Diabetic gastroparesis

Christophe Vanormelingen

, Jan Tack

, and Christopher N. Andrews

*

TARGID, KU Leuven, Belgium, and

Centre for Digestive Motility, Division of Gastroenterology,
Department of Medicine, University of Calgary, AB T2N 4N1 Calgary, Canada
Background: Diabetic gastroparesis (DGP) is a gastric complication of diabetes
mellitus that causes nausea, vomiting, early satiety, bloating and abdominal
pain, in addition to signicant morbidity.
Sources of data: Original and review articles were reviewed through PubMed,
including relevant guidelines from the European and American
Neurogastroenterology Societies.
Areas of agreement: Diagnosis of DGP requires endoscopy and measurement of
gastric emptying. Management requires prokinetic therapy, usually in addition
to antinausea or other medications.
Areas of controversy: The pathogenesis of DGP is poorly understood.
Management strategies are highly variable.
Growing points: Prokinetic and neuromodulatory medications are in human
clinical trials specically for gastroparesis.
Areas timely for developing research: Further understanding of the molecular
pathology leading to DGP is required to potentially arrest the development of
this serious diabetic complication. Evaluation of novel agents for use in DGP is
sorely needed.
Keywords: stomach/diabetes mellitus/dyspepsia/vomiting/abdominal pain/
diabetic complications/gastric emptying
Accepted: January 10, 2013
British Medical Bulletin 2013; 105: 213230
DOI:10.1093/bmb/ldt003
& The Author 2013. Published by Oxford University Press. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com
*Correspondence address.
Division of
Gastroenterology,
University of Calgary
Medical Clinic, 3330
Hospital Drive NW, AB
T2N 4N1 Calgary, Canada.
E-mail: candrews@
ucalgary.ca
Published Online January 29, 2013

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Introduction
Gastroparesis is a serious complication of diabetes mellitus (DM),
defined as a delay in gastric emptying without any mechanical obstruc-
tion in the stomach. Other non-diabetic causes of gastroparesis are
surgery, neurologic disorders, medication and idiopathic causes;
1
however, the outcomes for those with diabetic gastroparesis (DGP) are
worse.
2
This disorder causes a huge morbidity burden as well as signifi-
cantly impairing glucose control. In recent years, we have gained much
insight into the pathophysiology of DGP, in addition to increased
awareness of the disorder. However, different pathophysiologic
mechanisms and variable response to treatments make it still difficult
to optimize therapy.
Epidemiology
Population-based data on DGP are limited. In case series from tertiary
care centers, delayed gastric emptying is reported in one-third of dia-
betic patients with an equal prevalence in type 1 and type 2 diabetes.
However, at the population level, only 5% of type 1 and 1% of type 2
patients have a combination of delay in gastric emptying and presence
of typical symptoms consistent with DGP.
1
Gastroparesis typically
develops after at least 10 years of diabetes, and these patients generally
have evidence of autonomic dysfunction.
3,4
The disease affects females more than males in an approximate 4:1
ratio and typically presents in the fourth or fifth decades in the type 1
diabetic population.
2
One possible explanation for this gender differ-
ence is the fact that emptying in females is on average slower than in
males.
5,6
But, recent animal data suggest that the effect of diabetes on
the enteric nervous system (ENS) is more pronounced in the female
sex, which could be another explanation for the gender differences.
7,8
Patients with DGP are frequently hospitalized for symptom exacerba-
tions, with one study showing an increase of 158% in admissions over
the 19952004 period in the USA. The hospitalization rate increased
fairly dramatically after the year 2000, for reasons that are not clear;
however, both the removal of the prokinetic agent cisapride from the
market and approval of gastric electrical stimulation (which requires
hospitalization for implantation) occurred around that time.
9
Overall
mortality was higher in gastroparesis patients when compared with a
matched population in one study, although cause of death was not dir-
ectly related to gastroparesis itself.
2
C. Vanormelingen et al.
214 British Medical Bulletin 2013;105

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Pathophysiology
Normal gastric response to a meal
Gastric motility is regulated by a complex interplay between smooth
muscle cells, interstitial cells of Cajal (ICC), enteric nerves and the
vagus nerve (Fig. 1). The functional components of the stomach are
Fig. 1 Gastric function in the normal (A) and gastroparetic state (B). Numerous coordinated
processes are required for normal gastric function, which require an intact ENS. In DGP,
one or more of these processes may be disrupted, ultimately leading to delayed gastric
emptying and symptom generation.
Diabetic gastroparesis
British Medical Bulletin 2013;105 215

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divided into a proximal part (fundus) and a distal part (corpus and
antrum). When food is ingested, peristaltic propulsions of the esopha-
gus bring the bolus into the fundus that then relaxes to accommodate
the bolus. This accommodation is necessary to create a reservoir for
the ingested food. Initial accommodation occurs in response to the
presence of caloric food in the fundus, whereas increased filling will
distend mechanosensitive tension receptors and lead to further accom-
modation of the proximal stomach. Both these reflexes are mediated
through the vagus nerve.
Once the meal is ingested, pacemaker cells of the ICC network will
initiate contractions by triggering rhythmical electrical activity that is
propagated along the stomach. These cells are located at the border of
fundus and corpus on the large curvature. The slow waves, with a fre-
quency of three per minute, will induce peristaltic propulsions of the
muscle layer and push the food from the proximal to the distal
stomach. In the antrum, the rhythmic contractions grind the solid food
into smaller pieces against a closed pyloric sphincter. Once the food
particles are small enough, typically 12 mm, food will be emptied out
of the stomach via an antro-duodenal reflex into the duodenum for di-
gestion and absorption. Emptying rate is highly controlled to ensure
nutrients are received into the duodenum at an ideal size and rate to
optimize absorption. Thus liquids with a low caloric content are
emptied faster (less than 1 h) than liquid meals with a high caloric
content (12 h). Similarly, emptying of solids takes longer (34 h)
because they are retained in the stomach until they are adequately
processed.
10
Gastroparesis pathophysiology
Gastroparesis is defined by delayed gastric emptying in the absence of
any mechanical obstruction. It is associated with symptoms of early
satiety, nausea, bloating and vomiting.
11
Although the exact mechan-
ism of gastric dysfunction and symptom generation in DGP is
unknown, a number of contributing factors have been proposed, in-
cluding hyperglycemia, vagal dysfunction, loss of neural nitric oxide
synthase (nNOS) expression in the myenteric plexus, ICC network dis-
turbances and oxidative stress.
An acute increase or decrease in blood glucose (double or half of the
normal blood glucose level, 4 mmol/l) may result in respectively
delayed or accelerated gastric emptying.
12,13
Changes in gastric empty-
ing by diabetic patients can contribute to fluctuations in their blood
glucose level that can then further impair the gastric emptying rate,
thereby creating a vicious circle for the patient. Delayed emptying can
C. Vanormelingen et al.
216 British Medical Bulletin 2013;105

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be the result of the pyloric contractions and antral hypomotility
induced by the hyperglycemic state.
14
Hypoglycemia also stimulates
the vagal nerve causing a change in gastric emptying rate. It is unclear
however whether chronically elevated blood glucose has effects of
similar magnitude on gastric emptying. As with other diabetic compli-
cations, strict blood glucose control is the best prevention.
Unfortunately, once gastric function is excessively compromised,
ongoing strict control may become difficult.
Vagal dysfunction has also been postulated to play a role in DGP.
When food is ingested and gastric accommodation is impaired, patients
may experience symptoms such as early satiation, fullness and discom-
fort. Animal and human data suggest that vagal neuropathy can lead
to reduction in pyloric relaxation, impaired antral contraction and dis-
turbed antropyloric coordination.
1517
This makes vagal neuropathy a
relevant candidate mechanism underlying disturbed gastric emptying
and symptom generation in DGP.
ENS abnormalities also likely play a significant role in DGP patho-
genesis. A major component of the ENS is the myenteric plexus, a
network of nerves that is layered between the longitudinal and circular
muscle layer of the gut and coordinates gastric motor function. The
myenteric plexus comprises excitatory (cholinergic and purinergic) and
inhibitory (nitrergic and purinergic) motor neurons, as well as primary
afferent neurons and several classes of interneurons. The excitatory
motor neurons induce muscle contractions via release of neurotransmit-
ters such as acetylcholine and substance P, whereas the inhibitory
neurons will relax the muscle tissue via release of nitric oxide and also
ATP and vasoactive intestinal peptide. Pathologic changes in these
pathways, especially the nitergic nerves, will affect motor control and
may contribute to problems such as delayed emptying, impaired ac-
commodation and gastric dysrhythmia.
Evidence for a role of nitrergic nerves was already obtained in early
studies that demonstrated that nNOS knockout mice developed a
dilated stomach with hypertrophy of the circular muscle layer.
18
In other animal experiments, decreased expression of nNOS by
disease or pharmacologic interference with nitric oxide synthase is also
able to induce impaired gastric emptying.
19,20
Patient data on loss of
the enteric neurons or nervous function are limited, although immuno-
histochemistry data in a small case series revealed a decrease in nNOS
and substance-P expression in the ENS in the stomach of diabetic
patients when compared with controls.
21
Several mechanisms have been proposed to underlie the decreased
nNOS expression. Non-obese diabetic (NOD) mice showed a reversible
loss of gastric nNOS expression, suggesting that down-regulation of
nNOS without loss of nitrergic neurons occurs in the diabetic state.
22
Diabetic gastroparesis
British Medical Bulletin 2013;105 217

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A later study in rats administered streptozotocin (STZ) to induce dia-
betes found a reversible loss of nNOS after 48 weeks, which pro-
gressed to irreversible loss, through apoptotic cell loss, after 12 weeks.
These data show a biphasic loss of the nitrergic component that could
be induced by accumulation of toxic components or increased oxida-
tive stress seen in animal models and patients with diabetes.
23
Finally,
because the active nNOS enzyme is a dimerized protein, loss of this di-
merization can cause impaired neuromuscular function as has been
reported in the antrum of STZ-induced diabetic rats.
7
Loss of ICC has been reported in animal models and diabetic patients
with gastroparesis. NOD mice and STZ-induced rats show a loss of
ICC in both corpus and antrum, and this could contribute to the delay
in gastric emptying in these animals.
4
In human studies, loss of ICC in
the antrum of DGP patients accompanied loss of nNOS positive
neurons.
21
Recent data from the Gastroparesis Clinical Research Consortium in
the USA, which collected data from a large cohort of gastroparesis
patients, have correlated the cellular changes in gastric surgical full-
thickness biopsies to patient symptoms and gastric emptying rate.
24
Both a decrease in ICC and gastric emptying rate were observed in
DGP patients, and a significant correlation was found between both
changes. Although similar changes were also observed in idiopathic
gastroparesis patients, a significant correlation was lacking in this
group; this may reflect the fact that idiopathic gastroparesis is likely a
much more heterogenous disorder than DGP, with a less well under-
stood pathophysiology and may include patients with severe functional
dyspepsia. In contrast to previous animal and human data, nNOS ex-
pression was not significantly decreased in diabetic and idiopathic gas-
troparesis patients in that study. It should be noted that the
full-thickness biopsies were taken from patients who were undergoing
placement of a gastric neurostimulator and, thus, may represent a sub-
group that is not representative of the general population with DGP.
Oxidative stress is also a plausible etiologic factor underlying loss of
nitrergic function because it is well known that diabetes induces a
high oxidative stress state that can target various tissues. Oxidative
stress can be caused by increased reactive oxygen species and loss of
antioxidant protection such as heme-oxygenase-1 (HO-1) that is
up-regulated during oxidative stress. HO-1 is an enzyme that cata-
lyzes the degradation of heme into several products of which carbon
monoxide (CO) and biliverdin are suggested to have antioxidative
effects. Increased oxidative stress in NOD mice due to loss of macro-
phage HO-1, which normally protects against free radicals in the
ENS, was associated with loss of ICC and induced a delay in gastric
emptying.
25
In another mouse study, development of diabetes was
C. Vanormelingen et al.
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associated with an increased number of macrophages and up-
regulation of HO-1 in the ENS. Onset of delayed gastric emptying, as
the diabetes progressed, was associated with the loss of a subset of
HO-1 positive macrophages. Induction of HO-1 reversed the delay in
gastric emptying.
26
Because most of the histological changes described in DGP are only
present in the myenteric plexus or muscularis layers of the stomach,
full-thickness samples of the stomach (as opposed to mucosal biopsies
taken at endoscopy) are required for analysis. Full-thickness gastric bi-
opsies in gastroparesis have been proposed as a potential diagnostic
tool for clinical use, and classifications of morphologic abnormalities
have been proposed.
27
At present, this classification is descriptive, and
correlation with pathophysiologic mechanisms is limited in most cases.
Furthermore, issues with optimal sampling and normative data remain
to be clarified. Although most reports have used samples taken laparo-
scopically, less invasive percutaneous endoscopic approaches have been
described.
28
However, because the information gathered from biopsy at
present does not change the clinical management for the patient, as-
sessment of ENS integrity has not yet been adopted clinically, but may
be useful as a research tool.
Clinical features
DGP can cause a wide variety of symptoms.
5
Early in the course of the
disease, symptoms may be minimal. As the degree of dysfunction
worsens, symptoms become more common. Gastric stasis will typically
cause nausea, vomiting and dyspeptic symptoms (including early satiety,
fullness or postprandial discomfort and bloating) in addition to anorexia.
The vomiting may occur at any time. Typically, patients report vomiting
in the morning of undigested food they ate the previous day. As these
symptoms progress, weight loss and nutritional compromise commonly
occur. For reasons that are unclear, symptom occurrence in some patients
may have a cyclical nature, where they manifest as acute episodes or
attacks or vomiting that prevents any oral intake and typically requires
hospitalization. These attacks may be interspersed with periods of respite
(or at least improved symptoms) lasting weeks or months. Although some
patients may be able to identify triggers for their symptoms (such as
certain foods), unfortunately most do not. A validated score for measur-
ing DGP symptoms has been developed for use in research settings.
29
Abdominal pain is also a significant component of DGP symptom-
atology that is under-recognized. Similar to other forms of neuropathic
pain, the symptoms are often chronic and respond poorly to current
therapies.
Diabetic gastroparesis
British Medical Bulletin 2013;105 219

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In general, diabetic enteropathy occurs in parallel with other forms of
diabetic neuropathy, whether peripheral, autonomic or both. Although
the degree and extent of symptoms patients experience from diabetic
neuropathy is highly variable, it is unusual for patients to develop DGP
without some symptoms of other forms of diabetic neuropathy.
Associated features
With the unpredictability of gastric emptying, many patients experience
difficulty controlling their blood glucose. Insulin dosing is ideally given
before eating so that peak insulin action matches postprandial glucose
increases. If emptying is delayed or the patient vomits and the glucose
peak does not happen adequately, then the risk of hypoglycemia is
high. This risk will often lead patients to dose insulin mid-meal or even
after the meal, leading to further poor blood glucose control.
DGP may frequently be associated with other manifestations of dia-
betic enteropathy elsewhere in the gastrointestinal tract. For example,
neuropathy of the small or large intestine may lead to significant diar-
rhea (often called diabetic diarrhea) that can be difficult to manage.
This disorder is well recognized, but poorly understood. Unfortunately,
typical prokinetic treatment used for DGP may exacerbate diarrhea in
this situation. Alternatively, if midgut motility is also hampered similar
to the stomach, conditions may lead to small intestinal bacterial over-
growth that will often respond to prokinetics and/or antibiotics.
Finally, gastroesophageal reflux may occur commonly with DGP, due
to poor gastric emptying, and constipation is also prevalent in a large
subgroup of diabetic patients.
Diagnosis
The diagnosis of gastroparesis is made based on a typical clinical
history, exclusion of gastric outlet or other gastrointestinal (GI) obstruc-
tion, and confirmation of delayed gastric emptying.
30
Typical symptoms
described above in association with a diagnosis of DM are suggestive of
DGP. Other disorders that may mimic DGP include rumination syn-
drome, cyclic vomiting syndrome, bulimia nervosa or superior mesenter-
ic artery syndrome. The disorder may develop in both types of DM,
although Type 1 DM is a more common history. Similarly, although
DGP may develop shortly after diagnosis of DM, patients will generally
have a longer history of the disease (10 years or longer).
Exclusion of gastroduodenal obstruction, such as by gastric cancer or
peptic ulcer disease, requires endoscopy. Significant amounts of
retained food or gastric bezoars in a patient known to be fasting
C. Vanormelingen et al.
220 British Medical Bulletin 2013;105

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overnight are also highly suggestive of DGP. Cross-sectional imaging or
abdominal ultrasound is helpful to rule out more distal obstruction or
external compression of the GI tract and to rule out other causes of
chronic upper GI tract symptoms (such as gallstones).
Assessment of gastric emptying may be completed using a number of
validated tests such as scintigraphy,
13
C breath testing or wireless mo-
tility capsule (WMC). Although other methods for characterization of
gastric function have been described (including antroduodenal mano-
metry, ultrasound, MRI, gastric barostat and electrogastrography),
these either have not been validated or are not generally available
outside of research centers.
Scintigraphy requires technetium labeling of a standardized test meal
(eggs, bread and jam) that is then eaten by the patient.
31
The radio-
activity is then quantified in the gastric region and emptying measured
at regular intervals using a gamma scanner. Because hyperglycemia can
delay gastric emptying, blood glucose should be less than 15 mmol/l
before starting the test.
31
The test is widely available, but suffers from
a lack of standardization across centers, despite standardization guide-
lines co-published by international gut motility societies and nuclear
medicine societies. Specifically, diagnosis of gastroparesis has maximal
sensitivity and specificity at 4 h, with ,10% of the meal remaining
constituting the formal diagnosis for delayed gastric emptying.
32
However, many centers will rather image out to 90 or 120 min only
and extrapolate the emptying curve to provide an estimate of emptying
half time (T1/2) that is unreliable. Current guidelines suggest that
images be taken at 30 min, 1, 2 and 4 h with the percent meal remain-
ing stated at each time point.
31
If scintigraphy is not reported in this
format, then it may be better to choose another test.
Breath testing is another validated method to measure gastric empty-
ing, with the added advantage of having no radiation exposure.
33
A
non-radioactive
13
C-labeled substrate (typically octanoic acid or
Spirulina platensis) is added to a standardized solid or liquid meal.
When the labeled food enters the duodenum, it is absorbed and broken
down, with subsequent release of
13
CO
2
in the breath. The breath is
sampled at regular intervals and measurement of
13
CO
2
is used to cal-
culate an emptying curve. This test is well validated, simple to adminis-
ter outside the hospital setting and is relatively inexpensive. A number
of mathematical methods have been proposed for analysis of gastric
emptying breath test curves, and consensus on which of these is
optimal is currently lacking.
The WMC is a single-use, orally ingested, capsule that measures pH,
pressure and temperature throughout the GI tract (SmartPillw; Given
Imaging Inc., Yoqneam, Israel). It is available in the UK and USA for
the evaluation of suspected delayed gastric emptying (gastroparesis).
Diabetic gastroparesis
British Medical Bulletin 2013;105 221

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WMC transmits data to a portable recorder worn around the patients
neck for the duration of the study. The gastric emptying time is mea-
sured as the amount of time from capsule ingestion to the abrupt pH
rise when the capsule passes from the acidic stomach to the more alka-
line duodenum. This technology is validated and has the advantage of
being able to measure transit in other gut regions. However, the WMC
is 2 cm long and does not empty at the same time as the digestible
meal, and thus may not correlate exactly with other tests of emptying.
Treatment
Once the diagnosis of DGP is established, adequate symptomatic
control may be achieved with dietary modification and/or medical
therapy. The goals of therapy are symptom control and to improve
gastric emptying. Medication classes include prokinetics, antinauseants
and pain modulation therapies. It should be noted that no medication
has yet obtained a specific indication for management of gastroparesis
symptoms (diabetic or otherwise), and, thus, all are used off-label.
Similarly, medical treatment is mostly empirical and tailored to each in-
dividual patient. In medication-resistant cases, neurostimulation and/or
jejunal enteral feeding may need to be considered. A number of reviews
on this specific subject have been published
34,35
A suggested algorithm
is shown in Figure 2.
Diet
Dietary modifications are the first-line interventions for DGP. To be
expelled from the stomach, indigestible foodstuffs such as fiber or
roughage require coordinated gastric function and in particular gastric
phase III of the migrating motor complex; both of which may be ab-
normal in DGP. Thus, a diet low in fiber and residue will often reduce
symptoms.
36
Furthermore, liquid meals require minimal mechanical
processing by the stomach and will empty by gravity and with time.
Thus, switching to a liquid diet that contains dietetic nutritional drinks
may be very helpful, not only for symptoms but also to improve both
caloric intake and predictability of post-meal glucose peaks and to ul-
timately improve the effectiveness of insulin therapy.
Prokinetics
Prokinetics form the mainstay of medical management of DGP. These
medications improve gastric emptying with an intent to improve symp-
toms. A summary of prokinetics and their dosages are shown in Table 1.
C. Vanormelingen et al.
222 British Medical Bulletin 2013;105

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Antidopaminergic prokinetics
Domperidone and metoclopramide are well-known dopamine D
2
re-
ceptor blockers. Dopamine works predominantly peripherally, whereas
metoclopramide crosses the bloodbrain barrier and can cause more
central side effects. Although generally well tolerated, both have been
associated with potentially serious side effects relating to prolongation
of cardiac QT interval and risk of fatal arrhythmias.
Both domperidone and metoclopramide reduce nausea, but dom-
peridone is generally preferred due to its lower incidence of side
effects. Metoclopramide can cause extrapyramidal side effects (such as
stiffness) that may limit its use. Tardive dyskinesia is a catastrophic
permanent neurologic side effect that has also been reported with
metoclopramide, although its incidence appears to uncommon; care
Fig. 2 Algorithm for treatment of gastroparesis.
Diabetic gastroparesis
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should be taken in patients with a higher risk of this complication:
elderly, women, cirrhotic, uremic, alcoholic, schizophrenic, with a pre-
existing movement disorder, or are on concomitant neuroleptics.
37
Levosulpiride, an antipsychotic drug with D
2
antagonistic properties, is
available in some countries, but has limited evidence in DGP.
Similarly, itopride did not have any effect on gastric emptying in a
group of patients with DGP.
38
Serotoninergic prokinetics
The serotonin 5HT
4
receptor is widely expressed in the ENS, and its
stimulation is a key mediator of peristalsis in the gut. A number of
medications work through 5HT
4
receptor agonism to improve gastric
emptying.
39
Cisapride, the first widely-used serotonergic prokinetic,
was removed from most markets worldwide due to its interaction with
the hERG ion channel present in cardiac muscle, leading to prolonged
QT-interval and fatal arrhythmias. Prucalopride is the most recent
5HT
4
agonist available and was recently approved for the treatment of
chronic constipation; it does not currently have any published data for
its use in DGP. Other similar prokinetics, including mosapride and
renzapride, have only been reported anecdotally for their use in DGP.
38
Table 1 Prokinetic medications used in DGP
Prokinetic Typical oral
dosage

Comments
Antidopaminergic
Domperidone 10 mg TID May lead to QT prolongation. Doses above 30 mg daily
increase risk of side effects. Doses up to 2025 mg QID are
used anecdotally
Metoclopramide 10 mg TID Avoid for long-term use (domperidone preferred) because of
neurologic adverse events
Levosulpiride 25 mg TID Not available in the UK
Itopride 50 mg TID Not available in the UK
Motilin agonists
Erythromycin 250 mg QID Tachyphyllaxis may worsen symptoms. May lead to QT
prolongation
Azithromycin 250 mg thrice
weekly
Less risk of drug interactions than erythromycin
Serotonergic
Cisapride 10 mg QID High risk of drug interactions. No longer available in the UK
Tegaserod 6 mg BID Risk of drug interactions. Not available in the UK
Prucalopride 2 mg daily Not studied in DGP

None of these medications have a formal indication for treatment of DGP and thus are used off label.
Dosages listed are typically used in DGP and may not be appropriate for every patient. Use of
combination prokinetic therapy should be done with caution due to the risk of drug interactions.
C. Vanormelingen et al.
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Motilin agonists
Motilin is a gut-derived hormone that induces gastric emptying and peri-
stalsis through the motilin receptor. Motilin agonists include the macro-
lide antibiotics, with erythromycin being the classic agent used.
Erythromycin is generally not used as a first-line prokinetic due to issues
with tachyphylaxis and antibiotic resistance. Furthermore, its QT-
interval prolongation effects have led to suggestions that it should not be
used in conjunction with metoclopramide or domperidone due to the
risk of arrhythmia. Novel motilin receptor agonists without antimicro-
bial activity, such as GSK962040, are in late-phase trials for DGP.
Ghrelin agonists
Ghrelin is a stomach-derived peptide that stimulates interdigestive and
postprandial motor activit, and improves appetite. TZP-101, TZP-102
and RM-131 are novel ghrelin agonists that are under development for
the treatment of gastroparesis and postoperative ileus, with intraven-
ous, oral and subcutaneous routes of administration, respectively. Early
stage trials in DGP have shown a significantly enhanced gastric empty-
ing rate and reduced postprandial symptom ratings, in addition to
being well tolerated. Although there are no currently approved drugs
with this mechanism of action, this pathway appears promising and is
being applied directly to DGP patients.
Antinauseants
An exhaustive review of antinausea therapy is beyond the scope of this
paper, but is reviewed in detail elsewhere.
40
The general classes of anti-
nausea medications include 5HT3 antagonists, antimuscarinic anitcho-
linergics, D
2
antagonists, H
1
antagonists and NK
1
antagonists. Because
many of these agents ultimately lead to anticholinergic action (with the
exception of D
2
antagonists), they can counteract concurrent prokinetic
effects. However, they do form a mainstay of the management of DGP,
if nausea is a prominent symptom; however, given the lack of guide-
lines and the multitude of agents, their use is empiric. Patients may
require more than one agent and may require cycling through a
number of agents to find optimal response.
Pain modulators
Abdominal pain has increasingly been recognized as a significant com-
ponent in DGP in recent years. This makes sense, if DGP is understood
conceptually as an enteric neuropathy. In parallel, our understanding of
Diabetic gastroparesis
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neuropathic pain and visceral hypersensitivity has improved substantially
over the last decade.
41
Thus, medications used for these indications may
be helpful in DGP, especially in the advanced stage, where multimodal
medical therapy may be required. For example, low-dose tricyclic antide-
pressants (TCA) work through a variety of mechanisms to improve
symptoms of functional gut disorders. These include antagonism at cho-
linergic, histamine, dopamine and serotonin receptors. A case series of
TCA in diabetics with vomiting showed promising results
42
, and a large
prospective trial of nortriptyline is currently in progress for management
of idiopathic gastroparesis,
43
and results will likely be translatable to
DGP. Only anecdotal evidence is available for other antidepressants in
DGP. Because serotonin norepinephrine reuptake inhibitors do not
appear to be helpful in functional dyspepsia,
44
by extrapolation it could
be speculated that they may not be helpful in DGP either. Mirtazapine,
a 5HT
2
antagonist approved for depression, has antinausea effects and
theoretically could hold promise in DGP, but has not been studied.
Other medications that can be used for treatment of pain in diabetic
neuropathy, such as gabapentin, pregabalin or duloxetine, have not
been studied directly in DGP; however, if patients have coexisting per-
ipheral neuropathy and DGP, their DGP symptoms may improve with
this treatment.
Opiates should generally be avoided for DGP due to their well-known
inhibitory effects on gut motility. However, this is not always possible in
patients with severe symptoms. In those cases, use of weaker opioids
such as tramadol is ideal. If stronger pain control is required, transder-
mal administration (e.g. Fentanyl patch) is typically a preferred approach
due to the unpredictability of absorption of oral medications in DGP.
Alternative treatments
A single-blinded, sham-controlled trial of electroacupuncture in DGP
patients significantly reduced symptoms and accelerated gastric empty-
ing, and symptoms remained improved 2 weeks after the treatment.
45
Although this approach appears promising, further study is required to
draw definitive conclusions.
Endoscopic and surgical approaches to DGP, including
electrical stimulation
Pylorospasm was described in a portion of DGP patients in early
reports of gastroduodenal manometry. Based on this concept, injection
of botulinum toxin into the pylorus was reported as helpful in initial
case series. However, randomized blinded studies of this therapy failed
C. Vanormelingen et al.
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to show any improvement in either symptoms or emptying and theyare,
thus, not recommended.
46
Gastric neurostimulation (Enterraw Therapy) provides regular inter-
mittent application of electrical stimulation to the antral muscularis to
improve DGP symptoms refractory for medical therapy. The current is
provided by an implanted pulse generator inserted at laparoscopy or
laparotomy. Although often called a pacemaker, the therapy does not
in fact entrain gastric electrical activity nor improve gastric emptying,
but works through a mechanism that is not well understood. Initial
studies have suggested that it may induce increased descending noxious
inhibitory control by the brain via vagal afferent nerves from the
stomach.
47
Neurostimulation for DGP has been shown to improve
nausea and vomiting and decrease hospitalization and need for enteral
feeding in uncontrolled case series. However, randomized blinded con-
trolled studies have shown equivocal benefit.
48
Enteral feeding through a jejunal feeding tube ( placed surgically or
endoscopically) allows secure administration of nutrition and medica-
tion beyond the stomach and has been shown to reduce hospitalization
for gastroparesis symptoms.
30
Similarly, venting gastrostomy improved
gastroparesis symptoms in a small case series.
30
Surgical resection of the stomach ( partial, subtotal or total) for
severe refractory gastroparesis has been described in a small number of
uncontrolled case series in the literature, mostly for postvagotomy
( postsurgical) gastroparesis. Completion gastrectomy seems to provide
symptom relief in postsurgical gastroparesis, but benefits of gastric
surgery for other forms of gastroparesis are not adequately studied.
49
Given this lack of evidence, along with the invasiveness and morbidity
of this procedure in a patient with end-stage diabetes, gastrectomy for
DGP, is not recommended.
Conclusion
DGP is a serious complication of diabetes with major effects on quality of
life, morbidity and mortality. Its incidence is unfortunately also projected
to rise with increasing diabetes rates. Thankfully, it has been recognized
as a significant issue, and recent research has furthered our understanding
of its pathophysiology. Furthermore, with DGP-specific therapeutics in
late stage trials, the future is hopeful for patients with this disease.
Conflict of interest
C.V. has no conflicts to disclose. Jan Tack has acted as a scientific
advisor to Almirall, AstraZeneca, Danone, Ironwood, Menarini,
Diabetic gastroparesis
British Medical Bulletin 2013;105 227

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Novartis, Sanofi-aventis, Shire, SK Life Sciences, Takeda, Theravance,
Tranzyme Pharma and Zeria and has undertaken speaking engage-
ments for Abbott, Alfa Wasserman, Almirall, AstraZeneca, Janssen,
Menarini, Novartis, Nycomed, Takeda and Shire. C.N.A. has received
research support from GSK and has acted as a consultant and speaker
for Janssen Inc.
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