Cholecystokinin (CCK) – more than just a gallbladder hormone

4th January 2019, Dr Chee L Khoo

When you treat a medical condition with an agent with known intended effects, it is not uncommon that we come across some of the unintended effects of the agent. Glucagon-like peptide 1 receptor antagonists (GLP1-RAs) are very useful agents which not only improve glucose control via its known effects on insulin and glucagon but it is associated with modest weight loss. It achieves weight loss due to its effect on satiety as well as its effect on gastrointestinal motility. However, there are emerging reports linking GLP1-RAs with an increase in the frequency of biliary disorders including gallstones and cholecystitis.

When we start to investigate the plausible connection between GLP1-RAs and biliary disorders, the natural place to look would be the intestinal peptide, cholecystokinin (CCK). CCK, as the name suggest (chole-cysto as for gallbladder and kinin as for move), is the key regulator of gallbladder motility. But CCK does more than that. It relaxes the sphincter of Oddi to facilitate the release of bile into the duodenum. It inhibits gastric emptying, stimulates the pancreatic (exocrine) acinar cells to release its digestive juices and increased production of hepatic bile acids. When I started to delve further into CCK, matters became more and more complicated. Research over the last two decades have uncovered a lot more about CCK.

Secretion of CCK

CCK is secreted by the I cells in the mucosa lining of the small intestine (mainly duodenum and jejunum) in response to a meal, especially meals containing fatty acids and certain amino acids.  In addition, release of CCK is stimulated by monitor peptide (released by pancreatic acinar cells), CCK-releasing protein (via paracrine signalling mediated by enterocytes in the gastric and intestinal mucosa), and acetylcholine (released by the parasympathetic nerve fibres of the vagus nerve).

In addition to the intestinal tract, CCK is also produced in the central nervous system, peripheral nerves (including the vagus), thyroid gland, urogenital tract and cardiac myocytes. We are only beginning to explore the many other functions of CCK. Many of the functions of CCK in these tissues are still unknown.

CCK Structure

The CCK peptide exists in many different forms, each identified by the different number of amino-acids ii contains e.g. CCK58, CCK33, CCK22 and CCK8. The biological effects of CCK is in the C-terminal. Interestingly, gastrin also shares the same C-terminal sequence. What happens at the N-terminal is what determines the biological potency and the specificity for different CCK receptors. Some of the isoforms have a sulfate attached to the tyrosine residue in position 7 of the CCK peptide (1). This is crucial for its ability to activate specific CCK receptors (see below)

CCK receptors

The effects of CCK are mediated via two receptors, CCK1 receptor (also referred to as the CCK-A) and the CCK2 receptor (also referred to as the CCK-B receptors). CCK1, the so-called alimentary CCK, mediates gallbladder contraction, relaxation of the sphincter of Oddi, pancreatic growth and enzyme secretion, delay gastric emptying, and inhibits gastric acid secretion via fundic somatostatin. CCK1 receptors have also been found in the anterior pituitary, the myenteric plexus, and areas of the mid-brain. Sulphated CCK binds well to CCK1 receptors while non-sulfated CCK and gastrin binds negligibly to CCK1 receptors.

The CCK2 receptor, so-called brain CCK, is the predominant CCK receptor in the brain. It is less fussy than CCK1 in binding. It will bind all CCK peptides, sulphated or not, as well as gastrin peptide. CCK2 is also substantially expressed in the pancreatic cells in humans.

CCK/gastrin and cancers?

Both gastrin and CCK are trophic hormones and have been recognised as important regulators of growth of the GI tract and pancreas for years. There were some concerns years ago when proton pump inhibitors (PPIs) were noted to be associated with hypergastrinaemia and whether this could increase the risk of pancreatic cancers and cancers of other tissues with CCK receptors (2-5). Although a large study involving 130,000 patients with helicobacter infection reported a 4-times increase in colorectal cancers in those with high gastrin levels, hypergastrinaemia has been shown in subsequent studies NOT to be a co-carcinogen in gastrointestinal adenocarcinomas (6-8).

However, while studies have shown that both gastrin and CCK may not be mutagenic if elevated, they may increase the risk of patients in precancerous states (e.g. helicobacter pylori, colonic polyps, pancreatic intra-epithelial neoplasia (PanIN)) (9).

This is what we know:

  • Human gastrin is expressed in the developing foetal pancreas but is turned off at week 16. It is re-expressed in PanIN and markedly over-expressed in pancreatic cancers where it is found to stimulate growth of the cancers (10).
  • CCK is expressed at highly variable amounts in different neuroendocrine tumors, especially corticotrophic pituitary tumours, medullary thyroid carcinomas,  phaeochromocytomas, pancreatic islet cell tumours, Ewing’s sarcoma, cerebral gliomas, astrocytomas and acoustic neuromas.
  • Normally, only CCK2 receptors are expressed in normal pancreatic tissues but in pancreatic cancers, both CCK1 and CCK2 receptors are expressed (11). It is unclear whether this has any effect on the growth of the pancreatic cancers but various CCK receptor antagonists have been developed in an attempt to block the trophic effects of gastrin (and CCK).
  • At least in animal studies, there is evidence that CCK receptors may play an important role in PanIN progression and perpetuating the inflammatory milieu of chronic and relapsing pancreatitis (12).

Relevance to general practice?

So, how is this relevant to general practice? In particular, how does our knowledge of the many roles of CCK affect the use  of GLP1-RAs in the treatment of patients with type 2 diabetes?

We know that there are CCK receptors in the gallbladder wall and perhaps, GLP1-RAs may reduce gallbladder emptying. Indeed, Keller and Trautmann et al (13) showed that exenatide reduce gallbladder emptying significantly after infusion of exogenous CCK in fasting healthy subjects. In other words, exenatide blocks the action of CCK on the gallbladder.

Rehfeld et al recently examined the effects of GLP1-RAs on the secretion of CCK in 10 normal subjects and 10 patients with type 1 diabetes (14). Basal plasma concentrations of CCK were similar in the normal subjects and in the patients with diabetes. During the meal, the CCK concentrations rose significantly during saline infusion, whereas the GLP-1 infusion suppressed the secretion of CCK significantly in both normal subjects and in the patients with diabetes.

Thus, GLP1-RAs affects the gallbladder emptying in two ways: 1) GLP-1 RAs suppresses the meal-induced release of CCK peptides from the endocrine I-cells, and 2) GLP-1 reduces the CCK responsiveness of the gallbladder myocytes. Perhaps, this could offer an explanation for the increased risk of adverse gallbladder problems with patients on GLP-1 RAs.

In a population based cohort study using data from general practices contributing to the UK Clinical Practice Rsearch Datalink, the use of DPP-4 inhibitors and GLP-1 receptor agonists were both associated with increased risks for cholangiocarcinoma, compared with use of sulfonylureas or thiazolidinediones in patients with type 2 diabetes (15).

Patients with T2D are at increased risk of various gastrointestinal cancers including colonic and pancreatic cancers. Targeting the CCK/gastrin receptor interface may open up a whole new strategy in the treatment of these cancers. Already target specific therapies are showing promise.

References:

  1. Rehfeld JF (2017) Cholecystokinin— From Local Gut Hormone to Ubiquitous Messenger. Front. Endocrinol. 8:47. doi: 10.3389/fendo.2017.00047
  2. Brunner G, Creutzfeldt W. Omeprazole in the long-term management of patients with acid-related diseases resistant to ranitidine. Scand J Gastroenterol Suppl 1989; 166: 101-105.
  3. Chubineh S, Birk J. Proton pump inhibitors: the good, the bad, and the unwanted. South Med J 2012; 105: 613-618
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  5. Lamberts R, Creutzfeldt W, Struber HG, Brunner G, Solcia E. Long-term omeprazole therapy in peptic ulcer disease: gastrin, endocrine cell growth and gastritis. Gastroenterology 1993; 104: 1356-1370.
  6. Shah P, Rhim AD, Haynes K, Hwang WT, Yang YX. Diagnosis of pernicious anemia and the risk of pancreatic cancer. Pancreas 2014; 43: 422-426
  7. Orbuch M, Venzon DJ, Lubensky IA, Weber HC, Gibril F, Jensen RT. Prolonged hypergastrinemia does not increase the frequency of colonic neoplasia in patients with Zollinger-Ellison syndrome. Dig Dis Sci 1996; 41: 604-613.
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  10. Prasad NB, Biankin AV, Fukushima N, Maitra A, Dhara S, Elkahloun AG, Hruban RH, Goggins M, Leach SD. Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res 2005; 65: 1619-1626.
  11. Weinberg DS, Ruggeri B, Barber MT, Biswas S, Miknyocki S, Waldman SA. Cholecystokinin A and B receptors are differentially expressed in normal pancreas and pancreatic adenocarcinoma. J Clin Invest 1997; 100: 597-603.
  12. Smith JP, Solomon TE. Cholecystokinin and pancreatic cancer: the chicken or the egg? Am J Physiol Gastrointest Liver Physiol 2014; 306: G91-G101.
  13. Keller J, Trautmann ME, Haber H, et al. Effect of exenatide on cholecystokinin-induced gallbladder emptying in fasting healthy subjects. Regul Pept. 2012;179:77–83.
  14. Jens F. Rehfeld, Filip K. Knop, Ali Asmar, Sten Madsbad, Jens J. Holst & Meena Asmar (2018): Cholecystokinin secretion is suppressed by glucagon-like peptide-1: clue to the mechanism of the adverse gallbladder events of GLP-1-derived drugs, Scandinavian Journal of Gastroenterology
  15. Devin Abrahami,1,2 Antonios Douros,1,2,3 Hui Yin, Incretin based drugs and risk of cholangiocarcinoma among patients with type 2 diabetes: population based cohort study. BMJ 2018;363:k4880
  16. Jill P. Smith, Lionel K. Fonkoua, Terry W. Moody. The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies. International Journal of Biological Sciences 2016; 12(3): 283-291. doi: 10.7150/ijbs.14952