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Exendin-4(Lys[27] PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice.
Diabetes Metab Res Rev. 2019 Mar; 35(3):e3106.DM

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(Lys[27] PAL)/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(Lys[27] PAL)/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(Lys[27] PAL)/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(Lys[27] PAL)/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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK.

Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK.

Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK.

Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK.

Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK.

Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK.

Centre for Pharmacy and Diabetes, Ulster University, Coleraine, UK.

MeSH

AcylationAnimalsExenatideGastrinsGlucagon-Like Peptide 1InsulinMaleMiceMice, Inbred C57BLMice, Inbred StrainsObesityPeptide FragmentsThinness

Pub Type(s)

Journal Article

Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30499633

Citation

Hasib, Annie, et al. "Exendin-4(Lys[27] PAL)/gastrin/xenin-8-Gln: a Novel Acylated GLP-1/gastrin/xenin Hybrid Peptide That Improves Metabolic Status in Obese-diabetic (ob/ob) Mice." Diabetes/metabolism Research and Reviews, vol. 35, no. 3, 2019, pp. e3106.

Hasib A, Ng MT, Tanday N, et al. Exendin-4(Lys[27] PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice. Diabetes Metab Res Rev. 2019;35(3):e3106.

Hasib, A., Ng, M. T., Tanday, N., Craig, S. L., Gault, V. A., Flatt, P. R., & Irwin, N. (2019). Exendin-4(Lys[27] PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice. Diabetes/metabolism Research and Reviews, 35(3), e3106. https://doi.org/10.1002/dmrr.3106

Hasib A, et al. Exendin-4(Lys[27] PAL)/gastrin/xenin-8-Gln: a Novel Acylated GLP-1/gastrin/xenin Hybrid Peptide That Improves Metabolic Status in Obese-diabetic (ob/ob) Mice. Diabetes Metab Res Rev. 2019;35(3):e3106. PubMed PMID: 30499633.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Exendin-4(Lys[27] PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice. AU - Hasib,Annie, AU - Ng,Ming T, AU - Tanday,Neil, AU - Craig,Sarah L, AU - Gault,Victor A, AU - Flatt,Peter R, AU - Irwin,Nigel, Y1 - 2018/12/19/ PY - 2018/09/28/received PY - 2018/11/19/revised PY - 2018/11/27/accepted PY - 2018/12/1/pubmed PY - 2019/8/6/medline PY - 2018/12/1/entrez KW - gastrin KW - glucagon-like peptide-1 (GLP-1) KW - xenin SP - e3106 EP - e3106 JF - Diabetes/metabolism research and reviews JO - Diabetes Metab Res Rev VL - 35 IS - 3 N2 - 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(Lys[27] PAL)/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(Lys[27] PAL)/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(Lys[27] PAL)/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(Lys[27] PAL)/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. SN - 1520-7560 UR - https://www.unboundmedicine.com/medline/citation/30499633/Exendin_4_Lys DB - PRIME DP - Unbound Medicine ER -