Exendin-4(Lys27PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice
Annie Hasib
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorMing T. Ng
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorNeil Tanday
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorSarah L. Craig
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorVictor A. Gault
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorPeter R. Flatt
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorCorresponding Author
Nigel Irwin
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Correspondence
Nigel Irwin, SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK.
Email: [email protected]
Search for more papers by this authorAnnie Hasib
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorMing T. Ng
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorNeil Tanday
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorSarah L. Craig
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorVictor A. Gault
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorPeter R. Flatt
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Search for more papers by this authorCorresponding Author
Nigel Irwin
Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK
Correspondence
Nigel Irwin, SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK.
Email: [email protected]
Search for more papers by this authorAbstract
Background
Therapeutic benefits of peptide-based drugs is limited by rapid renal elimination.
Methods
Therefore, to prolong the biological action profile of the recently characterized triple-acting hybrid peptide, exendin-4/gastrin/xenin-8-Gln, a fatty acid (C-16) has been covalently attached, creating exendin-4(Lys27PAL)/gastrin/xenin-8-Gln. Exendin-4/gastrin and liraglutide/gastrin/xenin-8-Gln were also synthesized as direct comparator peptides.
Results
All hybrid peptides evoked significant concentration-dependent increases of insulin secretion from isolated murine islets and BRIN-BD11 cells. Following administration of peptides with glucose to mice, all hybrids significantly reduced the overall glycaemic excursion and increased insulin concentrations. In contrast to other treatments, exendin-4(Lys27PAL)/gastrin/xenin-8-Gln displayed impressive antihyperglycaemic actions even 12 hours after administration, highlighting protracted duration of effects. Exendin-4/gastrin/xenin-8-Gln, exendin-4/gastrin, and exendin-4(Lys27PAL)/gastrin/xenin-8-Gln were then progressed to a 31-day twice-daily treatment regimen in obese-diabetic ob/ob mice. All treatments decreased nonfasting glucose and HbA1c concentrations, as well as enhancing circulating and pancreatic insulin levels. Exendin-4/gastrin and exendin-4/gastrin/xenin-8-Gln also decreased food intake. Glucose tolerance was improved by all treatments, but only exendin-4(Lys27PAL)/gastrin/xenin-8-Gln augmented glucose-induced insulin secretion. Interestingly, treatment regimens that included a xenin component induced clear advantages on the metabolic response to glucose-dependent insulinotropic polypeptide (GIP) and the glucose-lowering actions of insulin.
Conclusion
This study emphasizes the therapeutic promise of long-acting, multi-targeting hybrid gut peptides for type 2 diabetes.
CONFLICT OF INTEREST
V.A.G., P.R.F., and N.I. are named on patents filed by the University of Ulster for exploitation of incretin-based drugs and other peptide therapeutics.
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