Local and regional control of calcium dynamics in the pancreatic islet

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Title: Local and regional control of calcium dynamics in the pancreatic islet
Author(s): Rutter, GA
Hodson, DJ
Chabosseau, P
Haythorne, E
Pullen, TJ
Leclerc, I
Item Type: Journal Article
Abstract: Ca2+ is the key intracellular regulator of insulin secretion, acting in the β-cell as the ultimate trigger for exocytosis. In response to high glucose, ATP-sensitive K+ channel closure and plasma membrane depolarization engage a sophisticated machinery to drive pulsatile cytosolic Ca2+ changes. Voltage-gated Ca2+ channels, Ca2+-activated K+ channels and Na+/Ca2+ exchange all play important roles. The use of targeted Ca2+ probes has revealed that during each cytosolic Ca2+ pulse, uptake of Ca2+ by mitochondria, endoplasmic reticulum (ER), secretory granules and lysosomes fine-tune cytosolic Ca2+ dynamics and control organellar function. For example, changes in the expression of the Ca2+-binding protein Sorcin appear to provide a link between ER Ca2+ levels and ER stress, affecting β-cell function and survival. Across the islet, intercellular communication between highly interconnected “hubs,” which act as pacemaker β-cells, and subservient “followers,” ensures efficient insulin secretion. Loss of connectivity is seen after the deletion of genes associated with type 2 diabetes (T2D) and follows metabolic and inflammatory insults that characterize this disease. Hubs, which typically comprise ~1%-10% of total β-cells, are repurposed for their specialized role by expression of high glucokinase (Gck) but lower Pdx1 and Nkx6.1 levels. Single cell-omics are poised to provide a deeper understanding of the nature of these cells and of the networks through which they communicate. New insights into the control of both the intra- and intercellular Ca2+ dynamics may thus shed light on T2D pathology and provide novel opportunities for therapy.
Publication Date: 7-Sep-2017
Date of Acceptance: 24-Apr-2017
URI: http://hdl.handle.net/10044/1/52009
DOI: https://dx.doi.org/10.1111/dom.12990
ISSN: 1462-8902
Publisher: Wiley
Start Page: 30
End Page: 41
Journal / Book Title: Diabetes, Obesity and Metabolism
Volume: 19
Copyright Statement: This is the peer reviewed version of the following article: Rutter GA, Hodson DJ, Chabosseau P, Haythorne E, Pullen TJ, Leclerc I. Local and regional control of calcium dynamics in the pancreatic islet. Diabetes Obes Metab. 2017;19:30–41, which has been published in final form at https://dx.doi.org/10.1111/dom.12990.  This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
Keywords: Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
Ca2+
connectivity
imaging
insulin
organelle
2-OXOGLUTARATE DEHYDROGENASE COMPLEX
CA2+-INDUCED CA2+ RELEASE
INSULIN-SECRETING CELLS
BETA-CELLS
GLUCOSE-METABOLISM
ATP SYNTHESIS
HORMONE-SECRETION
CYTOSOLIC CA2+
GLUTAMATE ACTS
ER STRESS
Ca2+
connectivity
imaging
insulin
organelle
Science & Technology
Life Sciences & Biomedicine
Endocrinology & Metabolism
Ca2+
connectivity
imaging
insulin
organelle
2-OXOGLUTARATE DEHYDROGENASE COMPLEX
CA2+-INDUCED CA2+ RELEASE
INSULIN-SECRETING CELLS
BETA-CELLS
GLUCOSE-METABOLISM
ATP SYNTHESIS
HORMONE-SECRETION
CYTOSOLIC CA2+
GLUTAMATE ACTS
ER STRESS
1103 Clinical Sciences
Endocrinology & Metabolism
Publication Status: Published
Appears in Collections:Department of Medicine
Faculty of Medicine



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