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Leader β-cells coordinate Ca2+ dynamics across pancreatic islets in vivo

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Title: Leader β-cells coordinate Ca2+ dynamics across pancreatic islets in vivo
Authors: Salem, V
Delgadillo Silva, L
Suba, K
Mousavy Gharavy, SN
Akhtar, N
Martin-Alonso, A
Gaboriau, DCA
Rothery, SM
Styliandes, T
Carrat, G
Pullen, TJ
Pal Singh, S
Hodson, DJ
Leclerc, I
Shapiro, AMJ
Marchetti, P
Briant, LB
Distaso, W
Ninov, N
Rutter, G
Georgiadou, E
Item Type: Journal Article
Abstract: Pancreatic β-cells form highly connected networks within isolated islets. Whether this behaviour pertains to the situation in vivo, after innervation and during continuous perfusion with blood, is unclear. In the present study, we used the recombinant Ca2+ sensor GCaMP6 to assess glucose-regulated connectivity in living zebrafish Danio rerio, and in murine or human islets transplanted into the anterior eye chamber. In each setting, Ca2+ waves emanated from temporally defined leader β-cells, and three-dimensional connectivity across the islet increased with glucose stimulation. Photoablation of zebrafish leader cells disrupted pan-islet signalling, identifying these as likely pacemakers. Correspondingly, in engrafted mouse islets, connectivity was sustained during prolonged glucose exposure, and super-connected ‘hub’ cells were identified. Granger causality analysis revealed a controlling role for temporally defined leaders, and transcriptomic analyses revealed a discrete hub cell fingerprint. We thus define a population of regulatory β-cells within coordinated islet networks in vivo. This population may drive Ca2+ dynamics and pulsatile insulin secretion.
Issue Date: 1-Jun-2019
Date of Acceptance: 8-May-2019
URI: http://hdl.handle.net/10044/1/71093
DOI: 10.1038/s42255-019-0075-2
ISSN: 2522-5812
Publisher: Nature Research
Start Page: 615
End Page: 629
Journal / Book Title: Nature Metabolism
Volume: 1
Issue: 6
Copyright Statement: © 2019 Springer Nature Publishing AG
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
MRC Programme Grant
Medical Research Council (MRC)
Wellcome Trust
Wellcome Trust
Wellcome Trust
Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
INNOVATIVE MEDICINES INITIATIVE
Diabetes UK
Medical Research Council (MRC)
Medical Research Council (MRC)
Diabetes UK
Biotechnology and Biological Sciences Research Council (BBSRC)
Diabetes UK
The Royal Society
Medical Research Council (MRC)
European Foundation for the Study of Diabetes
European Foundation for the Study of Diabetes
European Foundation for the Study of Diabetes
Diabetes UK
Sun Pharmaceutical Industries Limited
Diabetes UK
Diabetes UK
Funder's Grant Number: 212625/Z/18/Z
MR/K001981/1
16-0323
MR/R022259/1
MR/R022259/1
MR/R010676/1
097816/Z/11/ZR
105603/Z/14/Z
098424/Z/12/ZR
MR/N020472/1
MR/L02036X/1
MR/L02036X/1
115881
15 / 0005275
MR/M012646/1
R26199/CN001
15821
BB/J015873/1
12/0004601
WM100078
MR/K023667/1
N/A
n/a
15/0005374
N/A
BDA number 13/0004672
13/0004672
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
ZEBRAFISH PANCREAS
INSULIN-RELEASE
COMMUNICATION
PLASTICITY
MODEL
MICE
TOOL
Animals
Calcium
Glucose
In Vitro Techniques
Insulin
Insulin-Secreting Cells
Signal Transduction
Zebrafish
Animals
Zebrafish
Calcium
Insulin
Glucose
Signal Transduction
Insulin-Secreting Cells
In Vitro Techniques
Publication Status: Published
Online Publication Date: 2019-06-14
Appears in Collections:Imperial College Business School
Department of Metabolism, Digestion and Reproduction
Bioengineering
National Heart and Lung Institute
Faculty of Medicine
Grantham Institute for Climate Change
Faculty of Natural Sciences
Faculty of Engineering