Intercellular Ca2+ waves sustain coordinate insulin secretion in pig islets of Langerhans (original) (raw)
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Diabetes, 2006
Homeostasis of blood glucose is mainly regulated by the coordinated secretion of glucagon and insulin from ␣and -cells within the islets of Langerhans. The release of both hormones is Ca 2؉ dependent. In the current study, we used confocal microscopy and immunocytochemistry to unequivocally characterize the glucose-induced Ca 2؉ signals in ␣and -cells within intact human islets. Extracellular glucose stimulation induced an opposite response in these two cell types. Although the intracellular Ca 2؉ concentration ([Ca 2؉ ] i) in -cells remained stable at low glucose concentrations, ␣-cells exhibited an oscillatory [Ca 2؉ ] i response. Conversely, the elevation of extracellular glucose elicited an oscillatory [Ca 2؉ ] i pattern in -cells but inhibited lowglucose-induced [Ca 2؉ ] i signals in ␣-cells. These Ca 2؉ signals were synchronic among -cells grouped in clusters within the islet, although they were not coordinated among the whole -cell population. The response of ␣-cells was totally asynchronic. Therefore, both the ␣and -cell populations within human islets did not work as a syncitium in response to glucose. A deeper knowledge of ␣and -cell behavior within intact human islets is important to better understand the physiology of the human endocrine pancreas and may be useful to select high-quality islets for transplantation.
Diabetes, 1999
Normal mouse islets were used to determine whether oscillations of these three signals are able and necessary to trigger oscillations of insulin secretion. The approach was to minimize or abolish spontaneous oscillations and to compare the impact of forced oscillations of each signal on insulin secretion. In a control medium, repetitive increases in the glucose concentration triggered oscillations in metabolism [NAD(P)H fluorescence], [Ca 2+ ] i (fura-PE3 method), and insulin secretion. In the presence of diazoxide, metabolic oscillations persisted, but [Ca 2 + ] i and insulin oscillations were abolished. When the islets were depolarized with high K + with or without diazoxide, [ C a 2 + ] i was elevated, and insulin secretion was stimulated. Forced metabolic oscillations transiently decreased or did not affect [Ca 2 + ] i and potentiated insulin secretion with oscillations of small amplitude. These oscillations of secretion followed metabolic oscillations only when [Ca 2+ ] i did not change. When [Ca 2+ ] i fluctuated, these changes prevailed over those of metabolism for timing secretion.
Journal of Endocrinology, 2000
Oscillation of insulin release by the pancreatic islets was evaluated under stringent Ca 2+-free conditions for the first time. Isolated single rat islets were exposed to 16•7 mM glucose in the presence of 1•9 mM Ca 2+ , or under the stringent Ca 2+-free conditions (Ca 2+ omission with 1 mM EGTA, 6 µM forskolin and 100 nM phorbol 12-myristate 13-acetate). Fifteen minutes after the initiation of glucose stimulation, effluent was collected at a 6-s interval, insulin was determined in duplicate by a highly sensitive insulin radioimmunoassay, and oscillation and pulsatility of release statistically analyzed. Significant oscillation of insulin release was observed in all islets irrespective of presence and absence of Ca 2+. Significant pulsatility of release was detected in 7 of 11 islets in the presence of Ca 2+ and three of six islets in the absence of Ca 2+. In conclusion, high glucose elicits oscillatory insulin release both in the presence and absence of extracellular Ca 2+ .
Pfl�gers Archiv European Journal of Physiology, 1991
Pancreatic fi 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 Ca 2 + 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 fi cell bursting electrical activity. This observation suggests that each calcium wave is due to Ca 2 § 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 Ca 2"I" level, rather than its amplitude, that encodes for the primary response of insulin-secreting cells to fuel secretagogues.
FEBS Letters, 1989
Intracellular Ca2+ levels were monitored in single, acutely isolated mouse islets of Langerhans by dual emission Indo-l fluorometry. High-frequency (3.1 min-i) [Ca*+], oscillations with a brief rising time (1-2 s) and 10 s half-width ('fast' oscillations) were detected in 11 mM glucose. Raising the glucose concentration to 16.7 mM increased the duration of these oscillations, which were otherwise absent in 5.5 mM glucose. [Caz'], waves of lower frequency (0.5 mini) and longer rising time ('slow' oscillations) were also recorded. The data indicate that "fast" oscillations are directly related to p-cell bursting electrical activity, and suggest the existence of extensive networks of electrically coupled cells in the islet.
Endocrine, 2000
Ca 2+ influx through voltage-dependent Ca 2+ channels plays a crucial role in stimulus-secretion coupling in pancreatic islet-cells. Molecular and physiologic studies have identified multiple Ca 2+ channel subtypes in rodent islets and insulin-secreting cell lines. The differential targeting of Ca 2+ channel subtypes to the vicinity of the insulin secretory apparatus is likely to account for their selective coupling to glucose-dependent insulin secretion. In this article, I review these studies. In addition, I discuss temporal and spatial aspects of Ca 2+ signaling in-cells, the former involving the oscillatory activation of Ca 2+ channels during glucose-induced electrical bursting, and the latter involving [Ca 2+ ] i elevation in restricted microscopic "domains," as well as direct interactions between Ca 2+ channels and secretory SNARE proteins. Finally, I review the evidence supporting a possible role for Ca 2+ release from the endoplasmic reticulum in glucosedependent insulin secretion, and evidence to support the existence of novel Ca 2+ entry pathways. I also show that the-cell has an elaborate and complex set of [Ca 2+ ] i signaling mechanisms that are capable of generating diverse and extremely precise [Ca 2+ ] i patterns. These signals, in turn, are exquisitely coupled in space and time to the-cell secretory machinery to produce the precise minute-to-minute control of insulin secretion necessary for body energy homeostasis.
Endocrine, 2000
Ca 2+ influx through voltage-dependent Ca 2+ channels plays a crucial role in stimulus-secretion coupling in pancreatic islet-cells. Molecular and physiologic studies have identified multiple Ca 2+ channel subtypes in rodent islets and insulin-secreting cell lines. The differential targeting of Ca 2+ channel subtypes to the vicinity of the insulin secretory apparatus is likely to account for their selective coupling to glucose-dependent insulin secretion. In this article, I review these studies. In addition, I discuss temporal and spatial aspects of Ca 2+ signaling in-cells, the former involving the oscillatory activation of Ca 2+ channels during glucose-induced electrical bursting, and the latter involving [Ca 2+ ] i elevation in restricted microscopic "domains," as well as direct interactions between Ca 2+ channels and secretory SNARE proteins. Finally, I review the evidence supporting a possible role for Ca 2+ release from the endoplasmic reticulum in glucosedependent insulin secretion, and evidence to support the existence of novel Ca 2+ entry pathways. I also show that the-cell has an elaborate and complex set of [Ca 2+ ] i signaling mechanisms that are capable of generating diverse and extremely precise [Ca 2+ ] i patterns. These signals, in turn, are exquisitely coupled in space and time to the-cell secretory machinery to produce the precise minute-to-minute control of insulin secretion necessary for body energy homeostasis.