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Irwin, N. et al.

N. Irwin, P. Frizelle, I.A. Montgomery, R.C. Moffett, F. P. M. O'Harte, P.R. Flatt, P. Frizelle, I.A. Montgomery, R.C. Moffett, F. P. M. O'Harte, P.R. Flatt,

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

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.[1]

References

Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes. Irwin, N., Frizelle, P., Montgomery, I.A., Moffett, R.C., O'Harte, F.P., Flatt, P.R. Diabetologia (2012) [Pubmed]

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