Unique activities of cholecystokinin-58; physiological and pathological relevance

Green, Gary M.; Reeve, Joseph R.

doi:10.1097/med.0b013e3282f3d92b

Cited by 8 publications

(4 citation statements)

References 38 publications

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“…A key point is to choose antibodies, which allow quantification of the biologically active form of the peptide (acylated form of ghrelin, GLP‐1 7–36 amide and PYY 3–36 amide), which is relevant when a link with hunger or satiety must be established. For CCK, several isoforms coexist (such as CCK‐8, CCK‐33 and CCK‐58 (161,162)), that do not have similar biological activities. Even if selective antibodies are available, the price and the sensitivity of the method remain a problem in most cases.…”

Section: Selection Of Biological Targets and Biomarkersmentioning

confidence: 99%

Gastrointestinal targets of appetite regulation in humans

et al. 2010

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Summary The aim of this paper is to describe and discuss relevant aspects of the assessment of physiological functions – and related biomarkers – implicated in the regulation of appetite in humans. A short introduction provides the background and the present state of biomarker research as related to satiety and appetite. The main focus of the paper is on the gastrointestinal tract and its functions and biomarkers related to appetite for which sufficient data are available in human studies. The first section describes how gastric emptying, stomach distension and gut motility influence appetite; the second part describes how selected gastrointestinal peptides are involved in the control of satiety and appetite (ghrelin, cholecystokinin, glucagon‐like peptide, peptide tyrosin‐tyrosin) and can be used as potential biomarkers. For both sections, methodological aspects (adequacy, accuracy and limitation of the methods) are described. The last section focuses on new developments in techniques and methods for the assessment of physiological targets involved in appetite regulation (including brain imaging, interesting new experimental approaches, targets and markers). The conclusion estimates the relevance of selected biomarkers as representative markers of appetite regulation, in view of the current state of the art.

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Section: Selection Of Biological Targets and Biomarkersmentioning

confidence: 99%

Gastrointestinal targets of appetite regulation in humans

et al. 2010

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“…Further study is required to understand the role of high- and low-affinity CCK receptors in GI181771X-induced pancreatitis in rodents. The histological features of GI181771X-induced pancreatitis were similar to CCK-8 or cerulein (CCK analog)-induced pancreatitis in rodents, a widely used experimental model of human pancreatitis (Longnecker and Wilson 2002; Green and Reeve 2008). CCK-8 or cerulein-induced acute pancreatitis is rapid and highly reproducible and is caused by exaggerated stimulation of CCK1R.…”

Section: Discussionmentioning

confidence: 87%

“…Cerulein, a CCK analog, causes pancreatitis in many animals including mice, rats, rabbits, dogs, and pigs (Willemer, Elsasser, and Adler 1992; Gorelick, Adler, and Kerin 1993). Pancreatitis induced by high doses of cerulein in rats and mice is a widely used experimental model, and the histological presentation of this model is quite similar to the early phase of acute pancreatitis in humans (Longnecker and Wilson 2002; Green and Reeve 2008). Prolonged and sustained CCK-induced secretions may result in misdirection and autodigestion of adjacent tissues, disrupting the integrity of acini and their attendant ducts (Gaisano and Gorelick 2009).…”

Section: Introductionmentioning

confidence: 99%

Species- and Dose-Specific Pancreatic Responses and Progression in Single- and Repeat-Dose Studies with GI181771X

2013

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Compound-induced pancreatic injury is a serious liability in preclinical toxicity studies. However, its relevance to humans should be cautiously evaluated because of interspecies variations. To highlight such variations, we evaluated the species- and dose-specific pancreatic responses and progression caused by GI181771X, a novel cholecystokinin 1 receptor agonist investigated by GlaxoSmithKline for the treatment of obesity. Acute (up to 2,000 mg/kg GI181771X, as single dose) and repeat-dose studies in mice and/or rats (0.25-250 mg/kg/day for 7 days to 26 weeks) showed wide-ranging morphological changes in the pancreas that were dose and duration dependent, including necrotizing pancreatitis, acinar cell hypertrophy/atrophy, zymogen degranulation, focal acinar cell hyperplasia, and interstitial inflammation. In contrast to rodents, pancreatic changes were not observed in cynomolgus monkeys given GI181771X (1-500 mg/kg/day with higher systemic exposure than rats) for up to 52 weeks. Similarly, no GI181771X treatment-associated abnormalities in pancreatic structure were noted in a 24-week clinical trial with obese patients (body mass index >30 or >27 kg/m(2)) as assessed by abdominal ultrasound or by magnetic resonance imaging. Mechanisms for interspecies variations in the pancreatic response to CCK among rodents, monkeys, and humans and their relevance to human risk are discussed.

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“…Overall, post-meal pancreatic responses were mimicked more closely by CCK-58 than by CCK-8 [68]. Importantly, infusion of high doses of CCK-58 did not induce the pancreatic hypertrophy or pancreatitis typically observed after identical doses of exogenous CCK-8 in rats [24, 67]. These qualitative differences led us to suggest that generalized conclusions derived from functional studies using CCK-8 or other shorter forms of cholecystokinin may need re-evaluation using a major endocrine form of the peptide, CCK-58 [24, 45].…”

Section: Introductionmentioning

confidence: 99%

CCK-58 elicits both satiety and satiation in rats while CCK-8 elicits only satiation

Overduin¹,

Gibbs²,

Cummings³

et al. 2014

Peptides

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Reduction of food intake by exogenous cholecystokinin (CCK) has been demonstrated primarily for its short molecular form, CCK-8. Mounting evidence, however, implicates CCK-58 as a major physiologically active CCK form, with different neural and exocrine response profiles than CCK-8. In three studies, we compared meal-pattern effects of intraperitoneal injections CCK-8 vs. CCK-58 in undeprived male Sprague-Dawley rats consuming sweetened condensed milk. In study one, rats (N=10) received CCK-8, CCK-58 (0.45, 0.9, 1.8 and 3.6 nmole/kg) or vehicle before a 4-hour test-food presentation. At most doses, both CCK-8 and CCK-58 reduced meal size relative to vehicle. Meal-size reduction prompted a compensatory shortening of the intermeal interval (IMI) after CCK-8, but not after CCK-58, which uniquely increased the satiety ratio (IMI/size of the preceding meal). In the second study, lick patterns were monitored after administration of 0.9nmole/kg CCK-58, CCK-8 or vehicle. Lick cluster size, lick efficiency and interlick-interval distribution remained unaltered compared to vehicle, implying natural satiation, rather than illness, following both CCK forms. In study 3, threshold satiating doses of the two CCK forms were given at 5 and 30 minutes after meal termination, respectively. CCK 58, but not CCK-8 increased the intermeal interval and satiety ratio compared to vehicle. In conclusion, while CCK 58 and CCK-8 both stimulate satiation, thereby reducing meal size, CCK-58 consistently exerts a satiety effect, prolonging IMI. Given the physiological prominence of CCK-58, these results suggest that CCK’s role in food intake regulation may require reexamination.

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Unique activities of cholecystokinin-58; physiological and pathological relevance

Abstract: There is a compelling reason to reevaluate the role of cholecystokinin in health and disease because the predominant form of cholecystokinin, CCK58, has unique biological activities compared with forms of cholecystokinin used in previous basic and clinical studies.

Cited by 8 publications

References 38 publications

Gastrointestinal targets of appetite regulation in humans

Gastrointestinal targets of appetite regulation in humans

Species- and Dose-Specific Pancreatic Responses and Progression in Single- and Repeat-Dose Studies with GI181771X

CCK-58 elicits both satiety and satiation in rats while CCK-8 elicits only satiation

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