0021-972X/00/$03.00/0
The Journal of Clinical Endocrinology & Metabolism
Copyright © 2000 by The Endocrine Society
Vol. 85, No. 3
Printed in U.S.A.
Antidiabetogenic Action of Cholecystokinin-8 in
Type 2 Diabetes*
BO AHRÉN, JENS JUUL HOLST,
AND
SUAD EFENDIC
Department of Medicine, Lund University (B.A.), S-205 02Malmo, Sweden; Department of
Endocrinology and Metabolism, Panum Institute (J.J.H.), Copenhagen, Denmark; and Department of
Molecular Medicine, Karolinska Institute (S.E.), S-171 77 Stockholm, Sweden
ABSTRACT
Cholecystokinin (CCK) is a gut hormone and a neuropeptide that
has the capacity to stimulate insulin secretion. As insulin secretion
is impaired in type 2 diabetes, we explored whether exogenous administration of this peptide exerts antidiabetogenic action. The Cterminal octapeptide of CCK (CCK-8) was therefore infused iv (24
pmol/kg䡠h) for 90 min in six healthy postmenopausal women and in
six postmenopausal women with type 2 diabetes. At 15 min after start
of infusion, a meal was served and ingested during 10 min. On a
separate day, saline was infused instead of CCK-8. In both healthy
subjects and subjects with type 2 diabetes, CCK-8 reduced the increase in circulating glucose after meal ingestion and potentiated the
increase in circulating insulin. The ratio between the area under the
C
HOLECYSTOKININ (CCK) is both a gut hormone produced in endocrine cells in the upper small intestine
and a neuropeptide localized to nerve terminals in the central
and peripheral nervous systems (1). From small intestine
cells, CCK is released into the bloodstream after meal ingestion and functions as a gut hormone in the physiological
regulation of postprandial pancreatic exocrine secretion,
gallbladder contraction, gastric emptying, and bowel
motility (1).
CCK exerts a powerful stimulatory action on insulin secretion, as has been demonstrated under in vivo conditions in
dogs (2), pigs (3), and mice (4, 5) as well as under in vitro
conditions in the rat perfused pancreas (6, 7) and in isolated
rodent islets (8, 9). In rats, CCK might be involved in the
postprandial potentiation of insulin secretion, the so-called
incretin action, as a specific CCK receptor antagonist inhibits
postprandial insulin secretion in this species (10). Also in
humans, CCK has the capacity to stimulate insulin secretion
(11–13), although several studies demonstrated no effect of
CCK on insulin secretion in humans (14 –16). This discrepancy may be ascribed to the use of different doses, forms, or
sources of CCK and/or experimental conditions, such as the
glucose concentration at the time when CCK is given. However, in humans, CCK does not seem to be a physiological
Received September 13, 1999. Revision received November 4, 1999.
Accepted November 15, 1999.
Address all correspondence and requests for reprints to: Dr. Bo
Ahrén, Department of Medicine, Malmo University Hospital, S-205 02
Malmo, Sweden.
* This work was supported by the Swedish Medical Research Council
(Grant 6834); the Ernhold Lundström, Albert Påhlsson, and Novo Nordic Foundations; the Swedish Diabetes Association; Malmo University
Hospital; and the Faculty of Medicine, Lund University.
curves for serum insulin and plasma glucose during the 15- to 75-min
period after meal ingestion was increased by CCK-8 by 198 ⫾ 18% in
healthy subjects (P ⫽ 0.002) and by 474 ⫾ 151% (P ⫽ 0.038) in subjects
with type 2 diabetes. In contrast, the increase in the circulating levels
of gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP1), or glucagon after meal ingestion was not significantly affected by
CCK-8. The study therefore shows that CCK-8 exerts an antidiabetogenic action in both healthy subjects and type 2 diabetes through
an insulinotropic action that most likely is exerted trough a direct islet
effect. As at the same time, CCK-8 was infused without any adverse
effects, the study suggests that CCK is a potential treatment for type
2 diabetes. (J Clin Endocrinol Metab 85: 1043–1048, 2000)
so-called incretin hormone, i.e. a gut hormone of relevance
for the postprandial augmentation of glucose-stimulated insulin secretion, as carefully designed studies have shown
that at levels circulating postprandially, CCK does not affect
glucose-stimulated insulin secretion, and CCK receptor antagonism does not reduce postprandial insulin secretion in
man (11, 12, 14, 15, 17). As CCK is as well expressed in
pancreatic nerves (18, 19), the peptide may also be involved
in the neural regulation of insulin secretion (20).
Subjects with glucose intolerance and type 2 diabetes exhibit impaired insulin secretion (21–23). A previous study
demonstrated that administration of CCK to subjects with
type 2 diabetes reduced the postprandial glycemia without
affecting the postprandial insulinemia (24). This increased
insulin vs. glucose ratio suggested improved insulin secretion (24). This effect was, however, less pronounced than that
of another gut hormone, glucagon-like peptide-1 (GLP-1),
which strongly stimulates postprandial insulin secretion and
exerts a pronounced antidiabetogenic action in type 2 diabetes (25, 26). Whether the blood glucose-lowering effect of
CCK is exerted only through a direct insulinotropic effect or
also through the influence of CCK on the secretion of other
gastro-entero-pancreatic hormones is not known.
The purpose of this study was to examine the influence of
iv administration of the C-terminal octapeptide of CCK
(CCK-8) on circulating glucose and insulin levels after a meal
in healthy subjects and in patients with type 2 diabetes to
exploit a potential antidiabetogenic action of the hormone.
Also, the influence of CCK-8 on the postprandial release of
the two gluco-incretin hormones, gastric inhibitory polypeptide (GIP) and GLP-1, was studied, as GIP and GLP-1 are both
released after meal intake and potentiate glucose-stimulated
insulin secretion (27). Pancreatic glucagon was also deter-
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AHRÉN, HOLST, AND EFENDIC
mined, as glucagon is released after a meal and is of importance for glucose homeostasis (13, 28).
Subjects and Methods
Study subjects
We studied six postmenopausal women with type 2 diabetes (duration of disease, 2– 4 yr; age, 68 ⫾ 2.6 yr; 66 ⫾ 23 kg BW; mean ⫾ sd) and
six postmenopausal women with normal glucose tolerance according to
WHO criteria (29) (age, 68 ⫾ 2.2 yr; 62 ⫾ 9 kg BW). To keep the study
group homogenous, subjects of the same gender and matched for age
were included in the two groups. Of the six diabetics, three were treated
with sulfonylurea (glipizide, 2.5–7.5 mg/day; withheld 48 h before the
study), and three were given dietary treatment alone; fasting glucose
levels were 7.1 ⫾ 1.2 mmol/L, and hemoglobin A1c levels were 6.5 ⫾
1.6% (reference value, 4.0 –5.5%). All subjects had normal liver and
thyroid function tests, and none was taking any medication known to
affect glucose tolerance, except sulfonylurea in three subjects. All subjects received oral and written information concerning the aims and
methods of the study and signed a consent declaration before the start
of the study. The study protocol was approved by the ethics committee
of Lund University.
Experimental procedures
trapezoid rule. Differences in results with vs. without CCK-8 administration were evaluated with Student’s t test for paired observations.
Results
Glucose and insulin
The iv infusion of CCK-8 was well tolerated, with no
subjective adverse effects and no changes in blood pressure
or heart rate. In both healthy subjects and subjects with type
2 diabetes, CCK-8 did not affect baseline plasma glucose (Fig.
1). However, the increase in plasma glucose in response
to the breakfast was reduced by CCK-8; the difference in
levels was significant at 60, 75, and 90 min (P ⬍ 0.05). The
AUCglucose for the period from 30 –90 min was reduced from
120 ⫾ 26 mmol/L䡠60 min during infusion of saline to 86 ⫾
19 mmol/L䡠60 min during infusion of CCK-8 (P ⫽ 0.035) in
the healthy subjects and from 149 ⫾ 17 to 81 ⫾ 26 mmol/L䡠60
min in the subjects with diabetes (P ⫽ 0.048). Baseline serum
levels of insulin did not change during infusion of CCK-8
(Fig. 2). However, the increase in serum insulin after meal
ingestion was potentiated by CCK-8 in both healthy subjects
(difference between individual time points significant at 75
After an overnight fast, an iv cannula was inserted into one antecubital vein. Two baseline samples were then taken, whereafter CCK-8
(CLINALFA AG, Laeufelingen, Switzerland) was infused at a rate of 24
pmol/kg䡠h for 90 min. This is the rate of CCK-8 infusion that in a
previous study produced a reduction in postprandial glycemia in subjects with diabetes (24). It is lower than the dose rate in our previous
study (13), which in some cases caused abdominal discomfort. On a
separate occasion, saline was infused instead of CCK-8. Additional
samples were taken at 5, 10, and 15 min after the start of infusion,
whereafter breakfast was served and ingested over a 10-min period. The
breakfast consisted of two slices of bread, 10 g margarine, 10 g marmalade, a slice of 17% cheese, and a cup of black coffee. This breakfast
yields 350 Cal, with 28%, 22%, and 50% of the energy coming from
protein, fat, and carbohydrate, respectively. New blood samples were
taken every 15 min for another 90 min and then at 120 min. The subjects
spent the study period in a semirecumbent position. The two studies,
which were not blinded for the investigator, were undertaken in randomized order in all subjects at a 1-month interval.
Analyses
Blood samples were immediately centrifuged at 5 C, and serum or
plasma was frozen at ⫺20 C until analysis. Serum insulin concentrations
were analyzed with a double antibody RIA technique. Guinea pig antihuman insulin antibodies, human insulin standard, and mono[125I]Tyr-human insulin tracer (Linco Research, Inc., St. Louis, MO) were
used. Samples for analysis of GIP and GLP-1 were obtained in prechilled
test tubes containing ethylenediamine tetraacetate (2.8 mmol/L blood;
Sigma, St. Louis, MO) and aprotinin (250 kallikrein inhibitory units/mL
blood; Bayer Corp. AG, Leverkusen, Germany). Analyses of GIP concentrations were performed with a double antibody RIA technique using
rabbit antihuman GIP antibodies (R65), [125I]human GIP, and human
GIP standard (30). The antibody employed cross-reacts fully with human GIP, but not with so-called 8-kDa GIP, whose nature and relationship to the synthesis or secretion of GIP are still unclear (31, 32). Plasma
concentrations of GLP-1 were measured by RIA after extraction with
ethanol as previously described (33). The antiserum (code no. 89390) is
directed against the amidated C-terminus of GLP-1 and therefore mainly
measures GLP-1 of intestinal origin. Plasma glucose concentrations were
determined using the glucose oxidase method. Glucose, insulin, GIP,
and GLP-1 were analyzed in duplicate, and the mean values for each
time point are given in the results.
Calculations and statistics
Data are presented as the mean ⫾ se unless otherwise noted. The
areas under the concentration curves (AUCs) were calculated by the
FIG. 1. Plasma levels of glucose during iv infusion of CCK-8 (24
pmol/kg䡠h) or saline in six postmenopausal women with normal glucose tolerance and six postmenopausal women with type 2 diabetes.
At 15 min after the start of the iv infusion, a standard breakfast was
served, which was ingested during 10 min. The mean ⫾ SEM are
shown. Asterisks indicate the probability level of random difference
between the two studies: *, P ⬍ 0.05; **, P ⬍ 0.01.
ANTIDIABETOGENIC ACTION OF CCK-8
FIG. 2. Serum levels of insulin during iv infusion of CCK-8 (24 pmol/
kg䡠h) or saline in six postmenopausal women with normal glucose
tolerance and six postmenopausal women with type 2 diabetes. At 15
min after the start of the iv infusion, a standard breakfast was served,
which was ingested during 10 min. The mean ⫾ SEM are shown.
Asterisks indicate the probability level of random difference between
the two studies: *, P ⬍ 0.05.
and 90 min, P ⬍ 0.05) and in subjects with type 2 diabetes
(significant at 60 and 75 min, P ⬍ 0.05). The AUCinsulin during
30 –90 min increased by CCK-8 from 10.3 ⫾ 2.2 to 15.6 ⫾ 4.0
nmol/L䡠60 min in healthy subjects (P ⫽ 0.023) and from 4.6 ⫾
3.7 to 6.0 ⫾ 1.4 nmol/L䡠60 min in the subjects with diabetes
(P ⫽ 0.042). The ratio between AUCinsulin and AUCglucose
increased by CCK-8 from 116 ⫾ 33 to 229 ⫾ 67 pmol/mmol
(P ⫽ 0.02) in healthy subjects and from 33 ⫾ 6 to 151 ⫾ 46
pmol/mmol (P ⫽ 0.038) in subjects with type 2 diabetes.
GLP-1, GIP, and glucagon
Infusion of CCK-8 did not affect baseline levels of GLP-1,
GIP, or glucagon (Figs. 3-5). The circulating levels of these
three hormones all increased after the meal in both healthy
subjects and patients, with no significant difference between
these groups. CCK-8 did not significantly affect the circulating levels or the AUC of these three hormones after meal
ingestion (Table 1).
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FIG. 3. Plasma levels of GLP-1 during iv infusion of CCK-8 (24 pmol/
kg䡠h) or saline in six postmenopausal women with normal glucose
tolerance and six postmenopausal women with type 2 diabetes. At 15
min after the start of the iv infusion, a standard breakfast was served,
which was ingested during 10 min. The mean ⫾ SEM are shown.
Discussion
We show in this study that exogenous administration of
CCK-8 lowered postmeal glycemia in both healthy subjects
and subjects with type 2 diabetes. As circulating insulin at the
same time was higher during infusion of CCK-8 than in the
saline experiment, even though circulating glucose was
lower, it is most likely that the blood glucose-lowering action
of CCK-8 is mainly exerted through a stimulatory action on
insulin secretion. This is illustrated by the increased ratio of
AUCinsulin to AUCglucose caused by CCK-8. As the impaired
insulin secretion is an important target for treatment of diabetes, and the beneficial effects of CCK-8 on the insulin to
glucose ratio were achieved without any adverse effects, our
study suggests that CCK-8 is a potential treatment modality
for type 2 diabetes.
CCK-8 could exert its insulinotropic action through several different mechanisms besides directly stimulating secretion from the islet B cells. One potential mechanism is that
CCK-8 potentiates the release of other gut hormones during
meal ingestion and that these gut hormones potentiate in-
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Vol 85 • No 3
AHRÉN, HOLST, AND EFENDIC
FIG. 4. Plasma levels of GIP during iv infusion of CCK-8 (24 pmol/
kg䡠h) or saline in six postmenopausal women with normal glucose
tolerance and six postmenopausal women with type 2 diabetes. At 15
min after the start of the iv infusion, a standard breakfast was served,
which was ingested during 10 min. The mean ⫾ SEM are shown.
sulin secretion. We therefore also measured GIP and GLP-1
after meal ingestion, as both of these hormones are powerful
stimulators of insulin secretion (26, 27). Circulating GLP-1
and GIP were increased after meal intake both with and
without CCK-8 infusion, with no significant difference between healthy and diabetic subjects. Due to the low number
of subjects in each group, this does not exclude that diabetics
have an altered release pattern of these gut hormones. The
postprandial levels of the two hormones were not affected by
CCK-8. This suggests that CCK-8 does not affect the release
of GIP or GLP-1 in humans when administered at dose levels
that affect the release of insulin. However, a slight contribution by GLP-1 cannot be excluded, because although not
significantly different among these six subjects in each group,
during CCK-8 infusion the increase in GLP-1 started slightly
earlier than during saline infusion. Another potential mechanism explaining the increased circulating insulin levels during infusion of CCK-8 would be an influence of meal-induced
glucagon release. Glucagon is known to stimulate insulin
secretion (34) and to be of importance for glucose homeostasis (28), and previous experimental studies have presented
FIG. 5. Plasma levels of glucagon during iv infusion of CCK-8 (24
pmol/kg䡠h) or saline in six postmenopausal women with normal glucose tolerance and six postmenopausal women with type 2 diabetes.
At 15 min after the start of the iv infusion, a standard breakfast was
served, which was ingested during 10 min. The mean ⫾ SEM are
shown.
TABLE 1. AUC for insulin, glucagon, GIP, and GLP-1 during the
75 min after meal ingestion in healthy subjects and subjects with
type 2 diabetes with or without iv administration of CCK-8
Healthy subjects
Parameter
Insulin (nmol/
L 䡠 75 min)
GLP-1 (nmol/
L 䡠 75 min)
GIP (nmol/
L 䡠 75 min)
Glucagon (ng/
mL 䡠 75 min)
Saline
infusion
CCK-8
infusion
Diabetic subjects
Saline
infusion
CCK-8
infusion
16.9 ⫾ 6.5 22.7 ⫾ 9.5*a 12.1 ⫾ 3.2 15.3 ⫾ 4.4*a
1.9 ⫾ 0.1
1.8 ⫾ 0.1
1.6 ⫾ 0.2
1.8 ⫾ 0.2
5.9 ⫾ 1.6
5.1 ⫾ 1.3
5.1 ⫾ 0.7
4.6 ⫾ 0.6
3.4 ⫾ 0.2
3.4 ⫾ 0.3
4.2 ⫾ 0.4
5.0 ⫾ 0.5
The mean ⫾ SEM are shown.
a
*P ⬍ 0.05 between the infusions.
evidence for a stimulatory action of CCK on glucagon secretion (3, 6, 35, 36). However, in the present study, CCK did
not affect glucagon levels either under baseline conditions or
after meal ingestion, suggesting that CCK is not involved in
ANTIDIABETOGENIC ACTION OF CCK-8
the regulation of glucagon secretion in humans. Therefore,
the results suggest that the antidiabetic action of the peptide
is exerted through a direct stimulation of insulin secretion.
This is consistent with the well known and powerful insulinotropic action of CCK when administered at higher dose
levels in experimental animals (2–5) as well as in vitro (6 –9).
It should be emphasized that CCK-8 did not affect baseline
insulin levels, i.e. insulin levels before meal ingestion. This
suggests that a raised glucose level is a prerequisite for its
insulinotropic action in humans.
The dose of CCK-8 employed for this study was selected
from the previous study in humans, showing that at 24
pmol/kg䡠h, CCK-8 lowered the glycemic response to meal
ingestion (24). In that study, circulating CCK levels were also
determined and were elevated to approximately 15 pmol/L
by the infusion of CCK at this rate, which is higher than that
in healthy subjects after a meal (24). Similar results were
reported by Fieseler and collaborators (15). This emphasizes
that what we have observed in the present study may not be
taken as evidence for an incretin action of CCK in humans,
for which there is at present no clear evidence (11, 12, 14, 15,
17), but, rather, indicates a pharmacological insulinotropic
action that may be useful in the treatment of diabetes. Interestingly, Rushakoff and collaborators have also shown
that the meal-induced increase in CCK levels is lower in
diabetic subjects than in control subjects, suggesting that
type 2 diabetes is associated with impaired secretion of CCK
(24). Due to this discrepancy between healthy subjects and
diabetics, direct comparison between the effects of CCK in
the two study groups cannot be undertaken in the present
study, as CCK was administered at the same rate in the two
groups.
It is well known that CCK inhibits gastric emptying (37–
41), and through such an effect, CCK has been thought to be
of importance for the prevention of postprandial hyperglycemia (42). This action of CCK-8 might have contributed to
its antidiabetogenic action in the present study by reducing
or prolonging the intestinal uptake of glucose. However,
although the rate of gastric emptying was not measured in
the present study, such a contribution is probably of minor
importance for the antidiabetogenic action of CCK-8, as the
rate of increase in circulating glucose after the meal was the
same with vs. without CCK-8 in both healthy subjects and
patients.
In conclusion, this study has shown that in both healthy
subjects and subjects with type 2 diabetes, iv administration
of CCK-8 reduces glucose levels and increases insulin levels
after meal ingestion without significantly affecting the postprandial levels of GIP, GLP-1, or glucagon. The study, therefore, suggests that CCK may be explored for future use as a
treatment for diabetes, in analogy with the antidiabetogenic
action of the gut hormone, GLP-1.
Acknowledgments
We are grateful to Lilian Bengtsson, Ulrika Gustavsson, Margaretha
Persson, Lena Öhlund, Lena Bryngelsson, and Lena Albœk for expert
technical assistance.
1047
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