In a new study published in Journal of Extracellular Vesicles , Chen-Yu Zhang's group and Antonio Vidal-Puig's group at University of Cambridge report that pancreatic β cells secrete miR-29 family members (miR-29a, miR-29b and miR-29c) in response to high levels of free fatty acids (FFAs). These β cell-derived miR-29s are delivered to the liver, promoting insulin resistance and enhancing hepatic glucose output.
Over 100 years after insulin was discovered, it was believed that pancreatic β cells only secreted a single hormone--insulin. Pancreatic β cell-derived insulin regulates glucose homeostasis by binding with the insulin receptors located in the liver, skeletal muscle, adipose tissues and other peripheral organs. The discovery of insulin and its receptor was essential to understand the mechanisms controlling glucose homeostasis and the pathogenesis of type 2 diabetes defined by defective insulin secretion, signal transduction and insulin resistance. However, glucose homeostasis also depends on the integrated coordination of multiple organs, talking to each other to effectively control glucose metabolism. Understanding the crosstalk between organs is still incomplete, which has greatly limited the rational approach to type 2 diabetes treatment.
Previous work from Chen-Yu Zhang's group has identified extracellular miRNA as a new form of cell-to-cell communication. This group was the first reporting the different secretion of miRNAs in response to physiological or pathological states and the uptake and function of secreted miRNAs in recipient cells. In the current study, this group used three independent animal models (ob/ob, HFD and fasted mice) to show that pathological- and physiological- high levels of FFAs induce the secretion of miR-29s from pancreatic β cells. Of relevance, miR-29s is increased in the plasma of obese humans in comparison to lean humans. To address the target organ and functional role of secreted miR-29s, they generated three kinds of transgenic mice. First, mice overexpressed miR-29s or a traceable mutant miR-29a in pancreatic β cells showed that β cell-derived miR-29s is taken by the liver attenuating the normal suppression of insulin on glucose output mediated by targeting p85 α (a regulatory subunit of PI3K) promoting systemic insulin resistance. More importantly, miR-29s deficiency in β cells significantly improved the insulin sensitivity in mice fed on HFD, indicating that β cell-derived miR-29s play an essential role in the development of liver insulin resistance.
This work is essential for the following reasons:
Chen-Yu Zhang believes that pancreatic islet-derived miRNAs might contribute to a diversified functional spectrum. Thus, more studies are needed to discover the functional roles of pancreatic islet-derived miRNAs and subsequently establish mechanisms that underlie integrated multi-organ regulation on glucose homeostasis.
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The researchers of this project include Jing Li, Yujing Zhang, Yangyang Ye, Dameng Li, Yuchen Liu, Eunyoung Lee, Mingliang Zhang, Xin Dai, Xiang Zhang, Shibei Wang, Junfeng Zhang, Weiping Jia, Ke Zen, Antonio Vidal-Puig, Xiaohong Jiang, Chen-Yu Zhang.
This work was supported by grants the National Natural Science Foundation of China (31741066, 31200874, 31771666, 31200969, 81101330, 31271378, 81250044, and 31972912), the National Basic Research Program of China (973 Program) (No. 2011CB504803), the National Key Research and Development Program of China (2017YFC0909700), the Natural Science Foundation of Jiangsu Province, China (BK20130890, BK2011013 and BK2012014), the Fundamental Research Funds for the Central Universities (020814380148, 020514380226), the National Science Fund for Distinguished Young Scholars (81025019) and the programme for New Century Excellent Talents in University from the Ministry of Education, China (NCET-12-0261). Vidal-Puig is funded by MRC-MDU programme grant.
Li et al.: "Pancreatic β cells control glucose homeostasis via the secretion of exosomal miR-29 family" published on Journal of Extracellular Vesicle , 21 January 2021.
Author contact:
Prof. Chen-Yu Zhang
(Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, Chinese Academy of Medical Sciences Research Unit of Extracellular RNA, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), Institute of Artificial Intelligence Biomedicine, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China)
Tel: +86-25-89680245;
E-mail: cyzhang@nju.edu.cn
Journal of Extracellular Vesicles