Diabetic Autonomic Neuropathy of The Gastrointestinal Tract

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Diabetic autonomic neuropathy of the gastrointestinal tract

Author: Thomas Frieling, MD
Section Editors: Nicholas J Talley, MD, PhD, David M Nathan, MD
Deputy Editor: Shilpa Grover, MD, MPH, AGAF
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 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
https://www-uptodate-com.pbidi.unam.mx:2443/contents/diabetic-autonomic-neuropathy-of-the-gastrointestinal-tract/print 1/14
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)")
SUMMARY AND RECOMMENDATIONS
● 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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Topic 2643 Version 20.0
GRAPHICS
Putative mechanisms of delayed gastric emptying in diabetes mellitus
Altered gastric electrical activity ("tachygastria")
Decreased fundus tone
Decreased antral contraction amplitude and frequency (in fasting and fed state)
Impaired antroduodenal coordination (in fasting and fed state)
Increased postprandial frequency of isolated pyloric pressure waves
Decreased duodenal contraction amplitude and frequency (in fasting and fed state)
Small intestinal dysmotility (in fasting state)
Altered visceral perception
Graphic 66160 Version 2.0
Putative mechanisms of diabetic diarrhea
Due to autonomic neuropathy

Abnormal small intestinal motility
Bacterial overgrowth
Abnormal colonic motility
Anorectal dysfunction - lowered rectal sensory threshold, weak internal anal sphincter
Increased intestinal secretion
Exocrine pancreatic insufficiency (?)
Due to associated factors

Dietetic foods - sorbitol
Concurrent celiac sprue - similar genetic predisposition
Bile acid malabsorption (?)
Graphic 69533 Version 2.0

Diabetic Autonomic Neuropathy of The Gastrointestinal Tract - UpToDate

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27. Hasler WL. Gastroparesis. Curr Opin Gastroenterol 2012; 28:621.

Putative mechanisms of delayed gastric emptying in diabetes mellitus

Altered gastric electrical activity ("tachygastria")

Decreased fundus tone

Impaired antroduodenal coordination (in fasting and fed state)

Increased postprandial frequency of isolated pyloric pressure waves

Small intestinal dysmotility (in fasting state)

Altered visceral perception

Graphic 66160 Version 2.0

Putative mechanisms of diabetic diarrhea

Due to autonomic neuropathy

Abnormal colonic motility

Increased intestinal secretion

Exocrine pancreatic insufficiency (?)

Due to associated factors

Concurrent celiac sprue - similar genetic predisposition

Bile acid malabsorption (?)

Graphic 69533 Version 2.0

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