N Irwin1, P Frizelle2, I A Montgomery2, R C Moffett2, F P M O'Harte2, P R Flatt2. 1. SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK. n.irwin@ulster.ac.uk. 2. SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
Abstract
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.
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.
Authors: Jeremy A Lavine; Philipp W Raess; Donald S Stapleton; Mary E Rabaglia; Joshua I Suhonen; Kathryn L Schueler; James E Koltes; John A Dawson; Brian S Yandell; Linda C Samuelson; Margery C Beinfeld; Dawn Belt Davis; Marc K Hellerstein; Mark P Keller; Alan D Attie Journal: Endocrinology Date: 2010-06-09 Impact factor: 4.736
Authors: N H McClenaghan; C R Barnett; E Ah-Sing; Y H Abdel-Wahab; F P O'Harte; T W Yoon; S K Swanston-Flatt; P R Flatt Journal: Diabetes Date: 1996-08 Impact factor: 9.461
Authors: Jeremy A Lavine; Carly R Kibbe; Mieke Baan; Sirinart Sirinvaravong; Heidi M Umhoefer; Kimberly A Engler; Louise M Meske; Kaitlyn A Sacotte; Daniel P Erhardt; Dawn Belt Davis Journal: Am J Physiol Endocrinol Metab Date: 2015-09-22 Impact factor: 4.310
Authors: Robert E Steinert; Christine Feinle-Bisset; Lori Asarian; Michael Horowitz; Christoph Beglinger; Nori Geary Journal: Physiol Rev Date: 2017-01 Impact factor: 37.312
Authors: Hung Tae Kim; Arnaldo H Desouza; Heidi Umhoefer; Jeeyoung Han; Lucille Anzia; Steven J Sacotte; Rashaun A Williams; Joseph T Blumer; Jacob T Bartosiak; Danielle A Fontaine; Mieke Baan; Carly R Kibbe; Dawn Belt Davis Journal: Transl Res Date: 2021-11-03 Impact factor: 10.171
Authors: Neil Tanday; Andrew English; Ryan A Lafferty; Peter R Flatt; Nigel Irwin Journal: Front Endocrinol (Lausanne) Date: 2021-05-14 Impact factor: 5.555