Local and regional control of calcium dynamics in the pancreatic islet

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.