European Journal of Internal Medicine 23 (2012) 499–505

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European Journal of Internal Medicine

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Review article

Diabetic gastrointestinal autonomic neuropathy: Current status and new

achievements for everyday clinical practice
A. Gatopoulou a,⁎, N. Papanas a, b, E. Maltezos a, b
a
Second Department of Internal Medicine, Democritus University of Thrace, Greece
b
Outpatient Clinic of Obesity, Diabetes and Metabolism of the Second Department of Internal Medicine, Democritus University of Thrace, Greece

a r t i c l e i n f o a b s t r a c t

Article history: Gastrointestinal symptoms occur frequently among patients with diabetes mellitus and are associated with
Received 13 February 2012 considerable morbidity. Diabetic gastrointestinal autonomic neuropathy represents a complex disorder with
Received in revised form 27 February 2012 multifactorial pathogenesis, which is still not well understood. It appears to involve a spectrum of metabolic
Accepted 1 March 2012
and cellular changes that affect gastrointestinal motor and sensory control. It may affect any organ in the
Available online 28 March 2012
digestive system. Clinical manifestations are often underestimated, and therefore autonomic neuropathy
Keywords:
should be suspected in all diabetic patients with unexplained gastrointestinal symptoms. Advances in technol-
Diabetes mellitus ogy have now enabled assessment of gastrointestinal motor function. Moreover, novel pharmacological
Diagnosis approaches, along with endoscopic and surgical treatment options, contribute to improved outcomes. This
Autonomic neuropathy review summarises the progress achieved in diabetic gastrointestinal autonomic neuropathy during the last
Gastrointestinal system years, focusing on clinical issues of practical importance to the everyday clinician.
Gastroparesis © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
Treatment

1. Introduction motility. Symptoms appear to be more prevalent among women [6].

Gastrointestinal symptoms occur more commonly in diabetic
patients than in the general population and lead to a significant impair-
ment in the quality of life [1]. As high as 75% of patients with diabetes
may experience post-prandial fullness with nausea, bloating, abdomi-
nal pain, diarrhoea and/or constipation [1]. Such complaints represent
a major cause of morbidity and have a negative impact on healthcare
costs in diabetes [1,2]. However, they are often underestimated [2].
Gastrointestinal autonomic neuropathy may involve any organ in
the digestive system, such as the oesophagus, stomach, gallbladder,
pancreas, small and large intestine. Both abnormalities of gastric
function (sensor and motor modality) and impairment of gastrointes-
tinal hormonal secretion have already been described [3]. The under-
lying pathogenic mechanisms are still incompletely understood and
the best medical treatment remains to be defined [4,5].
This review summarises the progress achieved in diabetic gastro-
intestinal autonomic neuropathy during the last years, focusing on
clinical issues of practical importance to the busy everyday clinician.
2. Epidemiology
Gastrointestinal symptoms, malnutritional status and inadequate
glycaemic control may be associated with impaired gastrointestinal
⁎ Corresponding author at: 2nd, Odysseos Rd, Alexandroupolis, Greece. Tel.: + 30
2551074130.
E-mail address: gatop@otenet.gr (A. Gatopoulou).
There are miscellaneous oesophageal motility disorders in diabetes,
although these may be clinically silent, such as hypotensive lower
oesophageal construction, decreased amplitude of constructions and
simultaneous prolonged aperistaltic constructions in the body of the
oesophagus [7]. Usually, patients report heartburn, regurgitation
and dysphagia, suggesting acid reflux or pill-induced oesophageal
erosions. Candida should be suspected in cases with odynophagia [7].
The most important manifestation of gastrointestinal autonomic
neuropathy is gastroparesis. This is a symptomatic chronic disorder of
the stomach characterised by diminished gastric emptying after
exclusion of obstruction [8–10]. It is usually diagnosed in patients
presenting with intense and prolonged symptoms of nausea, vomiting,
early satiety and epigastric pain. Its prevalence has been estimated at
30–50% of patients with long-standing diabetes [9,10]. Both chronic
and acute hyperglycaemia may reduce gastric emptying [9–11].
Patients with gastroparesis, generally, show delayed gastric emptying
(28%–65%), but accelerated gastric emptying may also be the
case [9–11]. Poor post-prandial glucose control and post-prandial
upper abdominal symptoms usually occur in gastroparesis, both in
delayed and in accelerated gastric emptying [8]. Young females of child-
bearing age are mostly affected [12]. The reasons for this predilection
are unclear, but may be due, at least partly, to gender differences in
neuronal nitric oxide synthase [nNOS] dimerisation [9].
Likewise, abnormalities in oesophageal motility are detected in al-
most 50% of diabetic patients with autonomic neuropathy [13]. Re-
cent studies have confirmed that these perturbations tend to
aggravate with long diabetes duration [14]. Gastro-oesophageal

0953-6205/$ – see front matter © 2012 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2012.03.001
500 A. Gatopoulou et al. / European Journal of Internal Medicine 23 (2012) 499–505

reflux disease is seen more frequently in diabetic subjects and is asso-
ciated with neuropathy and poor glycaemic control [15].
Furthermore, lithogenic bile composition and stasis of bile in the
gallbladder may contribute to stone formation in diabetes, explaining
the relatively higher frequency of choledocholithiasis. Impaired gall-
bladder contraction may, possibly, be explained by a decreased sensi-
tivity of gallbladder smooth muscles to plasma cholecystokinin and
by a reduction of cholecystokinin receptors on gallbladder wall [16].
Moreover, a mutation in the gene encoding the expression of chole-
cystokinin A (CCK-A) receptor on the gallbladder smooth muscle in
diabetic patients with gallstones may be the cause of decreased gall-
bladder motility [17]. Insulin resistance per se has also been implicat-
ed in gallbladder dysmotility, leading to gallstone formation or
acalculus cholecystitis [18].
Faecal incontinence, particularly nocturnal, is another unpleasant
symptom. Overt steatorrhoea is noted only in a minority of patients
[19]. Autonomic dysfunction has been held responsible for the im-
pairment of normal internal anal relaxation [19]. Interestingly, gly-
caemic excursions may directly influence sphincter function. Indeed,
acute hyperglycaemia inhibits external anal sphincter function and
decreases rectal compliance, thereby, possibly, increasing the risk of
faecal incontinence [20].
Constipation is a further common complaint, affecting approxi-
mately 60% of patients with long-standing diabetes [21]. Severe
constipation with megacolon or colonic intestinal pseudo-obstruction
may, albeit rarely, occur as well. Complications of severe constipation
such as stercoral ulcer, perforation and overflow diarrhoea are infre-
quently encountered [22]. Based on studies with radio-opaque
markers to measure colonic segmental transit time, there is evidence
for slow transit constipation in the diabetic population [23]. However,
no difference has been observed between subjects with and those
without cardiovascular autonomic neuropathy [24].
Moreover, diarrhoea is a frequent symptom and may be reported
by up to 20% of patients. It reflects perturbations in small bowel
transit, while bacterial overgrowth may also be a contributory factor
[21]. It occurs at any time of the day, but it is most typically nocturnal.
Characteristically, it is seen in patients with poorly controlled insulin-
dependent diabetes mellitus exhibiting peripheral and autonomic
neuropathy [25].
Unexplained upper abdominal pain is another complaint that may
occur in diabetic patients with neuropathy, sometimes along with an-
orexia and weight loss [26]. According to one hypothesis, diabetic
radiculopathy or neuropathy of thoracic nerve roots could be the
cause [26]. Of note, depression rather than glycaemic control has
been linked with development of gastrointestinal symptoms in diabe-
tes, suggesting that emotional status is relevant to [27]. Another work
has shown that visceral neuropathy may reduce the perception of
typical gastrointestinal symptoms, as evidenced by the high preva-
lence of entirely asymptomatic or only poorly symptomatic severe
peptic ulcer disease in diabetes [8].
Finally, it is now known that autonomic neuropathy may develop
early and is, indeed, demonstrable in some patients with pre-diabetes
[28], but there is little information on gastrointestinal neuropathy in
this group.
3. Pathogenesis
The pathogenesis of gastrointestinal autonomic neuropathy is
multifaceted [4]. The main pathogenic mechanisms of both upper
and lower gastrointestinal dysfunction include abnormalities of
motor function, visceral hypersensitivity, altered secretion of gastro-
intestinal hormones, inflammatory state, autonomic dysfunction and
genetic predisposition [5] (Table 1). All these are enhanced in the
presence of acute or chronic hyperglycaemia [5]. The latter exerts a
particularly noxious effect on the interstitial Cajal cells, ultimately
leading to impaired gastric motility [29].
Both type 1 and type 2 diabetes mellitus are affected [4,5]. Generally,
patients with the former appear to have a relatively higher risk. Never-
theless, the potential differences in the pathogenic mechanisms be-
tween the two diabetes types are still unclear and most studies do not
distinguish between these two types [4,5]. Arguably, the relatively
higher risk in type 1 diabetes may be attributed to the longer duration
of hyperglycaemia, which, in turn, aggravates gastric emptying and
intestinal motility, but this is far from proven [4,9].
Gastroparesis is usually considered the most significant manifesta-
tion of gastrointestinal autonomic neuropathy [5]. An examination of
antral biopsies from patients with gastroparesis found that the total
number of nerve fibres was significantly reduced, in comparison to
non-diabetic controls [30]. In diabetic subjects, the myenteric plexus
was also more frequently infiltrated with lymphocytes [30]. In a further
work studying gastric mucosal biopsies obtained during endoscopy,
reduced density and abnormal morphology of gastric mucosal nerves
were detected in diabetic candidates for pancreas transplantation as
compared to control subjects [31].
Ghrelin, a hormone secreted by gastric entero-endocrine cells, has
been shown to enhance gastric emptying in diabetic gastroparesis,
suggesting that it may exert an additional contributory role [32].
Τhe nitric oxide (NO) produced by nNOS neurons (neuronal nitric
oxide synthese neurons) is a major non-adrenergic, non-cholinergic
inhibitory neurotransmitter, which mediates the smooth muscle
relaxation in the gastrointestinal tract and, hence, is important in
gut motility [33]. Loss of NO-mediated function in the stomach can
result in delayed gastric emptying or changes in gastric accommoda-
tion [34]. Loss of nNOS expression in diabetes may represent inhibition

Table 1
Summary of affected organs, common symptoms and pathogenic mechanisms.

Organ Abnormality Symptoms Pathogenesis⁎

Oesophagus Dysmotility, candidiasis Dysphagia, reflux odynophagia Multifactorial

Stomach Gastroparesis Nausea, vomiting, gastric outlet obstruction, bezoars • Abnormalities of gastrointestinal motor function
(i.e. ICC dysfunction, nerve density, loss of nNOS)
Small intestine Dysmotility, impaired fluid reabsorption Bacterial overgrowth, malabsorption diarrhoea • Visceral hypersensitivity
(central and peripheral mechanisms)
Large intestine Dysmotility, ischaemia Constipation, megacolon faecal incontinence, • Altered secretion of gastrointestinal hormones
ischaemic colitis, bowel infarction (i.e. ghrelin)
Gallbladder Dysmotility, gallstones, Biliary obstruction, sepsis • Autonomic dysfunction
cholelithiasis, choledocholithiasis • Oxidative stress (haem-1 oxygenase)
• Genetic predisposition
(Ano-1 expression, CCK-A receptor)
• Autoimmune (autoantibodies)
• Inflammation
• Growth factors (IGF-1)
• Hyperglycaemia

ICC: interstitial Cajal cells; CCK: cholecystokinin; IGF: insulin-like growth factor; nNOS: neuronal nitric oxide synthase.
⁎ Common pathogenic mechanisms of gastrointestinal autonomic neuropathy.
 A. Gatopoulou et al. / European Journal of Internal Medicine 23 (2012) 499–505
of nNOS by advanced glycation end-products, which can bind to
myenteric neurons and inhibit nNOS [9,34].
In the muscle layers, interstitial cells of Cajal (ICC) selectively
express Ano-1 [35]. The latter is a calcium-activated chloride channel
and participates in control mechanisms of smooth muscle contrac-
tion. Changes in Ano-1 expression may alter the electroplysiological
properties of the channel [35]. One study has recently found impaired
splicing of Ano-1 gene in diabetic gastroparesis. This defect was
accountable for the diminution of chloride currents and the delay in
contractility, as compared with non-diabetic controls [36]. It was
inferred that altered Ano-1 expression in ICC might be implicated in
the pathogenesis of diabetic gastroparesis [36].
Diabetes is characterised by high oxidative stress, which has recent-
ly been recognised to exert a decisive role in the pathogenesis of
gastrointestinal complications [37–39]. Recent data suggests that loss
of mechanisms normally conferring protection from increased oxida-
tive stress, such as upregulation of macrophage haeme oxygenase-1
(an important natural cytoprotective molecule) is of paramount im-
portance for the development of gastroparesis [39,40]. One study
demonstrated that inhibition of haeme oxygenase-1 activity in mice
caused a loss of receptor tyrosine kinase expression, thereby reducing
gastric emptying and inducing diabetic gastroparesis [40].
Recently, the role of autoimmune processes in the pathogenesis of
gastrointestinal neuromuscular disorders has attracted considerable
interest. It is now established that auto-antibodies play a pivotal
role in the development of gastric dysmotility [9,41]. However,
there is scant evidence supporting the autoimmune pathogenesis of
diabetic gastroenteropathies [42].
Diabetes leads to an imbalance between inhibitory and excitatory
enteric neuropeptide rations, which can directly cause altered gut
motility. A further putative mechanism involves the interaction of
neuropeptides from enteric nervous system with immune cells acti-
vating pro-inflammatory cytokine production, ultimately resulting
in inflammation and neuronal loss. Thus, inflammation may cause
nerve damage leading to gastrointestinal motility disorders [42–44].
Furthermore, there is strong evidence to support a role for various
growth factors in the pathogenesis of gastrointestinal autonomic neu-
ropathy. Recent studies have demonstrated that myopathy may play
a role in diabetic gastroparesis. A reduction in insulin/insulin-growth
factor 1 (IGF-I) signalling in diabetes causes ICC depletion, subsequent
stem cell factor depletion and resultant smooth muscle atrophy
[45,46]. In this context, insulin is of paramount importance. There is a
deficiency in insulin secretion and/or sensitivity, depending on type
of diabetes. In both types, however, insulin-growth factor I (IGF-I) is
reduced, resulting in smooth muscle atrophy, which, in turn, contrib-
utes to impaired gastrointestinal motility [24,35]. The administration
of growth factors, hormones and antioxidants has been extensively
studied. Impressively, IGF-1 may reverse experimental diabetic neu-
ropathy, providing further proof of concept for its pathogenic role [47].
Moreover, impaired vagal activity has been implicated in the path-
ogenesis of gastroparesis. Vagal nerve dysfunction, as manifested by a
reduced response to sham feeding-induced serum pancreatic poly-
peptide and ghrelin, is seen in patients with diabetic gastroparesis
[48]. Both afferent and efferent innervation of the gastrointestinal
tract is adversely affected in diabetes, more so in the presence of
gastroparesis [49].
In addition, visceral hypersensitivity is an important factor underly-
ing gastrointestinal discomfort [5]. In diabetic gastrointestinal autonom-
ic neuropathy, there is evidence of altered central processing of visceral
stimuli. Recently, one study has evaluated the brain processing of pain-
ful visceral stimuli in type 1 diabetic patients with autonomic neuropa-
thy and gastrointestinal symptoms in comparison to healthy volunteers
[50]. Diabetic patients exhibited higher sensory thresholds, as well as a
different pattern of electrical activity in many cerebral regions (anterior
cingulate cortex, posterior insula and medial frontal gyrus), indicating
altered central neuronal pain perception processing [50].
501
4. Diagnosis
Gastrointestinal autonomic neuropathy should be suspected in all
diabetic patients with unexplained unpleasant gastrointestinal symp-
toms. Its diagnosis is continuously being improved, as presented in
Table 2.
4.1. Gastroparesis
Clinical manifestations of diabetic gastrointestinal neuropathy
may overlap with symptoms occurring in organic disorders, notably
peptic ulcers, gastric or bowel obstruction, cancer and biliary disease.
Therefore, diagnosis should be reserved for patients with symptoms
and normal gastrointestinal imaging. Physical examination may be
entirely normal, as well [51]. Nonetheless, autonomic neuropathy
might be suspected by an exaggerated postural drop in systolic and
diastolic blood pressure and/or by a loss of normal sinus arrhythmia
on deep breathing [52]. Endoscopy and hepatobiliary ultrasound
need to be always performed to rule out other diagnoses. Proximal
small bowel obstruction should be excluded by double-contrast bari-
um study or computed tomography [52].
A definitive diagnosis is based on objective measurements of
gastric emptying [52]. Scintigraphy is the most common and widely
available method for measuring gastric emptying and is considered
the gold standard against which newer diagnostic tools are compared
[9,53]. The standard technique involves scintigraphic determination
of emptying of a solid meal. The American Neurogastroenterology
and Motility Society recommends the use of a 99 mTc (Technetium)
sulphur colloid-labelled egg, two slices of bread, strawberry jam and
water (255 Kcal). All medications that may affect gastric motility
should be stopped at least 48 h prior to the test. During the examina-
tion, blood glucose should be b15 mmol/l (270 mg/dl). The test is
based on determining the percentage of food remaining in the stom-
ach during the examination: normal values are 37%–90% at 1 h, 30–
60% at 2 h and 0–10% at 4 h [53,54].
The gastric emptying breath test using 13C, a stable, non-
radioactive isotope, has been validated in subjects with diabetes.
After an overnight fast, the patient ingests a meal with 13C-octanoic
acid, and breath samples are obtained before meal and every 15 min
to 3 h after the meal and then every 30 min up to 5 h. The ratio
13
CO2/ 12CO2 in the samples is measured by spectrometry. The result
is expressed as percentage of 13C recovery per hour (% dose/h) and
as a cumulative value over 5 h, providing a reliable measure of gastric
emptying [9].
A novel variation of the 13C-octanoic acid technique is the 13C-
Spiroulina platensis blue-green algae breath test. This is a promising
new method to evaluate gastric emptying non-invasively and without
radiation, but it is not yet approved by the Food and Drug Administra-
tion (FDA) or the European Medicine Agency (EMEA) [55]. A recent
study has validated the test using breath samples at 45, 150, and
180 min after digesting a shelf-stable 238 Kcal meal consisting of
Table 2
Progress achieved in the diagnosis of gastrointestinal autonomic neuropathy.
Oesophageal function testing: impedance, Bravo pH capsule monitoring,
high-resolution manometry
Standardisation of protocol for scintigraphy and 13C octanoic acid breath test
Use of 13C Spiroulina platensis breath test: a promising newer
non-invasive method
Smart Pill: a wireless capsule to measure pressure pH, gut transit time
Magnetic Resonance Imaging: validation needed
3-D Ultrasonography to measure gastric accommodation
Single photon emission computed tomography to measure gastric volume
and accommodation
GCSI-DD (Gastroparesis Cardinal Symptom Index Daily Diary):
a modified new questionnaire
Mucosal biopsies during endoscopy: the future diagnostic method?
502 A. Gatopoulou et al. / European Journal of Internal Medicine 23 (2012) 499–505
freeze-dried egg mix, saltine crackers and 100 mg 13C-Spiroulina
platensis. Sensitivity and specificity for the diagnosis of delayed
gastric emptying were 89% and 80%, respectively [56].
The Smart Pill (Smart Pill Corporation, Buffalo, NY, USA) is a
further new diagnostic adjunct, which has received FDA approval. It
is a non-digestible capsule measuring gastric emptying time, as well
as transit time in the small and large intestine [55]. The change in
pH between the distal stomach and the proximal small intestine
documents capsule movement along the gastrointestinal tract and,
therefore, provides a measure of the time from ingestion to arrival
in the small intestine [56]. This is usually associated with antral
phasic contractions at the maximal frequency of the migrating
motor complex [57]. The wireless capsule acquires data continuously
for up to 5 days, and this permits calculation of small bowel, colon
and whole gut transit. An “event” button is used to denote sleep,
meal, occurrence of symptoms etc. [55].
New imaging modalities include magnetic resonance imaging
(MRI), single photon emission computed tomography imaging
(SPECT) and ultrasonography. At the moment, MRI has not been
validated in the same degree as scintigraphy. Patients are typically
examined over 120 min and both diameters of proximal and distal
stomach, as well as the motor function, can be measured. It remains
a promising technology but is not widely validated [55,58]. SPECT
can measure total gastric volume during fasting and during the first
30 min following a liquid nutrient meal of 300 Kcal and demonstrates
the effects of disease on gastric volume and gastric accommodation
[59]. Three-dimensional ultrasonography or, most recently, 3D
reconstruction of images acquired by ordinary ultrasonography
assisted by magnetic scan-head tracking, can evaluate gastric func-
tion non-invasively providing information of intragastric meal distri-
bution and gastric volume. But it is time consuming and harder in
obese patients [9,60].
Andro-duodenal manometry and the barostat represent two
further diagnostic improvements [52,55]. The former measures
contractions in distal stomach and duodenum and may distinguish
neuropathic from muscle disease. It measures phasic not tonic
contractions in the distal stomach and duodenum, but it is invasive
and, currently, not widely available [55]. The latter measures the
tone of hollow organs and estimates changes in the tone by changing
the volume of the air in an intra-gastric balloon. It is rarely performed
in clinical practice [52,55].
Finally, the rhythm of the gastric pacemaker can be measured by
cutaneous electrogastrography (EGG) [55]. This provides information
about the gastric myoelectric frequency and the amplitude of the ECG
signal in the normal or abnormal frequency ranges. At the moment,
however, interpretation of results is rather controversial [55].
4.2. Oesophageal dysfunction
Τhe assessment of oesophageal motility has relied on conventional
manometry for many years. Recently, there have been two major
developments in this field: the wireless Bravo pH capsule, which
allows catheter-free monitoring; and impedance-pH measurement,
a catheter-based technique that enables detection of acidic and non-
acidic reflux. Two new procedures have also recently become avail-
able to assess esophageal motility: high-resolution manometry,
which uses many closely, spaced pressure sensors and provides spa-
tiotemporal plots of esophageal pressure changes; and impedance
manometry, a test that directly measures bolus transit and provides
conventional manometric data [61].
4.3. Diarrhoea/constipation
Similarly to upper gastrointestinal dysfunction, patients should
undergo endoscopic examinations, ultrasound, or computed tomog-
raphy to exclude other diagnoses. Colonic transit time may be
measured by a non-invasive, radio-opaque marker method. Tradi-
tionally, barostat and manometry can be used to study anorectal
and sensory function [19,20,23].
4.4. Gastrointestinal questionnaires
Several questionnaires have proven useful to quantify gastrointesti-
nal symptoms. These include the Diabetes Bowel Symptom Question-
naire (DBSQ), a measure of gastrointestinal symptoms and glycaemic
control in patients with diabetes [62]; the Gastroparesis Cardinal
Symptom index (GCSI) consisting of nine commonly reported symp-
toms [63]; and the new modified GCSI-DD (Gastroparesis Cardinal
Symptom index-daily diary). One advantage of the latter is that it
may give expression to daily symptom variability [4,9].
5. Treatment
Management of gastrointestinal autonomic neuropathy is, gener-
ally, suboptimal and needs to be improved. Therapeutic progress
achieved is summarised in Table 3. Ideally, it should target both
symptom relief and glycaemic control [4].
5.1. Nutritional status
It is important to assess patients' nutritional status, especially in
cases of gastroparesis and diarrhoea, and to recognise any dehydra-
tion, weight loss, and electrolyte imbalance. In malnourished patients
with over 5% weight loss over 3 months, enteral feeding should be
considered [9]. A satisfactory response to a trial of nasogastric or
nasojejunal feeding is an indication to attempt direct feeding through
a percutaneous endoscopically placed gastrostomy [PEG] or an endo-
scopically/surgically inserted jejunostomy [52]. Total parenteral
nutrition should be reserved only for patients who fail enteral feeding
[9]. Usually, nutritional consultation and dietary manipulation (low
fat/fibre, small portions meals) manage to improve symptoms [64].
5.2. Gastroparesis
Currently available pharmacological therapy for patients with
symptomatic gastroparesis mainly includes prokinetic drugs such as
metoclopramide, domperidone, erythromycin [65]. In patients with
oesophageal dysfunction and reflux disease, proton pump inhibitors
should be prescribed, as well [4]. Metoclopramide and domperidone
are dopamine D2 receptors antagonists, which accelerate gastric
emptying and improve symptoms but have central nervous system
side effects [66]. Erythromycin is a motilin receptor agonist that also
accelerates gastric emptying, but it is associated with rapid tachyphy-
laxis [67]. Antiemetics (phenothiazines and antihistamine agents)
have also been used. They relieve acute nausea but their efficacy for
chronic nausea is unclear [56]. One study has recently suggested
that continuous subcutaneous insulin infusion therapy in patients
Table 3
Therapeutic innovations for gastrointestinal autonomic neuropathy.
Novel prokinetic agents: prucalopride, ATI-7505 and velusetrag
Novel 5-HT-4 receptor agonists; acotiamide
Azithromycin: an alternative to erythromycin
Motilin agonist: GSK962040
Novel ghrelin agonist: TZP-101
Iberocast: an herbal mixture
Enterra device with gastric electrical stimulation electrode
endoscopically implanted
Two-channel gastric electrical stimulation
Exenatide: a X glucagon-like peptide 1 (GLP-1) agonist to reduce accelerated
gastric emptying
Stem cell-based therapies or cellular target agents such as haemin: future therapy?
 A. Gatopoulou et al. / European Journal of Internal Medicine 23 (2012) 499–505
with diabetic gastroparesis improved glycaemic control and de-
creased the number of hospitalisation days [68].
To further improve symptom relief, several potential novel proki-
netic agents are now being developed: prucalopride, ATI-7505 and
velusetrag are novel types of 5-HT-4 receptor agonist; acotiamide is
a M1 and M2 muscarinic antagonist [5,56,69]. Azithromycin is anoth-
er macrolide antibiotic providing an alternative to erythromycin for
gastroprokinetic applications [5]. GSK962040 is a small-molecule
motilin agonist nowadays being investigated for its potential efficacy
[70]. TZP-101 is a novel ghrelin agonist under development for the
treatment of gastroparesis and post-operative ileus [71]. Moreover,
iberocast, an herbal mixture, may have beneficial effects on functional
dyspepsia and gastroparesis but the underlying mechanism of action
is unclear [72]. Botulinum injection of the pylorus at endoscopy failed
to show significant symptomatic benefit [73].
In refractory gastroparesis, gastric electrical stimulation can be
considered as rescue therapy. The Enterra device (Medtronic, Inc)
has been clinically available but its efficacy is controversial [74]. In
one recent study, a gastric electrical stimulation electrode was endo-
scopically implanted in patients with gastroparesis, but further stud-
ies are needed to validate this approach [75]. A meta-analysis has
recently found that patients with diabetic gastroparesis seem to be
more responsive to gastric electrical stimulation both subjectively
and objectively compared to patients with idiopathic or postsurgical
gastroparesis [76]. Another study evaluated the effects of two-
channel gastric pacing in patients with gastroparesis and demonstrat-
ed that two channel gastric pacing seem to be a safe treatment
approach, which is able to normalise and enhance slow wave activity,
as well as accelerating gastric emptying in patients with diabetic
gastroparesis [77].
In extremely severe cases, gastrectomy may be performed. This
should be only attempted in highly selected patients after weighting
the risk of malnutrition and post-operative weight loss against antic-
ipated symptom relief [5].
In cases of accelerated emptying, dietary manoeuvres may be nec-
essary [78]. These mainly include avoidance of consuming fluids
during and 30 min after meals and addition of fibre supplements.
Treatment with the GLP-1 agonist exenatide also seems to delay
gastric emptying and reduce post-prandial glycaemia [79].
5.3. Oesophageal dysfunction
Conventional therapy with proton pump inhibitors is suggested to
manage oesophageal dysmotility especially associated with reflux.
Patients are also advised to drink fluids immediately after taking
medications in order to avoid pill-induced oesophagitis [4].
5.4. Diarrhoea
Given that bacterial overgrowth is found in almost 40% of diabetic
patients with diarrhoea [80], therapy should include intermittent
administration of selective antibiotics [81]. Rifaximin is the most
extensively studied antibiotic. This agent improves symptoms in
33%–92% and eradicates bacterial overgrowth in up to 80% of patients
[82]. In the event of severe diarrhoea, somatostatin analogues may be
required [4,83]. In cases with diarrhoea, constipation and faecal in-
continence, it is mandatory to exclude other common causes, notably
celiac or pancreatic disease [83]. Loperamide may prove helpful in
faecal incontinence [83]. Alosentron, a selective 5-HT3 antagonist,
was approved in 2000 for the treatment of diarrhoea-predominant
irritable bowel syndrome in females with no experience in diabetic
patients. It is thought to act by reducing inappropriate colonic motil-
ity and colorectal hypersensitivity. A small incidence of reversible
ischaemic colitis led to an initial withdrawal of alosendron, while
additional experience was more positive, allowing its re-introduction
but limiting its use to sever cases [84].
503
5.5. Constipation
Management of constipation involves traditional laxatives and is
still symptomatic aiming at symptom relief [4]. Lubiprostone, a
novel drug for constipation, has recently become available in the US.
It is approved for the treatment of chronic idiopathic constipation,
and acts by activating CIC-2 chloride channels and, thereby, modify-
ing intestinal transit time. This agent may prove useful for the future
treatment of constipation from gastrointestinal autonomic neuropa-
thy in diabetes [84].
5.6. Pain management
Analgesia is often challenging. Medications such as tricyclic and tet-
racyclic antidepressants, gabapentin and pregabalin can be used, but
opiates should be provided sparingly and only in refractory cases [9].
Medications commonly used for chronic pain such as tramadol are
usually effective, but there is currently limited experience with their
use in gastroparesis [9,85].
5.7. Emerging stem cell therapies
Stem cell-based therapies have been proposed to improve gastroin-
testinal motility [86,87]. This approach is based on the ability of mesen-
chymal stem cells to differentiate into several cell types including
gastrointestinal smooth muscle cells. Future studies are now desirable
to ascertain whether this approach can restore normal digestive func-
tion and reverse gastrointestinal complications in diabetic patients
[86,87].
6. Conclusions
Gastrointestinal autonomic neuropathy represents a major factor of
morbidity in diabetic patients and has a profound negative impact on
the quality of life [1,4]. Importantly, this complication can easily go
unrecognised for a long time [1–8]. Thus, a high index of suspicion is
required in the case of persistent gastrointestinal symptoms, especially
in patients with long-standing diabetes and other chronic complica-
tions [1–4,7]. Diagnosis will be confirmed by careful clinical examina-
tion, exclusion of other causes and use of specific tests, both
established and emerging [1–4].
The pathogenesis of gastrointestinal autonomic neuropathy is
complex and multifactorial. An array of metabolic and cellular
changes, along with hyperglycaemia, increased oxidative stress and,
arguably, autoimmune and genetic factors appear to be involved
[35]. Despite the great number of putative pathophysiological mech-
anisms, the exact contribution of each of these remains a matter of
controversy [44].
New technologies and advances in diagnosis are being applied in
diabetic subjects with gastrointestinal autonomic neuropathy
(Table 1) [56]. For instance, the SmartPill is a new promising diagnos-
tic tool. This is a wireless capsule that records luminal pH,
temperature and pressure during transit through the gastrointestinal
tract [5]. Early diagnosis with gastric mucosal biopsies performed
during endoscopy is another diagnostic innovation [31].
New therapeutic strategies and emerging pharmacological agents
are being evaluated [5,9,56]. These mainly include muscarinic receptor
antagonists, ghrelin receptors, motilin and 5-HT4 receptor agonists
[5,56]. Gastric electrical stimulation with endoscopically implanted
electrodes can be considered in refractory cases [75,76]. Τhe potential
use of stem cell-based therapies or new drugs with cellular target
such as haemin may improve treatment in the future [35,86].
Meanwhile, optimal patient management requires multidisciplin-
ary approach and should focus on the relief of gastrointestinal symp-
toms, as well as improvement in nutritional status and glycaemic
control [4]. This goal should be pursued by the everyday clinician.
504 A. Gatopoulou et al. / European Journal of Internal Medicine 23 (2012) 499–505
Learning points
• Gastrointestinal autonomic neuropathy represents a major factor of
morbidity in diabetic patients and should be suspected in all sub-
jects with unexplained unpleasant gastrointestinal symptoms in
everyday practice.
• The pathogenesis of gastrointestinal autonomic neuropathy is com-
plex, multifactorial and remains largely unclear.
• New technologies and advances in diagnosis are being applied to
improve diagnosis, such as the Smartpill, 3D-ultrasonography,
MRI, SPECT, and 13C Spiroulina platensis breath test.
• Emerging pharmacological agents and strategies are being evaluat-
ed, as well. The most important ones include muscarinic receptor
agonists, ghrelin receptor agonists, motilin and 5-HT4 receptor ago-
nists, and gastric electrical stimulation with endoscopically
implanted electrodes for refractory cases.
Conflicts of interest
This review was written independently. No company or institution
supported it financially. N Papanas has been an advisory board member
of Trigo Care International; has participated in sponsored studies by
Novo Nordisk and Novartis; received honoraria as a speaker for Novo
Nordisk and Pfizer; and attended conferences sponsored by TrigoCare
International, Novo Nordisk, sanofi-aventis and Pfizer. E Maltezos has
participated in sponsored studies by Novo Nordisk and Novartis; and
attended conferences sponsored by Wyeth, Pfizer and Bayer.
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