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
- 30 November 2018
- journal article
- research article
- Published by Wiley in Diabetes/Metabolism Research and Reviews
- Vol. 35 (3) , e3106
Abstract
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.Keywords
Funding Information
- European Foundation for the Study of Diabetes
This publication has 50 references indexed in Scilit:
- Emerging Poly‐Agonists for Obesity and Type 2 DiabetesObesity, 2017
- GLP-1/glucagon receptor co-agonism for treatment of obesityDiabetologia, 2017
- A novel chemically modified analogue of xenin-25 exhibits improved glucose-lowering and insulin-releasing propertiesBiochimica et Biophysica Acta (BBA) - General Subjects, 2016
- Synthesis and Evaluation of a Series of Long‐Acting Glucagon‐Like Peptide‐1 (GLP‐1) Pentasaccharide Conjugates for the Treatment of Type 2 DiabetesChemMedChem, 2015
- Xenin-25[Lys13PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potentialActa Diabetologica, 2014
- β-Cell Function in Obese-Hyperglycemic Mice (ob /ob Mice)2014
- A novel acylated form of (d-Ala2)GIP with improved antidiabetic potential, lacking effect on body fat storesBiochimica et Biophysica Acta (BBA) - General Subjects, 2013
- A DPP-IV-resistant triple-acting agonist of GIP, GLP-1 and glucagon receptors with potent glucose-lowering and insulinotropic actions in high-fat-fed miceDiabetologia, 2013
- Comparison of the anti‐diabetic effects of GIP‐ and GLP‐1‐receptor activation in obese diabetic (ob/ob) mice: studies with DPP IV resistant N‐AcGIP and exendin(1–39)amideDiabetes/Metabolism Research and Reviews, 2007
- Abnormal plasma glucose and insulin responses in heterozygous lean (ob/+) miceDiabetologia, 1981