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Antidiabetic compounds 8a, 8b, 8k, and 9h enhance insulin secretion: activity and mechanism

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Abstract

Purpose

This study primarily investigated the effects of hypoglycemic compounds (Imeglimin derivatives) on insulin secretion in type 2 diabetes mellitus (T2DM), and further explored the possible mechanism underlying these effects.

Methods

Firstly, Metformin was used as the initiating compound to synthesize three sets of derivatives which contained Imeglimin structure core. At the cellular level, we screened compounds with better effect on the activity of insulin receptor tyrosine protein kinase (IFcTPK) after the islet β cells were treated with the compounds of different concentrations. The insulin secretion was assessed using radioimmunoassay and the cytotoxicity to islet β cells was evaluated by means of MTT assay following treatment with the compounds. The Ca2+-related mechanism by which these compounds promote insulin secretion was elucidated with whole cell recordings from current-clamp mode.

Results

Totally, 48 synthesized compounds were generated, wherein 10 compounds could increase the activity of IFcTPK in HIT-T15 cells better among these compounds. The modified Imeglimin, especially in the structure of hydrophilic hydroxyl or piperidine rings, could improve the activity of the compound to promote insulin secretion. Furthermore, the compounds 8a, 8b, 8k, and 9h revealed high insulin secretion-promoting activity. These compounds enhanced insulin secretion in islet β cells by repressing the ATP-sensitive K(+) and voltage-gated K+ pathway.

Conclusions

Our findings indicate that the hypoglycemic compounds 8a, 8b, 8k, and 9h confer better promotive effect on insulin secretion, which provides a reference for the development of drugs with better hypoglycemic activity.

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Data availability

The datasets generated/analyzed during the current study are available.

Abbreviations

IFcTPK:

insulin receptor tyrosine protein kinase

T2DM:

Type 2 diabetes mellitus

TPK:

tyrosine protein kinase

PBS:

phosphate-buffered saline

ANOVA:

analysis of variance

TLC:

thin layer chromatography

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Acknowledgements

The authors would like to acknowledge the helpful comments on this paper received from the reviewers.

Funding

This work was supported by Qiqihar Science and Technology Bureau (No. SFGG-201940).

Author contributions

Conceived and designed research: L.H. and H.J.; Administrative support: L.H., H.J., and Z.J.; Provided materials or patients: Z.J., F.Y.L., Z.Y.X., S.X.Z., and Z.C.H.; Collected and assembled data: L.H., F.Y.L., Z.Y.X., Z.C.H., and W.F.; Analyzed and interpreted data: L.H. and H.J.; Drafted manuscript: L.H. and H.J.; Approved final version of manuscript: L.H. and H.J.

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Authors and Affiliations

  1. Department of Endocrinology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, 161000, PR China

    Hui Li, Jian Zhang, Yongli Fu, Yixin Zhang, Chunhui Zhang, Xiaozhu Sun & Jing He

  2. Department of Hepatology, The Seventh Hospital of Qiqihar, Qiqihar, 161000, PR China

    Fang Wu

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  1. Hui Li
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Li, H., Zhang, J., Fu, Y. et al. Antidiabetic compounds 8a, 8b, 8k, and 9h enhance insulin secretion: activity and mechanism. Endocrine 71, 365–377 (2021). https://doi.org/10.1007/s12020-020-02537-5

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