Wu Tongyu, Li Chun, Zhou Jing, Han Liang, Qiang Shaojia, Hu Zhuozhou, Liu Jingjing, Li Xiangxiang, Zhao Wenyang, Chen Xinping
Department of Pharmacy, Lanzhou University, Lanzhou, 730000 People's Republic of China.
State Key Laboratory of Veterinary Etiological Biology, College of Veterinary Medicine, Lanzhou, 730000 People's Republic of China.
J Diabetes Metab Disord. 2022 Sep 29;21(2):1731-1741. doi: 10.1007/s40200-022-01135-8. eCollection 2022 Dec.
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.
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.
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.
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.
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.
The online version contains supplementary material available at 10.1007/s40200-022-01135-8.
2型糖尿病（T2DM）在全球的流行增加了其并发症的发生率，如糖尿病肾病和心血管疾病。为了攻克这些并发症，迫切需要新的策略来逆转T2DM的恶化。在本项目中，我们旨在研究伯氨喹的降血糖作用并探索其特定靶点。
在HepG2细胞中建立体外T2DM胰岛素抵抗模型，以筛选潜在的抗糖尿病化学物质。另一方面，通过分子对接探索潜在的蛋白质靶点。据此，我们选择C57BL/6 N小鼠建立T2DM模型，以验证这些化学物质对降血糖和糖尿病并发症的作用。
通过靶向角蛋白7（K7）激活表皮生长因子受体（EGFR）/蛋白激酶B（Akt）葡萄糖代谢信号通路，伯氨喹具有显著的降血糖作用。乙酰辅酶A水平显著升高，支持伯氨喹上调有氧糖酵解。此外，伯氨喹通过减少尿蛋白和肌酐的分泌改善肾功能，尤其是尿素氮，与未治疗的T2DM小鼠相比显著降低。值得注意的是，伯氨喹将血浆低密度脂蛋白胆固醇（LDL-C）水平恢复至接近正常，将心血管疾病的发生率降至最低。
我们发现伯氨喹可能通过刺激EGFR/Akt信号轴逆转代谢失调，预防糖尿病并发症，为T2DM的治疗提供了新的思路。
胰岛素抵抗的特征是磷酸化Akt（p-Akt）减少和葡萄糖代谢降低，以无氧糖酵解为主。伯氨喹激活由K7和EGFR组成的复合物，进一步刺激Akt磷酸化。然后，p-Akt促进有氧葡萄糖代谢并上调乙酰辅酶A以推动三羧酸循环，提高胰岛素敏感性。
在线版本包含可在10.1007/s40200-022-01135-8获取的补充材料。
