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Primaquine activates Keratin 7 to treat diabetes and its complications

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Abstract

Background

The global prevalence of type 2 diabetes mellitus (T2DM) raises the rates of its complications, such as diabetic nephropathy and cardiovascular diseases. To conquer the complications, new strategies to reverse the deterioration of T2DM are urgently needed. In this project, we aimed to examine the hypoglycemic effect of primaquine and explore its specific target.

Methods

In vitro T2DM insulin resistance model was built in HepG2 cells to screen the potential anti-diabetic chemicals. On the other hand, the potential protein targets were explored by molecular docking. Accordingly, we chose C57BL/6 N mice to establish T2DM model to verify the effect of the chemicals on anti-hyperglycemia and diabetic complications.

Results

By targeting the Keratin 7 (K7) to activate EGFR/Akt glucose metabolism signaling pathway, primaquine poses a potent hypoglycemic effect. The level of acetyl-CoA is enhanced markedly, supporting that primaquine upregulates the aerobic glycolysis. Moreover, primaquine ameliorates kidney function by reducing the secretion of urinary proteins and creatinine, especially for the urea nitrogen which is significantly decreased compared to no-treatment T2DM mice. Notably, primaquine restores the level of plasma low-density lipoprotein cholesterol (LDL-C) nearly to normal, minimizing the incidence of cardiovascular diseases.

Conclusions

We find that primaquine may reverse the dysregulated metabolism to prevent diabetic complications by stimulating EGFR/Akt signaling axis, shedding new light on the therapy of T2DM.

Graphical abstract

Insulin resistance is characterized by reduced p-Akt and glucose metabolism, dominated by anaerobic glycolysis. Primaquine activates the complex made of K7 and EGFR, further stimulating Akt phosphorylation. Then, p-Akt promotes the aerobic glucose metabolism and upregulates Ac-CoA to mobilize TCA cycle, improving insulin sensitivity.

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Abbreviations

Ac-CoA:

Acetyl-CoA

DCVD:

Diabetic cardiovascular disease

DN:

Diabetic nephropathy

EGFR:

Epidermal growth factor

FFA:

Free fatty acids

HbA1c:

Glycated hemoglobin A1c

HFD:

High fat diet

HOMA-IR:

Homeostasis model of assessment-insulin resistance

IPGTT:

Intraperitoneal glucose tolerance test

IPITT:

Intraperitoneal insulin tolerance test

K7:

Keratin 7

LDH:

Lactic dehydrogenase

LDL-C:

Low-density lipoprotein cholesterol

MDA:

Malondialdehyde

MG:

Methylglyoxal

PB:

Primaquine phosphate

SD:

Standard Diet

STZ:

Streptozotocin

T2DM:

Type 2 diabetes mellitus

TC:

Total cholesterol

TCA:

Tricarboxylic acid cycle

T-SOD:

Total superoxide dismutase

VLDL:

Very low-density lipoprotein

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Acknowledgments

This research was bountifully supported by “Double First-Class” university project funding from Lanzhou University (561119201) and Fundamental Research Funds for the Central Universities (grant number lzujbky-2021-kb05). We express our sincere gratitude to the Center for Experimental Animals of Lanzhou University for their support.

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Author notes

  1. Tongyu Wu, Chun Li and **g Zhou contributed equally to this work as first authors.

Authors and Affiliations

  1. Department of Pharmacy, Lanzhou University, Lanzhou, 730000, People’s Republic of China

    Tongyu Wu, Chun Li, **g Zhou, Liang Han, Shaojia Qiang, Zhuozhou Hu, **g**g Liu, ** Chen

  2. State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou, 730000, People’s Republic of China

    ** Chen

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  1. Tongyu Wu
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Contributions

T.W. and C.L. contributed to most of the experiments and drafted the manuscript. J.Z. and L.H. developed and established the molecular experiment. S.Q. designed the molecular docking model. J.L. mainly responsible for in vitro technology guidance. X.L. and Z.H. helped with the most of in vivo mouse studies. W.Z. provided statistical advice. X.C. conceived the project, designed the studies, solved the experimental problems, helped analyze the results, and revised the manuscript. All authors reviewed and approved the manuscript.

Corresponding author

Correspondence to ** Chen.

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Conflict of interest

X.C., T.W., C.L., J.Z., and X.L. have applied for a patent, and we plan to benefit from the commercialization of the technology.

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Wu, T., Li, C., Zhou, J. et al. Primaquine activates Keratin 7 to treat diabetes and its complications. J Diabetes Metab Disord 21, 1731–1741 (2022). https://doi.org/10.1007/s40200-022-01135-8

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