Friend and foe: β-cell Ca2+ signaling and the development of diabetes

Abstract

Background: The divalent cation Calcium (Ca²⁺) regulates a wide range of processes in disparate cell types. Within insulin-producing β-cells, increases in cytosolic Ca²⁺ directly stimulate insulin vesicle exocytosis, but also initiate multiple signaling pathways. Mediated through activation of downstream kinases and transcription factors, Ca²⁺-regulated signaling pathways leverage substantial influence on a number of critical cellular processes within the β-cell. Additionally, there is evidence that prolonged activation of these same pathways is detrimental to β-cell health and may contribute to Type 2 Diabetes pathogenesis.

Scope of review: This review aims to briefly highlight canonical Ca²⁺ signaling pathways in β-cells and how β-cells regulate the movement of Ca²⁺ across numerous organelles and microdomains. As a main focus, this review synthesizes experimental data from in vitro and in vivo models on both the beneficial and detrimental effects of Ca²⁺ signaling pathways for β-cell function and health.

Major conclusions: Acute increases in intracellular Ca²⁺ stimulate a number of signaling cascades, resulting in (de-)phosphorylation events and activation of downstream transcription factors. The short-term stimulation of these Ca²⁺ signaling pathways promotes numerous cellular processes critical to β-cell function, including increased viability, replication, and insulin production and secretion. Conversely, chronic stimulation of Ca²⁺ signaling pathways increases β-cell ER stress and results in the loss of β-cell differentiation status. Together, decades of study demonstrate that Ca²⁺ movement is tightly regulated within the β-cell, which is at least partially due to its dual roles as a potent signaling molecule.

Keywords: CREB; Ca(2+); CaMK; Calcineurin; Calmodulin; Diabetes; NFAT; β-cells.