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Oscillations, Intercellular Coupling, and Insulin Secretion in Pancreatic β Cells

• Patrik Rorsman

Oscillations, Intercellular Coupling, and Insulin Secretion in Pancreatic β Cells

• Patrick Eastward MacDonald,
• Patrik Rorsman

x

• Published: Feb 14, 2006
• https://doi.org/x.1371/periodical.pbio.0040049

Figures

Commendation: MacDonald PE, Rorsman P (2006) Oscillations, Intercellular Coupling, and Insulin Secretion in Pancreatic β Cells. PLoS Biol 4(2): e49. https://doi.org/10.1371/periodical.pbio.0040049

Published: February 14, 2006

Copyright: © 2006 MacDonald and Rorsman. This is an open up-access article distributed under the terms of the Creative Eatables Attribution License, which permits unrestricted use, distribution, and reproduction in whatever medium, provided the original writer and source are credited.

Competing interests: The authors declare that no competing interests exist.

Abbreviations: UCP2, uncoupling protein-2; VDCC, voltage-dependent calcium channel

Information technology's piece of cake to say nosotros are what we eat, just this unproblematic statement belies the complexity of metabolic signalling that goes into balancing food intake with energy expenditure. One hormone in particular—insulin—is a critically important regulator of whole body energy metabolism. Information technology is secreted from the pancreas when blood glucose levels are high, and it acts to maintain glucose homeostasis by promoting glucose uptake and storage in muscle, fat, and liver. When insulin secretion is absent-minded or reduced, or when peripheral tissues fail to respond to insulin, the result is hyperglycaemia leading ultimately to diabetes. Diabetes affects more than than 170 million people worldwide and is associated with several long-term complications including nerve damage, kidney failure, microcirculatory damage, and a greater hazard for heart disease and stroke.

There are two types of secretion: exocrine and endocrine. In endocrine secretion, the secreted molecules terminate up in the blood and they reach their target cells throughout the body via the circulation. By dissimilarity, exocrine secretion does not involve the circulation and the products are released direct into the exterior world. Almost of the pancreas serves the exocrine function of secreting digestive enzymes into the gut. Less than 1% of the pancreatic tissue is devoted to an endocrine role. The endocrine tissue of the pancreas is organized as cell clusters, called the islets of Langerhans, which are dispersed throughout the pancreatic exocrine tissue and receive a rich vascular (blood vessel) supply (Figure ane). A pancreatic islet comprises three master cell types. Pancreatic α cells (fifteen%) occupy the islet periphery and secrete glucagon in response to low blood glucose. Glucagon opposes the deportment of insulin, thereby increasing circulating glucose levels. Pancreatic δ cells, the to the lowest degree abundant prison cell type (5%), are dispersed throughout the islet and secrete somatostatin, which has important paracrine effects that suppress insulin and glucagon secretion. The insulin-secreting β cells are the most abundant cell type (80%) and comprise the islet core.

Effigy one. Pancreatic Endocrine Tissue Comprises 1%, or Less, of the Pancreas and Is Organized every bit Clusters of Cells Dispersed throughout the Exocrine Pancreas

These cell clusters, the islets of Langerhans, are heterogeneous and composed of 3 main cell types that secrete distinct hormones. The majority of islet cells comprise insulin secreting β cells and act as glucose sensors, releasing insulin in response to increased circulating glucose. The machinery controlling regulated insulin secretion from β cells is shown in the right panel.

https://doi.org/10.1371/journal.pbio.0040049.g001

During development, the pancreas arises as an off-branching of early gut tissues, and develops every bit a prepare of branching tubules which give rise to clusters of endocrine and exocrine cells. Studies have shown that the cytokine TGF-β plays a major role in the development of pancreatic β cells during development of the organ [1, 2], and a newspaper past Smart et al. in this issue of PLoS Biology [3] demonstrates that TGF-β signalling is also critical in the maintenance of β cell functional identity in the adult. Smart and her colleagues were able to show that loss of TGF-β signalling in these cells causes reversion of these cells to an immature differentiated state and resulted in diabetes. Therefore, TGF-β is important for maintaining the functional characteristics of β cells.

In type i diabetes, the less common but more than astringent form of the disease, pancreatic β cells are destroyed by an autoimmune reaction. Type 2 diabetes accounts for greater than 85% of the cases of diabetes. In this course of the disease, the β cells persist, simply for reasons that remain to be established they fail to secrete insulin in sufficient quantities to maintain claret glucose within the normal range. Disrupted insulin secretion is observed prior to onset of type two diabetes [four], and when combined with the development of insulin resistance in peripheral tissues, results in chronic hyperglycaemia. Further deterioration of β cell function contributes to the progression of blazon 2 diabetes [five]. Type two diabetes is believed to effect from an unfortunate combination of variants (polymorphisms) in several diabetes susceptibility genes [half dozen]. Rarer monogenic forms of the disease result from mutations in genes encoding proteins that are critical to glucose-sensing in the β jail cell [7]. Thus, an appreciation of the mechanisms regulating β cell function and insulin secretion is crucial towards understanding the pathogenesis of type 2 diabetes.

The Stimulus-Secretion Coupling Mechanism

Glucose-dependent insulin secretion from β cells, by illustration to excitation–contraction coupling in musculus, is referred to equally stimulus-secretion coupling. Indeed, like musculus activation, the secretion of insulin is dependent on electrical activity and calcium, Ca^two+, entry. β cells have channels in their membranes that let for the flow of ions (mainly calcium, Ca²⁺, and potassium, K⁺) into and out of the cell. Considering ions are electrically charged, their flux across the membrane may give rising to sharp changes in voltage (action potentials). Glucose stimulation elicits depolarisation of the cell membrane and electrical activeness in β cells [viii–10]. This serves to open Ca^two+ channels in the membrane that answer to changes in voltage—voltage-dependent calcium channels (VDCCs)—and allow Ca²⁺ entry and activity potential firing. Ca²⁺ acts on the exocytotic machinery to stimulate fusion of insulin-containing vesicles with the plasma membrane for secretion into the bloodstream [xi]. Removal of extracellular Ca²⁺ prevents activeness potential firing [12] and insulin secretion [13, 14]. Numerous subsequent studies accept confirmed the essential roles of glucose-stimulated membrane depolarisation, activity potential firing, and entry of Caⁱⁱ⁺ in the regulation of insulin secretion.

Metabolism of glucose is essential for insulin secretion, and inhibition of mitochondrial metabolism blocks insulin secretion [xv]. Mechanisms of β cell glucose metabolism and metabolic signal generation accept been recently reviewed [16]. The breakdown of glucose results in the generation of ATP, one of the key molecules fueling cellular reactions. An increased ATP:ADP ratio represents the critical link betwixt mitochondrial metabolism and insulin secretion through its ability to close ATP-dependent K⁺ (K_ATP) channels and depolarise the cell [17] (Figure ane). K_ATP channels are equanimous of four pore-forming subunits (K_ir6.2 in β cells) and four accessory sulfonylurea receptor subunits (SUR1 in β cells). The latter are the target of the anti-diabetic sulphonylurea drugs which stimulate insulin secretion by mimicking the outcome of glucose to close K_ATP channels. Polymorphism in 1000_ATP subunits contribute to diabetes susceptibility by altering the biophysical properties of the channels [6].

Under low glucose conditions, K_ATP channels are open up, assuasive the outward flux of K⁺ and holding the cell membrane potential at about −70 mV. Closure of G_ATP channels, by glucose-induced increases in ATP, drives the membrane voltage to more positive potentials, and somewhen triggers the firing of action potentials resulting from activation of VDCCs (Figure ane). The major VDCC subtype expressed in β cells and that regulates insulin secretion is the L-type Ca²⁺ channel (Ca_vone.2). The essential role of this channel has been demonstrated both past pharmacological [eighteen] and genetic [19] inhibition of the channel. Both of these approaches event in a severe reduction in glucose stimulated insulin secretion. Although the L-type Caⁱⁱ⁺ aqueduct certainly plays a chief role in the regulation of insulin secretion, information technology is non the but VDCC expressed in β cells, and recent work suggests an important role for the R-type Ca²⁺ in insulin secretion during prolonged stimulation [twenty].

(United nations)Coupling Glucose Metabolism and ATP Production in β Cells

Because the membrane voltage is sensitive to changes in ATP levels within the jail cell, perturbations of the metabolic pathways that generate ATP can have a potent upshot on insulin secretion. ATP is generated in mitochondria through the electron transport chain, and is dependent upon the presence of a proton gradient (H⁺) beyond the mitochondrial membrane. In β cells, expression of uncoupling protein-2 (UCP2) can disrupt the generation of ATP in mitochondria by permitting protons to leak across the mitochondrial membrane. When UCP2 is overexpressed, the generation of ATP is bypassed [21], while loss of UCP2 expression results in increased ATP levels and as well enhanced insulin release past islets [22]. Accordingly, there may exist a correlation between expression levels of UCP2 and diabetes or obesity.

Although UCP2 clearly plays a role in regulating ATP product, the molecular pathways controlling its expression are not well understood. Bordone et al. (in a paper published in this issue of PLoS Biological science [23]) uncovered one potential regulator of UCP2 expression in their studies of Sirt1 expression and office in murine islets. The authors institute that Sirt1, a homologue of Sir2 (which itself is known to play diverse and important roles in regulating metabolism in organisms from yeast to mammals) is expressed in β cells, and that it downregulates UCP2 expression in these cells. This identifies Sirt1 every bit a positive regulator of insulin secretion from β cells.

Oscillatory Responses and Cell-to-Jail cell Coupling in β cells

Over the physiological range of glucose concentrations, β cell electric activity consists of oscillations in membrane potential between depolarised plateaux, on which bursts of activity potentials are superimposed, separated by repolarized electrically silent intervals. These oscillations in electrical activity are accompanied by changes in the cytoplasmic Ca²⁺ concentration [24], every bit demonstrated in Figure 2, which in plow give ascent to brief pulses (∼10 s) of insulin secretion [25–27].

Figure 2. The Responses of β Cells within Intact Islets Are Oscillatory and Synchronised

Here, the intracellular Ca²⁺ responses were measured using ratiometric methods and confocal microscopy. In islet β cells, marked R1-R6 in (A), glucose-stimulation results in increases in intracellular Ca²⁺ equally shown in (B). Oscillations in intracellular Ca²⁺, with a flow of ∼10 s, are observed. Furthermore, every bit seen in the expanded time scale in (C), these oscillations are synchronized within separate β cells throughout the islet.

https://doi.org/ten.1371/journal.pbio.0040049.g002

These oscillations reflect a rest betwixt activation of VDCCs (depolarization) and 1000⁺ channel activity (repolarization) [ten]. The depolarizing component predominates at the beginning of the outburst, merely the resultant influx of Ca^two+ during the plateau leads to a progressive Ca²⁺-induced increment in K⁺ channel activity. This occurs both via a directly effect on small-scale conductance Caⁱⁱ⁺-activated Chiliad⁺ (SK) channels [28], and via an indirect effect on Thou_ATP channels by lowering of the cytoplasmic ATP:ADP ratio due to increased Ca^two+ ATPase action [29]. The increase in Thou⁺ channel activity somewhen becomes big enough to repolarize the β cell, ending the burst. In this scenario, the wearisome pacemaker depolarization between 2 successive bursts results from the gradual restoration of [Ca²⁺]_i and the ATP:ADP ratio until SK and Grand_ATP channels are again closed and the background depolarizing conductance becomes sufficiently big to trigger a new outburst of action potentials.

Glucose produces a concentration-dependent increase in the duration of the bursts at the expense of the silent intervals until eventually, at glucose concentrations across twenty mM, uninterrupted action potential firing is observed. This may result from the higher rate of glucose metabolism at high concentrations of the carbohydrate and then that Ca²⁺ influx is unable to lower ATP sufficiently to produce an increment in 1000⁺ conductance large enough to trigger membrane repolarization. This model is supported by the ability of tolbutamide, a blocker of the M_ATP channel that has been used for more than than 50 years to treat diabetes, to suppress β cell membrane potential oscillations that results in continuous firing [29, thirty]. Thus, the role of 1000_ATP channels in the β cell extends across just serving as the glucose-regulated resting conductance. They besides contribute to the progressive stimulation of electric activity and insulin release by supra-threshold glucose levels.

In that location is an interesting dependence of oscillatory electric activity on islet integrity and the 10–xv s catamenia typically observed in intact pancreatic islets is for the most part lost in isolated cells maintained in brusque-term tissue civilisation [30]. This has been attributed to changes in channel expression [30], loss of paracrine signalling [31], and requirement of cell coupling [32]. Indeed, β cells within the aforementioned pancreatic islet are electrically coupled [33, 34], such that the [Ca²⁺ ]_i oscillations within dissimilar parts of the islet occur in stage (Figure ii). This synchronization presumably accounts for the observation of pulsatile insulin secretion from individual pancreatic islets [26]. Pancreatic β cells contain the gap junction protein connexin-36, ablation of which leads to loss of oscillatory insulin secretion, whereas [Ca²⁺]_i oscillations in the private cells is maintained [35].

Whereas β cells are electrically coupled to each other, electrical coupling [36] and synchronization of the [Ca^two+ ]_i oscillations [37] between β cells and non β cells and between non β cells appears much weaker if it exists at all. This it at variance with some of the early data looking at the period of an injected dye between cells which demonstrated the existence of both homotypic (i.e., β to β cell) and heterotypic (e.g., β to a cell) cell coupling [38, 39]. Nonetheless, more than contempo observations using noninvasive techniques suggest that dye coupling may be less all-encompassing than previously idea [xl].

In this issue of PLoS Biology, Rocheleau et al. [41] have studied the functional significance of electrical coupling between β cells using a novel and ingenious arroyo. They accept used genetically engineered mice in which the Thousand_ATP channel is rendered not-functional—by replacement of specific amino acids—in only some of the pancreatic β cells. This mosaic expression of the transgene (Kir6.2[AAA]) results in functional K_ATP channel knockout in ∼lxx% of the β cells. Somewhat surprisingly, intact islets from mice expressing the transgene exhibited an essentially normal glucose-dependent insulin secretion, when tested in vitro. Importantly, this required the integrity of the pancreatic islet since normal glucose regulation was lost upon dispersion of the islet into single cells. Insulin secretion from individual Kir6.2[AAA] islet cells occurred already at 1 mM glucose, which in normal cells is a not-stimulatory concentration. Moreover, insulin release was not further stimulated with increasing glucose concentrations. The observation that application of the gap junction inhibitor 18a-glycyrrhetinic acid to intact islets mimicked the effect of islet dispersion makes it probable that this difference results from electrical coupling that can only operate within the intact islet.

These data are consistent with the view that the islet functions as a syncytium (that is, an organ that in electrical terms behaves similar i cell) where K_ATP channel activeness in the private cells determines the excitability of the entire organ. This is reminiscent of the channel sharing concept originally proposed by Sherman et al. [42] to explain the membrane potential oscillations in islets. Piece of work on isolated cells, even when taken from the aforementioned animal, indicate a significant heterogeneity in the fourth dimension courses and magnitude of their responses to glucose stimulation. It seems possible that this reflects a metabolic heterogeneity and that some cells metabolise glucose better than others. This metabolic heterogeneity will result in variable Thou_ATP aqueduct activity in the individual cells. The written report by Rochelau et al. is significant besides in this context. They show that all cells inside an intact islet respond to glucose in the aforementioned fashion although the Grand_ATP channel activity in the individual cells ranged between zero and 100% of the normal. The only divergence from normality was a slight shift (∼2 mM) towards lower concentration in the glucose dose-response curve. Thus, a lowered K_ATP aqueduct activity in the Kir6.2[AAA] expressing cells will increase excitability in their normal neighbours and vice versa.

Can cell coupling exist of pathophysiological significance? Given that well-nigh of the ATP required for β cell function is of mitochondrial origin, processes that interfere with oxidative phosphorylation are likely to be important in the aetiology of type 2 diabetes. Heteroplasmy of mitochondrial cistron mutations leading to lowered ATP production (reviewed by [43]) and increased K_ATP channel activeness in a minority of the β cells within the cell may thus, via cell coupling, compromise electric activity and secretion in the entire islet, perhaps enough to result in clinical diabetes.

Acknowledgments

Supported by the Wellcome Trust. PEM is the European Foundation for the Written report of Diabetes/AstraZeneca Swain in Islet Biological science, and PR is a Imperial Society Wolfson Fellow.

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