Antidiabetogenic Action of Cholecystokinin-8 in Type 2 Diabetes*

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 C-terminal octapeptide of CCK (CCK-8) was therefore infused i.v. (24 pmol/kg x 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.

Effect of hormone therapy on the enteroinsular axis

“…The lack of any change in CCK concentrations observed in our study remains in agreement with recent reports that CCK does not stimulate insulin secretion under physiologic conditions in humans, but it does so after the administration of pharmacologic amounts. 37,38 Finally, we would like to address some methodological issues. The difference in the mean plasma estradiol levels between transdermal and oral HT groups resulted from the administered dose of estradiol.…”

MECHANISMS IN ENDOCRINOLOGY: Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion

“…In general, in humans, CCK does not fulfil the criteria for being a physiological incretin hormone, i.e. the ability to augment postprandial glucosestimulated insulin secretion (220,221,223). However, in a small study by Ahrén et al (220), CCK8 was infused into six healthy and six type 2 diabetic postmenopausal women during a meal test and it has been demonstrated that CCK8 (in doses that have been shown to increase insulin secretion) did not affect the postprandial secretion of GIP and GLP1.…”

“…However, in a small study by Ahrén et al (220), CCK8 was infused into six healthy and six type 2 diabetic postmenopausal women during a meal test and it has been demonstrated that CCK8 (in doses that have been shown to increase insulin secretion) did not affect the postprandial secretion of GIP and GLP1. Although the majority of studies do not support a role for CCK-induced, postprandial incretin secretion (220,223,224,225,226,227), it should be underlined that in the physiological setting of mixed meal intake, a stimulatory effect of CCK on postprandial GLP1 release may easily be overlooked due to the meal response, which could 'drown' the effect of CCK itself. Furthermore, any response must be seen in the light of potential effects of endogenous CCK in control experiments.…”

Gut peptides and type 2 diabetes mellitus treatment

“…However, although CCK is released after meal ingestion, it does not seem to work as an incretin in humans, because circulating levels of CCK after meal ingestion are not sufficient to stimulate insulin secretion and, furthermore, CCK receptor antagonism does not inhibit insulin secretion after meal ingestion [47]. Nevertheless, pharmacologic administration of the peptide was recently shown to be antidiabetogenic in subjects with type 2 diabetes by reducing postprandial glycemia [48]. This finding deserves further study.…”