Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 4, Pages 2205-2216Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.499111
Keywords
ATP; Calcium; Energy Metabolism; Imaging; Insulin; Pancreatic Islets
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Funding
- Platform for Dynamic Approaches to Living System from the Ministry of Education, Culture, Sports, Science, and Technology in Japan
- Precursory Research for Embryonic Science from the Japan Science and Technology Agency
- Japan Diabetes Foundation
- [22590977]
- Grants-in-Aid for Scientific Research [25251016, 25461346, 26111004, 24657101] Funding Source: KAKEN
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In pancreatic islets, insulin secretion occurs via synchronous elevation of Ca2+ levels throughout the islets during high glucose conditions. This Ca2+ elevation has two phases: a quick increase, observed after the glucose stimulus, followed by prolonged oscillations. In these processes, the elevation of intracellular ATP levels generated from glucose is assumed to inhibit ATP-sensitive K+ channels, leading to the depolarization of membranes, which in turn induces Ca2+ elevation in the islets. However, little is known about the dynamics of intracellular ATP levels and their correlation with Ca2+ levels in the islets in response to changing glucose levels. In this study, a genetically encoded fluorescent biosensor for ATP and a fluorescent Ca2+ dye were employed to simultaneously monitor the dynamics of intracellular ATP and Ca2+ levels, respectively, inside single isolated islets. We observed rapid increases in cytosolic and mitochondrial ATP levels after stimulation with glucose, as well as with methyl pyruvate or leucine/glutamine. High ATP levels were sustained as long as high glucose levels persisted. Inhibition of ATP production suppressed the initial Ca2+ increase, suggesting that enhanced energy metabolism triggers the initial phase of Ca2+ influx. On the other hand, cytosolic ATP levels did not fluctuate significantly with the Ca2+ level in the subsequent oscillation phases. Importantly, Ca2+ oscillations stopped immediately before ATP levels decreased significantly. These results might explain how food or glucose intake evokes insulin secretion and how the resulting decrease in plasma glucose levels leads to cessation of secretion.
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