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: The present 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 to 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 to p <0.01), body weight gain (p <0.05 to 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 hours post injection in untreated high fat fed mice.CONCLUSION: These studies highlight the potential of (pGlu-Gln)-CCK-8 alone and in combination with incretin hormones for the treatment of type 2 diabetes.