Cell Calcium 56 (2014) 297–301 Contents lists available at ScienceDirect Cell Calcium jou rn al hom epage: www.elsevier.com/locate/ceca Review Calcium signalling in diabetes Agustin Guerrero-Hernandez a,* , Alexei Verkhratsky b a Department of Biochemistry, CINVESTAV-IPN, Mexico City, D.F., Mexico b The University of Manchester, School of Biological Sciences, 1.124 Stopford Building, Oxford Road, Manchester M13 9PT, UK a r t i c l e i n f o Article history: Available online 27 August 2014 Keywords: Ca 2+ signalling Ca 2+ homeostasis Pathology Diabetes ATP production ER stress a b s t r a c t Molecular cascades responsible for Ca 2+ homeostasis and Ca 2+ signalling could be assembled in highly plastic toolkits that define physiological adaptation of cells to the environment and which are intimately involved in all types of cellular pathology. Control over Ca 2+ concentration in different cellular compart- ments is intimately linked to cell metabolism, because (i) ATP production requires low Ca 2+ , (ii) Ca 2+ homeostatic systems consume ATP and (iii) Ca 2+ signals in mitochondria stimulate ATP synthesis being an essential part of excitation–metabolic coupling. The communication between the ER and mitochon- dria plays an important role in this metabolic fine tuning. In the insulin resistance state and diabetes this communication has been impaired leading to different disorders, for instance, diminished insulin production by pancreatic  cells, reduced heart and skeletal muscle contractility, reduced NO production by endothelial cells, increased glucose production by liver, increased lipolysis by adipose cells, reduced immune responses, reduced cognitive functions, among others. All these processes eventually trigger degenerative events resulting in overt diabetes due to reduction of pancreatic  cell mass, and different complications of diabetes, such as retinopathy, nephropathy, neuropathy, and different cardiovascular diseases. © 2014 Elsevier Ltd. All rights reserved. 1. Molecular physiology of calcium signalling 1a. Historic prelude: calcium ions in life and death Numerous seminal experiments performed by Sydney Ringer in second half of 19th century established the foundations for physiology and pathophysiology of calcium signalling in living tis- sues. Ringer has demonstrated that Ca 2+ ions are indispensable for numerous vital processes being central elements for muscle con- traction, fertilization, development and animal survival [1–3]. In 1928, Herbert Pollack for the first time observed intracellular Ca 2+ dynamics in amoeba injected with alizarin (this dye was used in textile from antiquity and in histology from 1914 for detecting Ca 2+ salts [4]). Alizarin readily precipitates Ca 2+ ions and resulting salt appears in the form of purple crystals. Polack observed localized Ca 2+ elevations; moreover he also found that chelating of Ca 2+ by Abbreviations: ER, endoplasmic reticulum; NO, nitric oxide; SERCA pump, sarco- endoplasmic reticulum calcium ATPase; UCP, uncoupling protein. * Corresponding author at: Dept of Biochemistry, CINVESTAV, Apdo. Postal 14- 740, Mexico City 07000, D.F., Mexico. Tel.: +52 55 5747 3950. E-mail addresses: aguerrero@cinvestav.mx, agugro@gmail.com (A. Guerrero-Hernandez). alizarin transiently immobilized amoeba indicating physiological role of Ca 2+ for regulated movements [5]. The pathological role of Ca 2+ ions that, being in excess, act as uni- versal mediators of cell injury and death, had been recognized in late 1960s (see [6] for review) and in 1974 the key role of excessive plasmalemmal Ca 2+ entry and subsequent Ca 2+ overload in trigger- ing ischaemic death of cardiomyocytes was suggested by Albrecht Fleckenstein [7]. Some years later the same massive Ca 2+ influx was identified as a death signal in ischaemic cerebellar neurones [8], and soon the role of deregulation of Ca 2+ homeostasis in initiation of numerous death routines has been established [9–11]. 1b. Evolutionary routes Control over intracellular Ca 2+ concentration is the common fea- ture of all living forms (including humans) in our world. Calcium ion is arguably the most ubiquitous signalling molecule controlling a wide array of cellular functions [12]. Importantly, the cytosolic Ca 2+ concentration which is kept at very low levels of 50–100 nM against a huge gradient by both passive and active mechanisms; the former involves the activity of different Ca 2+ buffering proteins while the latter includes the consumption of ATP either directly by Ca 2+ pumps or indirectly by exchangers. This low cytoplasmic [Ca 2+ ] is critical for cell survival, and loss of tight control over cytosolic Ca 2+ http://dx.doi.org/10.1016/j.ceca.2014.08.009 0143-4160/© 2014 Elsevier Ltd. All rights reserved.