Local and regional control of calcium dynamics in the pancreatic islet

Research output: Contribution to journalArticle

Authors

  • Guy Rutter
  • David Hodson
  • Pauline Chabosseau
  • Timothy J Pullen
  • Isabelle Leclerc

Colleges, School and Institutes

External organisations

  • Imperial College London

Abstract

Ca2+ is the key intracellular regulator of insulin secretion, acting in the beta cell as the ultimate trigger for exocytosis. In response to high glucose, ATP-sensitive K+ channel closure and plasma membrane depolarisation engage a sophisticated machinery to drive pulsatile cytosolic Ca2+ changes. Voltagegated
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 beta cell function and survival. Across the islet, intercellular communication between highly interconnected “hubs”, which act as pacemaker beta 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 beta 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.

Details

Original languageEnglish
Pages (from-to)30–41
JournalDiabetes, Obesity and Metabolism
Volume19
Issue numberSupplement 1
Early online date7 Sep 2017
Publication statusPublished - Sep 2017