Widespread synchronous [Ca2+]i oscillations due to bursting electrical activity in single pancreatic islets

Abstract

Pancreatic beta cells, tightly organized in the islet of Langerhans, secrete insulin in response to glucose in a calcium-dependent manner. The calcium input required for this secretory activity is thought to be provided by an oscillatory electrical activity occurring in the form of "bursts" of calcium action potentials. The previous observation that islet intracellular free Ca2+ levels undergo spontaneous oscillations in the presence of glucose, together with the fact that islet cells are coupled through gap junctions, hinted at a highly effective co-ordination between individual islet cells. Through the use of simultaneous recordings of intracellular calcium and membrane potential it is now reported that the islet calcium waves are synchronized with the beta cell bursting electrical activity. This observation suggests that each calcium wave is due to Ca2+ entering the cells during a depolarized phase of electrical activity. Moreover, fura-2 fluorescence image analysis indicates that calcium oscillations occur synchronously across the whole islet tissue. The maximal phase shift between oscillations occurring in different islet cells is estimated as 2 s. This highly co-ordinated oscillatory calcium signalling system may underlie pulsatile insulin secretion and the islet behaviour as a secretory "syncytium". Since increasing glucose concentration lengthens calcium wave and burst duration without significantly affecting wave amplitude, we further propose that it is the fractional time at an enhanced Ca2+ level, rather than its amplitude, that encodes for the primary response of insulin-secreting cells to fuel secretagogues.

Oscillatory control of insulin secretion

“…Also the fast oscillations correlate with cyclic membrane depolarization with bursts of electrical activity (Santos et al, 1991). They somehow codepend on the Ca 2+ handling by the ER, since fast islet oscillations are immediately transformed into slow ones by SERCA inhibition (Liu et al, 1998).…”

The in vivo regulation of pulsatile insulin secretion

“…This coordination could be through electro-physiological coupling among beta cells [126]. Studies on intracellular calcium show that an intra-islet spreading of the calcium influx is observed following an increase in intracellular calcium in a beta cell [104,127,128]. Alternatively, an agent that can diffuse between cells provides intra-islet synchronization of insulin release.…”

“…Examining data on in vitro insulin release at increasing glucose concentrations indicate increasing pulsatile release, whereas the basal release could be constant and glucose-unaffected [115,118]. The mechanism by which glucose stimulates insulin release seems to involve cyclic glycolysis [105,107], which generates oscillating intracellular concentrations of ATP [143], closure of ATP-dependent potassium channels and depolarization [120], increase in intracellular calcium [104,105,127], and subsequently an (ATP-dependent ?) exocytotic process.…”

Beta-cell hubs maintain Ca2+ oscillations in human and mouse islet simulations

“…Robust, islet-wide oscillations in intracellular Ca 2+ are required for glucose-stimulated insulin secretion. 3,4 These oscillations are highly synchronized, due to gap junction (GJ) coupling between β-cells. 5-7 The nature of these oscillations depends on the proliferative, 8 developmental 9,10 and differentiated 11,12 state of the cell.…”