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Therapy Insight: gastrointestinal complications of diabetes—pathophysiology and management

Abstract

Patients with diabetes often have gastrointestinal symptoms, but the extent and severity of this problem and the specificity of the symptoms are not nearly as well defined as frequently assumed. Any part of the gastrointestinal tract can be affected, and the presenting symptoms depend on the composite of dysfunctional elements. Gastroesophageal reflux, Candida esophagitis, gastroparesis, diarrhea and constipation are among the many common gastrointestinal complications of diabetes. No specific risk factor for the development of these complications has been identified and their etiology is most likely to be multifactorial, involving both reversible and irreversible processes. Treatment should be directed at tighter glycemic and symptom control, which can bring about clinical improvement for many patients. For other patients, however, effective clinical management is problematic because no therapies are available to prevent or correct the underlying disease mechanisms. Studies now suggest that reduced levels of key trophic factors cause transdifferentiation of pacemaker interstitial cells of Cajal into a smooth-muscle-like phenotype. If this really is the case, therapies directed at restoring the normal milieu of trophic signals could correct the dysfunction of the interstitial cells of Cajal and resolve many gastrointestinal complications. Advances in stem cell technology also hold promise to provide a cure for diabetes and to correct abnormalities in gastrointestinal pathology.

Key Points

  • Gastrointestinal symptoms are common in patients with diabetes, but are also prevalent in the general population

  • Any part of the gastrointestinal tract can be affected and presenting symptoms depend on the composite of dysfunctional elements

  • No specific risk factor for the development of gastrointestinal complications in patients with diabetes has been identified and the etiology of these complications is probably multifactorial, involving both reversible and irreversible processes

  • Treatment should be directed at tighter glycemic and symptom control, which can bring about clinical improvement for many patients; for other patients, effective clinical management is problematic because no therapies are available to prevent or correct the underlying disease mechanisms

  • The development of new approaches, including restoration of normal levels of trophic factors and stem cell therapy, are key to the effective and specific treatment of intractable gastrointestinal complications of diabetes.

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Figure 1: Gastrointestinal complications associated with diabetes.
Figure 2: One possible therapeutic pyramid for diabetic gastroparesis.

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References

  1. Camilleri M (2007) Diabetic Gastroparesis. New Engl J Med 356: 820–829

    Article  CAS  Google Scholar 

  2. Bytzer P et al. (2001) Prevalence of gastrointestinal symptoms associated with diabetes mellitus: a population-based survey of 15,000 adults. Arch Intern Med 161: 1989–1996

    Article  CAS  Google Scholar 

  3. Verne GN and Sninsky CA (1998) Diabetes and the gastrointestinal tract. Gastroenterol Clin North Am 27: 861–874

    Article  CAS  Google Scholar 

  4. Moscoso GJ et al. (1986) A form of necrobiosis and atrophy of smooth muscle in diabetic gastric autonomic neuropathy. Pathol Res Pract 181: 188–194

    Article  CAS  Google Scholar 

  5. Maleki D et al. (2000) Gastrointestinal tract symptoms among persons with diabetes mellitus in the community. Arch Intern Med 160: 2808–2816

    Article  CAS  Google Scholar 

  6. Bytzer P et al. (2001) Oral hyproglycaemic drugs and gastrointestinal symptoms in diabetes mellitus. Aliment Pharmacol Ther 15: 137–142

    Article  CAS  Google Scholar 

  7. Snape WJ et al. (1982) Metoclopramide to treat gastroparesis due to diabetes mellitus. Ann Intern Med 96: 444–446

    Article  Google Scholar 

  8. Fedorak RN et al. (1985) Treatment of diabetic diarrhea with clonidine. Ann Intern Med 102: 197–199

    Article  CAS  Google Scholar 

  9. He C-L et al. (2001) Loss of interstitial cells of Cajal and inhibitory innervation in insulin-dependent diabetes. Gastroenterology 121: 427–434

    Article  CAS  Google Scholar 

  10. Lacy BE et al. (2004) The treatment of diabetic gastroparesis with botulinum toxin injection into the pylorus. Diabetes Care 27: 2341–2347

    Article  CAS  Google Scholar 

  11. Rabine JC and Barnett JL (2001) Management of the patient with gastroparesis. J Clin Gastroenterol 32: 11–21

    Article  CAS  Google Scholar 

  12. Takahara H et al. (2001) Changes in serotonin levels and 5-HT receptor activity in duodenum of streptozotocin-diabetic rats. Am J Physiol Gastrointest Liver Physiol 281: G798–G808

    Article  CAS  Google Scholar 

  13. Takahashi T et al. (2003) Inhibitory effects of hyperglycemia on neural activity of the vagus in rats. Intensive Care Med 29: 309–311

    Article  Google Scholar 

  14. Clouse RE and Lustman PF (1989) Gastrointestinal symptoms in diabetic patients: lack of association with neuropathy. Am J Gastroenterol 84: 868–872

    CAS  PubMed  Google Scholar 

  15. Mjörnheim AC et al. (2003) Gastrointestinal symptoms in type 1 diabetic patients, as compared to a general population. A questionnaire-based study. Digestion 68: 102–108

    Article  Google Scholar 

  16. Horvath VJ et al. (2006) Reduced stem cell factor links smooth myopathy and loss of interstitial cells of Cajal in murine diabetic gastroparesis. Gastroenterology 130: 759–770

    Article  CAS  Google Scholar 

  17. Rayner CK and Horowitz M (2006) Gastrointestinal moitility and glycemic control in diabetes: the chicken and the egg revisited? J Clin Invest 116: 299–301

    Article  CAS  Google Scholar 

  18. Sanders KM (2006) Interstitial cells of Cajal at the clinical and scientific interface. J Physiol 576: 683–687

    Article  CAS  Google Scholar 

  19. Leinninger GM et al. (2006) Mechanism of disease: mitochondria as new therapeutic target in diabetic neuropathy. Nat Clin Pract Neurol 2: 620–628

    Article  CAS  Google Scholar 

  20. Brownlee M (1992) Glycation products and the pathogenesis of diabetic complications. Diabetes Care 15: 1835–1843

    Article  CAS  Google Scholar 

  21. Hoeldtke RD et al. (2002) Nitrosative stress, uric acid, and peripheral nerve function in early type 1 diabetes. Diabetes 51: 2817–2825

    Article  CAS  Google Scholar 

  22. Anitha M et al. (2006) GDNF rescues hyperglycemia-induced diabetic enteric neuropathy through activation of the PI3K/Akt pathway. J Clin Invest 116: 344–356

    Article  CAS  Google Scholar 

  23. Fedorak RN (1987) Intestinal adaptation to diabetes. Altered Na-dependent nutrient absorption in streptozocin-treated chronically diabetic rats. J Clin Invest 79: 1571–1578

    Article  CAS  Google Scholar 

  24. Chang EB et al. (1985) Diarrhea in streptozocin-treated rats. Loss of adrenergic regulation of intestinal fluid and electrolyte transport. J Clin Invest 75: 1666–1670

    Article  CAS  Google Scholar 

  25. Kinekawa F et al. (2001) Relationship between esophageal dysfunction and neuropathy in diabetic patients. Am J Gastroenterol 96: 2026–2032

    Article  CAS  Google Scholar 

  26. Talley NJ (2003) Diabetic gastropathy and prokinetics. Am J Gastroenterol 98: 264–271

    Article  Google Scholar 

  27. Nishida T et al. (2004) Gastroesophageal reflux disease related to diabetes: analysis of 241 cases with type 2 diabetes mellitus. J Gastroenterol Hepatol 19: 258–265

    Article  Google Scholar 

  28. Darwazeh AM et al. (1991) Mixed salivary glucose levels and candidal carriage in patients with diabetes mellitus. J Oral Pathol Med 20: 280–283

    Article  CAS  Google Scholar 

  29. Wilson RM and Reeves WG (1986) Neutrophil phagocytosis and killing in insulin-dependent diabetes. Clin Exp Immunol 63: 478–484

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Horowitz M et al. (1989) Gastric and oesophageal emptying in patients with type 2 (non-insulin dependent) diabetes mellitus. Diabetologia 32: 151–159

    Article  CAS  Google Scholar 

  31. Lysy J et al. (2006) Relationships between hypoglycaemia and gastric emptying abnormalities in insulin-treated diabetic patients. Neurogastroenterol Motil 18: 433–440

    Article  CAS  Google Scholar 

  32. Kong MF and Horowitz M (1999) Gastric emptying in diabetes mellitus: relationship to blood-glucose control. Clin Geriatr Med 15: 321–328

    Article  CAS  Google Scholar 

  33. Abell TL et al. (2006) Treatment of gastroparesis: a multidisciplinary clinical review. Neurogastroenterol Motil 18: 263–283

    Article  CAS  Google Scholar 

  34. Vinik A et al. (2003) Diabetic autonomic neuropathy. Diabetes Care 26: 1553–1579

    Article  Google Scholar 

  35. Vittal H et al. (2007) Mechanisms of disease: the pathological basis of gastroparesis—a review of experimental and clinical studies. Nat Clin Pract Gastroenterol 4: 336–346

    Article  CAS  Google Scholar 

  36. Fraser RJ et al. (1990) Hyperglycaemia slows gastric emptying in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 33: 675–680

    Article  CAS  Google Scholar 

  37. Schvarcz E et al. (1997) Physiologic hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus. Gastroenterology 113: 60–66

    Article  CAS  Google Scholar 

  38. Fraser RJ et al. (1994) Postprandial antropyloroduodenal motility and gastric emptying in gastroparesis—effects of cisapride. Gut 35: 172–178

    Article  CAS  Google Scholar 

  39. Jebbink RJ et al. (1994) Hyperglycemia induces abnormalities of gastric myoelectrical activity in patients with type I diabetes mellitus. Gastroenterology 107: 1390–1397

    Article  CAS  Google Scholar 

  40. Janatuinen E et al. (1993) Gastrointestinal symptoms in middle-aged diabetic patients. Scand J Gastroenterol 28: 427–432

    Article  CAS  Google Scholar 

  41. Petrakis IE et al. (1999) Hyperglycaemia attenuates erythromycin-induced acceleration of solid phase gastric emptying in indiopathic and diabetic gastroparesis. Scand J Gastroenterol 34: 396–403

    Article  CAS  Google Scholar 

  42. Gangula PR et al. (2007) Diabetes induces sex-dependent changes in neuronal nitric oxide synthase dimerization and function in the rat gastric antrum. Am J Physiol Gastrointest Liver Physiol 292: G725–G733

    Article  CAS  Google Scholar 

  43. Talley NJ et al. (2001) Psychological distress is linked to gastrointestinal symptoms in diabetes mellitus. Am J Gastroenterol 96: 1033–1038

    Article  CAS  Google Scholar 

  44. Ziegler D et al. (1996) [13C] Octanoic acid breath test for non-invasive assessment of gastric emptying in diabetic patients: validation and relationship to gastric symptoms and cardiovascular autonomic function. Diabetologia 39: 823–830

    Article  CAS  Google Scholar 

  45. Lawal A et al. (2007) Rapid gastric emptying is more common than gastroparesis in patients with autonomic dysfunction. Am J Gastroenterol 102: 618–623

    Article  Google Scholar 

  46. Parkman HP et al. (2004) American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology 127: 1592–1622

    Article  Google Scholar 

  47. McCallum RW et al. (1983) A multicenter, placebo-controlled clinical trial of oral metoclopramide in diabetic gastroparesis. Diabetes Care 6: 463–467

    Article  CAS  Google Scholar 

  48. Perkel MSS et al. (1979) Metoclopramide therapy in patients with delayed gastric emptying. Dig Dis Sci 24: 662–666

    Article  CAS  Google Scholar 

  49. Lata PF and Pigarelli DL (2003) Chronic metoclopramide therapy for diabetic gastroparesis. Ann Pharmacother 37: 122–126

    Article  CAS  Google Scholar 

  50. Schade RR et al. (1985) Effect of metoclopramide on gastric liquid emptying in patients with diabetic gastroparesis. Dig Dis Sci 30: 10–15

    Article  CAS  Google Scholar 

  51. Ganzini L et al. (1993) The prevalence of metocolpramide-induced tardive dyskinesia and acute extrapyramidal movement disorders. Arch Intern Med 153: 1469–1475

    Article  CAS  Google Scholar 

  52. Horowitz M et al. (1985) Acute and chronic effects of domperidone on gastric emptying in diabetic autonomic neuropathy. Dig Dis Sci 30: 1–9

    Article  CAS  Google Scholar 

  53. Erbas T et al. (1993) Comparison of metoclopramide and erythromycin in the treatment of diabetic gastroparesis. Diabetes Care 16: 1511–1514

    Article  CAS  Google Scholar 

  54. Janssens J et al. (1990) Improvement of gastric emptying in diabetic gastroparesis by erythromycin. N Engl J Med 322: 1028–1031

    Article  CAS  Google Scholar 

  55. Richards RD et al. (1993) The treatment of idiopathic and diabetic gastroparesis with acute intravenous and chronic oral erythromycin. Am J Gastroenterol 88: 203–207

    CAS  PubMed  Google Scholar 

  56. Ehrenpreis ED et al. (1998) Which form of erthromycin should be used to treat gastroparesis? A pharmacologic analysis. Aliment Pharmacol Ther 12: 373–376

    Article  CAS  Google Scholar 

  57. Jones MP (2002) Access options for withdrawn motility-modifying agents. Am J Gastroenterol 97: 2184–2188

    Article  Google Scholar 

  58. Murray CD et al. (2005) Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut 54: 1693–1698

    Article  CAS  Google Scholar 

  59. Coleski R et al. (2005) Selective reversal of hyperglycemia-evoked gastric myoelectric dysrhythmias by nitrergic stimulation in healthy humans. J Pharmacol Exp Ther 312: 103–111

    Article  CAS  Google Scholar 

  60. Bromer MQ et al. (2005) Endoscopic pyloric injection of botulinum toxin A for treatment of refractory gastroparesis. Gastrointest Endosc 61: 833–839

    Article  Google Scholar 

  61. Miller LS et al. (2002) Treatment of idiopathic gastroparesis with injection of botulinum toxin into the pyloric sphincter muscle. Am J Gastroenterol 97: 1653–1660

    Article  CAS  Google Scholar 

  62. Abell T et al. (2003) Gastric electrical stimulation for medically refractory gastroparesis. Gastroenterology 125: 421–428

    Article  Google Scholar 

  63. Watkins PJ et al. (2003) Long-term outcome after gastrectomy for intractable diabetic gastroparesis. Diabet Med 20: 58–63

    Article  CAS  Google Scholar 

  64. Faigel DO and Metz DC (1996) Prevalence, etiology and prognostic significance of upper gastrointestinal hemorrhage in diabetic ketoacidosis. Dig Dis Sci 41: 1–8

    Article  CAS  Google Scholar 

  65. Chang EB et al. (1986) Experimental diabetic diarrhea in rats. Intestinal mucosal denervation hypersensitivity and treatment with clonidine. Gastroenterology 91: 564–569

    Article  CAS  Google Scholar 

  66. Rosa-e-Silva L et al. (1996) Rapid distal small bowel transit associated with sympathetic denervation in type I diabetes mellitus. Gut 39: 748–756

    Article  CAS  Google Scholar 

  67. Sellin JH and Hart R (1992) Glucose malabsorption associated with rapid intestinal transit. Am J Gastroenterol 87: 584–589

    CAS  PubMed  Google Scholar 

  68. Aktay AN et al. (2001) The prevalence and clinical characteristics of celiac disease in juvenile diabetes in Wisconsin. J Pediatr Gastroenterol Nutr 33: 462–465

    Article  CAS  Google Scholar 

  69. Rensch MJ et al. (1996) Gluten-sensitive enteropathy in patients with insulin-dependent diabetes mellitus. Ann Intern Med 124: 564–567

    Article  CAS  Google Scholar 

  70. Talal AH et al. (1997) Celiac disease in an adult population with insulin dependent diabetes mellitus: use of endomysial antibody testing. Am J Gastreoenterol 92: 1280–1284

    CAS  Google Scholar 

  71. Mourad FH et al. (1992) Effective treatment of diabetic diarrhoea with somatostatin analogue, octreotide. Gut 33: 1578–1580

    Article  CAS  Google Scholar 

  72. Ambizas EM and Ginzburg R (2007) Lubiprostone: a chloride channel activator for treatment of chronic constipation. Ann Pharmacother 41: 957–964

    Article  CAS  Google Scholar 

  73. Schiller LR et al. (1982) Pathogenesis of faecal incontinence in diabetes mellitus—evidence for internal-anal-sphincter dysfunction. N Engl J Med 307: 1666–1671

    Article  CAS  Google Scholar 

  74. Russo A et al. (2004) Effects of acute hyperglycaemia on anorectal motor and sensory function in diabetes mellitus. Diabet Med 21: 176–182

    Article  CAS  Google Scholar 

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Acknowledgements

Special thanks to Dr Jay Pasricha for his help and guidance in preparing this manuscript.

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Correspondence to Eugene B Chang.

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Sellin, J., Chang, E. Therapy Insight: gastrointestinal complications of diabetes—pathophysiology and management. Nat Rev Gastroenterol Hepatol 5, 162–171 (2008). https://doi.org/10.1038/ncpgasthep1054

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