Joana Almaça1,2,3, Tao Liang4, Herbert Y Gaisano4, Hong Gil Nam5, Per-Olof Berggren6,7,8,9, Alejandro Caicedo10,11,12. 1. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL, 33136, USA. jalmaca@med.miami.edu. 2. Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA. jalmaca@med.miami.edu. 3. Center for Plant Aging Research, Institute for Basic Science and Department of New Biology, DGIST, Daegu, Republic of Korea. jalmaca@med.miami.edu. 4. Department of Medicine, University of Toronto, Toronto, ON, Canada. 5. Center for Plant Aging Research, Institute for Basic Science and Department of New Biology, DGIST, Daegu, Republic of Korea. 6. Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL, 33136, USA. Per-Olof.Berggren@ki.se. 7. Rolf Luft Research Center for Diabetes & Endocrinology, Karolinska Institutet, Stockholm, Sweden. Per-Olof.Berggren@ki.se. 8. Lee Kong Chien School of Medicine, Nanyang Technical University, Singapore, Singapore. Per-Olof.Berggren@ki.se. 9. Imperial College, London, UK. Per-Olof.Berggren@ki.se. 10. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, 1580 NW 10th Ave, Miami, FL, 33136, USA. acaicedo@med.miami.edu. 11. Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, USA. acaicedo@med.miami.edu. 12. Program in Neuroscience, Miller School of Medicine, University of Miami, Miami, FL, USA. acaicedo@med.miami.edu.
Abstract
AIMS/HYPOTHESIS: Insulin secretion is widely studied because it plays a central role in glucose homeostasis and diabetes. Processes from insulin granule fusion in beta cells to in vivo insulin secretion have been elucidated, but data at the cellular level do not fully account for several aspects of the macroscopic secretory pattern. Here we investigated how individual secretory events are coordinated spatially and temporally within intact human islets. METHODS: We used the fluorescent probe neuropeptide Y (NPY)-pHluorin to visualise insulin granule secretion in isolated intact human islets. RESULTS: We found that individual beta cells respond to increases in glucose concentration by releasing insulin granules in very discrete bursts with periods consistent with in vivo pulsatile insulin secretion. In successive secretory bursts during prolonged exposure to high glucose levels, secretory events progressively localised to preferential release sites, coinciding with the transition to second phase insulin secretion. Granule secretion was very synchronised in neighbouring beta cells, forming discrete regional clusters of activity. CONCLUSIONS/ INTERPRETATION: These results reveal how individual secretory events are coordinated to produce pulsatile insulin secretion from human islets.
AIMS/HYPOTHESIS: Insulin secretion is widely studied because it plays a central role in glucose homeostasis and diabetes. Processes from insulin granule fusion in beta cells to in vivo insulin secretion have been elucidated, but data at the cellular level do not fully account for several aspects of the macroscopic secretory pattern. Here we investigated how individual secretory events are coordinated spatially and temporally within intact human islets. METHODS: We used the fluorescent probe neuropeptide Y (NPY)-pHluorin to visualise insulin granule secretion in isolated intact human islets. RESULTS: We found that individual beta cells respond to increases in glucose concentration by releasing insulin granules in very discrete bursts with periods consistent with in vivo pulsatile insulin secretion. In successive secretory bursts during prolonged exposure to high glucose levels, secretory events progressively localised to preferential release sites, coinciding with the transition to second phase insulin secretion. Granule secretion was very synchronised in neighbouring beta cells, forming discrete regional clusters of activity. CONCLUSIONS/ INTERPRETATION: These results reveal how individual secretory events are coordinated to produce pulsatile insulin secretion from human islets.
Entities:
Keywords:
Exocytosis; Human islets; Insulin granule; Pulsatile secretion
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