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Nature metabolism
Feb, 2024;6 (2): 238-253.

Readily releasable β cells with tight Ca-exocytosis coupling dictate biphasic glucose-stimulated insulin secretion.

Xiaohong Peng, Huixia Ren, Lu Yang, Shiyan Tong, Renjie Zhou, Haochen Long, Yunxiang Wu, Lifen Wang, Yi Wu, Yongdeng Zhang, Jiayu Shen, Junwei Zhang, Guohua Qiu, Jianyong Wang, Chengsheng Han, Yulin Zhang, Mengxuan Zhou, Yiwen Zhao, Tao Xu, Chao Tang, Zhixing Chen, Huisheng Liu, Liangyi Chen
Author Information
  1. Xiaohong Peng: 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. Huixia Ren: 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. ORCID
  3. Lu Yang: 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. ORCID
  4. Shiyan Tong: 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.
  5. Renjie Zhou: 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.
  6. Haochen Long: School of Software and Microelectronics, Peking University, Beijing, China.
  7. Yunxiang Wu: 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.
  8. Lifen Wang: Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  9. Yi Wu: 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.
  10. Yongdeng Zhang: School of Life Sciences, Westlake University, Hangzhou, China. ORCID
  11. Jiayu Shen: 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.
  12. Junwei Zhang: 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.
  13. Guohua Qiu: 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.
  14. Jianyong Wang: 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.
  15. Chengsheng Han: 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.
  16. Yulin Zhang: 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. ORCID
  17. Mengxuan Zhou: 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.
  18. Yiwen Zhao: 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.
  19. Tao Xu: Guangzhou National Laboratory, Guangzhou, China.
  20. Chao Tang: Center for Quantitative Biology and Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. ORCID
  21. Zhixing Chen: 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. ORCID
  22. Huisheng Liu: Bioland Laboratory, Guangzhou, China. liu_huisheng@grmh-gdl.cn. ORCID
  23. Liangyi Chen: 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. ORCID
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 Ca transients but exhibit Ca-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.

References

  1. Cerasi, E. & Luft, R. The plasma insulin response to glucose infusion in healthy subjects and in diabetes mellitus. Acta Endocrinol. (Copenh.) 55, 278–304 (1967). [PMID: 5338206]
  2. Simpson, R. G., Benedetti, A., Grodsky, G. M., Karam, J. H. & Forsham, P. H. Early phase of insulin release. Diabetes 17, 684–692 (1968). [PMID: 5687345]
  3. Martinussen, C. et al. Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass. Am. J. Physiol. Endocrinol. Metab. 308, E535–E544 (2015). [PMID: 25628424]
  4. Barg, S., Eliasson, L., Renstrom, E. & Rorsman, P. A subset of 50 secretory granules in close contact with ʟ-type Ca channels accounts for first-phase insulin secretion in mouse β-cells. Diabetes 51, S74–S82 (2002). [PMID: 11815462]
  5. Schulla, V. et al. Impaired insulin secretion and glucose tolerance in β cell-selective Ca1.2 Ca channel null mice. EMBO J. 22, 3844–3854 (2003). [PMID: 12881419]
  6. Jing, X. et al. Ca2.3 calcium channels control second-phase insulin release. J. Clin. Invest. 115, 146–154 (2005). [PMID: 15630454]
  7. Kang, L. et al. Munc13-1 is required for the sustained release of insulin from pancreatic β cells. Cell Metab. 3, 463–468 (2006). [PMID: 16697276]
  8. Pipeleers, D., Kiekens, R., Ling, Z., Wilikens, A. & Schuit, F. Physiologic relevance of heterogeneity in the pancreatic beta-cell population. Diabetologia 37, S57–S64 (1994). [PMID: 7821741]
  9. Pipeleers, D. G. Heterogeneity in pancreatic β-cell population. Diabetes 41, 777–781 (1992). [PMID: 1612191]
  10. Benninger, R. K. P. & Hodson, D. J. New understanding of β-cell heterogeneity and in situ islet function. Diabetes 67, 537–547 (2018). [PMID: 29559510]
  11. Westacott, M. J., Ludin, N. W. F. & Benninger, R. K. P. Spatially organized β-cell subpopulations control electrical dynamics across islets of Langerhans. Biophys. J. 113, 1093–1108 (2017). [PMID: 28877492]
  12. Dorrell, C. et al. Human islets contain four distinct subtypes of β cells. Nat. Commun. 7, 11756 (2016). [PMID: 27399229]
  13. Segerstolpe, A. et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab. 24, 593–607 (2016). [PMID: 27667667]
  14. Jetton, T. L. & Magnuson, M. A. Heterogeneous expression of glucokinase among pancreatic beta cells. Proc. Natl Acad. Sci. USA 89, 2619–2623 (1992). [PMID: 1557365]
  15. Piston, D. W., Knobel, S. M., Postic, C., Shelton, K. D. & Magnuson, M. A. Adenovirus-mediated knockout of a conditional glucokinase gene in isolated pancreatic islets reveals an essential role for proximal metabolic coupling events in glucose-stimulated insulin secretion. J. Biol. Chem. 274, 1000–1004 (1999). [PMID: 9873043]
  16. Salem, V. et al. Leader β-cells coordinate Ca dynamics across pancreatic islets in vivo. Nat. Metab. 1, 615–629 (2019). [PMID: 32694805]
  17. Johnston, N. R. et al. Beta cell hubs dictate pancreatic islet responses to glucose. Cell Metab. 24, 389–401 (2016). [PMID: 27452146]
  18. Wojtusciszyn, A., Armanet, M., Morel, P., Berney, T. & Bosco, D. Insulin secretion from human beta cells is heterogeneous and dependent on cell-to-cell contacts. Diabetologia 51, 1843–1852 (2008). [PMID: 18665347]
  19. Gaisano, H. Y., MacDonald, P. E. & Vranic, M. Glucagon secretion and signaling in the development of diabetes. Front. Physiol. 3, 349 (2012). [PMID: 22969729]
  20. Hauge-Evans, A. C. et al. Somatostatin secreted by islet δ-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 58, 403–411 (2009). [PMID: 18984743]
  21. Koh, D.-S., Cho, J.-H. & Chen, L. Paracrine interactions within islets of Langerhans. J. Mol. Neurosci. 48, 429–440 (2012). [PMID: 22528452]
  22. Takahashi, N., Kishimoto, T., Nemoto, T., Kadowaki, T. & Kasai, H. Fusion pore dynamics and insulin granule exocytosis in the pancreatic islet. Science 297, 1349–1352 (2002). [PMID: 12193788]
  23. Low, J. T. et al. Insulin secretion from beta cells in intact mouse islets is targeted towards the vasculature. Diabetologia 57, 1655–1663 (2014). [PMID: 24795086]
  24. Wang, Y. et al. An optical method to evaluate both mass and functional competence of pancreatic α- and β-cells. J. Cell Sci. 129, 2462–2471 (2016). [PMID: 27173492]
  25. Grodsky, G. M. A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. J. Clin. Invest. 51, 2047–2059 (1972). [PMID: 4559946]
  26. Henquin, J. C., Nenquin, M., Stiernet, P. & Ahren, B. In vivo and in vitro glucose-induced biphasic insulin secretion in the mouse: pattern and role of cytoplasmic Ca and amplification signals in β-cells. Diabetes 55, 441–451 (2006). [PMID: 16443779]
  27. Gini, C. Measurement of inequality of incomes. Econ. J. 31, 124–125 (1921). [DOI: 10.2307/2223319]
  28. Zhang, J. et al. Red- and far-red-emitting zinc probes with minimal phototoxicity for multiplexed recording of orchestrated insulin secretion. Angew. Chem. Int. Ed. 60, 25846–25855 (2021). [DOI: 10.1002/anie.202109510]
  29. Kravets, V. et al. Functional architecture of pancreatic islets identifies a population of first responder cells that drive the first-phase calcium response. PLoS Biol. 20, e3001761 (2022). [PMID: 36099294]
  30. Singh, V. et al. Somatostatin receptor subtype-2-deficient mice with diet-induced obesity have hyperglycemia, nonfasting hyperglucagonemia, and decreased hepatic glycogen deposition. Endocrinology 148, 3887–3899 (2007). [PMID: 17525126]
  31. Huising, M. O., van der Meulen, T., Huang, J. L., Pourhosseinzadeh, M. S. & Noguchi, G. M. The difference δ-cells make in glucose control. Physiology (Bethesda) 33, 403–411 (2018). [PMID: 30303773]
  32. He, S. et al. The discovery of MK-4256, a potent SSTR3 antagonist as a potential treatment of type 2 diabetes. ACS Med. Chem. Lett. 3, 484–489 (2012). [PMID: 24900499]
  33. DiGruccio, M. R. et al. Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. Mol. Metab. 5, 449–458 (2016). [PMID: 27408771]
  34. Zhang, Y. et al. Glucagon potentiates insulin secretion via β-cell GCGR at physiological concentrations of glucose. Cells 10, 2495 (2021). [PMID: 34572144]
  35. Svendsen, B. et al. Insulin secretion depends on intra-islet glucagon signaling. Cell Rep. 25, 1127–1134 (2018). [PMID: 30380405]
  36. Rutter, G. A., Ninov, N., Salem, V. & Hodson, D. J. Comment on Satin et al. “Take me to your leader”: an electrophysiological appraisal of the role of hub cells in pancreatic islets. Diabetes 69, 830–836 (2020). Diabetes 69, e10–e11 (2020).
  37. Satin, L. S., Zhang, Q. & Rorsman, P. “Take me to your leader”: an electrophysiological appraisal of the role of hub cells in pancreatic islets. Diabetes 69, 830–836 (2020). [PMID: 32312899]
  38. Kravets, V., Dwulet, J. M., Schleicher, W. E., Piscopio, R. A. & Benninger, R. K. P. Beta cells subpopulations: do they control islet function? Diabetologia 62, S133–S134 (2019).
  39. van der Meulen, T. et al. Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion. Nat. Med. 21, 769–776 (2015). [PMID: 26076035]
  40. Li, Q. et al. A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions. J. Clin. Invest. 127, 2631–2646 (2017). [PMID: 28604389]
  41. Kellard, J. A. et al. Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet. Mol. Metab. 40, 101021 (2020). [PMID: 32446876]
  42. Michael, D. J., Ritzel, R. A., Haataja, L. & Chow, R. H. Pancreatic β-cells secrete insulin in fast- and slow-release forms. Diabetes 55, 600–607 (2006). [PMID: 16505221]
  43. Li, D. et al. Imaging dynamic insulin release using a fluorescent zinc indicator for monitoring induced exocytotic release (ZIMIR). Proc. Natl Acad. Sci. USA 108, 21063–21068 (2011). [PMID: 22160693]
  44. Rorsman, P. et al. The cell physiology of biphasic insulin secretion. News Physiol. Sci. 15, 72–77 (2000). [PMID: 11390882]
  45. Yuan, T., Lu, J., Zhang, J., Zhang, Y. & Chen, L. Spatiotemporal detection and analysis of exocytosis reveal fusion “hotspots” organized by the cytoskeleton in endocrine cells. Biophys. J. 108, 251–260 (2015). [PMID: 25606674]
  46. Li, X. et al. Real-time denoising enables high-sensitivity fluorescence time-lapse imaging beyond the shot-noise limit. Nat. Biotechnol. 41, 282–292 (2023). [PMID: 36163547]

Grants

  1. 81925022/National Natural Science Foundation of China (National Science Foundation of China)
  2. 91750203/National Natural Science Foundation of China (National Science Foundation of China)
  3. T2288107/National Natural Science Foundation of China (National Science Foundation of China)
  4. 32227802/National Natural Science Foundation of China (National Science Foundation of China)
  5. 92150301/National Natural Science Foundation of China (National Science Foundation of China)
  6. 81602254/National Natural Science Foundation of China (National Science Foundation of China)

MeSH Term

Mice
Animals
Insulin Secretion
Biphasic Insulins
Glucose
Insulin-Secreting Cells
Insulin
Exocytosis

Chemicals

Biphasic Insulins
Glucose
Insulin
Journal Article
Article has an altmetric score of 52

Word Cloud

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