Abstract
Major part of a pancreatic islet is composed of β-cells that secrete insulin, a key hormone regulating influx of nutrients into all cells in a vertebrate organism to support nutrition, housekeeping or energy storage. β-cells constantly communicate with each other using both direct, short-range interactions through gap junctions, and paracrine long-range signaling. However, how these cell interactions shape collective sensing and cell behavior in islets that leads to insulin release is unknown. When stimulated by specific ligands, primarily glucose, β-cells collectively respond with expression of a series of transient Ca2+ changes on several temporal scales. Here we reanalyze a set of Ca2+ spike trains recorded in acute rodent pancreatic tissue slice under physiological conditions. We found strongly correlated states of co-spiking cells coexisting with mostly weak pairwise correlations widespread across the islet. Furthermore, the collective Ca2+ spiking activity in islet shows on-off intermittency with scaling of spiking amplitudes, and stimulus dependent autoassociative memory features. We use a simple spin glass-like model for the functional network of a β-cell collective to describe these findings and argue that Ca2+ spike trains produced by collective sensing of β-cells constitute part of the islet metabolic code that regulates insulin release and limits the islet size.
Highlights
Endocrine cells in vertebrates act both as coders and decoders of metabolic code (Tomkins, 1975) that carries information from primary endocrine sensors to target tissues
In an oversimplified medical physiology textbook interpretation, glucose is transported into a β-cell through facilitated diffusion, is phosphorylated and converted within a metabolic black box to ATP, leading to closure of KATP channels, cell membrane depolarization and activation of voltage-activated calcium channels (VACCs), followed by a rise in cytosolic Ca2+ to a micromolar range and triggering of SNARE-dependent insulin release (Ashcroft and Rorsman, 1989)
As the relation between the rate of insulin release and cytosolic Ca2+ activity shows saturation kinetics with high cooperativity (Skelin and Rupnik, 2011), the insulin release probability is significantly increased during these Ca2+ spikes
Summary
Endocrine cells in vertebrates act both as coders and decoders of metabolic code (Tomkins, 1975) that carries information from primary endocrine sensors to target tissues. In an oversimplified medical physiology textbook interpretation, glucose is transported into a β-cell through facilitated diffusion, is phosphorylated and converted within a metabolic black box to ATP, leading to closure of KATP channels, cell membrane depolarization and activation of voltage-activated calcium channels (VACCs), followed by a rise in cytosolic Ca2+ to a micromolar range and triggering of SNARE-dependent insulin release (Ashcroft and Rorsman, 1989). There may be alternative glucose entry routes, like for example active Na-glucose cotransport (Tomita, 1976; Trautmann and Wollheim, 1987), alternative calcium release sites, like ryanodine (Islam, 2002) and IP3 receptors (Lang, 1999) or glucose may directly activate the sweet taste receptor and initiate signaling (Henquin, 2012), to name a few.
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