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Novel Modified GLP-1 Derivatives with Prolonged Glucose-Lowering Ability In Vivo

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Abstract

The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl peptidase-IV (DPP-IV) has advanced new approaches to the generation of degradation-resistant GLP-1 analogs. Chemical coupling of GLP-1 analog to HSA is innovatively achieved by solid-phase peptide synthesis in this study and shows prolonged glucose-lowering ability in vivo. GLP-1(7–37)(Ala8Aib)-Cys-HSA was constructed by solid-phase peptide synthesis through two levels of modification: mutation of Ala8 to aminoisobutyric acid (Aib) to decrease DPP-IV degradation, and conjugation to large serum protein HSA by chemical modification to decrease renal filtration. Glucose tolerance test and insulin secretion assay were performed to examine the biological activity of GLP-1(7–37)(Ala8Aib)-Cys-HSA in vivo in the present research. Long-lasting glucose-lowering and insulin-releasing effects were evaluated up to 4 weeks in T2DM rats. GLP-1(7–37)(Ala8Aib)-Cys-HSA lowered blood glucose in normal mice and T2DM rats. Twice administration of GLP-1(7–37)(Ala8Aib)-Cys-HSA to T2DM rats daily significantly reduced glycemic excursion following IP glucose challenge (P < 0.01 to 0.05) and greatly increased insulin secretion during the 4-week study period. These findings demonstrate that the albumin-conjugated GLP-1 analog mimics the function of native GLP-1 with prolonged activity.

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Funding

This research was funded by the National Natural Science Foundation of China (No. 31571277, No. 31900906), Hunan Natural Science Foundation (No. 2018JJ2150, No. 17C0709, No. 2019JJ50207) and the Scientific Research Key Fund of Hunan Provincial Education Department (No. 18A318).

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Authors and Affiliations

  1. Key Laboratory of Hunan Province for Advanced Carbon-based Functional Materials, School of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, 414000, Hunan, China

    Yu Liu, Qing Wang, Dongsong Nie, Yuxia Zhang, Zhen Wang & Yunxiao Zhang

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  1. Yu Liu
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  2. Qing Wang
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  3. Dongsong Nie
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  4. Yuxia Zhang
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  5. Zhen Wang
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  6. Yunxiao Zhang
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Contributions

YL, DN and YZ conceived and designed the experiment; QW and Y.Z performed the experiments. ZW and QW analyzed the data; YL, ZW and YZ wrote and revised the paper. All authors read and approved the final version of the manuscript.

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Correspondence to Zhen Wang or Yunxiao Zhang.

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Liu, Y., Wang, Q., Nie, D. et al. Novel Modified GLP-1 Derivatives with Prolonged Glucose-Lowering Ability In Vivo. Int J Pept Res Ther 26, 1939–1947 (2020). https://doi.org/10.1007/s10989-019-09991-4

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  • DOI: https://doi.org/10.1007/s10989-019-09991-4

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