Comorbid and Pharmacologic Factors Increase Risk for Gastrointestinal Disorders in Diabetes

Gastrointestinal (GI) symptoms are prevalent in the general population, with estimates among adults ranging from 7% to 10% for bloating and 7% to 30% for constipation.¹ The prevalence of GI symptoms has been found to be even higher (≥70%) in patients with diabetes – especially women, although it is unclear whether these symptoms occur more frequently in type 1 diabetes (T1D) or type 2 diabetes (T2D).²

GI problems have been linked with substantially reduced quality of life and income, and they may affect the tolerability of diabetes drugs. In one study, a 40% reduction in adherence to metformin was observed among patients with newly diagnosed T2D who experienced GI symptoms.³

Broadly, GI disturbances in diabetes “can be regarded as the outcome of a disordered gut-brain axis,” according to a new review published in Diabetes Care.² “Potential pathogenic factors include autonomic (vagal and myenteric) and peripheral neuropathy, structural and functional central nervous system (CNS) changes (diabetic encephalopathy), acute and chronic dysglycemia, psychological dysfunction, and pharmacotherapy.”

Validated assessments should be used to assess GI symptoms in patients with diabetes, such as the Bowel Disease Questionnaire (BDQ), the Patient Assessment of Upper Gastrointestinal Symptom Severity Index (PAGI-SYM), the Diabetes Bowel Symptom Questionnaire (DBSQ), and the Gastroparesis Cardinal Symptom Index daily diary. Diagnostic and treatment approaches for these symptoms are often similar to those used in patients without diabetes.²

Examples of common symptoms related to sections of the GI tract are highlighted below.

Esophagus. Patients with diabetes commonly experience disorders of the esophagus, including esophageal candidiasis, esophageal dysmotility, and gastroesophageal reflux disease (GERD), which can result in pill-induced esophagitis, regurgitation, and dysphagia. Studies have found that 40% to 60% of patients with long-standing diabetes have impaired esophageal motility and transit, and findings from a population-based case-control study indicate that diabetes is linked to a 49% increase in the risk of Barrett’s esophagus.^3,4

Diagnostic tools for the evaluation of esophageal symptoms include endoscopy for mucosal complications, manometry for esophageal motor function, contrast video swallow radiology for structural and functional disorders, and pH studies for gastroesophageal reflux.⁵

Treatment for dysphagia and GERD in diabetes is similar as in the general population. In addition, patients “with delayed transit should drink a glass of water immediately after taking oral medications to reduce the risk of pill esophagitis,” wrote the authors of the review.²

Stomach. Prevalence estimates for gastroparesis in diabetes vary considerably, ranging from 5% to 47% in T2D and 10% to 30% in T1D, with significantly higher rates in women vs men.^2,6 Approximately one-third of patients with gastroparesis experience chronic symptoms with occasional exacerbations, while another one-third of patients have chronic worsening symptoms.⁷ “The clinician may find it helpful to consider clinically significant gastroparesis as delayed gastric emptying associated with symptoms, interfering with nutritional status and/or leading to abnormal changes in postprandial glycemic patterns…,” according to the new paper.²

Diabetic gastroparesis is associated with motor abnormalities such as impaired postprandial accommodation, disordered antroduodenal coordination, excessive pyloric pressure, and antral hypomotility.⁸ Scintigraphy is the gold standard approach for measuring gastric emptying; gastroparesis can be diagnosed based on gastric retention of >90% at 1 hour, >60% at 2 hours, or 10% at 4 hours.⁹ Stable isotope breath testing is another available method that can be conducted at the point of care and does not involve radiation exposure.

Due to the heterogeneous presentation of diabetic gastroparesis across patients, an individualized treatment approach is appropriate. “Important goals of treatment in addition to symptom relief include improving nutritional status, addressing weight loss, and optimizing glycemic control,” wrote the review authors.² The efficacy of pharmacologic agents has been shown to be limited in the management of gastroparesis. Various dietary modifications may help to reduce symptoms, and it is critical for patients to maintain sufficient hydration and electrolyte balance.⁹

Small and large intestines. Patients with diabetes often experience abnormalities in small intestinal transit and motility, as well as delayed colonic transit.^8,10 Slow intestinal transit may place patients at risk for small intestinal bacterial overgrowth (SIBO), which can result in diarrhea and malabsorption.

Clinicians should consider medications as potential causative agents of diarrhea, constipation, and other GI problems. Many agents used in the management of diabetes and comorbid disorders have been closely linked with adverse GI effects. Other diagnostic considerations may include celiac disease, pancreatic exocrine insufficiency, and microscopic colitis. Similar to the management of upper GI symptoms, treatment for intestinal issues generally aims to correct fluid and electrolyte levels, improve nutritional status and glycemic control, treat underlying causes, and relieve symptoms.

“GI symptoms occur frequently and have a substantial impact on quality of life in people with diabetes,” the authors concluded. “Symptoms may not be volunteered and should be specifically elicited and quantified by using validated measures.”

Endocrinology Advisor consulted Kevin M. Pantalone, DO, ECNU, FACE, staff endocrinologist and director of clinical research in the department of endocrinology at the Cleveland Clinic, for his take on the topic.

Endocrinology Advisor: Which GI symptoms are commonly seen in patients with diabetes?

Dr Pantalone: There are many common GI symptoms associated with diabetes. Some are related to acute poor control. Hyperglycemic hyperosmolar nonketotic coma (HONK) results from very high blood glucose levels in a patient with normal ketone levels, as seen in patients with T2D. Elevated ketone levels along with high blood sugar levels result in ketoacidosis, and this is seen more commonly in patients with T1D. These 2 conditions can be associated with nausea and vomiting. Symptoms often resolve with resolution of the hyperglycemic and/or ketotic state with intravenous (IV) fluid and insulin.

Endocrinology Advisor: What are the proposed mechanisms underlying these symptoms?

Dr Pantalone: Some GI symptoms are related to long-standing poor control as well as neuropathy. Often, when we think of neuropathy in diabetes, we think of the classic burning sensation or decreased lack of sensation in the feet. However, long-standing hyperglycemia can also affect the nerves elsewhere. Diabetic autonomic neuropathy can result in GI symptoms. Perhaps the most common GI manifestation of diabetic autonomic neuropathy is gastroparesis. Common complaints can be a “full sensation” very quickly after eating, nausea, vomiting, and abdominal discomfort. Another much less common manifestation is related to disordered motility of the intestines, in which patients may have chronic diarrhea.

Endocrinology Advisor: How should these GI issues be addressed in the clinical setting?

Dr Pantalone: In the acute setting, resolution of the ketoacidosis or HONK state is the treatment. Supportive measures include antiemetic agents while IV insulin and fluid are being administered.

In the chronic setting, getting the blood glucose under control to help lower the risk of worsening neuropathy is key. Agents that speed up gastric emptying, such as metoclopramide, can be administered to help with symptoms. In severe cases, gastric bypass or gastric pacemakers may be pursued. Chronic diarrhea related to diabetes often requires supportive treatment with agents like loperamide.

References

1. Mapel DW. Functional disorders of the gastrointestinal tract: cost effectiveness review. Best Pract Res Clin Gastroenterol. 2013;27(6):913-931.
2. Du YT, Rayner CK, Jones KL, Talley NJ, Horowitz M. Gastrointestinal symptoms in diabetes: prevalence, assessment, pathogenesis, and management. Diabetes Care. 2018;41(3):627-637.
3. Smout AJPM. Oesophageal function. In: Horowitz M, Samsom M, eds. Gastrointestinal Function in Diabetes Mellitus. Chichester, West Sussex: John Wiley & Sons, Ltd; 2004:97-116.
4. Iyer PG, Borah BJ, Heien HC, Das A, Cooper GS, Chak A. Association of Barrett’s esophagus with type II diabetes mellitus: results from a large population-based case-control study. Clin Gastroenterol Hepatol. 2013;11(9):1108-1114.
5. Wilson JA, Vela MF. New esophageal function testing (impedance, Bravo pH monitoring, and high-resolution manometry): clinical relevance. Curr Gastroenterol Rep. 2008;10(3):222-230.
6. Almogbel RA, Alhussan FA, Alnasser SA, Algeffari MA. Prevalence and risk factors of gastroparesis-related symptoms among patients with type 2 diabetes. Int J Health Sci (Qassim). 2016;10(3):397-404.
7. Parkman HP, Yates K, Hasler WL, et al; National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium. Similarities and differences between diabetic and idiopathic gastroparesis. Clin Gastroenterol Hepatol. 2011;9(12):1056-1064; quiz e133-e134.
8. Thazhath SS, Jones KL, Horowitz M, Rayner CK. Diabetic gastroparesis: recent insights into pathophysiology and implications for management. Expert Rev Gastroenterol Hepatol. 2013;7(2):127-139.
9. Parkman HP, Hasler WL, Fisher RS; American Gastroenterological Association. American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology. 2004;127(5):1592-1622.
10. Phillips LK, Rayner CK, Jones KL, Horowitz M. An update on autonomic neuropathy affecting the gastrointestinal tract. Curr Diab Rep. 2006;6(6):417-423.