Glucose Modulates (Ca21)i Oscillations in Pancreatic Islets via Ionic and Glycolytic Mechanisms (original) (raw)
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Glucose Modulates [Ca 2+] i Oscillations in Pancreatic Islets via Ionic and Glycolytic Mechanisms
Biophysical Journal, 2006
Pancreatic islets of Langerhans display complex intracellular calcium changes in response to glucose that include fast (seconds), slow (∼5min), and mixed fast/slow oscillations; the slow and mixed oscillations are likely responsible for the pulses of plasma insulin observed in vivo. To better understand the mechanisms underlying these diverse patterns, we systematically analyzed the effects of glucose on period, amplitude, and
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.
Calcium and Metabolic Oscillations in Pancreatic Islets: Who's Driving the Bus?
SIAM Journal on Applied Dynamical Systems, 2014
Pancreatic islets exhibit bursting oscillations in response to elevated blood glucose. These oscillations are accompanied by oscillations in the free cytosolic Ca 2+ concentration (Cac), which drives pulses of insulin secretion. Both islet Ca 2+ and metabolism oscillate, but there is some debate about their interrelationship. Recent experimental data show that metabolic oscillations in some cases persist after the addition of diazoxide (Dz), which opens K(ATP) channels, hyperpolarizing βcells and preventing Ca 2+ entry and Ca 2+ oscillations. Further, in some islets in which metabolic oscillations were eliminated with Dz, increasing the cytosolic Ca 2+ concentration by the addition of KCl could restart the metabolic oscillations. Here we address why metabolic oscillations persist in some islets but not others, and why raising Cac restarts oscillations in some islets but not others. We answer these questions using the dual oscillator model (DOM) for pancreatic islets. The DOM can reproduce the experimental data and shows that the model supports two different mechanisms for slow metabolic oscillations, one that requires calcium oscillations and one that does not.
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.
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
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.
Biophysical Journal, 2010
Plasma insulin is pulsatile and reflects oscillatory insulin secretion from pancreatic islets. Although both islet Ca 2þ and metabolism oscillate, there is disagreement over their interrelationship, and whether they can be dissociated. In some models of islet oscillations, Ca 2þ must oscillate for metabolic oscillations to occur, whereas in others metabolic oscillations can occur without Ca 2þ oscillations. We used NAD(P)H fluorescence to assay oscillatory metabolism in mouse islets stimulated by 11.1 mM glucose. After abolishing Ca 2þ oscillations with 200 mM diazoxide, we observed that oscillations in NAD(P)H persisted in 34% of islets (n ¼ 101). In the remainder of the islets (66%) both Ca 2þ and NAD(P)H oscillations were eliminated by diazoxide. However, in most of these islets NAD(P)H oscillations could be restored and amplified by raising extracellular KCl, which elevated the intracellular Ca 2þ level but did not restore Ca 2þ oscillations. Comparatively, we examined islets from ATP-sensitive K þ (K ATP) channel-deficient SUR1 À/À mice. Again NAD(P)H oscillations were evident even though Ca 2þ and membrane potential oscillations were abolished. These observations are predicted by the dual oscillator model, in which intrinsic metabolic oscillations and Ca 2þ feedback both contribute to the oscillatory islet behavior, but argue against other models that depend on Ca 2þ oscillations for metabolic oscillations to occur.
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.
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.
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.