Secondary Logo

Journal Logo

Why cholecystokinin and gastrin are also incretins

Rehfeld, Jens F.

Cardiovascular Endocrinology & Metabolism: September 2016 - Volume 5 - Issue 3 - p 99–101
doi: 10.1097/XCE.0000000000000095
Review Articles
Free

This review argues that cholecystokinin (CCK) and gastrin are incretins. The insulin cells are equipped with CCK2/gastrin receptors. CCK/gastrin peptides stimulate insulin secretion and potentiate the incretin effect of glucagon-like peptide-1. CCK/gastrin and insulin are released in significant amounts during normal mixed meals even at modest changes in blood glucose concentrations. Treatment of diabetes patients with combinatorial glucagon-like peptide-1 and CCK or gastrin-derived constructs therefore provides an expedient option.

Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

Correspondence to Jens F. Rehfeld, MD, Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark Tel: +45 3545 3018; fax: +45 3545 4640; e-mail: jens.f.rehfeld@rh.regionh.dk

Received July 7, 2016

Accepted July 7, 2016

Back to Top | Article Outline

Introduction

For years, the gut hormonal stimulation of insulin secretion (the incretin effect) has been attributed to two specific gut hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Nobody questions whether GIP and GLP-1 are important incretins. However, as discussed below, there are reasons to question whether they are the only incretins when seen in a broader physiological context with clinical perspectives. This article will argue that cholecystokinin (CCK) and gastrin peptides should also be looked upon as incretins, and perhaps even more of the many gut hormones should also be taken into consideration. The issue about CCK and gastrin as incretins was described in detail half-a-decade ago 1. The present article is an update based on that review.

Back to Top | Article Outline

Incretin

The first gut hormone to be discovered was secretin 2. The entire concept of endocrinology is founded on secretin. Starling, the co-discoverer of secretin, had already considered the possibility that secretin – in addition to its effect on pancreatic exocrine secretion – might also stimulate the ‘internal secretion’ of the pancreas. The term ‘incrétine’ was launched in 1932 by the Belgian physiologist La Barre 3 to match and distinguish the gut hormonal insulin-releasing activity from secretin.

The concept was, however, effectively revived in the 1960s, when insulin could be measured in plasma. Thus, McIntyre et al.4 and Elrick et al.5 showed that oral glucose induced a considerably larger insulin response compared with intravenous glucose. Subsequently, over several years, it was shown that GIP and truncated GLP-1 together could account for the observed difference in glucose-induced insulin secretion. In other words, GIP and GLP-1 sufficed to explain the intestinal insulin-releasing activity (incretin) after oral glucose ingestion. Since then, incretin effects of other gut hormones have been overlooked.

The problem is two-fold. First, a large oral intake of pure glucose is unphysiological. Neither humans nor other mammals obtain food and calories that way. Meals are mixtures of many components that release a multitude of gastrointestinal hormones. Second, the understanding of gut hormonal regulation has for more than a century been misled by the textbook concept of one hormone, one target: secretin stimulates pancreatic bicarbonate secretion, gastrin stimulates gastric acid secretion, CCK stimulates gallbladder contraction, GIP stimulates glucose-induced insulin secretion, motilin stimulates intestinal motility, etc. Today, the picture is different 6. We now know that the mammalian digestive tract expresses at least 20 different hormone genes, each prohormone being processed to several different bioactive forms so that more than a hundred hormonal bioactive peptides of intestinal origin participate in the regulation of digestion. Many hormone genes are expressed not only in enteroendocrine cells but also in gastrointestinal neurons and endocrine-like gut cells destined for local paracrine secretion 7. Moreover, the gut peptides often have multiple targets and thus more functions rather than a single or two cell types. Furthermore, gut peptides are not only acutely active as hormones and neurotransmitters but also have long-term growth effects. Finally, different gut peptides may interact in their activity, not only in terms of simple addition or inhibition but also in terms of having potentiating interactive effects; thus, a single hormone that in itself is without significant effect on a given target may be highly active in minute concentrations when acting together with other gut hormones. Such interaction is also suggested by the patterns of receptor expression on target cell membranes and by the subsequent intracellular cross-talking between different signal transduction pathways.

Back to Top | Article Outline

Gastrin and CCK peptides

The main production site of gastrin is antral G-cells wherein most bioactive gastrin is synthesized as gastrin-17 and gastrin-34, both of which occur in tyrosyl-sulphated and tyrosyl-nonsulphated form. Moreover, shorter and longer gastrins are synthesized, but only in small quantities. The synthesis of gastrin is cell-specific. Accordingly, foetal and neonatal G-cells in pancreatic islets synthesize only completely sulphated gastrin-17.

Similar to gastrin, CCK also occurs in different molecular forms. The main forms are synthesized in endocrine I-cells in the gut. They are CCK-58, CCK-33, CCK-22, and CCK-8, all of which are present in the circulation. Notably, the CCK gene is, however, also abundantly expressed in neurons, including pancreatic neurons that innervate islet cells and intrapancreatic ganglia 8. The major transmitter forms are sulphated CCK-8 and the short CCK-5. CCK-5 and perhaps CCK-4 may be of particular interest because of the high stimulatory potency for insulin release in the porcine and human pancreas 8–10.

Back to Top | Article Outline

Gastrin and CCK receptors

The targets for gastrin and CCK peptides are two 11,12 related G-protein-coupled receptors now called CCK-A (or CCK1) and CCK-B (or CCK2) receptors. The CCK1 receptor mediates gallbladder contraction, relaxation of the sphincter of Oddi, pancreatic growth and enzyme secretion, delay of gastric emptying, and inhibition of gastric acid secretion through somatostatin. The CCK1 receptor is also expressed in the pituitary, the myenteric plexus, and areas of the midbrain. The CCK receptor binds only CCK peptides that are amidated and sulphated with high affinity, whereas the affinity of nonsulphated CCK peptides and gastrins is negligible. Thus, nonsulphated CCKs, short CCKs (CCK-5) and the gastrins are not physiological ligands for the CCK1 receptor.

The CCK2 receptor is the predominant receptor for gastrin and CCK peptides in the central nervous system. It binds both sulphated and nonsulphated gastrin and CCK peptides, as well as short C-terminal fragments such as CCK-5 with high affinity. The CCK2 receptor is also abundantly expressed on enterochromaffin-like-cells in the stomach and on islet cells and ganglionic neurons in the pancreas of humans and pigs 13,14. Thus, islet cells are targets for both locally released gastrin (pancreatic G-cells) and CCK peptides (intrapancreatic CCK neurons), as well as from endocrine gastrin and CCK in circulation. Here, the concentrations of gastrin, however, are 10- to 20-fold above those of CCK 15. Notably, the CCK receptor expression in the pancreas is species specific. There are major discrepancies between humans and pigs (abundant islet-cell expression of the CCK2 receptor 13) and between rodents and dogs, where the CCK1 receptor is more abundant. Consequently, incretin results on CCK and gastrin obtained from rat, mice and dog studies do not necessarily apply to human physiology and pathophysiology.

Back to Top | Article Outline

Incretin studies of gastrin and CCK in humans and pigs

During the late 1960s and the 70s, a number of incretin studies on gastrin in humans were reported from several laboratories 8,9,16–20. The conclusions were that exogenous gastrin in dose–response studies does indeed release insulin, but that the endogenous gastrin release after oral glucose in normal individuals was too small to explain the insulin response during an oral glucose tolerance test. Therefore, using the oral-glucose-incretin definition, gastrin as such contributed only little to the incretin effect. However, review of these older studies suggests that this conclusion probably was false negative. Exogenous gastrin-17 in itself is quite a potent insulin-releaser together with intravenous glucose. An ordinary protein-rich meal releases, with expedient timing, both gastrin and insulin in substantial amounts, whereas the elevation in blood glucose concentration is small 18. Hence, in such daily meal-physiologic situation, gastrin is likely to stimulate the secretion of insulin significantly. Moreover, studies in endogenous hypergastrinaemia support an incretin effect of gastrin in humans 19.

The incretin effect of CCK has been less systematically examined in humans and pigs, because CCK studies entail several pitfalls in comparison with those of gastrin. Thus, sufficient amounts of pure CCK peptides have been difficult to obtain. Moreover, CCK peptides are less stable compared with the gastrins, and the studies have been hard to monitor due to shortage of reliable CCK assays for plasma measurements of CCK. Nevertheless, in studies of exogenous CCK, short peptides such as CCK-8, CCK-5, and CCK-4 have been shown to release insulin quite efficiently in humans and in the isolated perfused porcine pancreas 8,17,21.

Back to Top | Article Outline

Conclusion

Food and digestion are prerequisites for life. Accordingly, the gut is densely innervated and equipped with hormone-producing cells for neuroendocrine regulation of digestion and metabolic functions. The incretin function has, for years, been considered just one of the several extraintestinal activities of some gut hormones.

With the rapidly growing epidemics of obesity, diabetes mellitus and associated cardiovascular diseases, incretin has become a central issue, perhaps the clinically most important of all endocrine gut functions. The prospect of GLP-1 analogues as major drugs for the treatment of type 2 diabetes bears witness to this development and indicates that diabetes and obesity with derived cardiovascular complications should be considered gut endocrine diseases. Thus, the influence and control of insulin and glucagon secretion by gastrointestinal hormones and neurons have become a central issue. Perhaps the issue is too important to be left entirely to just two gut peptides, GLP-1 and GIP. Their history and the recognition of their functions are closely associated with unphysiological intake of large glucose loads. Considering that the daily food intake by normal individuals, diabetic patients and cardiovascular patients has different compositions, the time has come to look also at other gut hormones which may act in concert with one or both of the established incretins. In this context, it is interesting that in nonobese diabetic mice GLP-1, even in substantial doses, has no effect on pancreatic islet-cell/β-cell regeneration and hyperglycaemia. Moreover, gastrin on its own has no effect. However, when GLP-1 is combined with even very small doses of gastrin, the β-cells grow, insulin is secreted and the mice become normoglycaemic 22. The important factor in the observed mechanism is that interaction between gut hormones and gastrin, as well as CCK, seems worth while when insulin secretion is on the agenda. This point has also been emphasized in more recent combinatorial studies 23–25. Therefore, the early studies of the incretin effect of gastrin and CCK from the 1970s also deserve a second look.

Back to Top | Article Outline

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline

References

1. Rehfeld JF. Incretin physiology beyond glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide: cholecystokinin and gastrin peptides. Acta Physiol (Oxf) 2011; 201:405–411.
2. Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol 1902; 28:325–353.
3. La Barre J. On the possibility of treating diabetes with incretin. Bull Acad R Med Belg 1932; 12:620–634.
4. McIntyre N, Holdsworth CD, Turner DA. New interpretation of oral glucose tolerance. Lancet 1964; 2:20–21.
5. Elrick H, Stimmler L, Hlad CJ, Arai Y. Plasma insulin responses to oral and intravenous glucose administration. J Clin Endocrinol Metab 1964; 24:1076–1082.
6. Rehfeld JF. The new biology of gastrointestinal hormones. Physiol Rev 1998; 78:1087–1108.
7. Larsson LI, Goltermann N, de Magistris L, Rehfeld JF, Schwartz TW. Somatostatin cell processes as pathways for paracrine secretion. Science 1979; 205:1393–1395.
8. Rehfeld JF, Larsson LI, Goltermann NR, Schwartz TW, Holst JJ, Jensen SL, Morley JS. Neural regulation of pancreatic hormone secretion by the C-terminal tetrapeptide of CCK. Nature 1980; 284:33–38.
9. Ohgawara H, Mizuno Y, Tasaka Y, Kosaka K. Effect of the C-terminal tetrapeptide amide of gastrin on insulin secretion in man. J Clin Endocrinol Metab 1969; 29:1261–1262.
10. Rehfeld JF. Effect of gastrin and its C-terminal tetrapeptide on insulin secretion in man. Acta Endocrinol (Copenh) 1971; 66:169–176.
11. Kopin AS, Lee YM, McBride EW, Miller LJ, Lu M, Lin HY, et al.. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci USA 1992; 89:3605–3609.
12. Wank SA, Harkins R, Jensen RT, Shapira H, de Weerth A, Slattery T. Purification, molecular cloning, and functional expression of the cholecystokinin receptor from rat pancreas. Proc Natl Acad Sci USA 1992; 89:3125–3129.
13. Reubi JC, Waser B, Gugger M, Friess H, Kleeff J, Kayed H, et al.. Distribution of CCK1 and CCK2 receptors in normal and diseased human pancreatic tissue. Gastroenterology 2003; 125:98–106.
14. Saillan-Barreau C, Dufresne M, Clerc P, Sanchez D, Corominola H, Moriscot C, et al.. Evidence for a functional role of the cholecystokinin-B/gastrin receptor in the human fetal and adult pancreas. Diabetes 1999; 48:2015–2021.
15. Rehfeld JF. How to measure cholecystokinin in tissue, plasma and cerebrospinal fluid. Regul Pept 1998; 78:31–39.
16. Dupre J, Curtis JD, Unger RH, Waddell RW, Beck JC. Effects of secretin, pancreozymin, or gastrin on the response of the endocrine pancreas to administration of glucose or arginine in man. J Clin Invest 1969; 48:745–757.
17. Kaneto A, Tasaka Y, Kosaka K, Nakao K. Stimulation of insulin secretion by the C-terminal tetrapeptide amide of gastrin. Endocrinology 1969; 84:1098–1106.
18. Rehfeld JF, Stadil F. The effect of gastrin on basal- and glucose-stimulated insulin secretion in man. J Clin Invest 1973; 52:1415–1426.
19. Rehfeld JF. Disturbed islet-cell function related to endogenous gastrin release. Studies on insulin secretion and glucose tolerance in pernicious anemia. J Clin Invest 1976; 58:41–49.
20. Rehfeld JF, Holst JJ, Kühl C. The effect of gastrin on basal and aminoacid-stimulated insulin and glucagon secretion in man. Eur J Clin Invest 1978; 8:5–9.
21. Ahrén B, Mårtensson H, Nobin A. Cholecystokinin (CCK)-4 and CCK-8 stimulate islet hormone secretion in vivo in the pig. Pancreas 1988; 3:279–284.
22. Suarez-Pinzon WL, Power RF, Yan Y, Wasserfall C, Atkinson M, Rabinovitch A. Combination therapy with glucagon-like peptide-1 and gastrin restores normoglycemia in diabetic NOD mice. Diabetes 2008; 57:3281–3288.
23. Suarez-Pinzon WL, Rabinovitch A. Combination therapy with a dipeptidyl peptidase-4 inhibitor and a proton pump inhibitor induces β-cell neogenesis from adult human pancreatic duct cells implanted in immunodeficient mice. Cell Transplant 2011; 20:1343–1349.
24. Fosgerau K, Jessen L, Lind Tolborg J, Østerlund T, Schæffer Larsen K, Rolsted K, et al.. The novel GLP-1-gastrin dual agonist, ZP3022, increases β-cell mass and prevents diabetes in db/db mice. Diabetes Obes Metab 2013; 15:62–71.
25. Singh PK, Hota D, Dutta P, Sachdeva N, Chakrabarti A, Srinivasan A, et al.. Pantoprazole improves glycemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2012; 97:E2105–E2108.
Keywords:

cholecystokinin; gastrin; gut hormones; incretin; insulin secretion

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.