Local and regional control of calcium dynamics in the pancreatic islet

Rutter, Guy A.; Hodson, David J.; Chabosseau, Pauline; Haythorne, Elizabeth; Pullen, Timothy J.; Leclerc, Isabelle

doi:10.1111/dom.12990

Cited by 51 publications

(44 citation statements)

References 112 publications

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“…There are certainly several open questions regarding connectivity in general and the nature of hub cells in specific and they have been recently summarized in a comprehensive review. 190 Here we only wish to point out that in accordance with predictions, 182 , 185 evidence is accumulating that the hub or pacemaker cells are metabolically highly active, 186 , 191 and display some phenotypic characteristics of immature cells, such as high levels of glucokinase, a low insulin content and a low expression of pancreatic duodenum homeobox-1 (Pdx1) and NK6 homeobox 1 (Nkx6.1). A less mature phenotype is also consistent with a lower threshold for insulin secretion.…”

Section: The Relationship Between Membrane Potential and [Ca mentioning

confidence: 79%

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The triggering pathway to insulin secretion: Functional similarities and differences between the human and the mouse β cells and their translational relevance

Klemen

Dolenšek

Rupnik

et al. 2017

Islets

129

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In β cells, stimulation by metabolic, hormonal, neuronal, and pharmacological factors is coupled to secretion of insulin through different intracellular signaling pathways. Our knowledge about the molecular machinery supporting these pathways and the patterns of signals it generates comes mostly from rodent models, especially the laboratory mouse. The increased availability of human islets for research during the last few decades has yielded new insights into the specifics in signaling pathways leading to insulin secretion in humans. In this review, we follow the most central triggering pathway to insulin secretion from its very beginning when glucose enters the β cell to the calcium oscillations it produces to trigger fusion of insulin containing granules with the plasma membrane. Along the way, we describe the crucial building blocks that contribute to the flow of information and focus on their functional role in mice and humans and on their translational implications.

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Section: The Relationship Between Membrane Potential and [Ca mentioning

confidence: 79%

“… 56 To get a more complete picture of β cell connectivity as a target of various pathological processes and future therapies, see some resourceful recent reviews. 91 , 189 , 190 , 196 , 220 …”

Section: Changes In Coupling Membrane Potential and Ca Oscillationsmentioning

confidence: 99%

The triggering pathway to insulin secretion: Functional similarities and differences between the human and the mouse β cells and their translational relevance

Klemen

Dolenšek

Rupnik

et al. 2017

Islets

129

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“…Subsequent depolarization of the plasma membrane leads to opening of voltage-gated Ca 2+ channels, Ca 2+ dependent assembly of the SNARE (SNAP (Soluble NSF Attachment Protein) Receptor) complex and exocytosis [3]. In the intact islet, βcell-β-cell connections allow coordinated insulin secretion through propagation of Ca 2+ and other signals [4,5,6] a process impaired by glucolipotoxicity [7], and affected by genes implicated in diabetes risk through genome-wide association studies (GWAS) such as ADCY5 [8] and TCF7L2 [9].…”

Section: Introductionmentioning

confidence: 99%

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

Carrat

Haythorne

Tomás

et al. 2020

Preprint

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AbstractObjectiveRisk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 expression in the β-cell, impaired glucose-induced insulin secretion and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids, and thus the pathways through which STARD10 regulates β-cell function, are not understood. The aim of this study was to identify the lipids transported and affected by STARD10 in the β-cell and its effect on proinsulin processing and insulin granule biogenesis and maturation.MethodsWe used isolated islets from mice deleted selectively in the β-cell for Stard10 (βStarD10KO) and performed electron microscopy, pulse-chase, RNA sequencing and lipidomic analyses. Proteomic analysis of STARD10 binding partners was executed in INS1 (832/13) cell line. X-ray crystallography followed by molecular docking and lipid overlay assay were performed on purified STARD10 protein.ResultsβStarD10KO islets had a sharply altered dense core granule appearance, with a dramatic increase in the number of “rod-like” dense cores. Correspondingly, basal secretion of proinsulin was increased. Amongst the differentially expressed genes in βStarD10KO islets, expression of the phosphoinositide binding proteins Pirt and Synaptotagmin 1 were decreased while lipidomic analysis demonstrated changes in phosphatidyl inositol levels. The inositol lipid kinase PIP4K2C was also identified as a STARD10 binding partner. STARD10 bound to inositides phosphorylated at the 3’ position and solution of the crystal structure of STARD10 to 2.3 Å resolution revealed a binding pocket capable of accommodating polyphosphoinositides.ConclusionOur data indicate that STARD10 binds to, and may transport, phosphatidylinositides, influencing membrane lipid composition, insulin granule biosynthesis and insulin processing.

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“…15 However, few studies have been performed in vivo and most of them fail to achieve adequate single-cell resolution. 15 However, few studies have been performed in vivo and most of them fail to achieve adequate single-cell resolution.…”

Section: Imaging Setup For Single β-Cell [Ca 2+ ] I Dynamics Analysmentioning

confidence: 99%

In vivo Ca²⁺ dynamics in single pancreatic β cells

et al. 2019

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contributed equally to the presented work.Abbreviations: 2-NBDG, 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose; ACE, anterior chamber of the eye; EMCCD, electron multiplying charge-coupled device; HBSS, Hank's Balanced Salt Solution; Hyp/Mid, hypnorm/midazolam; IpGTT, intraperitoneal glucose tolerance test; IpITT, intraperitoneal insulin tolerance test; [Ca 2+ ] i , intracellular free calcium ion concentration; RIP, rat insulin promoter. AbstractThe dynamics of cytoplasmic free Ca 2+ concentration ([Ca 2+ ] i ) in pancreatic β cells is central to our understanding of β-cell physiology and pathology. In this context, there are numerous in vitro studies available but existing in vivo data are scarce. We now critically evaluate the anterior chamber of the eye as an in vivo, non-invasive, imaging site for measuring [Ca 2+ ] i dynamics longitudinally in three dimensions and at single-cell resolution. By applying a fluorescently labeled glucose analogue 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose in vivo, we followed how glucose almost simultaneously distributes to all cells within the islet volume, resulting in [Ca 2+ ] i changes. We found that almost all β cells in healthy mice responded to a glucose challenge, while in hyperinsulinemic, hyperglycemic mice about 80% of the β cells could not be further stimulated from fasting basal conditions. This finding indicates that our imaging modality can resolve functional heterogeneity within the β-cell population in terms of glucose responsiveness. Importantly, we demonstrate that glucose homeostasis is markedly affected using isoflurane compared to hypnorm/ midazolam anesthetics, which has major implications for [Ca 2+ ] i measurements. In summary, this setup offers a powerful tool to further investigate in vivo pancreatic β-cell [Ca 2+ ] i response patterns at single-cell resolution in health and disease. K E Y W O R D Scalcium dynamics, diabetes mellitus, fluorescence microscopy, in vivo imaging, pancreatic islets 946 | JACOB et Al.

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Local and regional control of calcium dynamics in the pancreatic islet

Cited by 51 publications

References 112 publications

The triggering pathway to insulin secretion: Functional similarities and differences between the human and the mouse β cells and their translational relevance

The triggering pathway to insulin secretion: Functional similarities and differences between the human and the mouse β cells and their translational relevance

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

In vivo Ca²⁺ dynamics in single pancreatic β cells

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Local and regional control of calcium dynamics in the pancreatic islet

Cited by 51 publications

References 112 publications

The triggering pathway to insulin secretion: Functional similarities and differences between the human and the mouse β cells and their translational relevance

The triggering pathway to insulin secretion: Functional similarities and differences between the human and the mouse β cells and their translational relevance

The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

In vivo Ca2+ dynamics in single pancreatic β cells

Contact Info

Product

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In vivo Ca²⁺ dynamics in single pancreatic β cells