Clinical Manifestations

  • Radovan Prijić
  • Silvija Čuković-ČavkaEmail author
Part of the Clinical Gastroenterology book series (CG)


Gastrointestinal (GI) complications of diabetes mellitus are increasing as the incidence of diabetes mellitus rises, and a large number of diabetic patients complain of GI symptoms. The most prevalent intestinal symptoms in diabetics are abdominal pain, distension, nausea, vomiting, constipation, and diarrhea. Gastrointestinal symptoms can be associated with diabetes mellitus complications, especially autonomic neuropathy and poor glycemic control. Severe and permanent intestinal symptoms can ruin health status and quality of life.


Diabetes Gastrointestinal symptoms Abdominal pain Distension Nausea Vomiting Constipation Diarrhea Diabetic enteropathy 


  1. 1.
    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.CrossRefPubMedGoogle Scholar
  2. 2.
    Kim JH, Park HS, Ko SY, Hong SN, Sung I-K, Shim CS, et al. Diabetic factors associated with gastrointestinal symptoms in patients with type 2 diabetes. World J Gastroenterol. 2010;16:1782–7.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Bytzer P, Talley NJ, Jones MP, Horowitz M. Oral hypoglycaemic drugs and gastrointestinal symptoms in diabetes mellitus. Aliment Pharmacol Ther. 2001;15:137–42.CrossRefPubMedGoogle Scholar
  4. 4.
    Rodrigues MLC, Motta MEFA. Mechanisms and factors associated with gastrointestinal symptoms in patients with diabetes mellitus. J Pediatr. 2012;88:17–24.CrossRefGoogle Scholar
  5. 5.
    Clouse RE, Lustman PJ. Gastrointestinal symptoms in diabetic patients: lack of association with neuropathy. Am J Gastroenterol. 1989;84:868–72.PubMedGoogle Scholar
  6. 6.
    Bytzer P, Talley NJ, Hammer J, Young LJ, Jones MP, Horowitz M. GI symptoms in diabetes mellitus are associated with both poor glycemic control and diabetic complications. Am J Gastroenterol. 2002;97:604–11.CrossRefPubMedGoogle Scholar
  7. 7.
    Phillips LK, Rayner CK, Jones KL, Horowitz M. An update on autonomic neuropathy affecting the gastrointestinal tract. Curr Diab Rep. 2006;6:417–23.CrossRefPubMedGoogle Scholar
  8. 8.
    Krishnan B, Babu S, Walker J, Walker AB, Pappachan JM. Gastrointestinal complications of diabetes mellitus. World J Diabetes. 2013;4:51–63.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Maisey A. A practical approach to gastrointestinal complications of diabetes. Diabetes Ther. 2016;7:379–86.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lysy J, Israeli E, Goldin E. The prevalence of chronic diarrhea among diabetic patients. Am J Gastroenterol. 1999;94:2165–70.CrossRefPubMedGoogle Scholar
  11. 11.
    Russo A, Botten R, Kong M-F, Chapman IM, Fraser RJL, Horowitz M, et al. Effects of acute hyperglycaemia on anorectal motor and sensory function in diabetes mellitus. Diabet Med. 2004;21:176–82.CrossRefPubMedGoogle Scholar
  12. 12.
    von der Ohe MR. Diarrhoea in patients with diabetes mellitus. Eur J Gastroenterol Hepatol. 1995;7:730–6.PubMedGoogle Scholar
  13. 13.
    Duchen LW, Anjorin A, Watkins PJ, Mackay JD. Pathology of autonomic neuropathy in diabetes mellitus. Ann Intern Med. 1980;92:301–3.CrossRefPubMedGoogle Scholar
  14. 14.
    Dandona P, Fonseca V, Mier A, Beckett AG. Diarrhea and metformin in a diabetic clinic. Diabetes Care. 1983;6:472–4.CrossRefPubMedGoogle Scholar
  15. 15.
    Wald A. Incontinence and anorectal dysfunction in patients with diabetes mellitus. Eur J Gastroenterol Hepatol. 1995;7:737–9.PubMedGoogle Scholar
  16. 16.
    Badiga MS, Jain NK, Casanova C, Pitchumoni CS. Diarrhea in diabetics: the role of sorbitol. J Am Coll Nutr. 1990;9:578–82.CrossRefPubMedGoogle Scholar
  17. 17.
    Ordög T, Hayashi Y, Gibbons SJ. Cellular pathogenesis of diabetic gastroenteropathy. Minerva Gastroenterol Dietol. 2009;55:315–43.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Chandrasekharan B, Srinivasan S. Diabetes and the enteric nervous system. Neurogastroenterol Motil. 2007;19:951–60.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Demedts I, Masaoka T, Kindt S, De Hertogh G, Geboes K, Farré R, et al. Gastrointestinal motility changes and myenteric plexus alterations in spontaneously diabetic biobreeding rats. Neurogastroenterol Motil. 2013;19:161–70.CrossRefGoogle Scholar
  20. 20.
    Zandecki M, Raeymaekers P, Janssens J, Tack J, Vanden Berghe P. The effect of nitric oxide donors on nitric oxide synthase-expressing myenteric neurones in culture. Neurogastroenterol Motil. 2006;18:307–15.CrossRefPubMedGoogle Scholar
  21. 21.
    Malaisse WJ, Courtois P, Scott FW. Insulin-dependent diabetes and gut dysfunction: the BB rat model. Horm Metab Res. 2004;36:585–94.CrossRefPubMedGoogle Scholar
  22. 22.
    Uranga-Ocio JA, Bastús-Díez S, Delkáder-Palacios D, García-Cristóbal N, Leal-García MÁ, Abalo-Delgado R. Enteric neuropathy associated to diabetes mellitus. Rev Esp Enferm Dig. 2015;107:366–73.PubMedGoogle Scholar
  23. 23.
    Chandrasekharan B, Anitha M, Blatt R, Shahnavaz N, Kooby D, Staley C, et al. Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress. Neurogastroenterol Motil. 2011;23:131–8.e26.CrossRefPubMedGoogle Scholar
  24. 24.
    Rayner CK, Samsom M, Jones KL, Horowitz M. Relationships of upper gastrointestinal motor and sensory function with glycemic control. Diabetes Care. 2001;24:371–81.CrossRefPubMedGoogle Scholar
  25. 25.
    Sogabe M, Okahisa T, Tsujigami K, Okita Y, Hayashi H, Taniki T, et al. Ultrasonographic assessment of gastric motility in diabetic gastroparesis before and after attaining glycemic control. J Gastroenterol. 2005;40:583–90.CrossRefPubMedGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    Izbéki F, Wittman T, Rosztóczy A, Linke N, Bódi N, Fekete E, et al. Immediate insulin treatment prevents gut motility alterations and loss of nitrergic neurons in the ileum and colon of rats with streptozotocin-induced diabetes. Diabetes Res Clin Pract. 2008;80:192–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Wada R, Yagihashi S. Role of advanced glycation end products and their receptors in development of diabetic neuropathy. Ann N Y Acad Sci. 2005;1043:598–604.CrossRefPubMedGoogle Scholar
  29. 29.
    Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes. 2017;8:249–69.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Bódi N, Talapka P, Poles MZ, Hermesz E, Jancsó Z, Katarova Z, et al. Gut region-specific diabetic damage to the capillary endothelium adjacent to the myenteric plexus. Microcirculation. 2012;19:316–26.CrossRefPubMedGoogle Scholar
  31. 31.
    Østergaard L, Finnerup NB, Terkelsen AJ, Olesen RA, Drasbek KR, Knudsen L, et al. The effects of capillary dysfunction on oxygen and glucose extraction in diabetic neuropathy. Diabetologia. 2015;58:666–77.CrossRefPubMedGoogle Scholar
  32. 32.
    Yagihashi S, Mizukami H, Sugimoto K. Mechanism of diabetic neuropathy: where are we now and where to go? J Diabetes Investig. 2011;2:18–32.CrossRefPubMedGoogle Scholar
  33. 33.
    Babizhayev MA, Strokov IA, Nosikov VV, Savel’yeva EL, Sitnikov VF, Yegorov YE, et al. The role of oxidative stress in diabetic neuropathy: generation of free radical species in the glycation reaction and gene polymorphisms encoding antioxidant enzymes to genetic susceptibility to diabetic neuropathy in population of type I diabetic patients. Cell Biochem Biophys. 2015;71:1425–43.CrossRefPubMedGoogle Scholar
  34. 34.
    Wahren J, Ekberg K, Johansson J, Henriksson M, Pramanik A, Johansson BL, et al. Role of C-peptide in human physiology. Am J Physiol Endocrinol Metab. 2000;278:E759–68.CrossRefPubMedGoogle Scholar
  35. 35.
    Vague P, Coste TC, Jannot MF, Raccah D, Tsimaratos M. C-peptide, Na+,K(+)-ATPase, and diabetes. Exp Diabesity Res. 2004;5:37–50.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zoubi SA, Williams MD, Mayhew TM, Sparrow RA. Number and ultrastructure of epithelial cells in crypts and villi along the streptozotocin-diabetic small intestine: a quantitative study on the effects of insulin and aldose reductase inhibition. Virchows Arch. 1995;427:187–93.CrossRefPubMedGoogle Scholar
  37. 37.
    Noda T, Iwakiri R, Fujimoto K, Yoshida T, Utsumi H, Sakata H, et al. Suppression of apoptosis is responsible for increased thickness of intestinal mucosa in streptozotocin-induced diabetic rats. Metabolism. 2001;50:259–64.CrossRefPubMedGoogle Scholar
  38. 38.
    Fischer KD, Dhanvantari S, Drucker DJ, Brubaker PL. Intestinal growth is associated with elevated levels of glucagon-like peptide 2 in diabetic rats. Am J Phys. 1997;273:E815–20.Google Scholar
  39. 39.
    Zhao J, Yang J, Gregersen H. Biomechanical and morphometric intestinal remodelling during experimental diabetes in rats. Diabetologia. 2003;46:1688–97.CrossRefPubMedGoogle Scholar
  40. 40.
    Zoubi SA, Mayhew TM, Sparrow RA. The small intestine in experimental diabetes: cellular adaptation in crypts and villi at different longitudinal sites. Virchows Arch. 1995;426:501–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Chen P, Zhao J, Gregersen H. Up-regulated expression of advanced glycation end-products and their receptor in the small intestine and colon of diabetic rats. Dig Dis Sci. 2012;57:48–57.CrossRefPubMedGoogle Scholar
  42. 42.
    Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. Understanding RAGE, the receptor for advanced glycation end products. J Mol Med (Berl). 2005;83:876–86.CrossRefGoogle Scholar
  43. 43.
    Iwasaki H, Kajimura M, Osawa S, Kanaoka S, Furuta T, Ikuma M, et al. 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.CrossRefPubMedGoogle Scholar
  44. 44.
    Domènech A, Pasquinelli G, De Giorgio R, Gori A, Bosch F, Pumarola M, et al. Morphofunctional changes underlying intestinal dysmotility in diabetic RIP-I/hIFNβ transgenic mice. Int J Exp Pathol. 2011;92:400–12.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Zhao J-B, Chen P-M, Gregersen H. Changes of phasic and tonic smooth muscle function of jejunum in type 2 diabetic Goto–Kakizaki rats. World J Diabetes. 2013;4:339–48.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Zhao J, Chen P, Gregersen H. Stress-strain analysis of contractility in the ileum in response to flow and ramp distension in streptozotocin-induced diabetic rats—association with advanced glycation end product formation. J Biomech. 2015;48:1075–83.CrossRefPubMedGoogle Scholar
  47. 47.
    de Boer SY, Masclee AA, lam WF, Schipper J, Jansen JB, Lamers CB. Hyperglycemia modulates gallbladder motility and small intestinal transit time in man. Dig Dis Sci. 1993;38:2228–35.CrossRefPubMedGoogle Scholar
  48. 48.
    Iida M, Ikeda M, Kishimoto M, Tsujino T, Kaneto H, Matsuhisa M, et al. Evaluation of gut motility in type II diabetes by the radiopaque marker method. J Gastroenterol Hepatol. 2000;15:381–5.CrossRefPubMedGoogle Scholar
  49. 49.
    Nguyen HN, Silny J, Wüller S, Marschall HU, Rau G, Matern S. Abnormal postprandial duodenal chyme transport in patients with long standing insulin dependent diabetes mellitus. Gut. 1997;41:624–31.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Dooley CP, el Newihi HM, Zeidler A, Valenzuela JE. Abnormalities of the migrating motor complex in diabetics with autonomic neuropathy and diarrhea. Scand J Gastroenterol. 1988;23:217–23.CrossRefPubMedGoogle Scholar
  51. 51.
    Frøkjaer JB, Andersen SD, Ejskaer N, Funch-Jensen P, Arendt-Nielsen L, Gregersen H, et al. Gut sensations in diabetic autonomic neuropathy. Pain. 2007;131:320–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Ebert EC. Gastrointestinal complications of diabetes mellitus. Dis Mon. 2005;51:620–63.CrossRefPubMedGoogle Scholar
  53. 53.
    Maleki D, Locke GR, Camilleri M, Zinsmeister AR, Yawn BP, Leibson C, et al. Gastrointestinal tract symptoms among persons with diabetes mellitus in the community. Arch Intern Med. 2000;160:2808–16.CrossRefPubMedGoogle Scholar
  54. 54.
    Thomsen RW, Riis AH, Kjeldsen S, Schønheyder HC. Impact of diabetes and poor glycaemic control on risk of bacteraemia with haemolytic streptococci groups A, B, and G. J Infect. 2011;63:8–16.CrossRefPubMedGoogle Scholar
  55. 55.
    Harmsen HJM, de Goffau MC. The human gut microbiota. Adv Exp Med Biol. 2016;902:95–108.CrossRefPubMedGoogle Scholar
  56. 56.
    Delzenne NM, Cani PD. Interaction between obesity and the gut microbiota: relevance in nutrition. Annu Rev Nutr. 2011;31:15–31.CrossRefPubMedGoogle Scholar
  57. 57.
    Tai N, Wong FS, Wen L. The role of gut microbiota in the development of type 1, type 2 diabetes mellitus and obesity. Rev Endocr Metab Disord. 2015;16:55–65.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Patterson E, Ryan PM, Cryan JF, Dinan TG, Ross RP, Fitzgerald GF, et al. Gut microbiota, obesity and diabetes. Postgrad Med J. 2016;92:286–300.CrossRefPubMedGoogle Scholar
  59. 59.
    Vaarala O, Atkinson MA, Neu J. The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity. Diabetes. 2008;57:2555–62.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Malago JJ. Contribution of microbiota to the intestinal physicochemical barrier. Benef Microbes. 2015;6:295–311.CrossRefPubMedGoogle Scholar
  61. 61.
    Guarino MPL, Cicala M, Putignani L, Severi C. Gastrointestinal neuromuscular apparatus: an underestimated target of gut microbiota. World J Gastroenterol. 2016;22:9871–9.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Yang M, Fukui H, Eda H, Xu X, Kitayama Y, Hara K, et al. Involvement of gut microbiota in association between GLP-1/GLP-1 receptor expression and gastrointestinal motility. Am J Physiol Gastrointest Liver Physiol. 2017;312:G367–73.CrossRefPubMedGoogle Scholar
  63. 63.
    Ohlsson B, Melander O, Thorsson O, Olsson R, Ekberg O, Sundkvist G. Oesophageal dysmotility, delayed gastric emptying and autonomic neuropathy correlate to disturbed glucose homeostasis. Diabetologia. 2006;49:2010–4.CrossRefPubMedGoogle Scholar
  64. 64.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Goldstein F, Wirts CW, Kowlessar OD. Diabetic diarrhea and steatorrhea. Microbiologic and clinical observations. Ann Intern Med. 1970;72:215–8.CrossRefPubMedGoogle Scholar
  66. 66.
    Gould M, Sellin JH. Diabetic diarrhea. Curr Gastroenterol Rep. 2009;11:354–9.CrossRefPubMedGoogle Scholar
  67. 67.
    Battle WM, Cohen JD, Snape WJ. Disorders of colonic motility in patients with diabetes mellitus. Yale J Biol Med. 1983;56:277–83.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Taba Taba Vakili S, Nezami BG, Shetty A, Chetty VK, Srinivasan S. Association of high dietary saturated fat intake and uncontrolled diabetes with constipation: evidence from the National Health and Nutrition Examination Survey. Neurogastroenterol Motil. 2015;27:1389–97.CrossRefPubMedGoogle Scholar
  69. 69.
    Ihana-Sugiyama N, Nagata N, Yamamoto-Honda R, Izawa E, Kajio H, Shimbo T, et al. Constipation, hard stools, fecal urgency, and incomplete evacuation, but not diarrhea is associated with diabetes and its related factors. World J Gastroenterol. 2016;22:3252–60.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Wirth R, Bódi N, Maróti G, Bagyánszki M, Talapka P, Fekete É, et al. Regionally distinct alterations in the composition of the gut microbiota in rats with streptozotocin-induced diabetes. PLoS One. 2014;9:e110440.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Kunze WA, Mao Y-K, Wang B, Huizinga JD, Ma X, Forsythe P, et al. Lactobacillus reuteri enhances excitability of colonic AH neurons by inhibiting calcium-dependent potassium channel opening. J Cell Mol Med. 2009;13:2261–70.CrossRefPubMedGoogle Scholar
  72. 72.
    Hyland NP, Cryan JF. Microbe–host interactions: influence of the gut microbiota on the enteric nervous system. Dev Biol. 2016;417:182–7.CrossRefPubMedGoogle Scholar
  73. 73.
    Su B, Liu H, Li J, Sunli Y, Liu B, Liu D, et al. Acarbose treatment affects the serum levels of inflammatory cytokines and the gut content of bifidobacteria in Chinese patients with type 2 diabetes mellitus. J Diabetes. 2015;7:729–39.CrossRefPubMedGoogle Scholar
  74. 74.
    Wang L, Li P, Tang Z, Yan X, Feng B. Structural modulation of the gut microbiota and the relationship with body weight: compared evaluation of liraglutide and saxagliptin treatment. Sci Rep. 2016;6:33251.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Lee H, Ko G. Effect of metformin on metabolic improvement and gut microbiota. Appl Environ Microbiol. 2014;80:5935–43.CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Gastroenterology and HepatologyUniversity Hospital Center ZagrebZagrebCroatia

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