Gastroparesis in Type 2 Diabetes
Mellitus: Prevalence, Etiology,
Diagnosis, and Treatment
Nicolas Intagliata, BA, and Kenneth L. Koch, MD
Corresponding author
Kenneth L. Koch, MD
Section on Gastroenterology, Wake Forest University Medical
Center, Nutrition Building, E-115, Medical Center Boulevard,
Winston-Salem, NC 27157, USA.
E-mail: kkoch@wfubmc.edu
Current Gastroenterology Reports 2007, 9:270–279
Current Medicine Group LLC ISSN 1522-8037
Copyright © 2007 by Current Medicine Group LLC
The worldwide epidemic of type 2 diabetes mellitus
(T2DM) is a substantial economic and social burden.
Although gastroparesis associated with type 1 dia-
betes mellitus (T1DM) has been recognized for years,
only recently have studies shown that patients with
T2DM also have high rates of gastroparesis. Individu-
als with T2DM constitute 90% to 95% of the diabetic
population. Unique characteristics that distinguish
this population are obesity, insulin resistance, and
associated comorbidities. These features highlight the
importance of investigating gastric emptying in individ-
uals with T2DM and upper gastrointestinal symptoms.
The purpose of this review is to examine the literature
pertaining to diabetes and the effect of diabetes on gas-
tric neuromuscular function, with a focus on T2DM. An
understanding of gastric motility in T2DM is important
to diagnose gastroparesis, to treat upper gastrointestinal
symptoms, and to restore normal gastric motility, which
may lead, in turn, to improved glucose control.
Introduction
The World Health Organization currently estimates that
180 million people have diabetes and 90% of these people
have type 2 diabetes mellitus (T2DM) [1]. In the United
States alone, T2DM affects nearly 20 million individu-
als, and one third of them are believed to be undiagnosed
[2]. The estimated direct and indirect medical expense of
diabetes in the United States in 2002 was a staggering
$132 billion [2].
Although linked by similar metabolic derangements of
hyperglycemia, patients with T2DM are substantially dif-
ferent from patients with type 1 diabetes mellitus (T1DM)
(Table 1). Major risk factors for developing T2DM include
obesity, age, and physical inactivity [3]. In T2DM there is
relative insulin deficiency and resistance, compared with
the absolute insulin deficiency characteristic of T1DM.
The onset of hyperglycemia in T2DM is gradual, with a
risk for developing complications in early asymptomatic
stages [3]. Certain comorbidities, such as vascular disease,
dyslipidemia, and hypertension, are common in T2DM.
As disease progresses in uncontrolled and unrecognized
diabetes, most organs, including those in the gastrointes-
tinal (GI) tract, begin to show evidence of damage.
The relationship between diabetes and GI dysfunction
has been noted for over 50 years [4–6]. In 1958, Kassander
[5] coined the phrase “gastroparesis diabeticorum” to
describe the syndrome of gastric retention observed in
six asymptomatic patients with T1DM. Since then, most
of the research on diabetic gastroparesis has focused on
individuals with T1DM. The conventional patient with
gastroparesis was considered to have advanced T1DM
with poorly controlled hyperglycemia [7]. The impact of
patients with T2DM with upper GI symptoms and gastro-
paresis on health-care delivery and gastroenterology will
become even more important as the number of patients
with T2DM continues to grow.
Prevalence of Upper GI Symptoms in T2DM
The prevalence of upper GI dysmotility symptoms, such
as early satiety, nausea, bloating, epigastric fullness, and
abdominal pain, in patients with T2DM was unknown
until recently. Studies traditionally focused on T1DM
patients [8] or did not distinguish between the two groups
[7]. Current literature suggests that upper GI symptoms
are common in T2DM, but in light of conflicting evidence
[9,10], this notion remains controversial.
Several studies have shown that upper GI symptoms are
more likely to occur in patients with T2DM, compared with
nondiabetic subjects [11–15]. A population-based study of
423 patients with diabetes (95% with T2DM) revealed that
GI symptoms were significantly more common (odds ratio
[OR] of 1.75; 95% CI, 1.34–2.29) in diabetic patients than
 Gastroparesis in Type 2 Diabetes Mellitus Intagliata and Koch 271

Table I. Differences between T1DM and T2DM

Type 1 Type 2
Prevalence 5% to 10% 90% to 95%
Age at onset* Younger Older
Pathogenesis Genetic basis (weaker), immunologic, Genetic basis (stronger) and environmental:
environmental: autoimmune, insulin resistance to insulin, decreased insulin secretion,
deficiency, idiopathic increased hepatic glucose production
Natural history Acute, early onset Long asymptomatic period
Risk factors Primary relative, genetic markers, insulin Family history, obesity, physical inactivity,
autoantibodies, environmental factors ethnicity, hypertension, dyslipidemia
Critical complications Diabetic ketoacidosis (DKA) Hyperglycemic hyperosmolar state (HHS)
Treatment Insulin required Lifestyle changes, diet, oral agents, insulin
†
Rodent models NOD mouse, BB rat, LEFTL rat, Ob/Ob mouse, db/db mouse, Zucker rat, GK rat,
Chinese hamster, streptozocin induced KK mouse, NSY mouse, OLET rat, Israel sand rat,
NZO mouse, diabetic Torri rat, CBA/Ca mouse
*Exceptions apply.
†
Data on rodent models from Rees and Alcolado [72].
BB rat—biobreeding rat; db/db mouse—diabetic mouse; GK rat—Goto-Kakizaki rat; NOD mouse—nonobese diabetic mouse;
NSY mouse—Nagoya-Shibata-Yasuda mouse; NZO mouse—New Zealand obese mouse; Ob/Ob mouse—obese leptin-deficient mice
OLET rat—Otsuka Long-Evans Tokushima fatty rat; T1DM—type 1 diabetes mellitus; T2DM—type 2 diabetes mellitus.

in the general population [11]. “Poor” glycemic control
was associated with higher rates of upper GI dysmotility
symptoms (OR of 2.45; 95% CI, 1.50–3.98). In another
study, 70% of patients with T2DM had higher rates of
such GI symptoms as diarrhea, constipation, and epigas-
tric fullness, compared with control subjects [13]. Overall,
44.3% of these patients with T2DM reported such upper
GI symptoms as epigastric fullness and early satiety, com-
pared with 24.6% of control subjects. Duration of diabetes
was the only independent variable that correlated with
total GI symptom score; body mass index (BMI), age, fast-
ing plasma glucose, and HbA1c (a measure of long-term
control of blood glucose) did not correlate with GI symp-
toms [13]. Swedish investigators found that, in individuals
with T2DM and T1DM, the frequency of heartburn and
abdominal pain (the only two upper GI symptoms reported)
occurred more often in the T2DM cohort: 31.7% of
patients with T2DM complained of heartburn symptoms,
compared with only 14% of control subjects [14]. Also,
28.3% of patients with T2DM had abdominal pain more
than once a month compared with 14% of control subjects.
Enck et al. [12] evaluated German individuals with T2DM
and T1DM to determine the frequency of GI symptoms.
Nausea was significantly more frequent in the group with
T2DM (11.8%) when compared with the control popula-
tion (2.9%). Ricci et al. [15] evaluated the prevalence of
upper GI symptoms in individuals with T2DM and T1DM
in a US community. The prevalence of one or more upper
GI symptom in the past month was 50% in the diabetic
group versus 38% in control subjects. Significant differ-
ences were reported for the upper GI symptoms of bloating
(21% in diabetic group vs 15.2% in controls) and early
satiety (32.2% in diabetic group vs 20.2% in controls) [15].
The authors did not distinguish between the types of dia-
betes, but approximately 75% of patients were diagnosed
with diabetes after the age of 40 years, with a median age
of onset of diabetes between 50 and 59 years, indicating
that most patients likely had T2DM.
Other studies, however, did not find a significant dif-
ference in GI symptoms between control subjects and
those with T2DM [9,10]. Janatuinen et al. [10] compared
upper GI symptoms in individuals with T2DM and
healthy subjects in Finland. Upper GI symptoms were
common in the population as a whole, but the frequency
was not significantly higher in patients with T2DM. For
example, 17% of patients with T2DM and 11% of control
subjects complained of nausea more than once a week. In
a community in Minnesota, the prevalence of upper GI
symptoms was similar in the T2DM cohort compared
with controls [9], leading the authors to conclude that
physicians should not assume that GI complaints always
represent a complication of diabetes as such. That is,
quite separate from diabetes, a variety of diseases have
the potential to produce upper GI symptoms in patients
with T2DM. It is imperative that clinicians consider com-
mon diseases (eg, cholecystitis, peptic ulcer disease, and
GERD) before attributing symptoms to the effects of dia-
betes on gastric neuromuscular dysfunction.
Prevalence of Delayed Gastric Emptying
in T2DM
The prevalence of delayed gastric emptying in T2DM
ranges from 30% to 50% [16–21] to as high as 70% in
one study of symptomatic patients [20]. However, these
studies are limited by small sample sizes, presence of
hyperglycemia during testing, and the variety of test meals
and stomach imaging methods used (Table 2).
Table 2. Delayed gastric emptying in patients with T2DM
272

T2DM Delayed
Study/year patients, n Method Meal type Result emptying, % Comments
Leatherdale et al. 10 Scintigraphy Porridge (400 mL) Rapid early ? Age range 41–75 y; 84% to
[16]/1982 phase emptying, 125% IBW; duration of DM,
prolonged 9.5 y
late phase
Sasaki et al. 10 Water dye dilution Water load (?) Delayed gastric ? Mean age 35.7 ± 2.6 y; mean
[17]/1983 technique emptying BMI 41.5 ± 3.75; duration of
DM, 2.8 y
Horowitz et al. 20 Scintigraphy, liquid/solid Ground beef (100 g); 10% dextrose Delayed gastric 30% solid, Mean age 60 y; mean BMI 27.8;
[18]/1989 phase (double isotope) water (150 mL) emptying 25% liquid duration of DM 8 y
Chang et al. 70* Scintigraphy, liquid/solid 2 fried eggs, 2 slices toast, 312 kcal Delayed gastric 58.6% solid, Mean age 68.6 y; mean BMI ?;
[19]/1996 phase (separate tests) (28% protein, 15% lipids, 57% carb), emptying 25.7% liquid duration of DM 9.8 y
5% glucose water (500 mL, 100 kcal)
Tung et al. 20* Scintigraphy, liquid/solid 2 fried eggs, 2 slices toast, 5% glucose Delayed gastric 70% solid, Mean age 67 y; mean BMI ?;
[20]/1997 phase (separate tests) water (500 mL), 412 kcal indigestible emptying 35% liquid, duration of DM 9.8 y
radiopaque marks; liquid phase: 70% indigestible
500 mL 5% glucose water
Annese et al. 25 Scintigraphy Chicken liver (20 g), beef (80 g), Delayed gastric 56% solid Age range 42–66 y;
[21]/1999 potatoes (100 g), white bread (10 g), emptying mean BMI ?; duration of
cream caramel (150 g), corn oil (10 g), DM ? (years)
Neuromuscular Disorders of the Gastrointestinal Tract

water (200 mL); 700 kcal total

Moldovan et al. 23 Ultrasound 25 g bread, 10 g butter, 1 boiled egg, Delayed gastric 52% mixed meal Mean age 59.9 ± 7.6 y;
[22]/2005 and 300 mL tea (400 kcal) emptying mean BMI ?; duration of
DM ? (years)
*Patients selected for upper gastrointestinal symptoms.
BMI—body mass index; DM—diabetes mellitus; IBW—ideal body weight; T2DM—type 2 diabetes mellitus; y—years.
 Gastroparesis in Type 2 Diabetes Mellitus Intagliata and Koch
In a study of gastric emptying reported in 1982,
patients with T2DM had significantly delayed reported
gastric emptying of a porridge meal [16]. Sasaki et al.
[17] examined a group of obese Pima Native Americans
with T2DM and found that gastric emptying of a water
load was significantly slower in the T2DM group when
compared with the obese control subjects.
The prevalence of delayed gastric emptying in a ran-
domly selected group of 20 individuals with T2DM was
30% and comparable with that for patients with T1DM
[18]. The percentage of individuals with a solid test meal
remaining in the stomach at 100 minutes was significantly
greater in the T2DM group compared with control sub-
jects. The emptying time for the liquid component of the
meal was also significantly delayed. Annese et al. [21]
assessed gastric emptying rate in 25 patients with T2DM.
The patients had significantly slower half-emptying time
for the solid test meal (134.3 ± 35 min) compared with
control subjects (85.5 ± 15.4 min). Another study in
patients with T2DM (n=23) and T1DM (n=13) used ultra-
sound to assess gastric emptying: 52.2% of the group with
T2DM and 53.8% of the group with T1DM had delayed
gastric emptying [22].
The prevalence of delayed gastric emptying in patients
with T2DM specifically selected for presence of upper
GI symptoms has been studied. Tung et al. [20] assessed
gastric emptying rates of solid and liquid meals and indi-
gestible markers in 20 individuals with T2DM and upper
GI dysmotility symptoms. Seventy percent of patients
had delayed emptying of the solid meal and indigestible
markers, and 35% of patients had delayed emptying of
the liquid meal. Chang et al. [19] found that 41 out of 70
male subjects (59%) with T2DM and upper GI dysmotil-
ity symptoms had delayed emptying of solids.
A large community-based study is needed to better
define the actual prevalence of delayed gastric emptying
in asymptomatic and symptomatic patients with T2DM.
Hyperglycemia delays gastric emptying [23–26], and
future studies should examine gastric emptying under
euglycemic conditions. Gastric emptying tests should
also be performed using a standardized meal and scin-
tigraphic method for more reliable comparisons between
institutions [27].
Relationship Between Upper GI Symptoms
and Gastroparesis in Patients with T2DM
Upper GI symptoms occur with a higher frequency in peo-
ple with T2DM, but these symptoms are poorly correlated
with delayed gastric emptying [18,21,28,29]. For example,
in one study 43% of the patients with T2DM and delayed
gastric emptying were asymptomatic [21]. In patients with
long-standing T2DM, Iber et al. [29] showed no correlation
between upper GI symptoms and delayed gastric emptying.
Chang et al. [30] studied a group of patients with T2DM
who had upper GI symptoms suggestive of delayed gastric
273
emptying. Gastric dysrhythmias, gastric emptying, and
total symptom score improved after 8 weeks of treatment
with cisapride, a prokinetic agent. However, no correlation
was shown between use of this agent and electrogastro-
gram (EGG) changes, improvement of upper GI symptoms,
or gastric emptying. In another study, improvement in
upper GI symptoms was associated with restoration of a
normal 3-cycle-per-minute EGG rhythm but not with nor-
malization of gastric emptying rate in patients with T1DM
treated with domperidone [31].
If improvement of symptoms does not necessarily
correlate with normalization of gastric emptying, then it
is likely that other mechanisms may produce symptoms.
As Horowitz et al. [32] remarked, “…it is appropriate
to regard delay in gastric emptying more as a marker of
gastroduodenal motor abnormality, rather than a direct
cause of symptoms, the aetiology [sic] of which is likely
to be multifactorial.” Fundic dysfunction, gastric dys-
rhythmias, and pylorospasm are other mechanisms that
may account for symptoms and delayed gastric emptying.
Visceral hyperalgesia or hypersensitivity may cause upper
GI symptoms in some diabetic individuals who have neu-
ronal impairment in peripheral and/or central nervous
system [33]. Also, hyperglycemia may directly affect
nerve function and sensation. In a cross-sectional study
of 1101 diabetic patients (956 patients had T2DM), poor
glycemic control was an independent risk factor for upper
GI symptoms [34]. Some patients with T2DM may have
unrelated functional GI disorders common to the general
population that may explain upper GI symptoms [9].
In contrast, many patients with T1DM and T2DM
and gastroparesis do not have upper GI symptoms. Kas-
sander noted in 1958 that food retention occurred in
asymptomatic diabetics and that gastroparesis was under-
appreciated [5]. In an effort to assess the relationship
between lack of symptoms and gastroparesis, Rathmann
et al. [35] measured cerebral evoked potentials during
esophageal stimulation in T1DM patients with delayed
gastric emptying. Increased perception thresholds, as
assessed by cerebral evoked potentials, were found in
seven of 10 patients with diabetes and gastric neuromus-
cular dysfunction. These results suggest that afferent
sensory information may be processed differently in the
nervous circuitry of some diabetic individuals, possibly
due to afferent vagal nerve damage.
Pathogenesis of Gastroparesis in T2DM
Autonomic neuropathy
Early on it was hypothesized that vagal damage from
chronic hyperglycemia caused gastroparesis [4–6].
Studies have since relied upon heart rate variability or
orthostatic blood pressure as a proxy from which to infer
GI autonomic function. Determination of the relation-
ship between autonomic neuropathy and gastroparesis
is limited by at least two important factors: the indirect
274 Neuromuscular Disorders of the Gastrointestinal Tract
assessment of vagal activity in the GI tract and the con-
founding variables inherent in gastric emptying tests in
this population.
A study in patients with T2DM and T1DM showed
a higher prevalence of delayed emptying in patients with
cardiac autonomic neuropathy (CAN) [36]. In 34 indi-
viduals with T2DM, the gastric emptying rate was slower
in the group with CAN (n=16) compared to the group
without CAN (n=18) and the control subjects (n=18) [37].
Furthermore, a positive correlation was found between
degree of autonomic dysfunction and gastric emptying
rate for both solids and liquids. Sasaki et al. [17] mea-
sured plasma gastrin in patients with T2DM as a marker
of vagal neuropathy. Fasting plasma gastrin was signifi-
cantly higher in the group with T2DM compared with the
control group. Furthermore, the patients with T2DM had
delayed gastric emptying of water.
In contrast, other studies have not demonstrated a
significant relationship between autonomic neuropathy
and gastroparesis in patients with T2DM. Buysschaert et
al. [36] showed that there was no significant association
between presence of CAN and gastric emptying in a group
of 21 individuals with T1DM or T2DM. Horowitz et al.
[18] reported no significant relationship between delayed
gastric emptying and total score for CAN in a group
with T2DM. Investigators in another study concluded
that presence of CAN had a poor predictive value for GI
neuromuscular disorders [21]. Finally, in a postmortem
study, Yoshida et al. [38] examined the abdominal vagus
nerve and gastric wall in diabetic individuals and found
no morphologic abnormalities in the myenteric plexus of
the stomachs. In summary, results of the studies described
here indicate that gastroparesis often occurs in patients
with T2DM who have no evidence of autonomic nerve
dysfunction. These findings suggest that other mecha-
nisms must contribute to the pathogenesis of gastroparesis
in patients with T2DM.
Acute and chronic hyperglycemia
Hyperglycemia and gastroparesis are related [23,24].
Acutely elevated levels of blood glucose delay gastric
emptying in patients with T1DM and in healthy subjects
[25,26]. Also, gastric motility is abnormal in hyperglyce-
mic states induced in healthy volunteers [39,40]. Barnett
and Owyang [39] measured interdigestive gastric motility
with manometry during hyperglycemia induced in healthy
volunteers. They found that glucose levels greater than
140 mg/dL significantly diminished antral contractions
and inhibited migratory motor complex (MMC) activity.
Fraser et al. [40] showed that acute hyperglycemia caused
pyloric contractions and suppressed antral motility in
healthy individuals. Hyperglycemia has also been shown
to induce gastric dysrhythmias (tachygastria) in individu-
als with T1DM [41]. Results from these studies indicate
that acute hyperglycemia produces effects on gastric neu-
romuscular function in healthy volunteers and patients
with T1DM. These results must be taken into account in
evaluation of findings from previous studies that exam-
ined gastric emptying rates in patients with T2DM under
hyperglycemic conditions [16–21].
The effect of plasma glucose levels on gastric emptying
in T2DM has been studied infrequently. Horowitz et al.
[18] showed that the lag phase of solid emptying was sig-
nificantly longer among those individuals with T2DM and
higher mean plasma glucose levels. In addition, the gastric
half-emptying time for liquid was significantly correlated
with plasma glucose concentrations in T2DM (r=0.58,
P<0.01). HbA1c levels did not correlate with delayed gas-
tric emptying, suggesting that acute hyperglycemia may
be more important than chronic hyperglycemia for gas-
tric emptying. Moldovan et al. [22], however, found that
individuals with T2DM and delayed gastric emptying had
higher plasma glucose and HbA1c levels when compared
with diabetic patients with normal gastric emptying. In
another study, gastric emptying was measured before
and after glucose control in hospitalized individuals with
T2DM and T1DM [42••]. After the patients achieved
adequate glycemic control over the course of a month
(mean postprandial plasma glucose levels before and after
treatment were 283 mg/dL and 166 mg/dL, respectively),
their antral motility, gastric emptying, and upper GI
symptoms were significantly improved. In contrast, these
authors noted no change in gastric emptying after mean
plasma glucose was reduced during treatment for 1 week
in 10 patients with T2DM [43]. In this study, the mean
postprandial plasma glucose level decreased only from
15.4 mmol/L (277 mg/dL) to 11.7 mmol/L (210 mg/dL).
The pathogenesis of diabetic gastroparesis likely
involves a combination of factors. Vagal neuropathy,
hyperglycemia, and other unknown factors probably play
a role in the pathogenesis of gastroparesis.
Rapid Gastric Emptying in TD2M
Rapid gastric emptying exists in patients with T2DM
(Table 3) [44]. Phillips et al. [45] examined the rate of
gastric emptying of an oral glucose solution in recently
diagnosed individuals with T2DM and no evidence of
autonomic neuropathy. The T2DM group had significantly
faster gastric emptying rates compared with control sub-
jects. The average emptying rate was 3.3 kcal/min in the
diabetic group and 1.6 kcal/min in the control group. The
plasma glucose levels for the group with T2DM showed a
steeper rise initially and peaked later than the glucose curve
for the control group. In contrast, a study using a similar
liquid glucose meal showed that gastric emptying rates in
16 patients with recently diagnosed T2DM were slower
compared with rates in control subjects, but the difference
was too negligible to have clinical significance [28].
Schwartz et al. [46] evaluated solid gastric emptying
in a recently diagnosed group of patients with T2DM.
The average half-emptying time in the T2DM group was
Table 3. Rapid gastric emptying in patients with T2DM
T2DM
Study/year patients, n Method Meal type Result Comments
†
Phillips et al. 9* Scintigraphy, Liquid meal: glucose (50 g) in 450 mL water Rapid liquid phase Age range 32–62 y; mean BMI ?;
[45]/1992 liquid phase gastric emptying duration of DM <2 y
Frank et al. 10* Scintigraphy, liquid Solid meal: 446 kcal (16% protein, Rapid liquid phase Mean age 62 ± 1.3 y; mean BMI 28.7
[47]/1995 and solid phase 48% carbohydrate, 36% fat); liquid meal: emptying, no difference ± 1.8; duration of DM 4.2 ± 1.2 y
(double isotope) 200 mL sugar-free gelatin with 50 g dextrose in solid phase emptying
Schwartz et al. 8*† Scintigraphy, Solid meal: 4 pancakes (273 kcal); Rapid solid phase Mean age 45.1 ± 3.1 y; median BMI
[46]/1996 solid phase liquid solution with 300 mL water with gastric emptying 30.5 ± 1.1; duration of DM <2 y
9.7 g protein drink (42 kcal; 23% protein,
69% carbohydrate, 8% fat)
Jones et al. 16† Scintigraphy, Liquid meal: glucose (75 g) in 350 mL water No difference in Age range 39–79 y; median BMI
[28]/1996 liquid phase liquid phase 29; duration of DM 3–12 mo; 4/16
patients with autonomic neuropathy
Weytjens et al. 20 Scintigraphy, Liquid meal: 100 mL (100 kcal; 15% protein, Rapid liquid phase gastric Mean age 62 ± 2 y; Mean body
[49]/1998 liquid phase 30% lipid, 55% carbohydrate) emptying (70%) weight (kg) 78 ± 2; duration of
DM 13 ± 1 y; 2/20 patients with
autonomic neuropathy
Bertin et al. 13* Scintigraphy, liquid Mixed meal: beef (70 g), bread (40 g), Rapid solid phase gastric Mean age 47.4 ± 8.6 y;
[48]/2001 and solid phase butter (10 g), sugar (10 g), egg white (30 g), emptying, no difference mean BMI 33.9 ± 4.8; duration of
(double isotope) milk 200 mL, water 150 mL (total 440 kcal; in liquid phase emptying DM 6.5 ± 8.5 y
26% protein, 38% carbohydrate, 36% fat)
*Asymptomatic, no evidence of neuropathy.
†
Recently diagnosed T2DM.
BMI—body mass index; DM—diabetes mellitus; mo—months; T2DM—type 2 diabetes mellitus; y—years.
Gastroparesis in Type 2 Diabetes Mellitus Intagliata and Koch
275
276 Neuromuscular Disorders of the Gastrointestinal Tract
approximately 45 minutes, compared with 60 minutes in
the control group (P=0.05). The authors also reported a
steeper rise in plasma glucose and a delayed glucose peak
in the group with T2DM.
Two studies using the double isotope technique in
asymptomatic T2DM patients with no evidence of auto-
nomic neuropathy revealed rapid emptying with liquids
[47] and solids [48]. Frank et al. [47] discovered normal
rates of emptying of solids but significantly faster rates
of liquid emptying in T2DM patients. Bertin at al. [48]
assessed solid and liquid phase emptying in 13 obese
patients with T2DM. In direct contrast to the results from
Frank et al. [47], they found no difference between liquid
and solid-phase emptying but did find a significant differ-
ence in half-emptying time of the solid meal, and rapid
emptying was more common among the diabetic group.
Weytjens et al. [49] assessed gastric emptying in patients
with long-term T2DM (mean duration of diabetes,
13 years); 70% of the patients in the diabetic group had
accelerated gastric emptying of a liquid meal.
This seemingly paradoxical evidence for rapid empty-
ing in early T2DM is convoluted and often contradictory.
Some patients with T2DM have rapid, not delayed, gastric
emptying. However, the patients with rapid gastric empty-
ing generally had a shorter duration of T2DM (<2 years)
with no evidence of autonomic neuropathy. Rapid gastric
emptying may represent a risk factor for development of
hyperglycemia and poor glucose control [45]. Although
gastric emptying undoubtedly plays an important role in
determining postprandial plasma glucose concentrations,
other factors, such as intestinal absorption, insufficient
insulin response, or hepatic glucose production [47], may
also contribute to the early postprandial rise in glucose
seen in T2DM. As with studies reporting delayed empty-
ing, these studies are limited by the wide variety of meal
compositions used and absence of euglycemia during
testing. It is not clear if rapid gastric emptying progresses
to normal or delayed gastric emptying. Further study is
needed to promote better understanding of the natural
history of T2DM in the GI tract.
Diagnosis of T2DM and Gastroparesis
Diagnosis of gastroparesis
Because upper GI symptoms are typically poorly cor-
related with delayed gastric emptying, these symptoms
in a patient with T2DM warrant further investigation.
An upper endoscopy or an upper GI series should be
obtained in patients with upper GI symptoms to evaluate
the mucosa and exclude obstruction. In an asymptomatic
patient with T2DM and poorly controlled glucose, a gas-
tric emptying test should be performed. These patients
may have normal, rapid, or delayed gastric emptying
rates. The abnormal gastric emptying rate may result in
a marked mismatch with insulin or other antihypergly-
cemic therapy [32].
A variety of methods exist to measure the rate of
gastric emptying [50]. Gastric emptying scintigraphy is
the standard for diagnosis of gastroparesis. This method
can measure emptying of solids, liquids, or both simul-
taneously using radioisotope labeled foodstuffs. Plasma
glucose levels should be at least 200 mg/dL or lower, and
patients should discontinue use of prokinetic or narcotic
medication before testing. Gastric emptying is determined
by scintigraphic imaging of the gastric contents. Investi-
gators in a large multicenter study using egg substitute to
test gastric emptying in healthy volunteers concluded that
gastric retention of 10% or less at 4 hours was normal
[51]. Ultrasound has also been used to measure rate of gas-
tric emptying. Ultrasound has the advantage of real-time
imaging to assess dynamic changes in gastric dimensions,
antral contractility, and fundic accommodation. How-
ever, it requires user expertise and has a large amount of
interobserver variability [50]. A breath test has also been
developed to measure rate of gastric emptying [50]. A new
encapsulated recording device, called SmartPill (SmartPill
Corporation, Buffalo, NY), measures gastric pH and pres-
sure to determine gastric emptying rates and can be used in
the ambulatory setting [52]. EGG is a unique tool used for
assessment of gastric neuromuscular function. Cutaneous
electrodes placed on the epigastrium measure the myoelec-
trical activity of the stomach. Abnormal electrical activity,
such as bradygastria and tachygastria, are associated with
gastroparesis and symptoms of nausea [53].
Treatment of Gastroparesis in Patients
with T2DM
Once a patient is diagnosed with diabetic gastroparesis,
a multidisciplinary treatment plan should encompass
medical, nutritional, and lifestyle interventions to alle-
viate gastric symptoms and improve glucose control.
Given that hyperglycemia itself elicits gastric dys-
rhythmias and delays gastric emptying in patients with
T2DM, the central goal of treatment is to normalize
glucose levels [54].
Because the stomach regulates delivery of food and
oral antihyperglycemic medication to the small intestine
for absorption, it follows that abnormal gastric empty-
ing will affect postprandial blood glucose levels [55].
Knowledge of the gastric emptying rate is important
for practitioners prescribing short-acting oral hypogly-
cemic agents or insulin to patients with T2DM. In one
investigation, absorption of glipizide was reduced in a
dose-dependent manner as higher levels of blood glucose
were induced in healthy volunteers [56]. At the highest
plasma glucose levels, the concentration of glipizide in the
blood was reduced by up to 50%. In gastroparesis, a mis-
match may occur between doses of insulin or oral agents
and postprandial plasma glucose levels [55]. Increasing
levels of hyperglycemia can worsen gastroparesis. Abell
et al. [54] suggest that patients with gastroparesis and
 Gastroparesis in Type 2 Diabetes Mellitus Intagliata and Koch
uncontrolled blood glucose on oral therapy may benefit
from the addition of basal, long-acting insulin, such as
insulin glargine, to prevent wide fluctuations in postpran-
dial plasma glucose levels.
In patients with recently diagnosed T2DM, administra-
tion of an oral proteinase inhibitor [57] or cholecystokinin
[58] significantly reduces postprandial glucose levels by
delaying gastric emptying. This change would be espe-
cially important if the patient had rapid gastric emptying.
Gonlachanvit et al. [59] examined the effect of altering
gastric emptying of a solid and liquid meal in nine patients
with T2DM in a double-blind, randomized, placebo-con-
trolled trial using erythromycin, morphine, and normal
saline. Morphine treatment reduced gastric emptying and
reduced the peak glucose levels during the first hour after
the meal. In contrast, erythromycin increased gastric emp-
tying rate, postprandial glucose levels, and peak glucose
levels, compared with placebo. Other antihyperglycemic
treatments that may lower postprandial plasma glucose
by delaying gastric emptying include pramlintide [60],
an amylin analogue, and glucagon-like peptide-1-(7-36)
(GLP-1)-(7-36) [61]. Gentilcore et al. [62] examined the
effects of olive oil on gastric emptying and postprandial
metabolic response in six individuals with T2DM. Inges-
tion of olive oil before a meal significantly delayed gastric
emptying, decreased plasma insulin and glucose, and
increased levels of GLP-1. In mild to moderate T2DM,
postprandial hyperglycemia contributes to most of the
levels in the HbA1c profile [63]. Delay of the gastric emp-
tying rate is an innovative approach that may improve
control of hyperglycemia in some patients.
For patients with symptomatic diabetic gastroparesis,
treatment is centered on prokinetic and antinausea ther-
apy. Erythromycin, metoclopramide, domperidone, and
cisapride are among prokinetic agents practitioners use to
treat patients with gastroparesis [64]. Acute hyperglycemia
decreases the prokinetic effects of erythromycin [65]. This
finding underscores the importance of maintaining normal
glucose control in T2DM patients with gastroparesis.
Evidence that chronic treatment with prokinetic
agents directly improves glucose control in T2DM is
scant. Erythromycin accelerates gastric emptying and
also independently increases insulin levels in patients with
T2DM, possibly by stimulating pancreatic beta cells [66].
Mosapride, a prokinetic serotonin 5HT T4 receptor agonist,
markedly improved gastric emptying but only modestly
improved glycemic control in T2DM patients with upper
GI symptoms [67]. Studies in patients with T1DM and
delayed gastric emptying showed that acceleration of
gastric emptying with cisapride did not improve glucose
control [68,69].
Dietary recommendations for gastroparetic patients
include the three-step gastroparesis diet [70]. This diet
focuses on small meals containing foods that are easy to
digest (sports drink, soups, rice, chicken) and avoiding
high-fat foods and indigestible fiber.
277
A prospective study in patients with T1DM and severe
gastroparesis showed that gastric electrical stimulation
not only improved upper GI symptoms and gastric emp-
tying but also significantly lowered HbA1c levels [71].
The role of gastric electrical stimulation in patients with
T2DM and refractory gastroparesis remains undefined.
Conclusions
Individuals with T2DM and T1DM differ in many
important ways. As the epidemic of T2DM continues
to grow, an increasing number of patients will develop
gastric neuromuscular dysfunction. Past studies of gas-
troparesis have focused primarily on T1DM or have not
distinguished between the two types of diabetes. The
prevalence of upper GI symptoms and gastroparesis in the
T2DM population is significant and underappreciated.
Large population-based, longitudinal studies are needed
to further define the prevalence of gastroparesis and to
resolve remaining controversies. Furthermore, a thorough
understanding of the natural history and pathogenesis of
gastroparesis in T2DM may allow for the development of
therapeutic interventions that will more effectively treat
gastroparesis, upper GI symptoms, and diabetes.
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