regalia J, Cai F, Helke C. Streptozotocin-induced diabetes and the neurochemistry of vagal afferent neurons. Brain Res 2002; 938: 7-14.
46. Fregonesi CE, Miranda-Neto MH, Molinari SL, Zanoni JN. Quantitative study of the myenteric plexus of the stomach of rats with streptozotocin-induced diabetes. Arq Neuropsiquiatr 2001; 59: 50-3.
47. Alves AM, Alves EP, Fregonesi CE, Defani MA, Stabille SR, Evangelista CC, Dos Santos CA, de Miranda Neto MH. Morphoquantitative aspects of NADH-diaphorase myenteric neurons in the ileum of diabetic rats treated with acetyl-L-carnitine. Anat Histol Embryol 2006; 35: 13-8.
48. Domenech A, Pasquinelli G, De Giorgio R, Gori A, Bosch F, Pumarola M, Jiménez M. Morphofunctional changes underlying intestinal dysmotility in diabetic RIP-I/hIFNbeta transgenic mice. Int J Exp Pathol 2011; 92: 400-12.
49. Zanoni JN, de Miranda Neto MH, Bazotte RB, de Souza RR. Morphological and quantitative analysis of the neurons of the myenteric plexus of the cecum of streptozotocin-induced diabetic rats. Arq Neuropsiquiatr 1997; 55: 696-702.
50. Du F, Wang L, Qian W, Liu S. Loss of enteric neurons accompanied by decreased expression of GDNF and PI3K/Akt pathway in diabetic rats. Neurogastroenterol Motil 2009; 21: 1229-e1114.
51. Furlan MM, Molinari SL, Miranda Neto MH. Morphoquantitative effects of acute diabetes on the myenteric neurons of the proximal colon of adult rats. Arq Neuropsiquiatr 2002; 60: 576-81.
52. Diani AR, Gerritsen GC, Stromsta S, Murray P. A study of the morphological changes in the small intestine of the spontaneously diabetic Chinese hamster. Diabetologia 1976; 12: 101-9.
53. Pereira RV, Tronchini EA, Tashima CM, Alves EP, Lima MM, Zanoni JN. L-glutamine supplementation prevents myenteric neuron loss and has gliatrophic effects in the ileum of diabetic rats. Dig Dis Sci 2011; 56: 3507-16.
54. Yoneda S, Kadowaki M, Kuramoto H, Fukui H, Takaki M. Enhanced colonic peristalsis by impairment of nitrergic enteric neurons in spontaneously diabetic rats. Auton Neurosci 2001; 92: 65-71.
55. Surendran S, Kondapaka SB. Altered expression of neuronal nitric oxide synthase in the duodenum longitudinal muscle-myenteric plexus of obesity induced diabetes mouse: implications on enteric neurodegeneration. Biochem Biophys Res Commun 2005; 338: 919-22.
56. Watkins CC, Sawa A, Jaffrey S, Blackshaw S, Barrow RK, Snyder SH, Ferris CD. Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy. J Clin Invest 2000; 106: 803.
57. Demedts I, Masaoka T, Kindt S, De Hertogh G, Geboes K, Farré R, Vanden Berghe P, Tack J. Gastrointestinal motility changes and myenteric plexus alterations in spontaneously diabetic biobreeding rats. J Neurogastroenterol Motil 2013; 19: 161-70.
58. Chandrasekharan B, Anitha M, Blatt R, Shahnavaz N, Kooby D, Staley C, Mwangi S, Jones DP et al. Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress. Neurogastroenterol Motil 2011; 23: 131-8, e126.
59. Miller SM, Narasimhan RA, Schmalz PF, Soffer EE, Walsh RM, Krishnamurthi V, Pasricha PJ, Szurszewski JH et al. Distribution of interstitial cells of Cajal and nitrergic neurons in normal and diabetic human appendix. Neurogastroenterol Motil 2008; 20: 349-57.
60. Anitha M, Gondha C, Sutliff R, Parsadanian A, Mwangi S, Sitaraman SV, Srinivasan S. GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway. J Clin Invest 2006; 116: 344-56.
61. Cellek S, Qu W, Schmidt AM, Moncada S. Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: a new insight into selective nitrergic neuropathy in diabetes. Diabetologia 2004; 47: 331-9.
62. Liu M, Seino S, Kirchgessner AL. Identification and characterization of glucoresponsive neurons in the enteric nervous system. J Neurosci 1999; 19: 10305-17.
63. Moriyama R, Tsukamura H, Kinoshita M, Okazaki H, Kato Y, Maeda K. In vitro increase in intracellular calcium concentrations induced by low or high extracellular glucose levels in ependymocytes and serotonergic neurons of the rat lower brainstem. Endocrinology 2004; 145: 2507-15.
64. Heuckeroth RO, Lampe PA, Johnson EM, Milbrandt J. Neurturin and GDNF promote proliferation and survival of enteric neuron and glial progenitors in vitro. Dev Biol 1998; 200: 116-29.
65. Srinivasan S, Anitha M, Mwangi S, Heuckeroth RO. Enteric neuroblasts require the phosphatidylinositol 3-kinase/Akt/Forkhead pathway for GDNF-stimulated survival. Mol Cell Neurosci 2005; 29: 107-19.
66. Takahashi M. The GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev 2001; 12: 361-73.
67. Delaney CL, Russell JW, Cheng HL, Feldman EL. Insulin-like growth factor-I and over-expression of Bcl-xL prevent glucose-mediated apoptosis in Schwann cells. J Neuropathol Exp Neurol 2001; 60: 147-60.
68. Leinninger GM, Backus C, Uhler MD, Lentz SI, Feldman EL. Phosphatidylinositol 3-kinase and Akt effectors mediate insulin-like growth factor-I neuroprotection in dorsal root ganglia neurons. FASEB J 2004; 18: 1544-6.
69. Middlemas A, Delcroix JD, Sayers NM, Tomlinson DR, Fernyhough P. Enhanced activation of axonally transported stress-activated protein kinases in peripheral nerve in diabetic neuropathy is prevented by neurotrophin-3. Brain 2003; 126: 1671-82.
70. Qi R, Yang W, Chen J. Role of enteric glial cells in gastric motility in diabetic rats at different stages. J Huazhong Univ Sci Technolog Med Sci 2013; 33: 496-500.
71. Stenkamp-Strahm C, Patterson S, Boren J, Gericke M, Balemba O. High-fat diet and age-dependent effects on enteric glial cell populations of mouse small intestine. Auton Neurosci 2013; 177: 199-210.
72. Nezami BG, Mwangi SM, Lee JE, Jeppsson S, Anitha M, Yarandi SS, Farris AB 3rd, Srinivasan S. MicroRNA 375 mediates palmitate-induced enteric neuronal damage and high-fat diet-induced delayed intestinal transit in mice. Gastroenterology 2014; 146: 473-83.
73. Voss U, Sand E, Olde B, Ekblad E. Enteric neuropathy can be induced by high fat diet in vivo and palmitic Acid exposure in vitro. PLoS ONE 2013; 8: e81413.
74. Honoré SM, Zelarayan LC, Genta SB, Sánchez SS. Neuronal loss and abnormal BMP/Smad signaling in the myenteric plexus of diabetic rats. Auton Neurosci 2011; 164: 51-61.
75. Choi KM, Gibbons SJ, Nguyen TV, Stoltz GJ, Lurken MS, Ordog T, Szurszewski JH, Farrugia G. Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis. Gastroenterology 2008; 135: 2055-64, 2064 e2051-2052.
76. Ferreira PE, Lopes CR, Alves AM, Alves ÉP, Linden DR, Zanoni JN, Buttow NC. Diabetic neuropathy: an evaluation of the use of quercetin in the cecum of rats. World J Gastroenterol 2013; 19: 6416-26.
77. Abdo H, Derkinderen P, Gomes P, Chevalier J, Aubert P, Masson D, Galmiche JP, Vanden Berghe P et al. Enteric glial cells protect neurons from oxidative stress in part via reduced glutathione. FASEB J 2010; 24: 1082-94.
78. Shotton HR, Lincoln J. Diabetes only affects nitric oxide synthase-containing myenteric neurons that do not contain heme oxygenase 2. Brain Res 2006; 1068: 248-56.
79. Golbidi S, Ebadi SA, Laher I. Antioxidants in the treatment of diabetes. Curr Diabetes Rev 2011; 7: 106-25.
80. Surendran S, Matalon R, Tyring SK. Upregulation of aspartoacylase activity in the duodenum of obesity induced diabetes mouse: implications on diabetic neuropathy. Biochem Biophys Res Commun 2006; 345: 973-5.
81. Savidge TC. S-nitrosothiol signals in the enteric nervous system: lessons learnt from big brother. Front Neurosci 2011; 5: 31.
82. Komuro T. Structure and organization of interstitial cells of Cajal in the gastrointestinal tract. J Physiol 2006; 576: 653-8.
83. Hanani M, Farrugia G, Komuro T. Intercellular coupling of interstitial cells of cajal in the digestive tract. Int Rev Cytol 2005; 242: 249-82.
84. 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: 369-75.
85. Huizinga JD, Thuneberg L, Kluppel M, Malysz J, Mikkelsen HB, Bernstein A. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 1995; 373: 347-9.
86. Ward SM, Burns AJ, Torihashi S, Sanders KM. Mutation of the proto-oncogene c-kit blocks development of interstitial cells and electrical rhythmicity in murine intestine. J Physiol 1994; 480(Pt 1): 91-7.
87. Ward SM, Morris G, Reese L, Wang XY, Sanders KM. Interstitial cells of Cajal mediate enteric inhibitory neurotransmission in the lower esophageal and pyloric sphincters. Gastroenterology 1998; 115: 314-29.
88. Ward SM, Sanders KM. Involvement of intramuscular interstitial cells of Cajal in neuroeffector transmission in the gastrointestinal tract. J Physiol 2006; 576: 675-82.
89. Long QL, Fang DC, Shi HT, Luo YH. Gastro-electric dysrhythm and lack of gastric interstitial cells of cajal. World J Gastroenterol 2004; 10: 1227-30.
90. Ordog 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: 1731-9.
91. Wang XY, Huizinga JD, Diamond J, Liu LW. 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: 1095-e1092.
92. He CL, Soffer EE, Ferris CD, Walsh RM, Szurszewski JH, Farrugia G. Loss of interstitial cells of cajal and inhibitory innervation in insulin-dependent diabetes. Gastroenterology 2001; 121: 427-34.
93. Forster J, Damjanov I, Lin Z, Sarosiek I, Wetzel P, McCallum RW. Absence of the interstitial cells of Cajal in patients with gastroparesis and correlation with clinical findings. J Gastrointest Surg 2005; 9: 102-8.
94. 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: 1076-87.
95. Nakahara M, Isozaki K, Hirota S, Vanderwinden JM, Takakura R, Kinoshita K, Miyagawa J, Chen H et al. Deficiency of KIT-positive cells in the colon of patients with diabetes mellitus. J Gastroenterol Hepatol 2002; 17: 666-70.
96. Yamamoto T, Watabe K, Nakahara M, Ogiyama H, Kiyohara T, Tsutsui S, Tamura S, Shinomura Y et al. Disturbed gastrointestinal motility and decreased interstitial cells of Cajal in diabetic db/db mice. J Gastroenterol Hepatol 2008; 23: 660-7.
97. Beckett EA, Takeda Y, Yanase H, Sanders KM, Ward SM. Synaptic specializations exist between enteric motor nerves and interstitial cells of Cajal in the murine stomach. J Comp Neurol 2005; 493: 193-206.
98. Iino S, Ward SM, Sanders KM. Interstitial cells of Cajal are functionally innervated by excitatory motor neurones in the murine intestine. J Physiol 2004; 556: 521-30.
99. Horvath VJ, Vittal H, Ordog 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: 1528-33.
100. Horváth VJ, Vittal H, Lörincz A, Chen H, Almeida-Porada G, Redelman D, Ordög T. Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis. Gastroenterology 2006; 130: 759-70.
101. Kong MF, Horowitz M. Gastric emptying in diabetes mellitus: relationship to blood-glucose control. Clin Geriatr Med 1999; 15: 321-38.
102. Furness JB. Types of neurons in the enteric nervous system. J Auton Nerv Syst 2000; 81: 87-96.
103. Brehmer A, Schrodl F, Neuhuber W. Morphology of VIP/nNOS-immunoreactive myenteric neurons in the human gut. Histochem Cell Biol 2006; 125: 557-65.
104. De Giorgio R, Parodi JE, Brecha NC, Brunicardi FC, Becker JM, Go VL, Sternini C. Nitric oxide producing neurons in the monkey and human digestive system. J Comp Neurol 1994; 342: 619-27.
105. Jarvinen MK, Wollmann WJ, Powrozek TA, Schultz JA, Powley TL. Nitric oxide synthase-containing neurons in the myenteric plexus of the rat gastrointestinal tract: distribution and regional density. Anat Embryol (Berl) 1999; 199: 99-112.
106. Román V, Bagyánszki M, Krecsmarik M, Horváth A, Resch BA, Fekete E. Spatial pattern analysis of nitrergic neurons in the developing myenteric plexus of the human fetal intestine. Cytometry A 2004; 57: 108-12.
107. Gangula PR, Maner WL, Micci MA, Garfield RE, Pasricha PJ. Diabetes induces sex-dependent changes in neuronal nitric oxide synthase dimerization and function in the rat gastric antrum. Am J Physiol Gastrointest Liver Physiol 2007; 292: G725-33.
108. Takahashi T, Nakamura K, Itoh H, Sima AA, Owyang C. Impaired expression of nitric oxide synthase in the gastric myenteric plexus of spontaneously diabetic rats. Gastroenterology 1997; 113: 1535-44.
109. Li C, Liu S, Guan Y, Qian W, du F, Hou X. Long pulse gastric electrical stimulation induces regeneration of myenteric plexus synaptic vesicles in diabetic rats. Neurogastroenterol Motil 2010; 22: 453-61, e108.
110. Cellek S. Point of NO return for nitrergic nerves in diabetes: a new insight into diabetic complications. Curr Pharm Des 2004; 10: 3683-95.
111. Cellek S, Foxwell NA, Moncada S. Two phases of nitrergic neuropathy in streptozotocin-induced diabetic rats. Diabetes 2003; 52: 2353-62.
112. Belai A, Lincoln J, Burnstock G. Lack of release of vasoactive intestinal polypeptide and calcitonin gene-related peptide during electrical stimulation of enteric nerves in streptozotocin-diabetic rats. Gastroenterology 1987; 93: 1034-40.
113. Belai A, Calcutt NA, Carrington AL, Diemel LT, Tomlinson DR, Burnstock G. Enteric neuropeptides in streptozotocin-diabetic rats; effects of insulin and aldose reductase inhibition. J Auton Nerv Syst 1996; 58: 163-9.
114. Jeyabal PV, Kumar R, Gangula PR, Micci MA, Pasricha PJ. Inhibitors of advanced glycation end-products prevent loss of enteric neuronal nitric oxide synthase in diabetic rats. Neurogastroenterol Motil 2008; 20: 253-61.
115. 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: G66-76.
116. Takahashi T, Kojima Y, Tsunoda Y, Beyer LA, Kamijo M, Sima AA, Owyang C. Impaired intracellular signal transduction in gastric smooth muscle of diabetic BB/W rats. Am J Physiol 1996; 270: G411-7.
117. Lin S, Kajimura M, Takeuchi K, Kodaira M, Hanai H, Nishimura M, Kaneko E. Alterations of GTP-binding proteins (Gsalpha and Gq/11alpha) in gastric smooth muscle cells from streptozotocin-induced and WBN/Kob diabetic rats. Dig Dis Sci 2000; 45: 1517-24.
118. Moscoso GJ, Driver M, Guy RJ. A form of necrobiosis and atrophy of smooth muscle in diabetic gastric autonomic neuropathy. Pathol Res Pract 1986; 181: 188-94.
119. He WQ, Peng YJ, Zhang WC, Lv N, Tang J, Chen C, Zhang CH, Gao S et al. Myosin light chain kinase is central to smooth muscle contraction and required for gastrointestinal motility in mice. Gastroenterology 2008; 135: 610-20.
120. Hu W, Feng P. Myosin light chain kinase is involved in the mechanism of gastrointestinal dysfunction in diabetic rats. Dig Dis Sci 2012; 57: 1197-202.
121. Duchen LW, Anjorin A, Watkins PJ, Mackay JD. Pathology of autonomic neuropathy in diabetes mellitus. Ann Intern Med 1980; 92: 301-3.
122. Jackson MW, Gordon TP, Waterman SA. Disruption of intestinal motility by a calcium channel-stimulating autoantibody in type 1 diabetes. Gastroenterology 2004; 126: 819-28.
123. Bódi N, Talapka P, Poles MZ, Hermesz E, Jancsó Z, Katarova Z, Izbéki F, Wittmann T et al. Gut region-specific diabetic damage to the capillary endothelium adjacent to the myenteric plexus. Microcirculation 2012; 19: 316-26.
124. Yoshiya K, Lapchak PH, Thai TH, Kannan L, Rani P, Dalle Lucca JJ, Tsokos GC. Depletion of gut commensal bacteria attenuates intestinal ischemia/reperfusion injury. Am J Physiol Gastrointest Liver Physiol 2011; 301: G1020-30.
125. Bagyanszki M, Bodi N. Diabetes-related alterations in the enteric nervous system and its microenvironment. World J Diabetes 2012; 3: 80-93.
126. Rhee SH, Pothoulakis C, Mayer EA. Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat Rev Gastroenterol Hepatol 2009; 6: 306-14.
127. Barbara G, Stanghellini V, Brandi G, Cremon C, Di Nardo G, De Giorgio R, Corinaldesi R. Interactions between commensal bacteria and gut sensorimotor function in health and disease. Am J Gastroenterol 2005; 100: 2560-8.
128. Dass NB, John AK, Bassil AK, Crumbley CW, Shehee WR, Maurio FP, Moore GB, Taylor CM et al. The relationship between the effects of short-chain fatty acids on intestinal motility in vitro and GPR43 receptor activation. Neurogastroenterol Motil 2007; 19: 66-74.
129. Malbert CH. The ileocolonic sphincter. Neurogastroenterol Motil 2005; 17(Suppl. 1): 41-9.
130. He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet 2004; 5: 522-31.
131. Park C, Yan W, Ward SM, Hwang SJ, Wu Q, Hatton WJ, Park JK, Sanders KM et al. MicroRNAs dynamically remodel gastrointestinal smooth muscle cells. PLoS ONE 2011; 6: e18628.
132. Sanders KM, Koh SD, Ro S, Ward SM. Regulation of gastrointestinal motility-insights from smooth muscle biology. Nat Rev Gastroenterol Hepatol 2012; 9: 633-45.
133. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132: 27-42.
134. Gonzalez CD, Lee M-S, Marchetti P, Pietropaolo M, Towns R, Vaccaro MI, Watada H, Wiley JW. The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy 2011; 7: 2-11.
135. Towns R, Kabeya Y, Yoshimori T, Guo C, Shangguan Y, Hong S, Kaplan M, Klionsky DJ et al. Sera from patients with type 2 diabetes and neuropathy induce autophagy and colocalization with mitochondria in SY5Y cells. Autophagy 2005; 1: 163-70.
136. Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol 2012; 11: 521-34.
137. Shi X, Chen Y, Nadeem L, Xu G. Beneficial effect of TNF-alpha inhibition on diabetic peripheral neuropathy. J Neuroinflammation 2013; 10: 69.
138. Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol 2011; 7: 573-83.
139. O'Brien PD, Hinder LM, Sakowski SA, Feldman EL. ER stress in diabetic peripheral neuropathy: a new therapeutic target. Antioxid Redox Signal 2014; In Press.
140. Kashyap P, Farrugia G. Oxidative stress: key player in gastrointestinal complications of diabetes. Neurogastroenterol Motil 2011; 23: 111-4.