Diabetes & Metabolism Journal

Original Articles

Pathophysiology
Deficiency of ASGR1 Alleviates Diet-Induced Systemic Insulin Resistance via Improved Hepatic Insulin Sensitivity: Xiaorui Yu, Jiawang Tao, Yuhang Wu, Yan Chen, Penghui Li, Fan Yang, Miaoxiu Tang, Abdul Sammad, Yu Tao, Yingying Xu, Yin-Xiong Li; Diabetes Metab J. 2024;48(4):802-815. Published online February 1, 2024; DOI: https://doi.org/10.4093/dmj.2023.0124

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Background
Insulin resistance (IR) is the key pathological basis of many metabolic disorders. Lack of asialoglycoprotein receptor 1 (ASGR1) decreased the serum lipid levels and reduced the risk of coronary artery disease. However, whether ASGR1 also participates in the regulatory network of insulin sensitivity and glucose metabolism remains unknown.
Methods
The constructed ASGR1 knockout mice and ASGR1^-/- HepG2 cell lines were used to establish the animal model of metabolic syndrome and the IR cell model by high-fat diet (HFD) or drug induction, respectively. Then we evaluated the glucose metabolism and insulin signaling in vivo and in vitro.
Results
ASGR1 deficiency ameliorated systemic IR in mice fed with HFD, evidenced by improved insulin intolerance, serum insulin, and homeostasis model assessment of IR index, mainly contributed from increased insulin signaling in the liver, but not in muscle or adipose tissues. Meanwhile, the insulin signal transduction was significantly enhanced in ASGR1^-/- HepG2 cells. By transcriptome analyses and comparison, those differentially expressed genes between ASGR1 null and wild type were enriched in the insulin signal pathway, particularly in phosphoinositide 3-kinase-AKT signaling. Notably, ASGR1 deficiency significantly reduced hepatic gluconeogenesis and glycogenolysis.
Conclusion
The ASGR1 deficiency was consequentially linked with improved hepatic insulin sensitivity under metabolic stress, hepatic IR was the core factor of systemic IR, and overcoming hepatic IR significantly relieved the systemic IR. It suggests that ASGR1 is a potential intervention target for improving systemic IR in metabolic disorders.

Citations

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Experimental cell models of insulin resistance: overview and appraisal
Ying Yang, Ting-ting Wang, Hu-ai Xie, Ping Ping Hu, Pan Li
Frontiers in Endocrinology.2024;[Epub] CrossRef

Basic Research
Sulforaphane Ameliorates Diabetes-Induced Renal Fibrosis through Epigenetic Up-Regulation of BMP-7: Lili Kong, Hongyue Wang, Chenhao Li, Huiyan Cheng, Yan Cui, Li Liu, Ying Zhao; Diabetes Metab J. 2021;45(6):909-920. Published online June 4, 2021; DOI: https://doi.org/10.4093/dmj.2020.0168

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Background
The dietary agent sulforaphane (SFN) has been reported to reduce diabetes-induced renal fibrosis, as well as inhibit histone deacetylase (HDAC) activity. Bone morphologic protein 7 (BMP-7) has been shown to reduce renal fibrosis induced by transforming growth factor-beta1. The aim of this study was to investigate the epigenetic effect of SFN on BMP-7 expression in diabetes-induced renal fibrosis.
Methods
Streptozotocin (STZ)-induced diabetic mice and age-matched controls were subcutaneously injected with SFN or vehicle for 4 months to measure the in vivo effects of SFN on the kidneys. The human renal proximal tubular (HK11) cell line was used to mimic diabetic conditions in vitro. HK11 cells were transfected to over-express HDAC2 and treated with high glucose/palmitate (HG/Pal) to explore the epigenetic modulation of BMP-7 in SFN-mediated protection against HG/Pal-induced renal fibrosis.
Results
SFN significantly attenuated diabetes-induced renal fibrosis in vivo. Among all of the HDACs we detected, HDAC2 activity was markedly elevated in the STZ-induced diabetic kidneys and HG/Pal-treated HK11 cells. SFN inhibited the diabetes-induced increase in HDAC2 activity which was associated with histone acetylation and transcriptional activation of the BMP-7 promoter. HDAC2 over-expression reduced BMP-7 expression and abolished the SFN-mediated protection against HG/Pal-induced fibrosis in vitro.
Conclusion
Our study demonstrates that the HDAC inhibitor SFN protects against diabetes-induced renal fibrosis through epigenetic up-regulation of BMP-7.

Citations

Citations to this article as recorded by

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Shengyu Pan, Tianhui Yuan, Yuqi Xia, Weimin Yu, Xiangjun Zhou, Fan Cheng
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Yanan Wang, Xiaoyun He, Nan Cheng, Kunlun Huang
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Di Zhang, Han Zhang, Shiqi Lv, Cheng Zhu, Shaomin Gong, Xixi Yu, Yulin Wang, Xinhui Huang, ShuangXin Yuan, Xiaoqiang Ding, Xiaoyan Zhang
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Aminu Mohammed, Hafsat Abdullahi Mohammed
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Christodoula Kourtidou, Konstantinos Tziomalos
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Da-Wei Lin, Yung-Chien Hsu, Cheng-Chih Chang, Ching-Chuan Hsieh, Chun-Liang Lin
International Journal of Molecular Sciences.2023; 24(7): 6053. CrossRef
Beneficial Effects of Sulforaphane on Diabetes and Its Complications via Both Nrf2-Dependent and Independent Mechanisms
Minhyuk Kim, Joo Young Lee
Food Supplements and Biomaterials for Health.2023;[Epub] CrossRef
Sulforaphane exhibits potent renoprotective effects in preclinical models of kidney diseases: A systematic review and meta-analysis
Elisa B. Monteiro, Matheus Ajackson, Milena B. Stockler-Pinto, Fitsum Guebre-Egziabher, Julio B. Daleprane, Christophe O. Soulage
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Hongzhou Lin, Huihui Chen, Rengcheng Qian, Guoqi Tang, Yinjuan Ding, Yalan Jiang, Congde Chen, Dexuan Wang, Maoping Chu, Xiaoling Guo
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BMP-7 Upregulates Id2 Through the MAPK Signaling Pathway to Improve Diabetic Tubulointerstitial Fibrosis and the Intervention of Oxymatrine
Yawen Xiao, Dan Liang, Zhiyang Li, Zhaowei Feng, Zhiping Yuan, Fan Zhang, Yuanyuan Wang, Yuxia Zhou, Mingjun Shi, Lingling Liu, Ying Xiao, Bing Guo
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HDAC1 Promotes Myocardial Fibrosis in Diabetic Cardiomyopathy by Inhibiting BMP-7 Transcription Through Histone Deacetylation
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