Metabolic memory of β-cells controls insulin secretion and is mediated by CaMKII

Ca2+/calmodulin-dependent protein kinase II (CaMKII) functions both in regulation of insulin secretion and neurotransmitter release through common downstream mediators. Therefore, we hypothesized that pancreatic beta-cells acquire and store the information contained in calcium pulses as a form of metabolic memory, just as neurons store cognitive information. To test this hypothesis, we developed a novel paradigm of pulsed exposure of beta-cells to intervals of high glucose, followed by a 24-h consolidation period to eliminate any acute metabolic effects. Strikingly, 8-cells exposed to this high-glucose pulse paradigm exhibited significantly stronger insulin secretion. This metabolic memory was entirely dependent on CaMKII. Metabolic memory was reflected on the protein level by increased expression of proteins involved in glucose sensing and Ca2+-dependent vesicle secretion, and by elevated levels of the key beta-cell transcription factor MAFA. In summary, like neurons, human and mouse beta-cells are able to acquire and retrieve information. (C) 2014 The Authors. Published by Elsevier GmbH.