Premises for Cholecystokinin and Gastrin Peptides in Diabetes Therapy

Abstract

Gastrin and cholecystokinin (CCK) are classical gastrointestinal peptide hormones. Their biogenesis, structures, and intestinal secretory patterns are well-known with the striking feature that their receptor-bound ‘active sites’ are highly homologous and that this structure is conserved for more than 500 million years during evolution. Consequently, gastrin and CCK are agonists for the same receptor (the CCK₂ receptor). But in addition, tyrosyl O-sulphated CCK are also bound to the specific CCK₁ receptor. The receptors are widely expressed in the body, including pancreatic islet-cell membranes. Moreover, CCK and gastrin peptides are at various developmental stages and diseases expressed in pancreatic islets; also in human islets. Accordingly, bioactive gastrin and CCK peptides stimulate islet-cell growth as well as insulin and glucagon secretion. In view of their insulinotropic effects, gastrin and CCK peptides have come into focus as drug targets, either alone or in combination with other insulinotropic gut hormones or growth factors. So far, modified CCK and gastrin peptides are being examined as potential drugs for therapy of type 1 as well as type 2 diabetes mellitus.

Keywords

Cholecystokinin (CCK)diabetes mellitus gastrin gastrointestinal endocrinology peptide drugs

Introduction

Four different lines of biomedical research during the last 4 decades are coming together in this review. The first entails the recognition that the digestive tract is by far the largest endocrine organ in the body. The gut expresses at least 20 different hormone genes, of which some are homologous. And as the prohormonal translation products are often heavily processed by endoproteolysis and amino acid derivatizations in neuroendocrine cells, the gastrointestinal tract releases an order of hundred different bioactive peptides to blood during and after a meal (for reviews, see Rehfeld^1,2).

The second line is the gut-islet-axis, according to which some gastrointestinal hormones – not least gastrin and cholecystokinin (CCK) – in addition to the gut are expressed within pancreatic islet cells. The expression may occur in specific endocrine cells, in the classical islet cells, or in intra-islet ganglia and neurones. Furthermore, the level of expression varies during ontogenesis, phylogenesis, and during disease.^3-15

The third line is the receptor-line, which has led to the recognition that receptors for hormonal gut peptides are widely expressed in extra-intestinal cells and organs. Hence, gut hormones contribute substantially to metabolic and growth regulation of a wide array of extra-intestinal functions all over the body. One of these functions is the secretion of insulin and glucagon from pancreatic islet cells.^16-18 The gut hormones that stimulate in islet-cell secretion and growth have been named incretins (for review, see Rehfeld¹⁹).

The last line is pharmacochemical and deals with derivatization of bioactive peptides to become useful drugs (‘peptide therapeutics’).^20,21 Recently, interest has focused on gut hormones with incretin-activity where, in particular, glucagon-like peptide-1 (GLP-1)-derived drugs have been applied to the treatment of type 2 diabetes mellitus.^22-24 There are, however, considerable amounts of evidence to suggest that also other gastrointestinal hormones may prove valuable in diabetes therapy. Among these are the homologous CCK and gastrin peptides, which will be discussed in the following.

CCK and Gastrin Peptides

As shown in Figure 1, the C-terminal α-amidated ‘active site’ sequences of CCK and gastrin are highly homologous. A significant difference is the position of the C-terminal tyrosyl residue: position 7 in CCK vs position 6 in gastrin (as counted from the C-terminal Phe·NH₂). However, not only is the sequence-position of the tyrosyl residue important but it is also noteworthy that in most of the CCK peptides, this residue is O-sulphated, whereas only half of the gastrins are tyrosyl O-sulphated.

Figure 1.

The C-terminal bioactive amino acid sequences of members of the gastrin/cholecystokinin family of peptides. Besides the sequences of mammalian cholecystokinin and gastrin, highly homologous sequences have been identified in extracts of frog skin glands (caerulein and phyllocaerulein) and the neural ganglion of the protochordate, Ciona intestinalis (cionin). Cionin with its disulphotyrosyl-containing sequence resembles a common ancestor candidate for gastrin and cholecystokinin.²⁵

The main production site of gastrin in adults is the antro-duodenal G-cells where most bioactive, ie, carboxyamidated, gastrin is synthesized as gastrin-17 and gastrin-34, both of which occur in tyrosyl O-sulphated and non-sulphated forms.^26-28 Also, shorter (gastrin-14 and gastrin-6) as well as longer gastrins (gastrin-71) are synthesized and secreted, but only in small quantities.^29-31 The synthesis of gastrin is cell-specific (for reviews, see Rehfeld,¹ Rehfeld et al,³² and Schubert and Rehfeld³³) Therefore, in the present context, it is noteworthy that the specific gastrin-producing cells in the foetal and neonatal pancreatic islets synthesize mainly O-sulphated gastrin-17.^4,34 The sulphation, however, does not change the insulinotropic activity of gastrin. The expression of gastrin peptides also outside the gastrointestinal tract and the pancreas is summarized in Table 1.

Table 1.

Expression of gastrin peptides in normal adult mammalian tissue.^a

Tissue	Total translation product (pmol/g)	Precursor percentage
Gastrointestinal tract
Antral mucosa	10 000	5
Duodenal mucosa	400	20
Jejunal mucosa	40	30
Ileal mucosa	20	85
Colonic mucosa	0.2	100
Neuroendocrine tissue
Cerebellum	5	20
Vagal nerve	8	10
Adenohypophysis	200	98
Neurohypophysis	30	5
Adrenal medulla	2	100
Pancreas	2	95
Genital tract
Ovaries	0.5	100
Testicles	6	100
Spermatozoa	2	55
Respiratory tract
Bronchial mucosa	0.3	100

Orders of magnitude based on examination of different mammalian species.

Like gastrin, CCK is also expressed in different molecular forms. The main forms are synthesized in endocrine I-cells in the duodenum, jejunum, ileum, and – in some species – also in the colon.^35,36 The circulating forms released from the gut to plasma are CCK-58, CCK-33, CCK-22, and CCK-8.^32,37,38 Notably, the predominant forms in blood are CCK-33 and CCK-58, whereas CCK-8 constitutes only a minor fraction in plasma.³⁷ As already mentioned, most of the intestinal hormonal CCK peptides are O-sulphated, but around 25% are not.³⁹ The CCK gene is, however, also abundantly expressed in cerebral and peripheral neurones, including pancreatic neurones that innervate islet cells and intrapancreatic ganglia.^8,40-43 The major neurotransmitter forms are O-sulphated CCK-8 and the short CCK-5.^40,41,44,45 CCK-5 and CCK-4 may be of particular interest in a diabetes context because of the high stimulatory potency for insulin release seen in the porcine and human pancreas.^8,46,47 The tissue expression of CCK peptides also outside the intestinal tract is summarized in Table 2. CCK peptides in central and peripheral neurones are neurotransmitters, whereas the CCK in non-neuroendocrine cells is assumed to act as local, paracrine peptide messengers.

Table 2.

Expression of CCK peptides in normal adult mammalian tissue.^a

Tissue	Total translation product (pmol/g)	Precursor percentage
Gastrointestinal tract
Duodenal mucosa	200	5
Jejunal mucosa	250	20
Ileal mucosa	20	50
Colonic mucosa	5	50
Neuroendocrine tissue
Adenohypophysis	25	100
Neurohypophysis	20	10
Thyroid gland	2	20
Adrenal medulla	1	50
Genital tract
Testicles	5	80
Spermatozoa^b	–	–
Central nervous system
Cerebral cortex	400	2
Hippocampus	350	2
Hypothalamus	200	2
Cerebellum	2	80

Abbreviation: CCK, cholecystokinin.

Orders of magnitude based on examination of different mammalian species.

Cholecystokinin peptides are present in spermatozoa of non-human mammals. The concentration, however, has not been quantitated.

Gastrin and CCK Receptors

The targets for gastrin and CCK are 2 related G-protein coupled receptors.^48,49 The original naming as CCK and gastrin receptor is simple and meaningful.^48,49 But a later nomenclature with names such as CCK-A or CCK₁ and CCK-B or CCK₂ receptors, respectively, has now gained a strong foothold (for reviews, see Dufresne et al¹⁸ and Reubi⁵⁰). Therefore, the CCK₁/CCK₂ receptor naming is used in the following.

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 via somatostatin.⁵¹ The CCK₁ receptor is also expressed in the pituitary, the myenteric plexus, and areas of the midbrain.^52,53 The CCK₁ receptor binds with high affinity only CCK peptides that are both carboxyamidated and tyrosyl O-sulphated, whereas the affinity of non-sulphated CCK peptides and gastrins is negligible.⁵⁴ Thus, non-sulphated, longer CCKs, short CCKs (CCK-5 and CCK-4), and the gastrins – irrespective of their degree of sulphation – are not physiological agonists for the CCK₁ receptor.

The CCK₂ receptor is the predominant receptor for gastrin and CCK peptides in the central nervous system (‘the brain receptor’).^54,55 It binds both sulphated and non-sulphated gastrin and CCK peptides, as well as short C-terminal fragments like CCK-5 and CCK-4 with high affinity. The CCK₂ receptor is also abundantly expressed on enterochromaffin (ECL) cells in the stomach,^56,57 and on islet cells and ganglionic neurones in the pancreas of man and pig.^16,58,59 Thus, islet cells are targets for both locally released gastrin (from specific pancreatic gastrin-cells and β-cells),^3-7 and CCK peptides (from intrapancreatic CCK neurones and islet cells),^8,10,11 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.^37,38,60 Notably, the CCK receptor expression in the pancreas is species-specific. There are major discrepancies between – on one hand – man and pig (abundant islet-cell expression of the CCK₂ receptor) and – on the other hand – between rodents and dogs, where the specific CCK₁ receptor is more abundant.^16,61,62 Consequently, results on the insulinotropic effects of CCK and gastrin obtained from rat, mice, and dog studies do not necessarily apply to human physiology and diabetes pathophysiology.

The Biological Linkage of Gastrin and CCK to Pancreatic Islets

As indicated above, an association between gastrin/CCK peptides and islet-cell functions (and hence a role for these peptides in diabetes therapy) has been discussed and examined in the last decades. The association includes a number of cellular, developmental, and pathological observations. First, the discovery that an essential part of gastrin in foetal and neonatal life in mammals is expressed in specific gastrin cells in pancreatic islets.^3-5 These cells are ultra-structurally similar to the antro-duodenal G-cells in adults, but differ as being ‘closed’ cells without luminal contact and because the foetal pancreatic gastrin product is more extensively O-sulphated.^3-5 The marked pancreatic expression precedes antral gastrin expression in the stomach,^3-5 but low-level pancreatic expression is maintained also in adult life, although in inactive prohormonal forms.⁶ Second, the finding that pancreatic CCK neurones innervate endocrine islet cells and intra-islet ganglions involves also small CCK peptides in islet-cell regulation.^8,43 Third, the observation that CCK₂ receptors are expressed fairly abundantly on beta and alpha cells in human islets indicates that both gastrin and CCK peptides influence insulin and glucagon secretion.^16,59 Fourth, there are also gastrin and CCK peptides in secretory granules within insulin cells of obese rodents and humans, where they apparently protect against β-cell apoptosis.^{7,10,11,63,64} Fifth, earlier literature has described islet-cell neogenesis and increased insulin secretion in endogenous hypergastrinaemia and during gastrin stimulation, emphasizing the growth stimulatory effects of gastrin and CCK peptides.^65-77 Sixth, there is the well-known occurrence of gastrin- and CCK-producing neuroendocrine tumours from pancreatic islets.^78-83 And, finally, there is the incretin effect of gastrin and CCK peptides as described below. The biological linkages of CCK and gastrin to islet cells are summarized in Table 3.

Table 3.

Biological linkages of gastrin and/or CCK to pancreatic islets.

Peptide(s)	Linkage	References
Gastrin	Expression in islet G-cells during foeto-/neonatal life	3 -7
CCK	Intra-islet CCK neurones	8, 42
Gastrin and CCK	CCK₂ receptor expression on islet cells	16, 17, 58, 60, 61
CCK	Expression in β-cells during obesity	10, 11, 62
Gastrin	Islet-cell neogenesis and increase in the insulin secretion in hypergastrinaemia	65, 67, 69, 71 -74
Gastrin and CCK	Neuroendocrine pancreatic tumours	77 -82
Gastrin and CCK	Incretin effect, also during meals	64, 84
Gastrin and CCK	Potentiation of other incretins	74, 85, 86
Gastrin	Expression preceding islet-cell neogenesis after pancreatic duct-ligation	75

Abbreviation: CCK, cholecystokinin.

Incretin Studies of Gastrin and CCK in Man and Pig

During the late 1960s and in the 1970s, a number of incretin studies of gastrin in man were reported from several laboratories.^{46,47,65-67,69,84} The conclusions in the 1970s from dose-response studies were that – on one hand – exogenous gastrin does indeed release insulin, but then – on the other hand – endogenous gastrin release after oral glucose in normal subjects was too small to explain the intestinal part of the insulin response during an oral glucose tolerance test.^65,71 Therefore, using the oral-glucose-incretin definition, gastrin as such was assumed to contribute only little to the incretin effect of gastrointestinal hormones. However, review of the older studies suggests that this negative conclusion was false. Exogenous gastrin-17 in itself is a quite potent insulin-releaser together with intravenous glucose.⁶⁵ Moreover, an ordinary protein-rich meal releases both gastrin and insulin in substantial amounts, whereas the elevation in blood glucose concentration is small.⁶⁵ Hence, during and after such a meal, gastrin is likely to stimulate the secretion of insulin significantly. Moreover, studies in endogenous hypergastrinaemia in man support the idea of an incretin effect of gastrin in man.⁶⁶

The incretin effect of CCK has been less extensively studied in man and pig; maybe because CCK studies entail several problems in comparison with those of gastrin. Thus, for exogenous studies, sufficient amounts of pure CCK peptides (especially CCK-58 and CCK-33) have been difficult to obtain. Moreover, larger CCKs are less stable than the gastrins, and the studies have been hard to monitor because of shortage of reliable CCK assays for plasma measurements of CCK.^38,60 Nevertheless, short CCK peptides such as CCK-8, CCK-5, and CCK-4 have been shown to release insulin quite efficiently in man and in the isolated perfused porcine pancreas.^{8,46,47,84,87}

Gastrin and CCK Analogues for Diabetes Therapy

CCK and gastrin analogues for stimulation of insulin secretion will have to target the CCK₂ receptor on the β-cells. Although CCK and gastrin peptides are all agonists for the CCK₂ receptor (because of the common C-terminus Gly-Trp-Met-Asp-Phe·NH₂ [see also Figure 1]), O-sulphated CCK peptides also activate the CCK₁ receptor on the gallbladder. Receptor-activated permanent gallbladder contraction, however, is inexpedient and may result in cholelithiasis and other gallbladder problems.⁸² Therefore, sulphated CCK-like peptides should probably not be used for therapy of human diabetes.

The CCK analogues under study were recently reviewed.⁸⁸ They include N-terminally glycosylated CCK-8 and other N-terminally protected CCK analogues (pGlu-Gln-CCK-8, and Ac-Y*-CCK-8).^85,86,89,90 Of these, the pGlu-Gln-CCK-8 designed and tested by Irwin et al⁹⁰ looks particularly promising, not least in combination with GLP-1.^86,91

Also, gastrin alone, or in combination with GLP-1 or relevant growth factors, shows promise in treatments of type 1 diabetic rodents.^72-75,92 Again, strikingly positive results were seen in the combinatorial treatment with gastrin and GLP-1.⁷⁵ Accordingly, a hybrid dual agonist between GLP-1 and the C-terminal hexapeptide amide fragment of gastrin has proved pretty beneficial in diabetic mice.^93,94

Interestingly, it has just been demonstrated that human β-cells after fibroblast growth factor 2 (FGF-2)-induced dedifferentiation express gastrin.⁹⁵ And also worth mentioning is the fact that postprandial CCK-secretion is increased in Roux-en-Y gastric bypass (RYGB)-operated obese patients.^96-98 Hence, endogenous CCK in these patients may contribute to the insulinotropic amelioration of their type 2 diabetes.

Conclusions

Food is a prerequisite for life. Therefore, regulation of digestion is essential for all multicellular organisms. Accordingly, the gut is densely innervated and equipped with endocrine cells for accurate regulation of digestion, absorption and metabolic functions in the body. For decades, studies of gastrointestinal hormones have probably focused too much on functions inside the gut. Studies of incretin did for many years so to speak fall between 2 stools: the traditional gastrointestinal physiologists were more interested in proper gut functions (secretion of digestive juices, digestive enzymes, motility, and emptying), and classical endocrinologists did not like the darkness of the bowel.

With the rapidly growing epidemics of obesity and diabetes mellitus, incretin, however, has become a central biomedical issue. The prospect of GLP-1 analogues as major drugs for treatment of type 2 and perhaps also type 1 diabetes bears witness to this development and indicates that diabetes and obesity can be profoundly influenced by gastrointestinal hormones. Among these, GLP-1 and GIP (gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide) are important, but not the only players. As described here and previously, the combinatorial effects of GLP-1 and GIP with CCK and gastrin peptides seem worth pursuing.^88,99-101

Footnotes

Acknowledgements

The skilful secretarial assistance of Connie Bundgaard (cand.phil.) is gratefully acknowledged. Studies from the author’s laboratory of relevance for the present review have been supported by the Danish State Biotechnology Centre for Cellular Communication.

Funding:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions

No other authors than Jens F. Rehfeld have contributed to this article.

ORCID iD

Jens F Rehfeld

References

Rehfeld

JF.

The new biology of gastrointestinal hormones. Physiol Rev. 1998;78:1087-1108.

Rehfeld

. The endocrine gut. In: Belfiore

LeRoith

, eds. Principles Endocrinol Hormone Action. London: Springer Nature; 2018:517-531.

Larsson

Rehfeld

Sundler

Håkanson

Pancreatic gastrin in foetal and neonatal rats. Nature. 1976;262:609-610.

Brand

Andersen

Rehfeld

JF.

Complete tyrosine-O-sulphation of gastrin in neonatal rat pancreas. Nature. 1984;309:456-458.

Brand

Fuller

PJ.

Differential gastrin gene expression in rat gastrointestinal tract and pancreas during neonatal development. J Biol Chem. 1988;263:5341-5347.

Bardram

Hilsted

Rehfeld

JF.

Progastrin expression in the mammalian pancreas. Proc Natl Acad Sci U S A. 1990;87:298-302.

Dahan

Ziv

Horwitz

, et al. Pancreatic β-cells express the fetal islet hormone gastrin in rodent and human diabetes. Diabetes. 2017;66:426-436.

Rehfeld

Larsson

Goltermann

, et al. Neural regulation of pancreatic hormone secretion by the C-terminal tetrapeptide of CCK. Nature. 1980;284:33-38.

Shimizu

Kato

Shiratori

, et al. Evidence for the existence of CCK-producing cells in rat pancreatic islets. Endocrinology. 1998;139:389-396.

10.

Lavine

Raess

Stapleton

, et al. Cholecystokinin is up-regulated in obese mouse islets and expands beta-cell mass by increasing beta-cell survival. Endocrinology. 2010;151:3577-3588.

11.

Lavine

Kibbe

Baan

, et al. Cholecystokinin expression in the β-cell leads to increased β-cell area in aged mice and protects from streptozotocin-induced diabetes and apoptosis. Am J Physiol Endocrinol Metab. 2015;309:E819-E828.

12.

Mojsov

Kopczynski

Habener

JF.

Both amidated and nonamidated forms of glucagon-like peptide I are synthesized in the rat intestine and the pancreas. J Biol Chem. 1990;265:8001-8008.

13.

Marchetti

Lupi

Bugliani

, et al. A local glucagon-like peptide 1 (GLP-1) system in human pancreatic islets. Diabetologia. 2012;55:3262-3272.

14.

Fujita

Wideman

Asadi

, et al. Glucose-dependent insulinotropic polypeptide is expressed in pancreatic islet alpha-cells and promotes insulin secretion. Gastroenterology. 2010;138:1966-1975.

15.

Vaudry

Burel

Galas

, et al. PACAP. In: Kastin

, ed. Handbook of Biologically Active Peptides. 2nd ed. New York, NY: Academic Press; 2013: 1038-1044.

16.

Reubi

Waser

Gugger

, et al. Distribution of CCK1 and CCK2 receptors in normal and diseased human pancreatic tissue. Gastroenterology. 2003;125: 98-106.

17.

Morisset

Julien

Lainé

Localization of cholecystokinin receptor subtypes in the endocrine pancreas. J Histochem Cytochem. 2003;51:1501-1513.

18.

Dufresne

Seva

Fourmy

Cholecystokinin and gastrin receptors. Physiol Rev. 2006;86:805-847.

19.

Rehfeld

JF.

The origin and understanding of the incretin concept. Front Endocrinol (Lausanne). 2018;9:387.

20.

Kaspar

Reichert

JM.

Future directions for peptide therapeutics development. Drug Discov Today. 2013;18:807-817.

21.

Fosgerau

Hoffmann

Peptide therapeutics: current status and future directions. Drug Discov Today. 2015;20:122-128.

22.

Davies

Bergenstal

Bode

, et al. Efficacy of liraglutide for weight loss among patients with type 2 diabetes: the SCALE diabetes randomized clinical trial. JAMA. 2015;314:687-699.

23.

Rosenstock

Buse

Azeem

, et al. Efficacy and safety of ITCA 650, a novel drug-device GLP-1 Receptor Agonist, in type 2 diabetes uncontrolled with oral antidiabetes drugs: the FREEDOM-1 trial. Diabetes Care. 2018;41:333-340.

24.

Waldrop

Zhong

Peters

, et al. Incretin-based therapy in type 2 diabetes: an evidence based systematic review and meta-analysis. J Diabetes Complications. 2018;32:113-122.

25.

Johnsen

Rehfeld

JF.

Cionin: a disulfotyrosyl hybrid of cholecystokinin and gastrin from the neural ganglion of the protochordate

Ciona intestinalis. J Biol Chem. 1990;265:3054-3058.

26.

Gregory

Tracy

HJ.

The constitution and properties of two gastrins extracted from hog antral mucosa. Gut. 1964;5:103-114.

27.

Gregory

Hardy

Jones

Kenner

Sheppard

RC.

The antral hormone gastrin. Structure of gastrin. Nature. 1964;204:931-933.

28.

Gregory

Tracy

HJ.

Isolation of two ‘big gastrins’ from Zollinger-Ellison tumour tissue. Lancet. 1972;2:797-799.

29.

Gregory

Tracy

Harris

, et al. Minigastrin; corrected structure and synthesis. Hoppe Seylers Z Physiol Chem. 1979;360:73-80.

30.

Rehfeld

Johnsen

AH.

Identification of gastrin component I as gastrin-71. The largest possible bioactive progastrin product. Eur J Biochem. 1994;223:765-773.

31.

Rehfeld

Hansen

Johnsen

AH.

Post-poly(Glu) cleavage and degradation modified by O-sulfated tyrosine: a novel post-translational processing mechanism. EMBO J. 1995;14:389-396.

32.

Rehfeld

Friis-Hansen

Goetze

Hansen

TV.

The biology of cholecystokinin and gastrin peptides. Curr Top Med Chem. 2007;7:1154-1165.

33.

Schubert

Rehfeld

. Gastric peptides – gastrin and somatostatin. Comprehensive Physiol. in press.

34.

Cantor

Andersen

Rehfeld

JF.

Complete tyrosine O-sulfation of gastrin in adult and neonatal cat pancreas. FEBS Lett. 1986;195:272-274.

35.

Fakhry

Wang

Martins

, et al. Distribution and characterisation of CCK containing enteroendocrine cells of the mouse small and large intestine. Cell Tissue Res. 2017;369:245-253.

36.

Zhang

Grosfeld

Williams

, et al. Fructose malabsorption induces cholecystokinin expression in the ileum and cecum by changing microbiota composition and metabolism. FASEB J. 2019;33:7126-7142.

37.

Rehfeld

Sun

Christensen

Hillingsø

JG.

The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33. J Clin Endocrinol Metab. 2001;86:251-258.

38.

Rehfeld

JF.

Accurate measurement of cholecystokinin in plasma. Clin Chem. 1998;44:991-1001.

39.

Agersnap

Rehfeld

JF.

Nonsulfated cholecystokinins in the small intestine of pigs and rats. Peptides. 2015;71:121-127.

40.

Rehfeld

. Immunochemical studies on cholecystokinin. II. Distribution and molecular heterogeneity in the central nervous system and small intestine of man and hog. J Biol Chem. 1978;253:4022-4030.

41.

Dockray

Gregory

Hutchison

Harris

Runswick

MJ.

Isolation, structure and biological activity of two cholecystokinin octapeptides from sheep brain. Nature. 1978;274:711-713.

42.

Larsson

Rehfeld

JF.

Localization and molecular heterogeneity of cholecystokinin in the central and peripheral nervous system. Brain Res. 1979;165: 201-218.

43.

Larsson

Rehfeld

JF.

Peptidergic and adrenergic innervation of pancreatic ganglia. Scand J Gastroenterol. 1979;14:433-437.

44.

Rehfeld

Hansen

HF.

Characterization of preprocholecystokinin products in the porcine cerebral cortex. Evidence of different processing pathways. J Biol Chem. 1986;261:5832-5840.

45.

Rehfeld

Bundgaard

Hannibal

, et al. The cell-specific pattern of cholecystokinin peptides in endocrine cells versus neurons is governed by the expression of prohormone convertases 1/3, 2, and 5/6. Endocrinology. 2008;149:1600-1608.

46.

Ohgawara

Mizuno

Tasaka

Kosaka

Effect of the C-terminal tetrapeptide amide of gastrin on insulin secretion in man. J Clin Endocrinol Metab. 1969;29:1261-1262.

47.

Rehfeld

JF.

Effect of gastrin and its C-terminal tetrapeptide on insulin secretion in man. Acta Endocrinol (Copenh). 1971;66:169-176.

48.

Kopin

Lee

McBride

, et al. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci U S A. 1992;89:3605-3609.

49.

Wank

Harkins

Jensen

Shapira

de Weerth

Slattery

Purification, molecular cloning, and functional expression of the cholecystokinin receptor from rat pancreas. Proc Natl Acad Sci U S A. 1992;89:3125-3129.

50.

Reubi

JC.

Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003;24:389-427.

51.

Chen

Zhao

Håkanson

Samuelson

Rehfeld

Friis-Hansen

Altered control of gastric acid secretion in gastrin-cholecystokinin double mutant mice. Gastroenterology. 2004;126:476-487.

52.

Honda

Wada

Battey

Wank

SA.

Differential gene expression of CCK(A) and CCK(B) receptors in the rat brain. Mol Cell Neurosci. 1993;4:143-154.

53.

You

Herrera-Marschitz

Pettersson

, et al. Modulation of neurotransmitter release by cholecystokinin in the neostriatum and substantia nigra of the rat: regional and receptor specificity. Neuroscience. 1996;74:793-804.

54.

Wank

SA.

Cholecystokinin receptors. Am J Physiol. 1995;269:G628-G646.

55.

Lee

Beinborn

McBride

Kolakowski

Jr Kopin

AS.

The human brain cholecystokinin-B/gastrin receptor. Cloning and characterization. J Biol Chem. 1993;268:8164-8169.

56.

Chen

Zhao

Yamada

Norlen

Håkanson

Novel aspects of gastrin-induced activation of histidine decarboxylase in rat stomach ECL cells. Regul Pept. 1998;77:169-175.

57.

Schmitz

Goke

Otte

, et al. Cellular expression of CCK-A and CCK-B/gastrin receptors in human gastric mucosa. Regul Pept. 2001;102: 101-110.

58.

Reubi

Schaer

Waser

Cholecystokinin(CCK)-A and CCK-B/gastrin receptors in human tumors. Cancer Res. 1997;57:1377-1386.

59.

Saillan-Barreau

Dufresne

Clerc

, 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.

60.

Rehfeld

JF.

How to measure cholecystokinin in tissue, plasma and cerebrospinal fluid. Regul Pept. 1998;78:31-39.

61.

Philippe

Lhoste

Dufresne

Moroder

Corring

Fourmy

Pharmacological and biochemical evidence for the simultaneous expression of CCKB/gastrin and CCKA receptors in the pig pancreas. Br J Pharmacol. 1997;120:447-454.

62.

Konno

Takahashi-Iwanaga

Uchigashima

, et al. Cellular and subcellular localization of cholecystokinin (CCK)-1 receptors in the pancreas, gallbladder, and stomach of mice. Histochem Cell Biol. 2015;143:301-312.

63.

Linnemann

Neuman

Battiola

Wisinski

Kimple

Davis

DB.

Glucagon-like peptide-1 regulates cholecystokinin production in β-cells to protect from apoptosis. Mol Endocrinol. 2015;29:978-987.

64.

Irwin

Montgomery

Moffett

Flatt

PR.

Chemical cholecystokinin receptor activation protects against obesity-diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice. Biochem Pharmacol. 2013;85:81-91.

65.

Rehfeld

Stadil

The effect of gastrin on basal- and glucose-stimulated insulin secretion in man. J Clin Invest. 1973;52:1415-1426.

66.

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.

67.

Rehfeld

Lauritsen

Stadil

Insulin secretion in the Zollinger-Ellison syndrome. Scand J Gastroenterol. 1976;37:63-66.

68.

Bani Sacchi

Bani

Biliotti

. Nesidioblastosis and islet cell changes related to endogenous hypergastrinemia. Virchows Arch B Cell Pathol Incl Mol Pathol. 1985;48:261-276.

69.

Dupre

Curtis

Unger

Waddell

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.

70.

Larsson

Ljungberg

Sundler

, et al. Antro-pyloric gastrinoma associated with pancreatic nesidioblastosis and proliferation of islets. Virchows Arch A Pathol Pathol Anat. 1973;360:305-314.

71.

Rehfeld

Holst

Kuhl

The effect of gastrin on basal and aminoacid-stimulated insulin and glucagon secretion in man. Eur J Clin Invest. 1978;8:5-9.

72.

Rooman

Lardon

Bouwens

Gastrin stimulates beta-cell neogenesis and increases islet mass from transdifferentiated but not from normal exocrine pancreas tissue. Diabetes. 2002;51:686-690.

73.

Rooman

Bouwens

Combined gastrin and epidermal growth factor treatment induces islet regeneration and restores normoglycaemia in C57Bl6/J mice treated with alloxan. Diabetologia. 2004;47:259-265.

74.

Suarez-Pinzon

Yan

Power

Brand

Rabinovitch

Combination therapy with epidermal growth factor and gastrin increases beta-cell mass and reverses hyperglycemia in diabetic NOD mice. Diabetes. 2005;54:2596-2601.

75.

Suarez-Pinzon

Power

Yan

Wasserfall

Atkinson

Rabinovitch

Combination therapy with glucagon-like peptide-1 and gastrin restores normoglycemia in diabetic NOD mice. Diabetes. 2008;57:3281-3288.

76.

Wang

Rehfeld

Nielsen

Kloppel

Expression of gastrin and transforming growth factor-alpha during duct to islet-cell differentiation in the pancreas of duct-ligated adult rats. Diabetologia. 1997;40:887-893.

77.

Wang

Bonner-Weir

Oates

, et al. Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells. J Clin Invest. 1993;92:1349-1356.

78.

Zollinger

Ellison

EH.

Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas. Ann Surg. 1955;142:709-723.

79.

Gregory

Grossman

Tracy

Bentley

PH.

Nature of the gastric secretagogue in Zollinger-Ellison tumours. Lancet. 1967;2:543-544.

80.

Rehfeld

van Solinge

WW.

The tumor biology of gastrin and cholecystokinin. Adv Cancer Res. 1994;63:295-347.

81.

Metz

Jensen

RT.

Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469-1492.

82.

Rehfeld

Federspiel

Agersnap

Knigge

Bardram

The uncovering and characterization of a CCKoma syndrome in enteropancreatic neuroendocrine tumor patients. Scand J Gastroenterol. 2016;51:1172-1178.

83.

Bonnavion

Teinturier

Jaafar

, et al. Islet cells serve as cells of origin of pancreatic gastrin-positive endocrine tumors. Mol Cell Biol. 2015;35:3274-3283.

84.

Kaneto

Tasaka

Kosaka

Nakao

Stimulation of insulin secretion by the C-terminal tetrapeptide amide of gastrin. Endocrinology. 1969;84:1098-1106.

85.

Irwin

Frizelle

O’Harte

Flatt

PR.

(pGlu-Gln)-CCK-8[mPEG]: a novel, long-acting, mini-PEGylated cholecystokinin (CCK) agonist that improves metabolic status in dietary-induced diabetes. Biochim Biophys Acta. 2013;1830:4009-4016.

86.

Trevaskis

Sun

Athanacio

, et al. Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents. Diabetes Obes Metab. 2015;17:61-73.

87.

Ahren

Martensson

Nobin

Cholecystokinin (CCK)-4 and CCK-8 stimulate islet hormone secretion in vivo in the pig. Pancreas. 1988;3: 279-284.

88.

Pathak

Flatt

Irwin

Cholecystokinin (CCK) and related adjunct peptide therapies for the treatment of obesity and type 2 diabetes. Peptides. 2018;100:229-235.

89.

O’Harte

Mooney

Kelly

Flatt

PR.

Glycated cholecystokinin-8 has an enhanced satiating activity and is protected against enzymatic degradation. Diabetes. 1998;47:1619-1624.

90.

Irwin

Frizelle

Montgomery

Moffett

O’Harte

FPM

Flatt

PR.

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes. Diabetologia. 2012;55:2747-2758.

91.

Irwin

Hunter

Montgomery

Flatt

PR.

Comparison of independent and combined metabolic effects of chronic treatment with (pGlu-Gln)-CCK-8 and long-acting GLP-1 and GIP mimetics in high fat-fed mice. Diabetes Obes Metab. 2013;15:650-659.

92.

Téllez

Joanny

Escoriza

Vilaseca

Montanya

Gastrin treatment stimulates β-cell regeneration and improves glucose tolerance in 95% pancreatectomized rats. Endocrinology. 2011;152:2580-2588.

93.

Fosgerau

Jessen

Lind Tolborg

, 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.

94.

Dalbøge

Almholt

Neerup

Vrang

Jelsing

Fosgerau

The novel GLP-1-gastrin dual agonist ZP3022 improves glucose homeostasis and increases β-cell mass without affecting islet number in db/db mice. J Pharmacol Exp Ther. 2014;350:353-360.

95.

Diedisheim

Oshima

Albagli

, et al. Modeling human pancreatic beta cell dedifferentiation. Mol Metab. 2018;10:74-86.

96.

Jacobsen

Olesen

Dirksen

, et al. Changes in gastrointestinal hormone responses, insulin sensitivity, and beta-cell function within 2 weeks after gastric bypass in non-diabetic subjects. Obes Surg. 2012;22:1084-1096.

97.

Dirksen

Jorgensen

Bojsen-Moller

, et al. Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass. Int J Obes (Lond). 2013;37:1452-1459.

98.

Svane

Bojsen-Møller

Martinussen

, et al. Postprandial nutrient handling and gastrointestinal hormone secretion after Roux-en-Y gastric bypass vs sleeve gastrectomy. Gastroenterology. 2019;156:1627-1641.

99.

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.

100.

Rehfeld

JF.

Why cholecystokinin and gastrin are also incretins. Cardiovasc Endocrinol. 2016;5:99-101.

101.

Rehfeld

JF.

CCK, gastrin and diabetes mellitus. Biomark Med. 2016;10:1125-1127.