LIFE SCIENCES
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2022
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IF 6.78
Zhuozhou Hu,Jing Zhou,Liang Han,Xiangxiang Li,Chun Li,Tongyu Wu,Jingjing Liu,Wenyang Zhao,Jia Kang,Xinping Chen
Aims Diabetes mellitus (DM) is a major global health threat characterized by insulin resistance. A new tactic to ameliorate insulin resistance, thereby reversing the exacerbation of DM, is urgently needed. The work is aiming to provide a new strategy for DM treatment as well as to identify new targets. Main methods C57BL/6 N mice were raised with high-fat diet (HFD) and infused with streptozotocin (STZ) to induce diabetes. The blood glucose, serum insulin, blood lipid and oxidative stress were detected. In vitro insulin resistance model experiment has been made to examine the molecular mechanisms underlying anti-diabetic effect of potential active chemicals in human hepatocellular carcinoma cells (HepG2). Key findings Acyclovir, an antiviral nucleotide analog, alleviates insulin resistance by reducing blood lipids as well as oxidative stress and elevating insulin sensitivity on diabetic mice, which is in accord with results in the insulin resistance model of HepG2 cells. Mechanically, acyclovir stimulates pyruvate kinase M1 (PKM1) directly to activate adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)/Sirtuin1 (SIRT1) signaling pathway, thus improving insulin resistance. Significance The present study supports that acyclovir should be translated to remedy DM, and PKM1 might be a valuable target to develop new medicines.
研究领域:
药理学
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内分泌学
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分子生物学
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糖尿病研究
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产品关联
DOI
PubMed
高影响因子
Nature Communications
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2025
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IF 15.7
Haopeng Lin,Xin Liu,Feng Zhang,Deqi Chen,Xiaoxiao Xie,Qifei Dong,Jiawei Yan,Jiaxiang Yin,Zirong Bi,Zhihua Dou,Yingling Jiang,Kuo Jiang,Tongran Zhang,Peng Xue,Wei Peng,Lihua Chen,Tao Xu,Zonghong Li,Yanying Guo,Huisheng Liu
Human stem cell-derived β (SC-β) cells still exhibit limited glucose response required for insulin secretion due to glycolytic bottlenecks, yet how these metabolic abnormalities impact glucose response and functional maturation of SC-β cells remains unclear. In this study, we identify a metabolic checkpoint located at PEP accumulation that impedes the functional maturation, which is rescued by restoration of pyruvate kinase M1 ( PKM1 ). Glucose-tracing metabolomics in human stem cell-derived islets reveal abnormal glycolytic PEP accumulation at resting condition, associated with impaired calcium response and insulin secretion upon high glucose or glycolytic metabolite stimulation. Mechanistically, elevated PEP significantly raises intracellular basal calcium levels and downregulates expression of genes involved in TCA cycle as elucidated by single cell transcriptomics. Furthermore, the activity of pyruvate kinase, which metabolizes PEP, is notably reduced due to low PKM1 expression. Overexpression of PKM1 alleviates PEP accumulation, restores TCA-related gene expression, and enhances glucose-stimulated calcium responses and insulin secretion. Together, our findings reveal a critical role of PKM1-regulated PEP metabolism in SC-β cell functional maturation and highlight the importance of metabolic reprogramming for advancing stem cell-based therapies for diabetes. Human stem cell–derived β cells accumulate high basal PEP, which disrupts glucose-stimulated insulin release. Restoring PKM1 lowers basal PEP and improves glucose responses, advancing the maturation of stem cell–derived islets for diabetes therapy.
研究领域:
糖尿病研究
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干细胞生物学
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代谢学
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再生医学
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细胞生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）