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Novel peptidic dual GLP-1/glucagon receptor agonist alleviates diabetes and diabetic complications in combination with low-intensity ultrasound.
Ding, W-X; Wang, H-Y; Peng, L-J; Zhang, F; Yuan, S; Zhao, L-H.
Afiliação
  • Ding WX; The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang Province, China. wxding@ncstmc.cn.
Eur Rev Med Pharmacol Sci ; 24(23): 12423-12436, 2020 12.
Article em En | MEDLINE | ID: mdl-33336763
ABSTRACT

OBJECTIVE:

To design and evaluate a novel oxyntomodulin (OXM) derivative with albumin-binding helix domain and dual GLP-1 receptor (GLP-1R) and glucagon receptor (GcgR) activation activity to achieve metabolize improvement on the diabetes-related complication. MATERIALS AND

METHODS:

Mutation (D-Ser2) on OXM was performed and then different helix albumin-binding domains were fused to the mutated OXM via a thrombin-cleavable linker to generate seven fusion peptides, named LM01-LM07. Seven LM peptides were synthesized and screened via in vitro receptor activation test, albumin binding measurement and protease cleavage assay to select potent candidate peptide for further in vivo study. Moreover, acute and chronic efficacy studies were conducted to evaluate the efficacy of selected candidate using db/db mice.

RESULTS:

LM06, as selected OXM derivative, exhibited higher albumin-binding affinity, sustained-release efficiency and balanced activation activities on both GLP-1R and GcgR compared with other ones. Moreover, LM06 was demonstrated with improved hypoglycemic and insulinotropic abilities in receptor-deficient mice via activating GLP-1R. In addition, prolonged anti-diabetic efficacies of LM06 were demonstrated via hypoglycemic duration assay and OGTT in db/db mice. Further pharmacokinetic test of LM06 in both rats and monkeys identified improved half-life and other metabolic characteristics. Nevertheless, 8-week subcutaneously dosed LM06 in db/db mice achieved prominent efficacies on glucostasis, weight-lowering, pancreatic function and adipogenesis via activating GLP-1R and GcgR. Moreover, LM06 also could accelerate diabetic skin wound closure in combination with low-intensity ultrasound.

CONCLUSIONS:

LM06, as a long-acting dual GLP-1R/GcgR agonist, exerts potential as a once-weekly therapeutic candidate against diabetes-related complication in combination with low-intensity ultrasound.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de Glucagon / Complicações do Diabetes / Diabetes Mellitus / Oxintomodulina / Receptor do Peptídeo Semelhante ao Glucagon 1 / Hipoglicemiantes Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Eur Rev Med Pharmacol Sci Assunto da revista: FARMACOLOGIA / TOXICOLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de Glucagon / Complicações do Diabetes / Diabetes Mellitus / Oxintomodulina / Receptor do Peptídeo Semelhante ao Glucagon 1 / Hipoglicemiantes Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Eur Rev Med Pharmacol Sci Assunto da revista: FARMACOLOGIA / TOXICOLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: China