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Diabetic autonomic neuropathy of the gastrointestinal tract

Diabetic autonomic neuropathy of the gastrointestinal tract
Thomas Frieling, MD
Section Editors:
Nicholas J Talley, MD, PhD
David M Nathan, MD
Deputy Editor:
Shilpa Grover, MD, MPH, AGAF
Literature review current through: Dec 2022. | This topic last updated: Aug 10, 2022.

INTRODUCTION — Diabetic autonomic neuropathy may involve the cardiovascular, genitourinary, and the neuroendocrine systems as well as the upper and lower gastrointestinal (GI) tract. Abnormalities of GI function in diabetics are thought to be related, at least in part, to autonomic neuropathy of the enteric nervous system [1,2]. This topic will review the GI manifestations of diabetic autonomic neuropathy. The other manifestations of diabetic autonomic neuropathy are discussed separately. (See "Diabetic autonomic neuropathy".)

EPIDEMIOLOGY — Most studies assessing the prevalence of gastrointestinal GI symptoms in patients with diabetes mellitus have suggested that diabetics are more likely to experience GI symptoms as compared with controls [3-14]. Upper GI symptoms may be more common in patients with long-term type 1 diabetes mellitus [15]. However, discordant data have also been reported. The difference among studies may in part be related to the inclusion of patients with varying disease severity and/or glycemic control. Furthermore, studies have not consistently used validated measures of GI symptoms [16], and differences in prevalence may be due to the attention to recognize the signs and symptoms of gastroenteropathy [17,18].

Although esophagus motoric function may be altered by neuropathy of myenteric plexus, which regulates the activity of smooth muscle fibers in the esophagus and lower esophageal sphincter, clinically relevant dysphagia caused by diabetic esophageal dysmotility is rare [19]. Odynophagia is commonly caused by candida esophagitis [20].

The true prevalence of gastroparesis in patients with diabetes is unknown, and prevalence estimates have varied widely [21,22]. While in early studies in tertiary medical centers, up to 60 percent of patients with longstanding type 1 diabetes mellitus and GI symptoms had diabetic gastroparesis, these studies predated the use of intensive insulin treatment [23]. In a population-based study, the 10-year incidence of symptomatic gastroparesis in patients with type 1 and 2 diabetes were 5 and 1 percent, respectively [24,25]. Risk factors for gastroparesis in patients with diabetes include the presence of microangiopathy complications, neuropathy, nephropathy, female sex, obesity, poor glycemic control, duration of diabetes for more than 10 years, and the presence of other diabetic complications [18,26-30].

Estimates of the prevalence of diabetic diarrhea have varied widely between 8 and 22 percent [10,31]. It is likely, however, that the true incidence is substantially lower. In a population-based study, for example, no differences in the prevalence of diarrhea were detected among non-insulin-dependent diabetics, insulin-dependent diabetics, and healthy controls [14]. In another study that included 200 diabetic patients attending an outpatient clinic, only two complained of nocturnal diarrhea, both of whom had autonomic neuropathy [13]. In a study in type 2 diabetics, 59 of the 134 patients had diarrhea that showed significant overlap with other gastrointestinal symptoms [32].

GASTROESOPHAGEAL REFLUX DISEASE — Gastroesophageal reflux refers to the retrograde passage of gastric contents into the esophagus. This is a normal, physiologic process. Gastroesophageal reflux disease (GERD) is present when reflux is associated with symptoms or complications [33].

Pathogenesis — In patients with diabetes, GERD may be caused by autonomic neuropathy with decreased lower esophageal sphincter (LES) pressure, increased number of transient LES relaxations due to hyperglycemia, impaired clearance function of the tubular esophagus, or delayed gastric emptying [26]. (See "Pathophysiology of reflux esophagitis", section on 'Gastroesophageal junction incompetence'.)

Clinical manifestations — The most common symptoms of GERD are heartburn (pyrosis) and regurgitation. Other extraesophageal manifestations of GERD include bronchospasm, laryngitis, and chronic cough. Dysphagia for liquids and/or solids is rarely seen in diabetes mellitus, even when disturbance of esophageal peristalsis can be found in esophageal manometry. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Clinical features'.)

Diagnosis — A presumptive diagnosis of GERD can be based upon clinical symptoms alone. The role of evaluation with upper endoscopy and ambulatory pH monitoring in patients with symptoms of GERD is discussed in detail, separately. (See "Clinical manifestations and diagnosis of gastroesophageal reflux in adults", section on 'Evaluation in selected patients'.)

Management — The management of GERD is based on the frequency and severity of symptoms or complications. The medical and surgical management of GERD are discussed in detail, separately. (See "Medical management of gastroesophageal reflux disease in adults".)

GASTROPARESIS — Gastroparesis is a syndrome of objectively delayed gastric emptying in the absence of a mechanical obstruction and cardinal symptoms of nausea, vomiting, early satiety, bloating, and/or upper abdominal pain [19]. Gastric emptying for liquids and solids does not usually become more delayed over time in long-term type 2 diabetes, and abnormally slow gastric emptying of solids may improve [34,35].

Pathogenesis — Diabetic gastroparesis is thought to result from impaired neural control of gastric function. This involves the vagal nerve, abnormal myenteric neurotransmission, impairment of the inhibitory nitric oxide-containing nerves, damage of the pacemaker interstitial cells of Cajal, and underlying smooth muscle dysfunction [21,22,36-39]. Morphologic abnormalities include inflammatory changes in some autonomic ganglia and dropout of vagal myelinated fibers [21,36]. Various gastric myoelectric and motor abnormalities have been observed in patients with diabetic gastroparesis (table 1).

However, abnormalities of gastric emptying in diabetics are not strongly correlated with either disturbed gastroduodenal motility during manometry or clinical indices of autonomic neuropathy [40-43]. There is also poor correlation between delayed gastric emptying and symptoms in diabetes mellitus [44,45] that may be due to the involvement of the afferent sensory nerve fibers by autonomic neuropathy, thereby decreasing perception of symptoms [46]. Studies have failed to consistently find a clinically relevant relation between gastric emptying and symptomatology [44,47-55]. However, this may be due to differences in methodology. A metaanalysis of 899 studies found no significant association between change in gastric emptying and upper gastrointestinal symptoms. However, when only studies with optimal gastric emptying test methods were evaluated, there was a significant positive association between improvement in gastric emptying with prokinetics and upper gastrointestinal symptoms [56]. (See "Pathogenesis of delayed gastric emptying".)

Effect of serum glucose on gastric emptying — There is a close, bidirectional relationship between gastric emptying and postprandial glycemia [7,21,57-63].

Acute elevation – Acute elevations in the plasma glucose concentration affect gastric sensory and motor function [64]. In diabetics with autonomic neuropathy, the induction of hyperglycemia stimulates gastric electric activity (tachygastria), whereas the electric rhythm may be normal under normoglycemic conditions [59,60]. In healthy controls and patients with type 1 diabetes, marked acute hyperglycemia relaxes the proximal stomach; suppresses the frequency, propagation, and contraction amplitude of antral pressure waves under fasting and postprandial conditions; and stimulates phasic pyloric pressure waves, all of which retard gastric emptying [41,57,61,65]. In addition, changes in blood glucose level within the physiological postprandial range also slow gastric emptying [58]. In contrast, hypoglycemia leads to accelerated gastric emptying even in patients with delayed gastric emptying [66]. The effect of acute hyperglycemia on gastric emptying in patients with type 2 diabetes has not been well studied, although both the emptying of liquids and the lag phase for solids appear to be related to the blood glucose concentration [67]. These findings suggest that gastrointestinal (GI) motor function is influenced by the glycemic state and varies over relatively brief intervals [61]. The slowing of gastric emptying associated with elevation of the blood glucose concentration to postprandial levels is likely to constitute a physiological mechanism that regulates the release of nutrients into the small intestine.

Acute hyperglycemia also affects the sensitivity of the GI tract. In the esophagus, the threshold for perception of balloon distension is reduced by acute elevations of blood glucose concentration even within the physiological range.

Increased sensitivity of the proximal stomach may be responsible for postprandial dyspeptic symptoms when the stomach is distended by a meal [26]. As a result, patients with type 1 diabetes mellitus may exhibit increased perception of gastric distension with exaggerated nausea, fullness, and epigastric pain for a given distending stimulus [21].

Chronic hyperglycemia – The effect of chronic hyperglycemia on gastric emptying is less clear. In one study of 87 randomly selected diabetic patients, gastric emptying of a liquid meal was slower in those with blood glucose values above 270 mg/dL (15 mmol/L) [47]. However, evidence that long-term improvement in glycemic control improves gastric emptying is lacking [68-72].

Hypoglycemia – In contrast to the effect of acute hyperglycemia, insulin-induced hypoglycemia accelerates gastric emptying markedly in patients with uncomplicated [73] and complicated [66] type 1 diabetes, and probably serves as an important counter-regulatory mechanism by increasing the rate of carbohydrate absorption.

Effect of gastric emptying on serum glucose — The rate of gastric emptying has a substantial impact on carbohydrate absorption through the release of gut peptides, such as the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide [69]. In turn, higher serum glucose levels may further worsen gastroparesis. Gastroparesis can also impair absorption of oral hypoglycemic drugs [18,29,74,75]. Accelerated gastric emptying may result in hyperglycemia [76,77]. Conversely, abnormally delayed gastric emptying may predispose to hypoglycemia [78]. In addition, delayed gastric emptying may produce a lower but more prolonged postprandial hyperglycemia and is associated with a longer time to reach the glycemic peak, with a consequent mismatch between postprandial glucose elevation and the timing of premeal insulin action [79]. (See 'Effect of serum glucose on gastric emptying' above.)

Clinical manifestations — Symptoms of gastroparesis include nausea, vomiting, abdominal pain, early satiety, postprandial fullness, bloating, and, in severe cases, weight loss [38,69]. Several studies suggest that improved glycemic control may reduce symptoms of gastroparesis in type 1 and 2 diabetes, although the magnitude of the effect is uncertain [7,8,80,81]. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Diabetes-related complications'.)

Diagnosis — Diabetic gastroparesis is usually suspected in patients with nausea, vomiting, abdominal pain, early satiety, postprandial fullness, bloating, or poor glycemic control despite treatment. The diagnosis is established by evidence of delayed gastric emptying on scintigraphy in the absence of an obstructing structural lesion in the stomach or small intestine by endoscopy or imaging (eg, computed tomography or magnetic resonance enterography) [22,41]. Diagnostic evaluation in patients with suspected gastroparesis is discussed in detail, separately. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Evaluation'.)

Management — Diabetic gastroparesis is not progressive, and treatment is directed toward alleviating symptoms [82,83]. Primary treatment of gastroparesis includes improved glycemic control, dietary modification, administration of antiemetic and prokinetic agents, endoscopic treatment, and finally, surgery in patients with persistent symptoms [84]. Incretin-based therapies such as pramlintide and GLP-1 analogues (eg, exenatide) that retard gastric emptying should be discontinued before instituting medical treatment for gastroparesis. The management of gastroparesis is discussed separately. (See "Treatment of gastroparesis".)

DIABETIC DIARRHEA — Chronic diarrhea, and, rarely, steatorrhea can occur in patients with long-term diabetes [85]. Diarrhea covers 20 percent of intestinal symptoms in diabetes mellitus patients [1,86].

Pathophysiology — The pathogenesis of diabetic diarrhea is unclear, but multiple underlying mechanisms may be involved (table 2).

Disordered motility – Functional impairment of the enteric nervous system (ENS) can result in disordered motility of the small bowel and the colon [85,87,88]. Diabetic autonomic neuropathy may include vagal nerve dysfunction as well as sympathetic nerve damage [89,90]. Acute changes in blood glucose concentrations can also alter gastrointestinal sensory and motor functions. The impairment in fasting and fed intestinal motor function can cause either delayed or accelerated small bowel transit [31].

Increased intestinal secretion – Autonomic neuropathy of the ENS can also directly alter mucosal water transport and ion fluxes, resulting in intestinal fluid secretion.

Small intestinal bacterial overgrowth (SIBO) – SIBO may result from abnormal small bowel motility. Diarrhea and impaired absorption of nutrients in SIBO result from either maldigestion in the intestinal lumen, or from malabsorption at the level of the intestinal microvillus membrane due to enterocyte damage. (See "Small intestinal bacterial overgrowth: Etiology and pathogenesis", section on 'Pathophysiology' and "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis".)

Fecal incontinence – Fecal incontinence can result from voluminous stools overwhelming otherwise normal continence mechanisms in older patients or underlying anorectal dysfunction [91]. Anorectal manometry in patients with fecal incontinence associated with diabetes demonstrates decreased anorectal sensation during balloon distension and reduced resting anal sphincter pressures with normal squeeze pressures [92,93]. (See "Fecal incontinence in adults: Etiology and evaluation", section on 'Etiology and pathogenesis'.)

Medications – Medications such as metformin, alpha-glucosidase inhibitor, glucagon-like peptide [GLP]-1 agonist, and dipeptidyl peptidase-4 [DPP4] inhibitors) and artificial sweeteners (eg, sorbitol or polyols) can cause diarrhea in patients with diabetic mellitus [31,94-97].

Other – Other rare causes of diarrhea include exocrine pancreatic insufficiency and celiac sprue, the latter being more common in type 1 diabetes [85,98-100]. (See "Diagnosis of celiac disease in adults".)

Reduction in the endogenous bile salt pool can potentially result from impaired ileal reabsorption secondary to accelerated small bowel transit or bile acid deconjugation due to SIBO. However, the contribution of increased fecal secretions of hydroxy fatty acids and bile salts in the pathogenesis of diabetic diarrhea remains controversial [85].

Clinical manifestations — In patients with diabetic enteropathy, the diarrhea is usually watery and painless and can occur at night. Diarrhea may be associated with fecal incontinence due to dysfunction of external and internal anal sphincter and rectum contraction. Bouts of diarrhea can be episodic with intermittent normal bowel habits or even alternating with periods of constipation.

Diagnostic evaluation — The diagnostic evaluation serves to exclude other etiologies of chronic diarrhea (eg, infection, microscopic colitis) and evaluate the underlying cause of diabetic diarrhea (eg, SIBO, pancreatic insufficiency, bile salt malabsorption). A combination of several factors is present in many patients (table 2) [101]. The evaluation of chronic diarrhea and fecal incontinence is discussed in detail, separately. (See "Approach to the adult with chronic diarrhea in resource-abundant settings", section on 'Initial evaluation' and "Fecal incontinence in adults: Etiology and evaluation", section on 'Evaluation'.)

Differential diagnosis — The differential diagnosis of diabetic enteropathy includes other causes of chronic watery diarrhea.

Irritable bowel syndrome (IBS) – Patients with IBS can have chronic diarrhea with loose, watery stool, but associated recurrent abdominal pain is a primary characteristic of IBS. Patients usually experience the onset of symptoms as young adults. Symptoms of IBS often correlate with episodes of psychologic stress. Diarrhea is usually characterized as frequent loose stools of small to moderate volume. Stools generally occur during waking hours, most often in the morning or after meals. (See "Clinical manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Diagnostic criteria'.)

Microscopic colitis – Microscopic colitis is characterized by chronic watery (secretory) diarrhea without bleeding. On colonoscopy, patients with microscopic colitis usually have normal-appearing colonic mucosa; biopsy is necessary to establish the diagnosis of microscopic colitis. (See "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations, diagnosis, and management", section on 'Diagnostic approach'.)

Management — The management of patients with diabetic diarrhea begins with general measures such as hydration and correction of electrolyte and nutrient deficiency, symptomatic treatment of diarrhea, and treatment of the underlying cause.

Supportive care — Initial management should focus on correction of water and electrolyte imbalances, glycemic control, and restoration of associated nutritional deficiencies (eg, zinc, iron, folate, vitamin A, calcium, magnesium). Intravenous hyperalimentation may be necessary in some patients because of frequent hypoglycemic episodes resulting from insulin administration to a patient with impaired enteral delivery or delayed absorption [84,85].

Treatment of underlying cause — Treatment should be directed at the underlying cause of diarrhea. Patients with bacterial overgrowth should be treated with antibiotics [101]. Patients with concurrent celiac disease or exocrine pancreatic insufficiency should be treated with a gluten-free diet and pancreatic enzyme supplementation, respectively. (See "Management of celiac disease in adults", section on 'Dietary counseling' and "Small intestinal bacterial overgrowth: Management" and "Chronic pancreatitis: Management", section on 'Pancreatic enzyme replacement therapy'.)

Symptomatic treatment — Antidiarrheal agents may be used to control symptoms of diarrhea by inhibiting peristalsis, prolonging transit time, and reducing fecal volume (eg, loperamide 2 to 4 mg four times daily, codeine 30 mg four times daily, or diphenoxylate 5 mg four times daily) [85].

Treatment of fecal incontinence involves bulking agents and antidiarrheals to reduce stool frequency and improve stool consistency and biofeedback therapy [102,103]. (See "Fecal incontinence in adults: Management".)

Other — Although other therapies have been evaluated in patients with diabetic diarrhea, there are limited data to support their use and they cannot be routinely recommended.

Clonidine – Clonidine decreases intestinal transit and small intestinal secretion, but its use is limited by adverse effects (eg, orthostatic hypotension, delayed gastric emptying) [104,105].

Octreotide – Data on the use of long-acting somatostatin analogue octreotide (50 to 75 mcg subcutaneously twice daily to three times daily) in patients with diabetic diarrhea are limited to a small number of case reports [85,106-109]. In addition, the use of octreotide may be complicated by recurrent episodes of hypoglycemia that may be related to reduced secretion of counter-regulatory hormones [108,110]. Furthermore, octreotide may inhibit exocrine pancreatic secretion and can therefore aggravate steatorrhea.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathy" and "Society guideline links: Neuropathic pain".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Gastroparesis (delayed gastric emptying) (The Basics)")


Abnormalities of gastrointestinal (GI) function in diabetics are thought to be related, at least in part, to autonomic neuropathy of the enteric nervous system.

GI manifestations of diabetic autonomic neuropathy include gastroesophageal reflux disease (GERD), gastroparesis, and chronic diarrhea. Upper GI symptoms may be more common in patients with longstanding type 1 diabetes mellitus. Poor glycemic control may be an independent risk factor for upper GI symptoms. (See 'Epidemiology' above.)

GERD may be caused by autonomic neuropathy with decreased lower esophageal sphincter (LES) pressure, increased number of transient LES relaxations due to hyperglycemia, impaired clearance function of the tubular esophagus, or delayed gastric emptying. (See 'Gastroesophageal reflux disease' above.)

The 10-year incidence of symptomatic gastroparesis in patients with type 1 and 2 diabetes are 5 and 1 percent, respectively. Symptoms of gastroparesis include nausea, vomiting, early satiety, bloating, and/or upper abdominal pain. Patients with diabetic gastroparesis may also present with symptoms that are not directly related to the gastroparesis, but are due to complications of poor glycemic control. (See 'Clinical manifestations' above.)

The diagnosis of diabetic gastroparesis is established by evidence of delayed gastric emptying on scintigraphy in the absence of an obstructing structural lesion in the stomach or small intestine by endoscopy or imaging (eg, computed tomography or magnetic resonance enterography). (See 'Diagnosis' above.)

Primary treatment of diabetic gastroparesis includes improved glycemic control, dietary modification, and administration of antiemetic and prokinetic agents in symptomatic patients. Incretin-based therapies such as pramlintide and glucagon-like peptide-1 analogues (eg, exenatide) that delay gastric emptying should be discontinued before initiating pharmacologic therapy for gastroparesis. (See 'Management' above and "Treatment of gastroparesis".)

Diarrhea, and rarely steatorrhea, can occur in diabetics, particularly those with advanced disease. The diarrhea is watery and painless, occurs at night, and may be associated with fecal incontinence. Bouts of diarrhea can be episodic with intermittent, normal bowel habits or even alternating with periods of constipation. (See 'Clinical manifestations' above.)

Diabetic diarrhea may be due to altered motility, increased fluid secretion, small intestinal bacterial overgrowth (SIBO), celiac disease, exocrine pancreatic insufficiency, bile salt malabsorption, medications, sorbitol-containing foods, or fecal incontinence due to anorectal dysfunction. (See 'Pathophysiology' above.)

Management of diabetic diarrhea includes general measures such as hydration and correction of electrolyte and nutrient deficiency, symptomatic treatment of diarrhea with antidiarrheals, and treatment of the underlying cause (eg, SIBO, celiac disease). (See 'Management' above.)

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