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

• Published in: Diabetes, obesity & metabolism Vol. 15; no. 7; pp. 650 - 659
• Main Authors: Irwin, N., Hunter, K., Montgomery, I. A., Flatt, P. R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2013; Wiley Subscription Services, Inc
• Subjects: Animals; Anti-Obesity Agents - pharmacology; Anti-Obesity Agents - therapeutic use; Appetite Regulation - drug effects; Cell Line; cholecystokinin; Diabetes; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diet, High-Fat - adverse effects; Drug Therapy, Combination; Exenatide; Gastric Inhibitory Polypeptide - analogs & derivatives; Gastric Inhibitory Polypeptide - pharmacology; Gastric Inhibitory Polypeptide - therapeutic use; glucagon-like peptide-1; Glucose; glucose tolerance; glucose-dependent insulinotropic polypeptide; Hyperglycemia - prevention & control; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Incretins - pharmacology; Incretins - therapeutic use; Insulin; Insulin - agonists; Insulin - metabolism; Insulin Resistance; Insulin Secretion; insulin sensitivity; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Male; Mice; Mice, Inbred Strains; obesity; Obesity - complications; Obesity - drug therapy; Obesity - etiology; Peptides - pharmacology; Peptides - therapeutic use; Rats; Sincalide - analogs & derivatives; Sincalide - pharmacology; Sincalide - therapeutic use; Time Factors; Venoms - pharmacology; Venoms - therapeutic use
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.12079

ABSTRACT Aim The incretin hormones, glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) and cholecystokinin (CCK) are gastrointestinal peptides with important physiological effects. However, rapid enzymatic degradation results in short‐lived biological actions. Methods This study has examined metabolic actions of exendin‐4, GIP[mPEG] and a novel CCK‐8 analogue, (pGlu‐Gln)‐CCK‐8 as enzymatically stable forms of GLP‐1, GIP and CCK, respectively. Results All peptides significantly (p < 0.01–p < 0.001) stimulated insulin secretion from BRIN BD11 cells, and acute in vivo experiments confirmed prominent antihyperglycaemic and insulinotropic responses to GLP‐1 or GIP receptor activation in normal mice. Twice daily injection of (pGlu‐Gln)‐CCK‐8 alone and in combination with exendin‐4 or GIP[mPEG] in high fat‐fed mice significantly decreased accumulated food intake (p < 0.05–p < 0.01), body weight gain (p < 0.05–p < 0.01) and improved (p < 0.05) insulin sensitivity in high fat‐fed mice. However, there was no evidence for superior effects compared to (pGlu‐Gln)‐CCK‐8 alone. Combined treatment of (pGlu‐Gln)‐CCK‐8 and exendin‐4 resulted in significantly (p < 0.05) lowered circulating glucose levels and improved (p < 0.05) intraperitoneal glucose tolerance. These effects were superior to either treatment regime alone but not associated with altered insulin concentrations. A single injection of (pGlu‐Gln)‐CCK‐8, or combined with exendin‐4, significantly (p < 0.05) lowered blood glucose levels 24 h post injection in untreated high fat‐fed mice. Conclusion This study highlights the potential of (pGlu‐Gln)‐CCK‐8 alone and in combination with incretin hormones for the treatment of type 2 diabetes.