Widespread synchronous [Ca2+]i oscillations due to bursting electrical activity in single pancreatic islets (original) (raw)
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Electrical bursting, calcium oscillations, and synchronization of pancreatic islets
Advances in experimental medicine and biology, 2010
Oscillations are an integral part of insulin secretion and are ultimately due to oscillations in the electrical activity of pancreatic beta-cells, called bursting. In this chapter we discuss islet bursting oscillations and a unified biophysical model for this multi-scale behavior. We describe how electrical bursting is related to oscillations in the intracellular Ca(2+) concentration within beta-cells and the role played by metabolic oscillations. Finally, we discuss two potential mechanisms for the synchronization of islets within the pancreas. Some degree of synchronization must occur, since distinct oscillations in insulin levels have been observed in hepatic portal blood and in peripheral blood sampling of rats, dogs, and humans. Our central hypothesis, supported by several lines of evidence, is that insulin oscillations are crucial to normal glucose homeostasis. Disturbance of oscillations, either at the level of the individual islet or at the level of islet synchronization, is...
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.
Electrical, Calcium, and Metabolic Oscillations in Pancreatic Islets
Oscillations are an integral part of insulin secretion, and are due ultimately to oscillations in the electrical activity of pancreatic β-cells, called bursting. We discuss the underlying mechanisms for bursting oscillations in mouse islets and the parallel oscillations in intracellular calcium and metabolism. We present a unified biophysical model, called the Dual Oscillator Model, in which fast electrical oscillations are due to the feedback of Ca 2+ onto K + ion channels, and the slow component is due to oscillations in glycolysis. The combination of these mechanisms can produce the wide variety of bursting and Ca 2+ oscillations observed in islets, including fast, slow, compound, and accordion bursting. We close with a description of recent experimental studies that have tested unintuitive predictions of the model and have thereby provided the best evidence to date that oscillations in glycolysis underlie the slow (~5 min) component of electrical, calcium, and metabolic oscillations in mouse islets.
Intercellular Ca2+ waves sustain coordinate insulin secretion in pig islets of Langerhans
FEBS Letters, 1996
Insulin release was investigated in parallel with changes in cytosolic calcium concentration, [Ca2+]i, in pig islets stimulated by glucose. After two days in culture, glucose stimulation failed to induce insulin release, and caused limited [Ca2+]i changes in few cells. After ten days, insulin response was partially restored and [Ca~+L recordings revealed a slow oscillatory activity of the whole islet. Slow oscillations appeared to be due to the average [Ca2+]i variations resulting from the spreading of waves throughout the islet. These waves demonstrate the reestablishment of functional cell coupling, which appears to play a critical role in insulin release.
Glucoseminduced [Ca2+]i oscillations in single human pancreatic islets
Cell Calcium, 1996
Changes in cytosolic free calcium concentration ([Ca"],) in response to stimulatory glucose concentrations were investigated in human pancreatic islets, using Fura-fluorescence imaging. Increasing glucose concentration from 3 to 11 mM caused a triphasic [Ca*+], response in human islets: an initial decrease (phase l), a rapid and transient increase (phase 2) and periodic oscillations with a frequency of 1 + 0.3 min (phase 3). Raising the glucose concentration from 11 to 16.7 mM lowered the frequency of the glucose-induced [Ca'+], oscillations to 0.15 + 0.2 min, without changes in their amplitude. Human islet [Ca'+], response to stimulatory glucose concentrations is synchronous throughout the islet. Freshly isolated human islets responded to tolbutamide (50 uM) with a rise in [Ca"+],. An increase in glucose concentration, from 3 to 16 mM, in the presence of 100 uM diazoxide, produced a decrease in [Ca'+],. It is concluded that human islets respond to glucose with regular [Ca'+], oscillations that are synchronous throughout the islet and whose duration is modulated by glucose.
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.
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.
The Interaction of Calcium and Metabolic Oscillations in Pancreatic Beta-cells
SPORA: A Journal of Biomathematics, 2017
Diabetes is a disease characterized by an excessive level of glucose in the bloodstream, which may be a result of improper insulin secretion. Insulin is secreted in a bursting behavior of pancreatic β-cells in islets, which is affected by oscillations of cytosolic calcium concentration. We used the Dual Oscillator Model to explore the role of calcium in calcium oscillation independent and calcium oscillation dependent modes and the synchronization of metabolic oscillations in electrically coupled β-cells. We implemented a synchronization index in order to better measure the synchronization of the β-cells within an islet, and we studied heterogeneous modes of coupled β-cells. We saw that increasing calcium coupling or voltage coupling in heterogeneous cases increases synchronization; however, in certain cases increasing both voltage and calcium coupling causes desynchronization. To better represent an islet, we altered previous code to allow for a greater number of cells to be simulated.
Diabetologia, 1994
Plasma insulin levels in healthy subjects oscillate and non-insulin-dependent diabetic patients display an irregular pattern of such oscillations. Since an increase in cytoplasmic free Ca 2+ concentration ([Ca 2+ ]i) in the pancreatic beta cell is the major stimulus for insulin release, this study was undertaken to investigate the dynamics of electrical activity, [Ca a+ ]i-changes and insulin release, in stimulated islets from subjects of varying glucose tolerance. In four patients it was possible to investigate more than one of these three parameters. Stimulation of pancreatic islets with glucose and tolbutamide sometimes resulted in the appearance of oscillations in [ Ca2+ ]i, lasting 2-3 rain. Such oscillations were observed even in some islets from patients with impaired glucose tolerance. In one islet from a diabetic patient there was no response to glucose, whereas that islet displayed [Ca 2+ ]i-oscillations in response to tolbutamide, suggesting that sulphonylurea treatment can mimic the complex pattern of glucose-in-duced [Ca 2+ ]i-oscillations. We also, for the first time, made patch-clamp recordings of membrane currents in beta-cells in situ in the islet. Stimulation with glucose and tolbutamide resulted in depolarization and appearance of action potentials. The islet preparations responded to stimulation with a number of different secretagogues with release of insulin. The present study shows that human islets can respond to stimulation with glucose and sulphonylurea with oscillations in [Ca 2+ ]i, which is the signal probably underlying the oscillations in plasma insulin levels observed in healthy subjects. Interestingly, even subjects with impaired glucose tolerance had islets that responded with oscillations in [Ca 2+ ]i upon glucose stimulation, although it is not known to what extent the response of these islets was representative of most islets in these patients. [Diabetologia (1994[Diabetologia ( ) 37: 1121[Diabetologia ( -1131
Glucose-induced oscillations of cytoplasmic Ca2+ in the pancreatic β-cell
Biochemical and Biophysical Research Communications, 1988
The cytoplasmic calcium concentration (Ca2+i) was measured in individual mouse pancreatic G-cells loaded with fura-2 by recording the 340/380 nm fluorescence excitation ratio. An increase of the glucose concentration from 3 to 20 mM, caused initial lowering of Ca2+i followed by a rise with a peak preceding constant elevation at an intermediary level. However, at ii mM glucose there were large Ca2+i oscillations with a frequency of 1 cycle per 2-6 min. The results indicate that both first and second phase secretion depend on elevated Ca2+i, and that many electrically coupled cells collectively determine the pace of rhythmic depolarization.