Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999), pp.

1061± 1075

REVIEW ARTICLE

Diabetic Gastropathy
Gastric Neuromuscular Dysfunction in Diabetes Mellitus
A Review of Symptoms, Pathophysiology, and Treatment
KENNETH L. KOCH, MD

Diabe tic gastropathy is a te rm that encompasse s a numbe r of ne uromuscular dysfunctions of

the stomach, including abnorm alitie s of gastric contractility, tone , and myoelectrical activity
in patie nts with diabe tes. These abnormalitie s range from tachygastrias to antral hypom otility
and frank gastropare sis. Diabe tic gastropathie s may be acute ly produce d during hype rglyce -
mia. Symptom s of chronic diabe tic gastropathy include chronic nause a, vague e pigastric
discomfort, postprandial fullne ss, e arly satie ty, and vomiting. Because these symptoms are
nonspe ci® c, othe r disorde rs such as mechanical obstruction of the gastrointe stinal tract,
gastroe sophage al re ¯ ux dise ase , chole cystitis, pancre atitis, mese nte ric ischemia, and drug
e ffe cts should be conside re d. Neuromuscular abnormalitie s of the stomach may be asse ssed
noninvasive ly with gastric e mptying te sts, e le ctrogastrograph y, and ultrasound. Gastrokine tic
age nts such as metoclopramide , cisapride , dompe ridone , and e rythromycin incre ase fundic or
antral contractions and/or eradicate gastric dysrhythmias. Diet and glucose control also are
important in the manage ment of diabe tic gastropathy. As the pathophysiology of diabe tic
gastropathy is be tte r unde rstood, more speci® c and improve d tre atme nts will e volve .

KEY WORDS: diabete s mellitus; gastropathy; gastropare sis; gastric dysrhythmias; gastrokine tic agents; nausea and
vomiting.

Uppe r gastrointe stinal symptoms, particularly post-
prandial nause a, vomiting, and abdom inal discomfort,
occur in 30 ± 60% of patie nts with type 1 diabe te s
mellitus (1, 2). In a surve y of diabe tic patie nts, 76%
had chronic or re current gastrointe stinal symptoms;
29% had nause a and vomiting, and 34% had abdom-
inal pain (1). These are nonspe ci® c symptoms and a
broad differe ntial diagnosis, including diabe tic gas-
tropathy, must be conside red whe n e valuating the se
symptoms in diabe tic patie nts. Early satie ty, fullne ss,
and bloating are also common symptoms associate d
with diabe tic gastropare sis (1± 4). As many as 50% of
patie nts with type 1 diabe te s have de laye d gastric
Manuscript re ce ived October 7, 1998; re vised manuscript re -
ce ived January 22, 1999; accepte d February 10, 1999.
From the Department of Me dicine, Gastroente rology Division,
The Milton S. He rshey Medical Ce nter, Hershey, Pennsylvania.
Address for re print requests: Dr. Ke nne th L. Koch, Departme nt
of Medicine, Gastroe nterology Division, The Milton S. He rshe y
Medical Cente r, He rshe y, Pe nnsylvania 17033.
e mptying or gastropare sis (4). In this review, uppe r
gastrointe stinal symptoms in diabe tic patie nts and the
re lationships betwe en symptoms and gastric motility
dysfunction, ie, gastric neurom uscular dysfunction
(diabe tic gastropathie s), will be addre sse d.
Diabe tic gastropathy re fe rs to a varie ty of neuro-
muscular abnormalitie s of the stomach that have bee n
de scribe d in patie nts with diabe te s. The se abnormal-
ities range from gastric dysrhythmias (5± 7) to antral
dilation (2), antral hypomotility (6, 8), and gastropa-
re sis (5± 9). The corre lation be twee n symptom seve r-
ity and the rate of gastric e mptying status has bee n
poor. This poor corre lation be twee n symptoms and
obje ctive ® ndings may be similar to the atypical pre -
se ntations of chole cystitis or silent myocardial isch-
e mia fre que ntly se en in patie nts with diabe te s melli-
tus. Gene ralize d periphe ral or autonomic ne uropathy
is not always a re liable pre dictor of the prese nce of
diabe tic gastropare sis (10) . Furthe rmore , common

Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999) 1061
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diseases that cause the nonspe ci® c symptoms that are
associate d with diabe tic gastropathy must be e xclude d
before gastric ne uromuscular disorde rs can be diag-
nose d con® dently and treate d e ffe ctive ly with protro-
kine tic drug the rapy and diet counse ling (11) .
In this re vie w, the clinical pre sentation of diabe tic
gastropathy will be de scribe d, normal and abnormal
gastric ne uromuscular activity will be re vie wed, and
drug and die tary tre atme nt options will be outline d.
NORMAL GASTRIC MOTILITY
Healthy individuals experience ple asant, satisfying
se nsations in the e pigastrium afte r me als. The se
ple asant postprand ial se nsations occur while the
stomach is performing the work of gastric emptying.
In contrast, patie nts with diabe tic gastropathy e xpe -
rience dyspe psia-like symptomsÐ nause a, unple asant
fullne ss, e arly satie ty and vague e pigastric discom-
fortÐ after meals. Be fore de scribing the gastric ne u-
romuscular abnormalit ie s in diabe tic gastropathy,
normal gastric ne uromuscular function will be re -
viewed.
The e sse ntial neuromuscular functions of the stom-
ach are to re ceive , mix, and empty nutrie nts from the
stomach into the small bowel for absorption (12) .
Solid foods must be triturate d, or broke n down, into
tiny particle s, mixed with acid and pepsin, and the n
e mptie d from the stomach (12) . The gastric myoe lec-
trical and contractile activitie s that occur during these
physiolog ic functions are controlle d by e xtrinsic
(parasympathe tic and sympathe tic) and intrinsic (e n-
te ric) ne rvous system activity. The autonomic nervous
syste m links the activity of the central nervous system
(CNS) and the e nte ric ne rvous syste m in orde r to
modulate gastrointe stinal motility (13, 14) . The pre -
cise role s of various ne urotransm itte rs, neurope p-
tide s, and classic gut hormone s such as gastrin and
motilin in modulating gastric electrical and contrac-
tile functions are still not fully e stablishe d.
During a meal, the fundus must re lax to re ceive or
accommodate the volume of inge ste d food. Relax-
ation of the proxim al stomach is mediate d by vagal
e ffere nt ® be rs and nitric oxide pathways. Receptive
re laxation is the initial ne uromuscular activity of the
proximal stomach as a meal is inge ste d (Figure 1)
(12) .
Afte r inge stion of the meal, regular gastric contrac-
tile activity be gins in the body± antrum to mix and
triturate the inge sted food. Emptying of solids doe s
not be gin until particle s are , 1 mm in diam eter in the
nutrie nt suspe nsion or chyme (Figure 1). The pe riod
1062
KOCH
Fig 1. Postprandial gastric motility e vents include fundic re ceptive
re laxation to accommodate the inge sted food, and re curre nt gastric
peristaltic contractions in the corpus and antrum for mixing and
e mptying the chyme into the duodenum. Gastric pe ristalsis occurs
at approximate ly 3/min. Antroduodenal coordination is necessary
for e f® cie nt emptying. (See text for de tails). Reprinted with per-
mission from KL Koch (12) .
before emptying be gins lasts about 30 ± 40 min de -
pe nding on caloric and physical characte ristics of the
food. This period is calle d the lag phase (9, 12, 13) .
O nce e mptying be gins, nutrie nts are e mptied in a
line ar fashion from the antrum into the duode num.
Undige stible ® be rs such as roughage are re taine d and
e mptie d last or during phase III of the fasting or
inte rdige stive pe riod of gastric motility (12, 13) .
Gastric pe ristalsis is controlle d by the intrinsic e le c-
trical activity of gastric pace make r cells, which is
probably gene rated by interstitial cells of Cajal (15) .
The gastric pace make r are a is locate d in a re gion at
the junction of the fundus and body on the gre ate r
curvature (Figure 2) (16, 17) . Gastric pacese tte r po-
te ntials or slow waves depolarize and re polarize at a
fre que ncy of approximate ly 3 cycles per minute (cpm)
as re corded by sensal or cutane ous electrode s (16,
18) . The slow waves are associate d with very small
contractions, but chie ¯ y coordinate the freque ncy of
circular muscle contractions in the body and antrum.
The onse t of circular muscle contraction also de pe nds
on actional pote ntials and plate au pote ntials, which
are affected by ongoing ne ural and hormonal inputs
as well as physical characte ristics of the meal.
To summarize , in the normal postprandial situa-
tion, the stomach accomplishe s the following neuro-
muscular activitie s: fundic re laxation, accommoda-
tion of the vo lu me inge ste d, fund ic e m ptying,
pe ristaltic contractions of body± antrum for mixing,
trituration and emptying of chyme , and coordination
of pe ristaltic contractions from antrum to duode num.
These ne uromuscular eve nts are coordinate d by gas-
tric pacese tter wave s, and the appropriate action and
Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)
DIABETIC GASTROPATHY

Fig 2. Gastric pace se tter potentials or slow wave s originate from the pacemake r are a. Pacesette r potentials trave l in a
circumfere ntial and aboral direction at a rate of approximately 3 cpm. The cutane ously re corded e lectrogastrogram
(EGG) shows a 3-cpm wave patte rn. The fundus has no rhythmical ele ctrical activity. Re printed with permission from
KL Koch (12) .

plate au pote ntials that unde rlie circular muscle con-
tractions (Figure 3).
DIABETIC GASTROPATHYÐ A SPECTRUM OF
NEUROMUSCULAR ABNORMALITIES
Gastrop aresis
As describe d above , diabe tic gastropathy e ncom-
passe s a varie ty of pathophysiologic neuromuscular
e vents of the stomach in the patie nt with diabe te s
mellitus. The most se vere ne uromuscular abnormality
is diabe tic gastropare sis, which is diagnose d whe n
de laye d e mptying of food from the stomach is docu-
mented (3, 5± 7, 19) . Gastropare sis has be en found in
up to 50% of patie nts with type 1 diabe te s mellitus
and 30% of patie nts with type 2 diabe tes mellitus (4,
20) . In the past, gastropare sis diabe ticorum was con-
side re d to be an e nd-stage compone nt of long-
standing type 1 diabe te s (21) . Autonomic ne uropathy
rathe r than myopathy was belie ved to be the unde r-
lying cause of the gastropare sis (22) . Howe ver, auto-
nomic nervous syste m dysfunction doe s not ne cessar-
ily predict gastropare sis in the type 1 diabe tic patie nt
(10) .
Kassande r sugge ste d many ye ars ago that diabe tic
patie nts had ª autovagotomyº be cause of the similar-
ity betwe en radiographic ® ndings of gastropare sis and
the gastric atony observe d after surgical vagotomy
(19) . Howeve r, Yoshida e t al found no histologic or
anatomic abnormalitie s in vagal ne rve tissue obtaine d
from diabe tic patie nts (23) . O n the othe r hand, a
re cent study showe d vagal ne rve dysfunction as re -
¯ e cted in abnormal respiratory sinus arrhythm ia in
diabe tic patie nts with gastropare sis (2). Thus, subtle
and/or se vere dysfunction of vagal affere nt or effe rent
ne urons is like ly pre se nt in patie nts with a varie ty of
diabe tic gastropathie s ranging from gastropare sis to
gastric dysrhythm ias.
Gastric Dysrhyth m ias
Gastric dysrhythm ias have also be en recorde d in
patie nts with diabe te s mellitus and the meal-re late d
symptoms described above (Figure 4) (5± 7). Gastric
dysrhythm ias are de® ne d as bradygastrias (1.0 ± 2.4

Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999) 1063

Fig 3. The ele ctrical events that occur during a gastric peristaltic wave are shown. Action potentials occur in
association with propagate d pace setter potentials during the myoele ctrical and contractile e vents of gastric pe ristalsis.
The amplitude of the E GG waves is increase d. Re printed with permission from KL Koch (12) .
cpm activity) , tachygastrias (3.6 ± 9.9 cpm activity) , or
tachyarrhythmias, which are a combination of both
bradygastrias and tachygastrias (24, 25) . Gastric dys-
rhythm ias inte rfere with the normal 3-pe r-minute
gastric peristaltic contractions, which mix and empty
food from the stomach. In patie nts with gastric dys-
rhythmias, abnormal gastric e mptying is found 85±
90% of the time (6). In some studie s, gastric dysrhyth-
mias have be e n found in 100% of diabe tic patie nts
with meal-re late d symptoms (5), but the incide nce of
gastric dysrhythmias probably de pe nds on the pre -
dominant symptoms reporte d by the patie nt group
studie d (5± 7, 26). The pre sence of gastric dysrhyth-
mias is important because corre ction of the dysrhyth-
mias is associate d with improve ment in nause a and
uppe r abdominal symptoms (see tre atme nt se ction
below) (5, 7, 27) . Figure 4 shows a bradygastria dys-
rhythmia in a symptomatic patie nt with diabe tic gas-
tropare sis be fore drug tre atment and e stablishm ent
of normal 3 cpm gastric myoe le ctrical activity afte r
tre atment with dompe ridone .
1064
KOCH
Antral Hypom otility
Antral hypom otility has be en re corded with intralu-
minal pre ssure transduce rs in patie nts with diabe te s
mellitus (8). Poor antral contractility re sults in de -
laye d emptying of food from the stomach and gastro-
pare sis. Low amplitude or irre gular contractions of
the antrum also lead to poor antral± duode nal coor-
dination in the function of providing the prope r peri-
staltic waves to empty chyme into the duode num
(9, 13) .
Antral Dilation
In studie s using ultrasound to de te rmine the diam-
e ter of the gastric antrum, symptom atic diabe tic pa-
tie nts were found to have a signi® cantly large r antral
diame te r in the postprandial condition compare d
with healthy controls (2). In patie nts with functional
dyspe psia, incre asing antral dilation correlate d with
the symptom of bloating (28) , which is also ve ry
common in the diabe tic patie nt population.
Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)
DIABETIC GASTROPATHY

Fig 4. Gastric dysrhythmia (bradygastria) recorded from a symptomatic patient with type I diabete s me llitus and gastroparesis.
(A) Flat-line bradygastria at month 0. During tre atme nt with dompe ridone, the bradygastria disappe are d and the EGG
appe ared normal (3 cpm) . The patient’ s symptoms of nause a and vomiting also disappe ared. (B) The running spectral analysis
of the E GG signal recorded at month 0 and month 12. Note the change from no fre quencie s in the EGG signal at month 0
to cle ar pe aks at 3 cpm at month 12.

Antrod uod enal Coor din ation
The most e f® cient movement of chyme from the
stomach to the duode num require s antroduode nal
coordination (9, 12) . The pylorus and duode num offe r
re sistance to e mptying of chyme from the antrum
(29) . Pylorospasm or uncoordinate d pyloric contrac-
tions provide resistance to gastric e mptying and has
bee n re porte d as a cause of delaye d gastric e mptying
in diabe tic patie nts (29) .
Gastric Ton e
In diabe tic patie nts the fundic tone doe s not relax
normally in response to balloon distension whe n com-
pare d with control subje cts (30). Fundic tone abnor-
malitie s may also have a role in dyspe psia-like symp-
toms expe rie nce d by diabe tic patie nts.
To summarize, Figure 5 illustrate s the various ne u-
romuscular abnormalitie s that may af¯ ict the stomach
in patie nts with diabe te s mellitus. In the patie nt at the
e xtre me e nd of the spectrum, diabe tic gastropare sis,
gastric dysrhythm ias, dilate d antrum , and antral hy-
pomotility may all be pre sent and re pre sent the un-
de rlying pathophysiology of symptoms. Pylorospasm
and duode nal resistance may contribute to the delay
in gastric e mptying. Other patie nts may have predom-
inantly dilate d antrum or gastric dysrhythmias as the
primary pathophysiologic e vent that correlate s with
meal-re late d symptoms. Most rese arch has focuse d
on the diabe tic patie nt with se vere symptom s. Studie s
of gastric ne uromuscular function in a continuum of
diabe tic patie nts are ne eded.
Diabe tic patie nts may have single or multiple e le -
ments of diabe tic gastropathy describe d above and
summarized in Figure 5. Because of the variable
de gre e of vagal affere nt and e ffe rent dysfunction, the
corre lation be twee n diabe tic gastropathie s and par-
ticular symptom s is not always straightforward. How-
e ver, patie nts with diabe tes mellitus may have uppe r
gastrointe stinal symptoms in the abse nce of frank
gastropare sis, because the othe r gastric pathophysio-

Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999) 1065
 KOCH

Fig 5. Summary illustration of the spectrum of gastric ne uromuscular abnormalities that may
occur in diabetic gastropathy. The abnormalitie s include impaired fundic re laxation, gastric
dysrhythmias, dilated antrum, antral hypomotility and gastroparesis. Decre ase d vagal tone may be
pre sent as well as visceral hyposensitivity. Adapte d from KL Koch (17) .

logic mechanism s describe d above may be re sponsible
for the se symptoms.
MECHANISMS OF DIABETIC GASTROPATHY
The unde rlying mechanism( s) of the diabe tic gas-
tropathie s are not pre cisely known. As with the othe r
se que lae of diabe te s mellitus, such as retinopathy,
pe riphe ral neuropathy, and ne phropathy, there are
se veral mechanisms of injury that may be re sponsible
for the ® ndings of diabe tic gastropathy.
Autonomic ne uropathie s that involve the parasym-
pathe tic or sympathe tic nervous syste m may be re -
sponsible for some of the gastric neuromuscular prob-
lems outline d above . Loss of vagal tone and incre ase d
sympathe tic ne rvous syste m activity have bee n asso-
ciate d with gastric dysrhythmias (31, 32) , and this may
be a factor in the de ve lopme nt of gastric dysrhythm ias
in some diabe tic patie nts. Damage to enteric neurons
or interstitial cell of Cajal or subtle dysfunction of
these ele ments may also be mechanisms of diabe tic
gastropathy.
Microangiopathie s contribute to retinal damage as
well as pe riphe ral ne uropathie s de scribe d in patie nts
with diabe tes mellitus. Microangiopathie s may affe ct
re le vant nerve and muscle function of the stomach
and may contribute to the e volution of diabe tic gas-
tropathy.
Postprandia l hormone re le ase of glucagon and
pancre atic polype ptide , as well as the re le ase of ne u-
rotransmitte rs, may be alte re d in the patie nt with
diabe te s mellitus. Hormonal response s are comple x
issues, particularly as the wide varie ty of foods in-
gested will evoke differe nt gastric and ne urohormonal
re sponse s.
Finally, glucose toxicity itself may play a role in the
e nd-organ ne uromuscular dysfuncti ons de scribe d
above . Hype rglyce mia affe cts both intrace llular met-
abolic pathways as well as membrane function in
ne ural cells. The acute effects of hype rglyce mia have
bee n studie d in he althy subje cts and in patie nts with
diabe te s mellitus. Antral contractions in the post-
prandial condition were signi® cantly de crease d dur-
ing induce d hype rglyce mia (33) . In this situation,
pyloric contractions may be evoke d while antral con-
tractions are de crease d, a situation that would lead to
pote ntial gastric stasis (34) .
Hasle r e t al showed that increasing plasma glucose
from normal leve ls to 230 mg/dl signi® cantly de -
creased the antral motility inde x in he althy subje cts
(33) . An e quivale nt le ve l of insulin infusion did not
suppre ss antral motility, indicating hype rinsuline mia
was not the factor that affects antral motility. In
similar studie s, it was shown that the pe rcentage of
tachygastria activity increased signi® cantly as plasma

1066 Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)
DIABETIC GASTROPATHY
glucose was incre ase d from normal to 230 mg/dl using
the glucose clamp te chnique (33) . Figure 6 illustrate s
normal gastric e le ctrical activity during euglyce mia
compare d with tachygastrias e voke d during hype rgly-
ce mia. The incre ase in tachygastria activity was
blocke d by pre tre atme nt with indom ethacin, sugge st-
ing a prostaglandin-se nsitive pathway was re late d to
the hype rglyce mia-induce d tachygastria. Take n to-
gether, the se studie s indicate that acute hype rglyce -
mia in healthy subje cts can e voke tachygastrias and
suppre ss antral contractions, all of which may le ad to
de crease d gastric e mptying.
In diabe tic patie nts, e xpe rime ntally induce d hype r-
glyce mia re sulte d in a prolonge d lag phase of gastric
e mptying afte r a standard meal (35) . In the hype rgly-
cemic setting, the amount of time re quire d for 50% of
the solid meal to be e mptied was also signi® cantly
prolonge d (35) . A re cent study by Schvarcz et al
showe d that e ven whe n glucose le vels incre ase from
low normal to the uppe r limits of the normal range of
glyce mia, an effe ct on gastric emptying can be mea-
sure d in both he althy subje cts and patie nts with type
1 diabe tes mellitus (36) . The se studie s showe d that
re lative ly subtle incre ase s in plasma glucose delay the
rate of gastric emptying. The mechanism of the delay
in gastric e mptying was not de te rmine d, but it is
possible that gastric emptying was slowed by the gly-
cemic e ffe ct on gastric myoe lectrical rhythm and on
the amplitude of antral contractions.
In summary, the mechanisms whe re by diabe tic gas-
tropathy de velops is a multifactorial and comple x
issue, much like the progre ssive neuropathy, re tinop-
athy, and ne phropathy conditions that are well appre -
ciate d. In terms of the diabe tic stomach, there are no
data re garding the timeline for the de velopme nt and
progre ssion of the various pathophysiologic ® ndings
de scribe d above (Figure 7). Do multiple acute e pi-
sode s of hype rglyce mia that cause acute gastric dys-
rhythmias and antral hypomotility le ad to chronic and
pe rsistent gastric dysrhythmias and antral hypomotil-
ity? Much more inve stigation is nee ded to clarify the
natural history of the de velopme nt of diabe tic gas-
tropathy.
CLINICAL PRESENTATION
Patie nts with insulin-de pe nde nt diabe te s mellitus
commonly have uppe r gastrointe stinal symptoms. Al-
most 30% of diabe tes patie nts reporte d nause a and
vomiting (1). Typical uppe r gastrointe stinal symp-
toms are e arly satie ty, nause a and vomiting, abdomi-
nal discomfort, and postprandial fullne ss and bloating
Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)
(1, 37) . Be zoar formation may occur in patie nts with
se vere diabe tic gastropare sis and e xacerbate post-
prandial fullne ss and discomfort. Symptoms liste d
above are increased after the inge stion of meals,
particularly by solid foods. The symptomatic patie nt
may or may not have manife stations of periphe ral and
autonomic neuropathy, ne phropathy, and re tinopa-
thy; howe ve r, the se othe r complications of long-
standing diabe te s are not consiste ntly found e ven in
patie nts with frank gastropare sis (1, 4, 10, 38, 39) .
Some diabe tic patie nts with de laye d gastric e mpty-
ing may be asymptomatic (4, 19, 38) . This should not
be surprising, since more than 90% of ische mic ST-
se gme nt change s re corde d on Holte r monitor in pa-
tie nts with type 1 diabe tes were not associate d with
re ports of chest discomfort or pain (40) . Furthe r-
more , patie nts with meal-re late d symptom s may ob-
tain temporary re lief by making subtle change s in
their diet.
The only clue that gastric ne uromuscular dysfunc-
tion is prese nt may be poor glyce mic control (4, 41) .
Delaye d gastric emptying in diabe tic patie nts may
also account for episode s of hypoglyce mia, which
occur as a result of the dyssynchrony of insulin ad-
ministration and e mptying of nutrie nts from the
stomach to the small inte stine (41) . Infe ction and
othe r cause s of hype rglyce mia also must be consid-
e re d.
DIFFERENTIAL DIAGNOSIS OF DIABETIC
GASTROPATHY
The symptom s associate d with diabe tic gastropathy
are nonspe ci® c dyspe psia-type symptoms: e arly sati-
e ty, abdom inal discom fort, nause a, bloating, and
postprandial fullne ss (1, 2, 4, 5, 41, 42) . The se symp-
toms may be cause d by mechanical obstruction of the
gastrointe stinal tract, pe ptic ulce r disease, gastro-
e sophage al re ¯ ux dise ase (GERD), chronic chole cys-
titis or pancre atitis, or metabolic abnorm alitie s such
as ure mia, hype rcalcemia, hypokale mia, hypocortisol-
e mia, or hypothyroidism (9, 11, 43) .
Seve ral medications can also slow gastric e mptying
(Table 1) (9, 11, 41, 42) and contribute to gastropa-
re sis. Eating disorde rs such as anore xia ne rvosa occur
in adole scents, including adole scents with diabe te s
mellitus (44) , and the se patie nts may prese nt with the
nonspe ci® c dyspe psia-like symptoms of diabe tic gas-
tropathy.
1067
 KOCH

Fig 6. Hype rglyce mia induces gastric dysrhythmias in healthy subjects. A: Normal 3-cpm gastric
ele ctrical rhythm in the EGG tracing and 3-cpm pe aks be fore and after the me al in the running
spectral analysis of the EGG signal. B: The e ffect of hyperglycemi a (230 mg/dl) on gastric
myoe lectrical activity. The EGG tracing shows a tachygastria at 5± 6 cpm and loss of the 3-cpm
activity during hype rglyce mia. The spectral analysis shows many pe aks in the tachygastria
ranging from 3.6 to 9 cpm. Re printed with pe rmission from WL Hasle r e t al (33).

1068 Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)
DIABETIC GASTROPATHY

EVALUATION OF PATIENTS SUSPECTED OF

HAVING DIABETIC GASTROPATHY

General Evalu ation

Fig 7. Elemen ts of diabetic gastropathy are shown. Individual
patie nts may have one , se veral, or all of these gastric neuromuscu-
lar abnormalities. The temporal de velopme nt of these neuromus-
cular abnormalitie s in individual patie nts is unknown. From a
neuromuscular vie wpoint, gastropare sis indicates end-stage dis-
e ase .
Evaluation of patie nts with diabe te s mellitus and
the symptoms de scribed above or with poor glyce mic
control should include a de taile d history and physical
e xamination. Insulin dosing, blood glucose patte rns,
and die t should be re vie wed and adjuste d as neces-
sary. Basic diagnostic te sts include routine laboratory
te sts (blood counts and chemistries), e ndoscopy or
uppe r gastrointe stinal series to exclude structural or
mucosal abnorm alitie s of the e sophagus, stomach,
and duode num, and an ultrasound of the gallbladde r
and pancre as to e xclude diseases of the se organs that
may also produce postprandial symptoms. If no ab-
normalitie s are found and symptoms and/or blood
glucose le vels remain dif® cult to control, then te sts of
gastric ne uromuscular function should be conside red.

Evalu ation of Gastric Neu rom uscular

Abn orm alities in Patien ts with Diab etic
Gastrop ath y
T ABLE 1. M EDICATIONS THAT CAN SLOW G ASTRIC E MPTYING
Diagnostic te sts that measure gastric myoelectrical
Anticholinergic agents activity and gastric emptying are indicate d whe n the
Antidepressants
re sults of standard diagnostic te sts are negative and
b -Adre nergic agonists
Calcium channel blocke rs symptoms pe rsist. The re are a numbe r of methods
Ganglion-blocking age nts available for asse ssing gastric myoe lectrical and con-
Le vodopa
Nicotine
tractile eve nts (Table 2). Some te sts are invasive and
Octre otide are used primarily for rese arch studie s; othe rs are
Opiates noninvasive and available for clinical use.
Tranquilizers
V incristine
Curre ntly, gastric motility is ge nerally asse ssed us-
ing gastric scintigraphy, a noninvasive means of mea-

T ABLE 2. M ETHODS FOR E VALUATING G ASTRIC M YOELECTRICAL

AND C ONTRACTILE E VENTS

Test Measures Advantages Disadvantages

Noninvasive ; solid- and liquid-phase

Gastric scintigraphy
Ele ctrogastrography
Ultrasonography
Magne tic re sonance imaging
13
Bre ath tests C emptying
Antroduodenal manome try
Rate of stomach studies; asse sse s global stomach Wide normal range; radiation
emptying ne uromuscular activity e xposure; take s 2± 4 hr
Gastric myoe lectrical Movement artifact; dif® cult to
activity Noninvasive ; e asily repe ate d interpret
Require s expe rtise in imaging
and interpretation; more
Rate of e mptying; accurate for liquid than
antral diamete r Noninvasive solid emptying
Rate of e mptying Noninvasive Time-consuming; e xpensive
Require s normal intestinal
Indirect measure of absorption, liver
Noninvasive metabolism, lung function
Invasive; radiation exposure ;
time-consuming ( . 4 hr);
Asse sse s stressful for patient;
lume n-occluding Distinguishes fasting and re cordings dif® cult to
contractions postprandial contraction patte rns interpret

Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999) 1069

suring the rate of gastric emptying. The se tests re -
quire inge stion of a meal (usually scramble d e ggs or
ste w) labe le d with radionuclide s (9, 39) . The te st is
pe rforme d in the morning after an overnight fast.
Agents that can accelerate or delay gastric e mptying
must be discontinue d 48 ± 72 hr be fore the proce dure .
Diabe tic patie nts are instructe d to take one half of
their normal morning insulin dose to avoid hype rgly-
cemia, which can de lay gastric emptying. Although
both solid- and liquid-phase studie s can be obtaine d,
solid-phase studie s are more sensitive for docume nt-
ing gastropare sis (9). Gastric e mptying is reporte d as
the pe rcentage of the meal e mptied (or re taine d)
afte r a spe ci® c pe riod of time (usually 2 hr) or the
time to emptying 50% of the meal (9, 39) . The normal
range of solid-phase gastric e mptying is quite vari-
able , and re sults can be affe cted to some de gre e by
physiologic factors such as age , obesity, and men-
strual cycle (9, 45) . Emptying may be normal in pa-
tie nts with uppe r gastrointe stinal symptom s, sugge st-
ing othe r more subtle abnormalitie s, such as gastric
dysrhythm ias, may be pre sent (Figure 3).
Breath tests to measure gastric emptying are be ing
de velope d. 13 C-labe led foods are inge ste d and the 13 C
e xhale d in bre ath is de termined (46) . For the 13 C to
be pre sent in the bre ath, it must be e mptied from the
stomach, absorbe d from the inte stine, metabolize d by
the live r, se crete d into the blood, and ® nally e xpire d
from the lungs for measure ment. The rate of e mpty-
ing of the food from the stomach is the n e stimate d
from the 13 C value s in the e xpire d breath.
E le ctrogastrography (E GG) noninvasive ly me a-
sure s fasting and postprandial gastric myoelectrical
activity (24, 25) . EGG records gastric myoele ctric
activity via electrode s place d on the skin in the e pi-
gastrium. EGG accurate ly re¯ e cts the normal 3 cpm
e le ctrical rhythm and abnorm al gastric dysrhythm ias
te rmed tachygastrias (3.6 ± 9.9 cpm) and bradygastrias
(1.0 ± 2.4 cpm) (24, 25) . Care must be take n to kee p
the patie nt still, since artifacts in the EGG signal may
be create d by patie nt movement (25) .
Ultrasonograph y is a noninvasive tool for evaluat-
ing gastric wall motion and gastric e mptying of liq-
uids, but conside rable e xpe rtise in stomach imaging
and inte rpretation is re quire d (45, 47) . The e mptying
of liquids from the stomach can be measure d with this
te chnique . Magne tic resonance imaging can accu-
rately measure gastric e mptying rates but is expe n-
sive , time -consum ing, and facilitie s are limite d
(45, 48) .
Antroduode nal manome try involve s the position-
ing of a cathe te r in the antrum and duode num with
1070
KOCH
T ABLE 3. G ASTRIC NEUROMUSCULAR T EST R ESULTS AND
A SSOCIATED SYMPTOM ( S)
Test Resu lt Associated sym ptom (s)
Early satiety,
abdominal
Gastric scintigraphy De laye d emptying discomfort, fullness,
(solid-phase) (gastropare sis) vomiting
Abdominal
Rapid e mptying discomfort, nausea,
(dumping) distention, diarrhea
Tachygastria,
E lectrogastrography bradygastria Nause a
Ultrasonography Antral dilation Bloating
¯ uoroscopic guidance for intraluminal pre ssure mea-
sure ments during fasting and postprandial pe riods
(45) . Small intestinal manome try can detect patte rns
re ¯ ecting disorde rs of neuropathic versus myopathic
origin (45) . Antroduode nal and inte stinal motility
te sts are invasive , re quire ¯ uoroscopy, are stre ssful
for patie nts, and recordings can be dif® cult to inte r-
pre t (45, 49) . Table 3 lists motility te st results and
symptoms associate d with abnorm al te st results.
Diabetic Gastrop ath iesÐ A Practical Approach to
Diagn osis
A practical approach to diagnosing diabe tic gas-
tropathie s in patie nts with dyspe psia-type symptoms
is to start with the noninvasive gastric motility tests
and use invasive tests if furthe r information is de sire d
or ne cessary. The solid-phase gastric e mptying test
and the EGG will reve al abnormalitie s in overall
e mptying (a global re ¯ ection of gastric contractile
function) and gastric myoelectrical abnorm alitie s, re -
spe ctively (50) . If furthe r insights into gastroduode nal
function are nee ded, then ultrasound of the stomach,
antroduode nal manom etry, or barostat studie s can be
obtaine d.
TREATMENT OF DIABETIC GASTROPATHY
The tre atment of diabe tic gastropathie s include s
sustaine d attention to glyce mic control, dietary mod-
i® cations, and appropriate use of pharm ace utical
age nts. The goal of treatment is reduction in the
uppe r gastrointe stinal symptoms of nause a, vomiting,
bloating, and e arly satie ty or fullne ss; and improve -
ment in glyce mic control. In the most seve re case s of
diabe tic gastropare sis, a gastrostomy may be indi-
cated to vent the stomach to preve nt recurre nt vom-
iting, and a je junostomy may be ne ede d for e nte ral
fe eding if weight loss has occurred due to failure of
the various tre atment modalitie s (39, 42) .
Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)
DIABETIC GASTROPATHY
T ABLE 4. NAUSEA
Diet
Step 1: Gatorade and bouillon
For se vere nause a and vomiting:
c Small volumes of liquids such as Gatorade
and bouillon (ie, salty, with some caloric
content) to avoid dehydration
c Multiple vitamin
Step 2: Soups
If Gatorade or bouillon tolerated:
c Soup with noodles or rice and crackers
c Peanut butter, che ese , and crackers in small
amounts
c Carame ls or other che wy confe ctions
c Ingest above foods in at least 6 small-volume
meals/day
c Multiple vitamin
Step 3: Starche s, chicken, ® sh
c Noodles, pastas, potatoes (mashed or
bake d), rice , baked chicken breast, ® sh (all
easily mixed and e mptied by the stomach)
c Ingest solids in at least 6 small-volume
meals/day
c Multiple vitamin
* Modi® e d from Koch (11) .
Dietary Mod i® cation s
Patie nts with symptom s of diabe tic gastropathy
may not tole rate standard American Diabe tes Asso-
ciation diets. For e xample , patie nts with gastropare sis
should have a diet that is low in ® be r and dige stible
roughage , because these foods may be retaine d in the
stomach and result in bezoar formation. A low-fat
diet ( , 40 g/day) also is advise d since lipids slow
gastric e mptying rate s (9, 41) . Patie nts should also be
e ncourage d to e at small meals four to six time s daily
rathe r than consume thre e re gular meals per day. The
ne uromuscular work of gastric e mptying is reduce d
with the smalle r individual meals, and some de crease
in symptoms may also be e xpe rienced by the patie nt
(11, 17) . With the six smalle r meals there may also be
a slow but ste adie r rate of delive ry of nutrie nts into
the small bowe l for absorption.
A thre e-step nause a and vomiting diet has helpe d
patie nts with idiopathic gastropare sis and idiopathic
nause a (Table 4) (11) . This die t may be tried in the
diabe tic patie nt with uppe r gastrointe stinal symptoms
with or without frank gastropare sis. Total pare nte ral
nutrition is rarely necessary, but some patie nts may
re quire a je junal fe e ding tube for enteral nutrition if
Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)
AND V OMITING (G ASTROPARESIS ) D IET*
G oal Avoid
1000± 1500 cc/day in multiple servings (e g, Citrus drinks of all kinds; highly
12 4-oz servings over 12± 14 hr) swe ete ned drinks
Patie nt can sip 1± 2 oz at a time to re ach
approximately 4 oz/hr
Approximate ly 1500 calories/day to avoid Cre amy, milk-base d liquids
de hydration and maintain weight (often
more realistic than weight gain)
Common foods that patie nt ® nds Fatty foods that delay gastric
interesting and satisfying and that evoke e mptying; red meats and
minimal nausea/vomiti ng symptoms fresh ve ge tables that re quire
conside rable trituration;
pulpy ® brous foods that
promote formation of be zoars
gastropare sis and nause a and vomiting are seve re and
re sult in une xceptable weight loss. A ve nting gastros-
tomy may also be ne ede d if uncontrolle d vomiting is
a proble m.
As de scribed above , studie s in diabe tic patie nts
showe d that increase d blood glucose le ve ls are asso-
ciate d with prolongation of the lag phase of gastric
e mptying (35, 36) . Even if glucose le vels are incre ase d
from low normal to the uppe r limits of normal range s,
this change in plasma glucose le ve l slows the rate of
gastric e mptying (36) . The se studie s sugge st anothe r
re ason to work dilige ntly for good glucose control,
since acute or chronic hype rglyce mia alone has ad-
ve rse e ffe cts on gastric e mptying activity.
Drug Therap y
Diabe tic patie nts with or without gastropare sis may
de ve lop the dyspe psia-like symptom s de scribe d
above . Some of the patie nts with normal gastric e mp-
tying may have gastric dysrhythmias, alte re d fundic
re laxation, or othe r subtle ne uromuscular mecha-
nisms that cause nause a and othe r symptoms. Gastro-
kine tic drugs use d to tre at diabe tic gastropathy are
metoclopramide , cisapride , erythromycin, and dom-
1071

T ABLE 5. G ASTROKINETIC A GENTS U SED TO T REAT SYMPTOMS A SSOCIATED
Drug Mechanism s of action
Me toclopramide Dopamine (D 2 ) re ce ptor antagonist,
5-HT 3-rece ptor antagonist
(ce ntral and pe ripheral)
Domperidone D 2 -receptor antagonist (peripheral)
Cisapride 5-HT 4 -receptor agonist (? )
Erythromycin Motilin agonist
pe ridone . The se age nts differ with re spect to mecha-
nism of action, ef® cacy, and side-e ffe ct pro® le (Table
5).
Metoclop ram id e. Me toclopramide has be en in use
as a gastrokine tic drug for many ye ars, but the rapy
with this age nt is limited by CNS side effe cts, which
include extrapyramidal symptoms (11, 51) . Metoclo-
pramide is a central and pe riphe ral dopamine (D 2 )
re ceptor antagonist, a 5-HT 4 agonist, a 5-HT 3 antag-
onist, and choline sterase inhibitor (41, 42, 51) . Met-
oclopramide improve s gastric emptying by de creasing
re ceptive relaxation in the uppe r stomach and in-
creasing antral contractions (39) . Me toclopramide
also acts on dopamine receptors in the are a postre ma
to produce an antie metic e ffe ct, which may be as
important as the drug’ s e ffects on the stomach in
re lieving the symptoms of gastropathy.
Dom p er id on e. Dom pe ridone , like me toclopra-
mide, also antagonize s the periphe ral D 2 re ceptor in
the stomach, but dompe ridone doe s not readily pe n-
e trate the blood± brain barrie r. There fore , dompe ri-
done is a periphe ral D2 -receptor antagonist with a
low incide nce of the CNS side e ffe cts that limit the
use of metoclopramide (52) . Howe ver, dompe ridone
e nte rs the pituitary and prolactin is rele ased, resulting
in prolactin- re late d symptoms. Dompe ridone im-
prove s gastrointe stinal motility by inhibiting fundic
re ceptive re laxation and e nhancing antral contrac-
tions (52) . Domperidone re ache s the area postre ma
whe re its antie metic action is produce d.
The ability of dompe ridone to improve symptom s
attribute d to delaye d e mptying in diabe tic patie nts is
well docum ented (5, 52, 53) . In a re cent multice nter,
double -blind, place bo-controlle d trial, 77% of dia-
betic patie nts with symptom s of gastropathy e xpe ri-
e nce d signi® cant re ductions in symptom se ve rity fol-
lowing tre atme nt with dompe ridone (54) . More over,
symptoms were alle viate d re gardle ss of the patie nt’ s
gastric emptying status. There fore , re duction in symp-
toms is not solely due to drug effects on the rate of
gastric e mptying. Domperidone also affe cts gastric
1072
KOCH
WITH D IABETIC G ASTROPATHIES
Oral dosage Side effects
5± 20 mg before me als Extrapyramidal symptoms, dystonic
and at be dtime reactions, anxie ty, drowsiness,
hype rprolactinemia
10± 20 mg before meals Hyperprolactinemia
and at be dtime
5± 20 mg before me als Diarrhea, abdominal discomfort
125± 250 mg four times Nausea, diarrhea, abdominal
daily cramps, rash
myoe lectrical activity by eradicating gastric dysrhyth-
mias and reducing symptom s in patie nts with diabe tic
gastropare sis while mode stly improving the rate of
stomach e mptying (5).
In a multice nte r, double -blind comparison of dom-
pe ridone an d me toclopr am ide , the drugs were
e qually e ffective in relie ving symptoms of nause a,
vomiting, e arly satie ty, and bloating/diste nsion in 93
patie nts with insulin-re quiring diabe te s, but side-
e ffect pro® le s were signi® cantly differe nt (55) . The
se verity in e licite d CNS side effects, including somno-
lence and reduce d mental acuity, was gre ater during
me toclopram ide tre atme nt. O pe n-labe l, long-te rm
use of dompe ridone continue d to control symptom s
of diabe tic gastropathy (56) .
Cisap rid e. Cisapride improve s gastric e mptying
through the re le ase of acetylcholine in the mye nte ric
plexus neurons of the stomach via 5-HT 4 re ceptors
(57) . Cisapride doe s not pass the blood± brain barrie r
and is thus fre e of CNS or prolactin-re late d side
e ffects. Cisapride stimulate s antral contractions and
improve s the emptying of both solids and liquids (58,
59) . In the United State s, cisapride is approve d for
the tre atme nt of nocturnal he artburn, but this thera-
pe utic bene ® t is achie ve d by improving lower e soph-
age al sphincte r pre ssure and e nhancing gastric e mp-
tying. Thus, a the rape utic trial of cisapride (5± 20 mg
four times a day) is a reasonable option for the
patie nt with symptomatic diabe tic gastropathy.
Eryth rom ycin . Erythromycin binds to the motilin
re ceptor in the stomach, resulting in strong contrac-
tions of the antrum. Compare d with place bo, intrave -
nous e rythrom ycin signi® cantly improve d the gastric
e mptying rate s of solids and liquids in insulin-
re quiring diabe tes patie nts with seve re gastropare sis
(60, 61) . Long-te rm oral e rythromycin also improve d
gastric e mptying and re duce d symptoms, but dose -
de pende nt cramps and abdominal pain were common
(61) . Many patie nts are unable to tole rate erythromy-
cin due to the se side e ffects. New motilin-re ceptor
agonists are base d on the macrolide (lactone -ring)
Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)
DIABETIC GASTROPATHY
structure . Other macrolide molecules are in de ve lop-
ment and will be available in the future to treat
diabe tic gastropare sis.
O the r age nts with possible gastrokine tic e ffe cts are
unde r inve stigation. These include 5-HT 4-re ceptor
agonists, chole cystokinin antagonists, and opiate re -
ceptor age nts.
Non dru g Treatm en ts
Nondrug tre atme nt of nause a and vomiting re late d
to gastropare sis or diabe tic gastropare sis include s
acustimulatio n at P6, a traditional Chine se acupunc-
ture point (62) , and gastric e le ctrical stimulation us-
ing cardiac pacemaker te chnology (63) . Acustimula-
tion at P6 re duces nause a re late d to the ® rst trime ste r
of pregnancy (64) , postope rative nause a and vomiting
( 65) , and cance r che mothe rapy tre atme nts ( 66) .
Acustimulation treatment reduce d idiopathic nause a
approximate ly 40% in patie nts whose symptoms were
re fractory to drug the rapy (62) . The mechanism of
action of acustimulation at P6 is unknown and furthe r
studie s are ne ede d.
For patie nts with drug-re fractory gastropare sis who
have also lost weight and re quire nutritional support,
gastric e le ctrical stimulation may have a role in the
future . Pre liminary studie s have shown that elec-
trode s positione d on the gastric corpus and stimu-
late d at nove l param eters re duce the incide nce of
vomiting and nause a episode s (63) . O ngoing studie s
will clarify the patie nts for whom this is most suited as
well as the e f® cacy of long-te rm gastric electrical
stimulation.
CONCLUSIONS
Diabe tic gastropathie s e ncompass a spectrum of
gastric neuromuscular dysfunctions, from gastric dys-
rhythmias to gastropare sis (Figure 7). The uppe r gas-
trointe stinal symptoms describe d above that are as-
sociate d with gastric neuromuscular dysfunction are
common in patie nts with diabe te s mellitus. Some
diabe tic patie nts have gastropare sis, but the symp-
toms of nause a and vomiting, abdominal discomfort,
postprandial fullne ss and bloating, and e arly satie ty
do not always corre late with the pre sence of gastro-
pare sis. O the r gastric neurom uscular dysfunctions
such as dysrhythmias or alte re d fundic or antral tone
may be more re le vant to symptoms.
Symptoms can be tre ate d with die tary modi® ca-
tions, attention to glyce mia and insulin dosing, and
gastrokine tic the rapie s with metoclopramide , cisa-
pride , and e rythrom ycin. A fourth gastrokine tic
Digestive Diseases and Sciences, Vol. 44, No. 6 (June 1999)
drugÐ dompe ridone Ð is unde r re vie w and should be
available in the ne ar future . Furthe r studie s are
ne ede d to asse ss the utility of acustimulatio n and
gastric e le ctrical stimulation in diabe tic gastropathie s.
In addition, drug combinations should be studie d in
more detail be fore recommendations can be made;
the combination of cisapride and e rythromycin must
be avoide d. As the pathophysiology of the diabe tic
gastropathie s are be tte r unde rstood, more speci® c
and e ffective the rapie s can be deve lope d.
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