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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 3 1043-1048
Copyright © 2000 by The Endocrine Society

Original Studies

Antidiabetogenic Action of Cholecystokinin-8 in Type 2 Diabetes1

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

Address all correspondence and requests for reprints to: Dr. Bo Ahrén, Department of Medicine, Malmo University Hospital, S-205 02 Malmo, Sweden.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
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 C-terminal octapeptide of CCK (CCK-8) was therefore infused iv (24 pmol/kg·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 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 (GLP-1), 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.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CHOLECYSTOKININ (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, 12, 13), although several studies demonstrated no effect of CCK on insulin secretion in humans (14, 15, 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 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, 22, 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 determined, as glucagon is released after a meal and is of importance for glucose homeostasis (13, 28).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
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

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·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 trapezoid rule. Differences in results with vs. without CCK-8 administration were evaluated with Student’s t test for paired observations.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
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. 1Go). 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·60 min during infusion of saline to 86 ± 19 mmol/L·60 min during infusion of CCK-8 (P = 0.035) in the healthy subjects and from 149 ± 17 to 81 ± 26 mmol/L·60 min in the subjects with diabetes (P = 0.048). Baseline serum levels of insulin did not change during infusion of CCK-8 (Fig. 2Go). 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 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·60 min in healthy subjects (P = 0.023) and from 4.6 ± 3.7 to 6.0 ± 1.4 nmol/L·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.



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  		Figure 1. Plasma levels of glucose during iv infusion of CCK-8 (24 pmol/kg·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.

 


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  		Figure 2. Serum levels of insulin during iv infusion of CCK-8 (24 pmol/kg·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.

 
GLP-1, GIP, and glucagon

Infusion of CCK-8 did not affect baseline levels of GLP-1, GIP, or glucagon (Figs. 3Go-5GoGo). 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 1Go).



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  		Figure 3. Plasma levels of GLP-1 during iv infusion of CCK-8 (24 pmol/kg·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.

 


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  		Figure 4. Plasma levels of GIP during iv infusion of CCK-8 (24 pmol/kg·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.

 


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  		Figure 5. Plasma levels of glucagon during iv infusion of CCK-8 (24 pmol/kg·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.

 

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  		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

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
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 insulin 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 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 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, 3, 4, 5) as well as in vitro (6, 7, 8, 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·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, 38, 39, 40, 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 Alboek for expert technical assistance.


   Footnotes
 
1 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. Back

Received September 13, 1999.

Revised November 4, 1999.

Accepted November 15, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals