2. Academic Validation
  3. Readily releasable β cells with tight Ca2+-exocytosis coupling dictate biphasic glucose-stimulated insulin secretion

Readily releasable β cells with tight Ca2+-exocytosis coupling dictate biphasic glucose-stimulated insulin secretion

  • Nat Metab. 2024 Jan 26. doi: 10.1038/s42255-023-00962-0.
Xiaohong Peng # 1 2 3,  Huixia Ren # 1 4,  Lu Yang # 1 5,  Shiyan Tong # 1 6,  Renjie Zhou 1,  Haochen Long 7,  Yunxiang Wu 1,  Lifen Wang 8,  Yi Wu 1,  Yongdeng Zhang 9,  Jiayu Shen 1,  Junwei Zhang 1,  Guohua Qiu 1,  Jianyong Wang 1,  Chengsheng Han 1,  Yulin Zhang 1,  Mengxuan Zhou 1,  Yiwen Zhao 1,  Tao Xu 10 11,  Chao Tang 4,  Zhixing Chen 12,  Huisheng Liu 13 14 15,  Liangyi Chen 16 17
Affiliations

Affiliations

  • 1 New Cornerstone Science Laboratory, National Biomedical Imaging Center, State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, School of Future Technology, Center for Life Sciences, Peking University, Beijing, China.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 3 Bioland Laboratory, Guangzhou, China.
  • 4 Center for Quantitative Biology and Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
  • 5 The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
  • 6 School of Life Sciences, Peking University, Beijing, China.
  • 7 School of Software and Microelectronics, Peking University, Beijing, China.
  • 8 Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 9 School of Life Sciences, Westlake University, Hangzhou, China.
  • 10 Guangzhou National Laboratory, Guangzhou, China.
  • 11 School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, China.
  • 12 National Biomedical Imaging Center, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, School of Future Technology, Center for Life Sciences, Peking University, Beijing, China.
  • 13 Bioland Laboratory, Guangzhou, China. liu_huisheng@grmh-gdl.cn.
  • 14 Guangzhou National Laboratory, Guangzhou, China. liu_huisheng@grmh-gdl.cn.
  • 15 School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, China. liu_huisheng@grmh-gdl.cn.
  • 16 New Cornerstone Science Laboratory, National Biomedical Imaging Center, State Key Laboratory of Membrane Biology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Institute of Molecular Medicine, School of Future Technology, Center for Life Sciences, Peking University, Beijing, China. lychen@pku.edu.cn.
  • 17 PKU-IDG/McGovern Institute for Brain Research, Beijing, China. lychen@pku.edu.cn.
  • # Contributed equally.
PMID: 38278946 DOI: 10.1038/s42255-023-00962-0
Abstract

Biphasic glucose-stimulated Insulin secretion (GSIS) is essential for blood glucose regulation, but a mechanistic model incorporating the recently identified islet β cell heterogeneity remains elusive. Here, we show that Insulin secretion is spatially and dynamically heterogeneous across the islet. Using a zinc-based fluorophore with spinning-disc confocal microscopy, we reveal that approximately 40% of islet cells, which we call readily releasable β cells (RRβs), are responsible for 80% of Insulin exocytosis events. Although glucose up to 18.2 mM fully mobilized RRβs to release Insulin synchronously (first phase), even higher glucose concentrations enhanced the sustained secretion from these cells (second phase). Release-incompetent β cells show similarities to RRβs in glucose-evoked CA2+ transients but exhibit CA2+-exocytosis coupling deficiency. A decreased number of RRβs and their altered secretory ability are associated with impaired GSIS progression in ob/ob mice. Our data reveal functional heterogeneity at the level of exocytosis among β cells and identify RRβs as a subpopulation of β cells that make a disproportionally large contribution to biphasic GSIS from mouse islets.

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