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DR10601, a novel recombinant long-acting dual glucagon-like peptide-1 and glucagon receptor agonist for the treatment of obesity and type 2 diabetes mellitus

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Abstract

Purpose

Both glucagon-like peptide-1 (GLP-1) and glucagon (GCG) belong to the incretin family. This study aimed to investigate the pharmacokinetics and pharmacodynamics of DR10601, a fully recombinant hybrid peptide with dual GLP-1/GCG receptor agonistic activity.

Methods

The agonistic ability of DR10601 was indirectly assessed by inducing cAMP accumulation in Chinese hamster ovary cells transfected with GLP-1R or GCGR in vitro. Following s.c. administration, the plasma pharmacokinetics of DR10601 were analysed in male Sprague-Dawley rats. The antiobesity effects and improved glycaemic control of DR10601 in vivo were evaluated by administering DR10601 to high-fat DIO mice and ICR mice as a single dose or repeated s.c. doses once every 4 days for 24 days.

Results

DR10601 exhibits dual agonistic activity on GLP-1 and glucagon receptors. The plasma half-life of DR10601 in Sprague-Dawley rats following s.c. administration was 51.9 ± 12.2 h. In an IPGTT, a single s.c. dose of DR10601 (30 nmol/kg) produced similar glycaemic control effects and a longer duration of action compared to dulaglutide (10 nmol/kg). Compared with that achieved with liraglutide (40 nmol/kg) s.c. administered daily, DR10601 administered s.c. once every 4 days at 90 nmol/kg exerted a nearly equivalent effect on food intake and significantly reduced the body weights of high-fat DIO mice at 24 days.

Conclusions

Repeated administration of DR1060 provides potent and sustained glycemic control and body weight loss effect in high-fat DIO mice. DR10601 is a promising long-acting agent deserving further investigation for the treatment of type 2 diabetes and obesity.

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Abbreviations

AST:

Aspartate aminotransferase

ALT:

Alanine aminotransferase

DIO:

Diet-induced obese

FDA:

Food and Drug Administration

GCGR:

Glucagon receptor

GIP:

Glucose-dependent insulinotropic polypeptide

GLP-1:

Glucagon-like peptide-1

GLP1R:

GLP-1 receptor

HRP:

Horseradish peroxidase

OXY:

Oxyntomodulin

PYY:

Peptide YY

TMB:

3,3′5,5′-Tetramethylbenzidine

SD rats:

Sprague-Dawley rats

CHO cells:

Chinese hamster ovary cells

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Authors and Affiliations

  1. Department of Pharmacy, College of Life Sciences, China Jiliang University, Hangzhou, Zhejiang, China

    W. Wang

  2. Zhejiang Doer Biologics Corporation, No. 452 Avenue 6, Hangzhou Economic and Technological Development Zone, Hangzhou, 310018, Zhejiang, China

    W. Wang, X. Wen, W. Duan, X. Wang, Y. Chen, J. Dong, Z. Yang, J. Fang, Z. Zhou, G. Yao, Y. Fang & Y. Huang

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Contributions

WW designed DR10601 and wrote the manuscript. WW, WD and YH conceived and designed the study. XW, JD, GY and ZZ constructed the expression vector and performed the protein expression experiment. ZY and YC separated and purified the target protein. XW, YF and JF were responsible for the relevant experimental analyses. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Y. Huang.

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Conflict of interests

The authors have no conflicts of interest to declare.

Ethical approval

The experimental animals used in this paper were purchased from the animal experiment center of the Zhejiang Academy of Medical Sciences, All experiments were performed according to the guidelines of the administration for the administration of affairs concerning experimental animals of PR China. The mouse experiments were Approved by the Zhejiang Academy of Medical Sciences Animal Ethics Committee (no. 201786-89).

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Wang, W., Wen, X., Duan, W. et al. DR10601, a novel recombinant long-acting dual glucagon-like peptide-1 and glucagon receptor agonist for the treatment of obesity and type 2 diabetes mellitus. J Endocrinol Invest 43, 653–662 (2020). https://doi.org/10.1007/s40618-019-01153-z

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