Full text of DOI:10.1007/s00261-001-0058-z

Abdom Imaging 27:309–314 (2002)
DOI: 10.1007/s00261-001-0058-z
A
bdominal
maging
I
© Springer-Verlag New York Inc. 2002
Hyperglycemia attenuates erythromycin-induced acceleration of
solid-phase gastric emptying in healthy subjects
I. E. Petrakis, N. Kogerakis, N. Vrachassotakis, I. Stiakakis, G. Zacharioudakis, G. Chalkiadakis
Department of General Surgery, University of Crete, University General Hospital, GR 71110, Herakleion Crete, Greece
Received: 23 October 2000/Revision accepted: 4 April 2001
Abstract
rate through two distinct pathways: cholinergic and non-
cholinergic.
Background: Acute hyperglycemia has been associated
with delayed gastric emptying of solid foods in healthy
control subjects. Erythromycin has been found to be a
gastrointestinal prokinetic agent in humans. We examined
whether acute steady-state hyperglycemia reduces the
erythromycin-induced acceleration of gastric emptying of
a solid meal after a fasted state in healthy subjects.
Methods: Twelve healthy subjects ate standard solid
meals that had been radiolabeled. Gastric emptying was
measured by scintigraphy during normoglycemia (5–8.9
mmol/L glucose) and hyperglycemia induced by intrave-
nous glucose (16–19 mmol/L glucose) after administra-
tion of placebo or 200 mg of erythromycin intravenously.
Emptying was measured randomly on 4 different days.
Results: Administration of erythromycin during normo-
glycemia or induced hyperglycemia compared with pla-
cebo accelerated the gastric emptying of the solid meal
but did not completely normalize the delay caused by
hyperglycemia versus normoglycemia (p Ͻ 0.001). In
both conditions, erythromycin versus placebo signifi-
cantly reduced the lag-phase duration (9.7 Ϯ 2.3 min and
22.0 Ϯ 3.9 min vs. 38.3 Ϯ 5.7 min and 49.5 Ϯ 6.0 min,
respectively; p Ͻ 0.001), gastric emptying of the half
meal (39.2 Ϯ 4.0 min and 52.0 Ϯ 7.1 min vs. 75.7 Ϯ 11.8
min and 94.0 Ϯ 13.4 min, respectively; p Ͻ 0.001), and
the percentage of meal retained in the stomach 120 min
postprandially (p Ͻ 0.001).
Key words: Hyperglycemia—Erythromycin—Scinti-
graphic gastric emptying—Gastric motility.
Erythromycin recently has been found to be a gastroin-
testinal prokinetic agent in humans and other animals.
Those effects are believed to be mediated by the ability of
erythromycin to bind to the receptors of the gastrointes-
tinal peptide motilin and not its antibiotic characteristics
[1–4]. However, it is still uncertain as to whether eryth-
romycin binds to motilin receptors on smooth muscle or
nerve tissue [5]. Administration of low doses of erythro-
mycin (40 mg) can induce phase III of the migrating
motor complex (MMC) in humans [6] and dogs [7]. In
addition, a 200-mg dose of erythromycin increases antral
contractile activity during fasting and gastric emptying of
solid foods in normal subjects, patients with gastropare-
sis, and patients with delayed gastric emptying after gas-
tric surgery [8–13], increases the amplitude of antral
contractions, and improves antroduodenal coordination
[14, 15].
Acute hyperglycemia is associated with decreased
pressure waves in the antrum, loss of phase III interdi-
gestive MMC in the stomach, and slowing of gastric
emptying [16–18]. Most studies have dealt with diabetic
patients with neuropathy, but healthy individuals also
have shown slowing of gastric emptying during acute
hyperglycemia [19–21]. A recent study found that hyper-
glycemia reduces motility in the stomach and inhibits
motility in the duodenum and jejunum, with a significant
effect on small intestinal motility [22], whereas another
recent study found no consistent effects of hyperglycemia
on the duodenum or others parts of the small intestine
except the stomach [23]. In that study, most of the sub-
Conclusion: The erythromycin-induced acceleration ef-
fect on gastric emptying was related to the plasma glucose
level. Hyperglycemia might have chosen a cholinergic
antagonist pathway that delayed gastric emptying of sol-
ids. Even though induced hyperglycemia inhibited gastric
emptying, erythromycin accelerated the gastric emptying
Correspondence to: I. E. Petrakis

310
I. E. Petrakis et al.: Gastric emptying and erythromycin in hyperglycemia
jects showed a phase III–like activity in the duodenum
within 15 min after the onset of hyperglycemia [23].
Barnett et al. [17] showed that the motility index in the
duodenum did not change significantly during hypergly-
cemia. Modern computerized recordings and detailed
analysis of individual gastroduodenal contractions have
shown that the last part of phase III in the proximal
duodenum works as a retroperistaltic pump [22]. It is not
known whether that pattern is altered by metabolic fac-
tors. Our group recently demonstrated the attenuated ef-
fect of hyperglycemia on the erythromycin-induced ac-
celeration of solid and liquid gastric emptying in patients
with idiopathic and diabetic gastroparesis and diabetic
type I, respectively [24, 25]. Further, we found a similar
hyperglycemic effect not mediated by the vagus [26]. In
those patients erythromycin accelerated gastric emptying
during normoglycemia and hyperglycemia but did not
completely normalize the delay caused by the induced
hyperglycemia. In the present study, we examined the
effects of acute steady-state hyperglycemia induced by
intravenous glucose infusion and “clamping” of the glu-
cose level on the erythromycin-induced (a motilin ago-
nist) acceleration on gastric emptying of solid food after
a fast in healthy subjects.
12.00 PM. Gastric emptying of the standard solid meal was
studied on four different occasions, 1 week apart, in
random order, after intravenous administration of 40 mL
of normal saline (placebo) or 200 mg of erythromycin
lactobionate (Abbott Laboratories, Abbott Park, IL,
USA), which increases antral contractile activity [6, 8,
10], diluted in 40 mL of water during normoglycemia or
hyperglycemia. Any medication that might have influ-
enced gastrointestinal motility was discontinued at least 3
days before each study.
Measurement of gastric emptying
The standard meal consisted of a hamburger and 140 g of
fresh tomato. The hamburger consisted of 100 g of
minced beef meat, 20 g of toasted bread, 10 g of olive oil,
and half an egg that had been labeled with 500 ␮Ci of
99mTc sulphur colloid. The meal contained 1633 kJ (32%
protein, 52% fat, and 16% carbohydrate) of energy and
was consumed within 10 min. Immediately after the meal
was completed, a reference scan for time 0 was acquired;
subjects were then given infusions of placebo or erythro-
mycin for normoglycemia or hyperglycemia, which con-
tinued another 10 min. With subjects seated in front of a
␥-camera (GE Maxi II; General Electric, Milwaukee, WI,
USA) that had been fitted with a low-energy collimator,
abdominal scans were acquired for 1 min, every 5 min,
and for a total of 120 min. The same nuclear medicine
technologist, who had no interest in the outcome of the
study, measured the radioactivity over the gastric area
that was defined by hand with the use of a light pen. The
counts were corrected for movement, Compton scatter,
␥-ray attenuation, and physical isotope decay [27]. The
data were computer generated, expressed as a percentage
over the initial value (first scan at time 0), and plotted
against time to generate profiles of the gastric emptying.
From those profiles the following parameters were ob-
tained: (a) shape of the emptying curves; (b) duration of
the lag phase, if present; (c) t1/2 (the time between com-
pletion of the meal to the point at which half of the meal
had left the stomach); (d) time from the onset of emptying
into the duodenum to the point at which half the meal had
left the stomach (postlag t1/2 ϭ t1/2 Ϫ tlag); and (e) the
percentage of meal remaining in the stomach 120 min
after the meal had been consumed.
Patients and methods
Twelve healthy subjects (seven men, five women; mean
age ϭ 35.5 years, range ϭ 24–58 years; mean body
weight ϭ 74 kg, range ϭ 54–92 kg; mean body mass
index ϭ 22.1 kg/m2, range ϭ 18.9–25.1 kg/m2) without
gastrointestinal symptoms participated. All subjects gave
written informed consent, and the Ethical Committee of
the University of Crete approved the study protocol.
Protocol
In a double-blind fashion, gastric emptying was measured
in all subjects during normoglycemia (5–8.9 mmol/L) or
induced hyperglycemia (16–19 mmol/L) after adminis-
tration of placebo or erythromycin on 4 different days at
1-week intervals and in random order. Subjects fasted
16 h (from 8 PM the previous day to 12 PM). Two cannulas
were inserted into the anticubital veins in each arm; one
cannula was used for the infusion of glucose and insulin
and the other was used for administration of erythromycin
or placebo. Blood samples were drawn from another
(third) venous cannula on the dorsal surface of the hand,
and the blood glucose concentration was measured every
10 min. Blood glucose concentrations were stabilized
within the normoglycemic or hyperglycemic range for at
least 1 h before consumption of the solid meal. After
stable blood glucose concentrations were taken, subjects
ate radioisotopically labeled test meals at approximately
Blood glucose stabilization
Normoglycemia and hyperglycemia were induced by in-
travenous infusion of 20% glucose and insulin (Actrapid,
HM Novo Nordisk, Bagsvaerd, Denmark) [28]. The rate
of 20% glucose was adjusted to maintain blood glucose
concentrations at 5–8.9 or 16–19 mmol/L. Blood samples
were drawn from the cannulas inserted into the dorsal

I. E. Petrakis et al.: Gastric emptying and erythromycin in hyperglycemia
311
Fig. 1. Emptying curves of solids in healthy controls (mean Ϯ SD). The
typical dual-phase curve was obtained after placebo administration
during normoglycemia (open circles) and a similar parallel curve was
obtained with an increased lag-phase period during induced hypergly-
cemia (solid circles). Intravenous administration of 200 mg of erythro-
mycin during normoglycemia (open squares) and induced hyperglyce-
mia (solid squares) compared with placebo accelerated gastric emptying
of solids by abolishing lag-phase duration and reducing the overall
gastric emptying time; however, it did not completely normalize the
delayed gastric emptying rate caused by hyperglycemia and thus pro-
duced two parallel emptying curves.
surfaces of the opposite hands; glucose concentrations
were measured every 10 min with test strips (BM-test
glycemie R 1-44, Boehringer, Mannheim, Germany).
The mean (SEM) blood glucose concentrations were
7.8 (0.5) mmol/L during normoglycemia and 17.5 (0.5)
mmol/L during hyperglycemia. The glucose concentra-
tions were 4.3 (0.8) mmol/L at 0 min and 8.2 (2.8)
mmol/L at 60 min.
placebo significantly reduced the t1/2 of gastric emptying
(39.2 Ϯ 4.0 min vs. 75.7 Ϯ 11.8 min, p Ͻ 0.001) but did
not affect the postlag t1/2 of gastric emptying. Signifi-
cantly less food was retained in the stomach 120 min
postprandially after erythromycin than after placebo ad-
ministration (11.8 Ϯ 2.8% vs. 30.0 Ϯ 3.4%, respectively;
p Ͻ 0.001).
During induced hyperglycemia after administration of
placebo or erythromycin, the emptying curves shifted to
the right compared with those obtained during normogly-
cemia, and ran parallel, as shown in Figure 1, because of
the prolonged lag phase, dual-phase curve, and decrease
in the overall gastric emptying rate.
During induced hyperglycemia, erythromycin versus
placebo administration significantly accelerated the over-
all gastric emptying rate. Erythromycin administration
during induced hyperglycemia significantly decreased the
lag phase (22.0 Ϯ 3.9 min vs. 49.5 Ϯ 6 min, p Ͻ 0.001),
t1/2 of gastric emptying (52.0 Ϯ 7.1 min vs. 94.0 Ϯ 13.4
min, p Ͻ 0.001), and the percentage of retained meal in
the stomach at 120 min postprandially (21.2 Ϯ 3.3% vs.
39.6 Ϯ 5.3%, p Ͻ 0.001). However, erythromycin did not
normalize the delay caused by the hyperglycemic condi-
tions versus normoglycemia. After erythromycin admin-
istration, the lag phase was significantly prolonged, pro-
ducing a dual-phase curve compared with the linear
model after erythromycin administration in normoglyce-
mia (22.0 Ϯ 3.9 min vs. 9.7 Ϯ 2.3 min, p Ͻ 0.001).
Placebo administration during induced hyperglycemia
Statistical analysis
All values were expressed as mean Ϯ SD, and p Ͻ 0.05
was considered significant. Analysis of variance for re-
peated measures measured differences between treat-
ments.
Results
During normoglycemia after placebo administration, gas-
tric emptying of the meal was fitted to a typical dual-
phase (lag phase: virtually no emptying, postlag phase:
actual emptying) curve, according to a linear model (Fig.
1). During normoglycemia, administration of erythromy-
cin as opposed to placebo almost abolished the lag phase
(9.7 Ϯ 2.3 min vs. 38.3 Ϯ 5.7 min, respectively; p Ͻ
0.001) and the appearance of the curve was almost that of
the linear model (Fig. 1). Erythromycin as opposed to

312
I. E. Petrakis et al.: Gastric emptying and erythromycin in hyperglycemia
versus normoglycemia significantly prolonged the lag
phase (49.5 Ϯ 6.0 min vs. 38.3 Ϯ 5.7 min, p Ͻ 0.001).
The postlag phase of actual emptying was similar to
that of the linear model after administration of placebo or
erythromycin during hyperglycemia. Further, hyperglyce-
mia versus normoglycemia after administration of pla-
cebo or erythromycin significantly increased t1/2 of gastric
emptying (94.0 Ϯ 13.4 min vs. 75.7 Ϯ 11.8 min and
52.0 Ϯ 7.1 min vs. 39.2 Ϯ 4.0 min, respectively; p Ͻ
0.001) but did not affect the postlag t1/2 of the gastric
emptying rate. The percentage of meal remaining in the
stomach at 120 min postprandially after administration of
placebo or erythromycin during hyperglycemia was sig-
nificantly greater compared with the percentage during
normoglycemia (39.6 Ϯ 5.3% vs. 30.0 Ϯ 3.4% and
21.2 Ϯ 3.3% vs. 11.8 Ϯ 2.8%, respectively; p Ͻ 0.001).
thereby overcoming the inhibitory enterogastric osmotic
reflex or antroduodenal coordination [8, 10]. The present
findings confirmed those of previous reports [6, 10] in
which 200 mg of intravenous erythromycin increased
gastric contractile activity during fasting and accelerated
gastric emptying in healthy subjects by almost abolishing
the lag phase and reducing by half the overall gastric
emptying period, thereby overcoming antroduodenal co-
ordination, which controls trituration and emptying of
solid food.
Hyperglycemia decreases the rate of gastric emptying
in healthy subjects [16]. Acute hyperglycemia affects
antral activity with loss of antral MMC phase III [17, 26].
The pressure activity in the antrum, expressed as the
motility index, is significantly reduced after the onset of
hyperglycemia as opposed to normoglycemia, and the
absence of MMC phase III in the antrum during hyper-
glycemia seems to abolish this component in healthy
subjects [27]. Bjo¨rnsson et al. [22] found that acute hy-
perglycemia is accompanied by a decrease in gastric
interdigestive motility and a significant inhibition of con-
tractions in the duodenum and proximal jejunum, al-
though long clusters of contractions were more common
during hyperglycemia in healthy subjects. They also
found that hyperglycemia decreases motilin and pancre-
atic polypeptide (PP) levels, probably by suppressing
cholinergic transmission, and that efferent activity in the
vagal nerve might be disturbed in some way during acute
hyperglycemia as evident by the inhibition of gastric and
small intestine motility [22]. Samson et al. [41] found that
hyperglycemia delays gastric emptying of solids by pro-
longing the lag phase and decreasing the postlag empty-
ing rate. The present study confirmed the role of blood
glucose level and its metabolic control in the gastric
emptying of solids and the results of Samson et al. [41],
further showing that acute hyperglycemia rather than
normoglycemia attenuates the erythromycin-induced ac-
celeration on gastric emptying of solids. Nevertheless,
erythromycin accelerated gastric emptying of solids dur-
ing hyperglycemia but did not normalize the delay caused
by hyperglycemia compared with normoglycemia. De-
spite the administration of erythromycin, a motilin ago-
nist that overcomes the inhibitory effect of excited
antroduodenal coordination on gastric emptying of solids
[6, 10, 22], the gastric emptying rate decreased signifi-
cantly during hyperglycemia compared with normoglyce-
mia. Therefore, hyperglycemia likely uses a cholinergic
antagonist pathway that suppresses the cholinergic trans-
mission and efferent activity of the vagal nerve and re-
ducees gastrointestinal motility. Hence, we confirmed the
results of Bjo¨rnsson et al. [22] by showing that suppres-
sion of cholinergic transmission is probably mediated
through activation of a cholinergic antagonist pathway
that also attenuates the erythromycin-induced accelera-
tion of gastric emptying and its indirect action via a
cholinergic pathway [38–40]. In that way, erythromycin
Discussion
Gastric emptying of solids has two phases known as lag
and postlag [27, 29]. The lag phase corresponds to food
coursing from the fundus to the antrum and trituration of
that food to particles no larger than approximately 1 mm
by the antral mill [29, 30]. The duration of the lag phase
is inversely related to antral pressure [29]. The postlag
phase corresponds to propulsion of food particles through
the pylorus into the duodenum [29–31]. The emptying
rate during that period is directly related to antral pressure
[29]. However, the resistance of the pylorus and the
motility of the duodenum also affect postlag emptying
[29, 31, 32]. Houghton et al. [33] found that, during the
lag phase of emptying, the stomach gets rid of excess
fluid and leaves the solid ball of food in the fundus and
that trituration is minimal. Grinding of solid food to small
particles by antral contractions and emptying into the
duodenum occur during the postlag period.
The properties of erythromycin as a motilin agonist
explain its action on the gastric emptying of solids in
healthy individuals and patients with gastroparesis or
delayed emptying after gastric surgery [6, 8, 10–13].
Motilin receptors in humans are confined to the stomach
and duodenum [34], and increased plasma motilin con-
centrations in blood are detected when phase III of the
MMC begins from the stomach [35]. Erythromycin in-
creases antral and not jejunal postprandial motor activity
in healthy individuals and patients with diabetic gastro-
paresis [7, 8, 10, 30, 36]. One recent found that erythro-
mycin also affects proximal gastric tone in humans [37],
whereas some in vivo studies suggested an indirect action
through a cholinergic pathway [38–40]. Erythromycin
also induces powerful contractions that obliterate the lu-
men of the gastric antrum [8], and antral motor activity is
inversely related to the duration of the lag phase [29].
Moreover, erythromycin enhances the gastric emptying
and accelerates the emptying rate of liquids and solids,

I. E. Petrakis et al.: Gastric emptying and erythromycin in hyperglycemia
313
11. Xynos E, Mantides A, Papgeorgiou A, et al. Erythromycin accel-
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between solids and liquids. J Nucl Med 1990;31:1490–1493
13. Petrakis I, Vassilakis JS, Karkavitsas N, et al. Enhancement of
gastric emptying of solids by erythromycin in patients with Roux-
en-Y gastrojejunostomy. Arch Surg 1998;133:709–714
14. Fraser R, Shearer T, Fuller J, et al. Intravenous erythromycin
overcomes small intestinal feedback on antral, pyloric, and duode-
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may act through two distinct pathways, cholinergic and
noncholinergic, hence, its effect in patients with vagot-
omy [26].
The present findings also might be relevant for dia-
betics. Intestinal dysmotility was found in most patients
with diabetes mellitus and gastroparesis [42–44]. More-
over, gastric emptying during hyperglycemia was delayed
in subjects with diabetes mellitus type I or II [18]. In
diabetic patients with gastroparesis, 40% had an affected
gastric component of the MMC [42]. The blood glucose
level might affect gastric emptying in diabetic patients or
healthy control subjects [18, 27]. Pioneer studies of gas-
tric emptying after placebo or erythromycin administra-
tion in diabetic patients might not have controlled the
metabolisms of those patients in an optimal way. There-
fore, the changes in gastric emptying, at least part, might
have been due to inadequate regulation of glucose level
rather than irreversible neuropathy.
The erythromycin-induced acceleration effect on gas-
tric emptying is related to the plasma glucose level.
Hyperglycemia might use a cholinergic antagonist path-
way that delays gastric emptying of solids. Erythromycin
accelerated gastric emptying during normoglycemia and
hyperglycemia by acting through cholinergic and noncho-
linergic pathways and might be a useful prokinetic agent
even during hyperglycemia.
22. Bjo¨rnsson ES, Urbanavicius V, Eliasson B, et al. Effects of hyper-
glycemia on interdigestive gastrointestinal motility in humans.
Scand J Gastroenterol 1994;29:1096–1104
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