Stimulation of Cholecystokinin-A Receptors With GI181771X does not Cause Weight Loss in Overweight or Obese Patients

Jordan, Jens; Greenway, FL; Leiter, LA; Li, Z; Jacobson, Peter; Murphy, Karen; Hill, J. D.; Kler, Lata; Aftring, R. Paul

doi:10.1038/sj.clpt.6100272

Cited by 103 publications

(73 citation statements)

References 25 publications

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“…Despite encouraging preclinical data (5,9-12), the development of CCK-based drugs for monotherapy of human obesity-related diabetes remains elusive (21). By contrast, GLP-1 mimetics have been adopted into the diabetic clinic with great vigor, although weight loss and metabolic control are not as impressive as first hoped (7).…”

Section: Discussionmentioning

confidence: 99%

A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

2015

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Glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) exert important complementary beneficial metabolic effects. This study assessed the biological actions and therapeutic utility of a novel (pGlu-Gln)-CCK-8/exendin-4 hybrid peptide compared with the stable GLP-1 and CCK mimetics exendin-4 and (pGlu-Gln)-CCK-8, respectively. All peptides significantly enhanced in vitro insulin secretion. Administration of the peptides, except (pGlu-Gln)-CCK-8 alone, in combination with glucose significantly lowered plasma glucose and increased plasma insulin in mice. All treatments elicited appetite-suppressive effects. Twice-daily administration of the novel (pGlu-Gln)-CCK-8/exendin-4 hybrid, (pGlu-Gln)-CCK-8 alone, or (pGlu-Gln)-CCK-8 in combination with exendin-4 for 21 days to high-fat–fed mice significantly decreased energy intake, body weight, and circulating plasma glucose. HbA1c was reduced in the (pGlu-Gln)-CCK-8/exendin-4 hybrid and combined parent peptide treatment groups. Glucose tolerance and insulin sensitivity also were improved by all treatment modalities. Interestingly, locomotor activity was decreased in the hybrid peptide group, and these mice also exhibited reductions in circulating triglyceride and cholesterol levels. Pancreatic islet number and area, as well β-cell area and insulinotropic responsiveness, were dramatically improved by all treatments. These studies highlight the clear potential of dual activation of GLP-1 and CCK1 receptors for the treatment of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

2015

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“…Indeed, the therapeutic potential of previous CCKbased drugs has been severely limited due to lack of specificity between receptor subtypes [10]. The most recent specific CCK 1 receptor agonist, GI181771X, to undergo clinical trials for obesity was abandoned after phase IIb [29]. Initial studies with GI181771X showed it to cause significant weight loss when participants were fed ad libitum [30].…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

et al. 2012

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Aims/hypothesis Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8. Methods The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice. Results (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p<0.05 to p<0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p<0.01 to p<0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p<0.05 to p<0.001), accumulated food intake (p< 0.05 to p<0.001), non-fasting glucose (p<0.05) and triacylglycerol deposition in pancreatic (p<0.01), adipose (p< 0.05) and liver (p<0.001) tissue, and improved oral (p< 0.05) and i.p. (p<0.05) glucose tolerance and insulin sensitivity (p<0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology. Conclusions/interpretation These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.

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“…Thus, GI181771X (a CCK receptor agonist) did not elicit body weight loss when administered to more than 700 obese subjects (tested in a 24-week, cross-over, double-blinded setting) [90]. On the other hand, animal studies with CCK receptor agonists have demonstrated promising results [91,92].…”

Section: Cholecystokininmentioning

confidence: 99%

Therapy for Obesity Based on Gastrointestinal Hormones

Christensen¹,

Knop²,

Vilsbøll³

2011

Rev Diabet Stud

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■ AbstractIt has long been known that peptide hormones from the gastrointestinal tract have significant impact on the regulation of nutrient metabolism. Among these hormones, incretins have been found to increase insulin secretion, and thus incretin-based therapies have emerged as new modalities for the treatment of type 2 diabetes. In contrast to other antidiabetic treatments, these agents have a positive outcome profile on body weight. Worldwide there are 500 million obese people, and 3 million are dying every year from obesityrelated diseases. Recently, incretin-based therapy was proposed for the treatment of obesity. Currently two different incretin therapies are widely used in the treatment of type 2 diabetes: 1) the GLP-1 receptor agonists which cause significant and sustained weight loss in overweight patients, and 2) dipeptidyl peptidase 4 (DPP-4) inhibitors being weight neutral. These findings have led to a greater interest in the physiology of intestinal peptides with potential weightreducing properties. This review discusses the effects of the incretin-based therapies in obesity, and provides an overview of intestinal peptides with promising effects as potential new treatments for obesity.

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Stimulation of Cholecystokinin-A Receptors With GI181771X does not Cause Weight Loss in Overweight or Obese Patients

Cited by 103 publications

References 25 publications

A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

A Novel CCK-8/GLP-1 Hybrid Peptide Exhibiting Prominent Insulinotropic, Glucose-Lowering, and Satiety Actions With Significant Therapeutic Potential in High-Fat–Fed Mice

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes

Therapy for Obesity Based on Gastrointestinal Hormones

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