atp and insulin

The entry of glucose into the beta cell, the phosphorylation of glucose, and the generation of adenosine triphosphate (ATP) by this or other nutrients result in insulin release. The reported loss of ATP sensitivity coupled with high open probability in the Q52R, C42R, Y330C, I1296L, and V59G mutations suggests such a mechanism in these disease mutations (38,39). ATP max is a valid in vivo measure of mitochondrial ATP synthesis capacity based on the high correlation with mitochondrial content and oxidative type I fibers. It seems likely that increased palmitoyl-CoA sensitivity in the latter study, as well as increased MgADP sensitivity and reduced ATP sensitivity in the previous study, all reflect just such an increase. Diabetes. Importantly, the inhibitory concentration of ATP causing half-maximal channel inhibition is in the micromolar range (K1/2[ATP] ∼10 μmol/l for native KATP channel) (77), yet cytosolic [ATP] is in the millimolar range (1–5 mmol/l) and changes little in the presence of high glucose (78). In some cases, these “open-state stability” mutations are located in transmembrane segments, a significant distance from the putative ATP-binding domain (86,91). Proc Natl Acad Sci U S A. ISPAD, International Society for Pediatric and Adolescent Diabetes. 2011 May;54(5):1087-97. doi: 10.1007/s00125-010-2039-7. The ac-tivity of the KATP channel sets the resting membrane potential of the unstimulated beta cell and its closure decreases the membrane K+ permeability, producing membrane depolarization and insulin … ATP and insulin are co-stored and co-secreted 24,25. In skeletal muscle, or in neurons, overactive KATP channel could potentially underlie the muscle weakness reported in syndromic permanent neonatal diabetes (27,29). Insulin and glucose perfusions during resuscitation of rats from hemorrhagic shock increase the hepatic ATP content. The prediction that K ATP … and Washington University Diabetes Research and Training Center Pilot and Feasibility Award DK20579 (to J.C.K.). The first part of this review will detail the rapidly emerging clinical evidence for involvement of KATP channel mutations in neonatal and type 2 diabetes and the cellular basis of the disease. Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Although none have been reported, it remains possible that neonatal diabetes could also result from gain of function due to an increased affinity for PIP2. Because it converts glucose into ATP, which is the most basic unit of energy that we use in the body. Prevention and treatment information (HHS). Defects in beta cell Ca²+ signalling, glucose metabolism and insulin secretion in a murine model of K(ATP) channel-induced neonatal diabetes mellitus. ATP and insulin individually stimulated DNA synthesis by 4- and 2-fold, respectively; however, they acted synergistically to stimulate an increase of 17-fold over basal. A : paradigmatic role of the ATP-sensitive potassium (K ATP ) channel in normal coupling of glucose levels to insulin secretion. While these hyperexcitable mice, with reduced KATP channel activity, thus have a very different response to those with overactive KATP channels, they do suggest that profound nonelectrical consequences can follow an initial electrical disturbance. Residues are classified as those putatively involved in ATP binding (red and pink) or in regulation of open-state stability (blue and green). These include Wolcott-Rallison syndrome, characterized by infancy-onset diabetes along with growth and mental retardation and caused by mutations in EIF2AK3, a regulator of protein synthesis (20,21). NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. An effect on the gate region of the channel might then explain the diabetes-causing effects of mutations at residue K170 (K170N and K170R; Fig. Sign In to Email Alerts with your Email Address. Such mutations are found throughout the Kir6.2 subunit. There is no doubt that K ATP channels in β-cells are critical in regulation of glucose-induced insulin secretion (Cook et al. ATP and ADP levels are critical regulators of glucose-stimulated insulin secretion. In addition to Kir6.2 defects, loss or reduction of KATP channel activity can also occur due to loss-of-function mutations of the regulatory SUR1 subunit; such mutations are the most frequent cause of CHI (5). Conversely, a decrease in the metabolic signal is predicted to open KATP channels and suppress the electrical trigger of insulin secretion. The ATP-sensitive K+ channel (K ATP channel) senses metabolic changes in the pancreatic beta-cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. A clear picture is now emerging from both animal and human studies that such KATP channel mutations can indeed cause diabetes. Within a single pedigree, one Kir6.2 mutation (C42R) is shown to underlie transient neonatal diabetes, childhood-onset diabetes, as well an apparently type 2 diabetes, all in different carriers (33). Importantly, several patients have now been weaned from insulin onto glibenclamide therapy, and at 1- to 6-month follow-ups, blood glucose has been well controlled without insulin supplement (31,36). Diabetes Print ISSN: 0012-1797, Online ISSN: 1939-327X. Role of K ATP channel in coupling glucose levels to insulin secretion. A: Upper left: In Kir6.2[ΔN30]-expressing transgenic (TG) mice, only 3 of ∼150 F1 transgenic mice survived to weaning (11). Diabetes Metab. Active transport is the movement of molecules or ions against their concentration gradient, using energy in the form of ATP, across a plasma membrane. 2006 Nov;55(11):3075-82. doi: 10.2337/db06-0637. This site needs JavaScript to work properly. By suppressing excitability, KATP channel polymorphisms that increase channel activity could, in combination with other environmental and genetic factors, contribute to chronically impaired β-cell function. Treatment and long-term prognosis. Until recently, the cause of the majority of permanent neonatal diabetes cases has remained unknown. The mature KATP channel exists as an octamer of Kir6.2 and SUR1 subunits in a 4:4 stoichiometry (Fig. The ATP release mechanism and its regulation were tested in cells exposed to adrenergic agonists, insulin, glucose load and pharmacological inhibitors. At the other end, severe "activating" mutations underlie syndromic neonatal diabetes, with multiple organ involvement and complete failure of glucose-dependent insulin secretion, reflecting K ATP channel "overactivity" in both pancreatic and extrapancreatic tissues. Please enable it to take advantage of the complete set of features! Tarasov AI, Welters HJ, Senkel S, Ryffel GU, Hattersley AT, Morgan NG, Ashcroft FM. Untargeted Metabolomic Approach Shows No Differences in Subcutaneous Adipose Tissue of Diabetic and Non-Diabetic Subjects Undergoing Bariatric Surgery: An Exploratory Study. 2020 Aug 13;16(14):2704-2711. doi: 10.7150/ijbs.42965. The electrical pathway is modulated by KATP channel–independent mechanisms; nutrient metabolites and incretins affect secretion at various stages downstream of KATP channel (3,4), but the drug effects underscore the central role of KATP channel–dependent regulation. Mechanism of pharmacochaperoning in a mammalian K. Successful Use of Octreotide Therapy for Refractory Levofloxacin-Induced Hypoglycemia: A Case Report and Literature Review. A similar synergistic stimulation of extracellular signal-regulated kinase (ERK) and mitogen-activated protein or ERK kinase activities was observed (ATP, 7-fold; insulin, 2-fold; and ATP + insulin, 16-fold over basal). This metabolic signal closes KATP channels, causing depolarization, activation of voltage-dependent Ca2+ channels, Ca2+ entry, and insulin exocytosis. This rapid exocytosis is a feature of early prediabetic state, as well as seen in progressive type II diabetes mellitus. Recent genetic studies demonstrate that heterozygous mutations in KCNJ11, encoding the Kir6.2 subunit of the KATP channel, underlie neonatal diabetes in humans, accounting for both permanent neonatal diabetes (26–31), in which type 1 autoantibodies are absent, and relapsing transient neonatal diabetes, in which chromosome 6 abnormalities were excluded (32,33). 2019 May 9;2019:3560608. doi: 10.1155/2019/3560608. This progression is a dramatic demonstration of the power of multidisciplinary biology in disease analysis. Clinical data indicate that CHI patients carrying SUR1 mutations can also progress to glucose intolerance and, in some cases, overt diabetes (66). Epub 2004 Dec 6. These mutations could reduce ATP sensitivity 1) directly by decreasing the affinity of the ATP-binding pocket for the nucleotide, 2) indirectly by an increase in the intrinsic stability of the open state of the channel, or 3) indirectly by an increased sensitivity to the counteractivation by MgADP or by phosphatidylinositol-4,5-bisphosphate (PIP2) or other phospholipids. Conversely, mutations that result in “overactive” channels should decrease membrane excitability and impair glucose sensing by the β-cell. Transgenic mice lacking KATP channels in ∼70% of β-cells, due to β-cell expression of dominant-negative Kir6.2 transgene, hypersecrete throughout as adults (14), but mice completely lacking KATP channels are reportedly hyperinsulinemic as neonates and then progress to reduced GSIS and glucose intolerance as adults (62–64). Similarly, many mutations in KATP are likely to affect apparent PIP2 sensitivity by changes in intrinsic open-state stability (54) or by change in affinity. The prediction that KATP channel “overactivity” should cause a diabetic state due to undersecretion of insulin has been dramatically borne out by recent genetic studies implicating “activating” mutations in the Kir6.2 subunit of KATP channel as causal in human diabetes. Complete understanding of the mechanisms by which Kir6.2 mutations cause neonatal diabetes will require mechanistic molecular analysis of disease-causing mutations (32,33,38,39), generation of transgenic mouse models of neonatal diabetes (11), and analysis of virally infected β-cells or insulinoma cell lines expressing altered KATP channel. OBJECTIVE Steatosis associates with insulin resistance and may even predict type 2 diabetes and cardiovascular complications. When K ATP channels open, beta-cells hyperpolarize and insulin secretion is suppressed. A few additional residues in the NH2- and COOH-terminus are also likely to be involved in ATP binding (71,73,75,76,88,89), and we speculate that substitutions at these residues would also be disease causing. Cell metabolism was monitored using Seahorse respirometry and expression analysis of pannexin‐1 was performed on … Both de novo appearance of Kir6.2 mutations and familial transmission have been reported (26–31). Moreover, a recent transgenic study overexpressing the transient neonatal diabetes locus (6q24) implicated fluctuations in β-cell mass and insulin content in the progression of transient neonatal diabetes from the neonatal diabetic phase into remission and ultimately to late-onset diabetes (61). Bethesda, MD 20894, Copyright (In our unpublished studies of E23K, reconstituted KATP channels carried both the I337V and A1369S polymorphisms.). Consistent with a direct effect on binding, R50, I182, Y330, F333, and R201 have all previously been implicated as putative ATP-binding residues in Kir6.2 (27,74,85). The 10-year effort that first yielded the molecular basis of KATP channel activity (77,79) permitted the generation of animal models of channel dysfunction (11) and paved the way to genetic determination of predisposing polymorphisms in type 2 diabetes (41,45,46,95) and disease-causing mutations in both CHI (5) and neonatal diabetes (27,29,33). A similar mechanistic progression may occur in KATP channel–induced permanent neonatal diabetes and may underlie some of the reduced sulfonylurea-sensitive insulin release (27). 3B) (59,69,70). In islets exposed to high FFA concentration, a PPAR-gamma antagonist was able to prevent UCP-2 overexpression and to restore insulin secretion and the ATP/ADP ratio. 2A), blood insulin is at or below the level of detection but insulin is clearly present in the pancreas (11). Consequent activation of voltage-dependent Ca2+ channels causes a rise in [Ca2+]i, which stimulates insulin release (Fig. Mutations in KATP channel that reduce channel expression, decrease stimulation of the channel by MgADP, or abolish channel activity account for a majority of all CHI mutations (6,7,8,9). The second part will consider the structure-function relationships of the KATP channel and molecular mechanisms that underlie diabetes in which mutations in KATP are causal. 2009;56(2):165-75. doi: 10.1507/endocrj.k08e-160. We do not capture any email address. The ATP-sensitive K + channel (K ATP channel) senses metabolic changes in the pancreatic β-cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. Batch experiments showed that 16.7 mM glucose-induced insulin release (for 30 min) from CDKAL1 KO b cells was decreased (,19%) relative to that from WT b cells (P=NS) (Fig. Glucose metabolism through glycolysis in the cytosol and then through the tricarboxylic acid (TCA) cycle in mitochondria has been proposed to promote glucose-induced insulin secretion through generation of metabolic signals such as adenosine triphosphate (ATP) or an increase in the ratio of ATP to adenosine diphosphate (ADP) in pancreatic β cells . This may occur due to lack of formation of ATP-(insulin) n polymer. Address correspondence and reprint requests to Joseph C. Koster PhD, Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110. Mutations of Kir2.1, a related K channel subunit, underlie Andersen’s syndrome, which is characterized by dysmorphic facial features, epilepsy, and cardiac arrhythmias (93,94). ATP + D-fructose 6-phosphate → ADP + D-fructose 1,6-bisphosphate. For the E23K polymorphism, the effect on nucleotide sensitivity is modest, and only in the proper genetic and environmental background may channel overactivity appreciably influence β-cell function. © 2021 by the American Diabetes Association. Alterations in the metabolic signal, in the sensitivity of KATP channel to metabolites, or in the number of active KATP channels, could each disrupt electrical signaling in the β-cell and alter insulin release. Capodanno Y, Buishand FO, Pang LY, Kirpensteijn J, Mol JA, Elders R, Argyle DJ. In the most severe cases, KATP channel overactivity in extrapancreatic tissue likely contributes to multiorgan syndromic permanent neonatal diabetes. Sulfonylureas may provide dramatic improvement in therapeutic options for neonatal diabetes (27,31,33), but the sulfonylurea-desensitizing effect of open-state–stabilizing mutations (39,56,96) and the possibility of secondary nonelectrical consequences heed caution regarding whether this is a panacea. Gloyn et al. Morphologically, the size, distribution, and architecture of the islets are unperturbed at the earliest stages of diabetes (days 1–3), but collapse of islet architecture, with diffuse distribution of the α- and β-cells throughout the pancreas, was observed at later stages (after day 3). Mice with overactive β-cell KATP channels are profoundly diabetic within a few days of birth (11). Mutations resulting in greater gain of function may still be found to underlie childhood diabetes, while mutations that result in more significant gain of function are likely to give rise to an earlier and more severe form of diabetes, as in permanent neonatal diabetes. Given the above paradigm, any gain of KATP channel function is expected to suppress GSIS. In all cases, the net effect will be reduced glucose sensing by the β-cell, and, in support, a small effect of the E23K variant on insulin release was observed during intravenous and oral glucose tolerance tests (43,57,58). Privacy, Help Biol Res Nurs. SUR1 mutations that abolish MgADP action, but do not alter ATP sensitivity, also abolish channel activity in vivo and underlie CHI (8,84). The K(ATP) channel and neonatal diabetes. Assuming a 1:1 expression and random assembly, 16 different subunit arrangements are formally possible, making the analysis of mixed expression very complex (51,53,59,60). Enter multiple addresses on separate lines or separate them with commas. Nucleotide hydrolysis at the SUR1 nucleotide-binding folds (NBFs), or MgADP binding, is thought to counteract the inhibitory effect of ATP. At this juncture, we cannot preclude nonelectrical secondary mechanisms underlying KATP channel–induced diabetes. Okay, instead of storing the energy of glucose in ATP, insulin can cause glucose to undergo what's called "glycogenesis." The effect of the A1369S polymorphism on channel activity is not known (51,55), but the possibility should be acknowledged that alone or in combination with E23K, it contributes to altered ATP sensitivity. Another study reported no reduction of ATP sensitivity of E23K/I337V channels, but instead showed enhanced stimulatory effects of palmitoyl-CoA on E23K/I337V mutant Kir6.2 channels (55). The degree of KATP channel “overactivity” correlates with the severity of the diabetic phenotype. In glucose absorption, there is an initially high concentration of glucose in the lumen of the gut as carbohydrates break down. Significantly, in all examined families, neonatal diabetes was observed only in individuals carrying the Kir6.2 mutations and not in other family members. Again, much lesser shifts were observed in heterozygous expression, but, without analyzing each subunit combination separately, it remains speculative as to exactly what channel activity can be expected in vivo. Various additional effectors, including PIP2 and acyl CoAs, act to modulate ATP sensitivity of the channel and can thereby affect the coupling of metabolism to secretion. Unable to load your collection due to an error, Unable to load your delegates due to an error. Finally, non–β-cell mechanisms must be considered. In this regard, one or two rare mutations engineered into SUR1 (83,92) increase activation by MgADP, and they could potentially appear spontaneously. In addition to serving as a major cellular energy source, ATP plays a unique role in insulin secretion in the pancreatic β cell. Insulin secretion induced by methylsuccinate is K ATP channel-dependent but insensitive to oligomycin. This article summarizes the emerging picture of KATP channel as a major cause of neonatal diabetes and of a polymorphism in KATP channel (E23K) as a type 2 diabetes risk factor. Thus, the two substrates of this enzyme are ATP and D-fructose 6-phosphate, whereas its two products are ADP and D-fructose 1,6-bisphosphate.. E23K is in linkage disequilibrium with another Kir6.2 polymorphism, I337V, which itself has no reported effect on channel activity (51,53). ATP inhibits KATP channels by binding to the Kir6.2 subunit. This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Clipboard, Search History, and several other advanced features are temporarily unavailable. In each case, acute neonatal hyperglycemia together with ketoacidosis, leading to death within a few days, was observed. The type 2 diabetes–associated polymorphism E23K is located in the far NH2-terminus, for which a predicted structural location is unavailable. The ATP-sensitive K+ channel (KATP channel) senses metabolic changes in the pancreatic β-cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. Y330C accounted for three cases of permanent neonatal diabetes (28,30), whereas K170 substitutions accounted for two permanent neonatal diabetes cases (K170N and K170R) (29). One patient was diagnosed at only 26 weeks of age (27) and another at 5 years (32). To date, the role of insulin in the correlation of the net hepatic flux of ATP and glycogen has not been described, although previous reports point to a link between carbohydrate metabolism and ATP pathways. After stabilizing the body weight and blood glucose levels of the diabetic mice, the researchers withdrew the insulin treatment. In the case of I182V, R201C, R201H, and F333I, these mutations do not alter gating of the channel and are, therefore, likely to directly alter ATP affinity at the binding pocket. 3A). Both Y330 and F333 also predicted to lie close to the phosphate tail in the binding pocket (87). Careers. It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses that either interfere with ATP production (eg, deprivation for glucose or oxygen) or that accelerate ATP consumption (eg, muscle contraction). When K ATP channels open, β-cells hyperpolarize and insulin secretion is suppressed. And that's an important distinction. In enzymology, 1-phosphofructokinase (PFK1) (EC 2.7.1.56) is an enzyme that catalyzes the chemical reaction. Multiple permanent neonatal diabetes mutations have now been identified in Kir6.2 (Fig. Epub 2008 Jun 20. Heterologously expressed Kir.2[E23K]-SUR1 channels exhibit even more modest 2- and 1.5-fold reductions in ATP sensitivity for homozygous (Kir6.2[E23K]) and heterozygous (Kir6.2[E23K] + Kir6.2wt) channels, respectively (51 and J.C.K., unpublished observations: K1/2 [ATP] for Kir6.2wt = 10.7 ± 1.9 μmol/l, Kir6.2[E23K] = 17.6 ± 0.9 μmol/l [expressed in COSm6 cells]), as well as enhanced MgADP stimulation (51,52,53,54). C: Ribbon diagram of two opposing cytoplasmic domains and two opposing transmembrane domains of Kir6.2, modeled on the crystal structure of KirBac1.1 (86). If a similar pathophysiology occurs in transient neonatal diabetes patients carrying Kir6.2 mutations, this would be consistent with secondary, nonelectrical consequences of altered β-cell KATP channel activity. These latter classes of KATP channels can be classified as being either sarcolemmal, mitochondrial, or nuclear. Elevated blood glucose increases glucose metabolism in the β-cell and elevates [ATP]/[ADP]i. Effects of CDKAL1 KO on glucose-induced biphasic insulin exocytosis We next investigated the effects of CDKAL1 KO on glucose-induced insulin release from b cells. Importantly, when exposed to a high-fat diet, both Kir6.2−/− mice and Kir6.2[AAA] transgenic mice progress rapidly to severely undersecreting diabetes (65). Adenosine triphosphate (ATP) synthesis and release in mitochondria play critical roles in regulating insulin secretion in pancreatic β cells. Importantly, a recent haplotype analysis of the Kir6.2/SUR1 gene region has demonstrated a strong allelic association of E23K in Kir6.2 with a polymorphism in SUR1 (A1369S), raising the possibility that E23K alone may not entirely account for the reported association with type 2 diabetes (49). In the pancreatic β-cell, the ATP-sensitive K+ channel (KATP channel) plays an essential role in coupling membrane excitability with glucose-stimulated insulin secretion (GSIS) (1). 1). KATP channel–dependent diabetes in mouse and humans. In transient neonatal diabetes, which is milder, hyperglycemia usually resolves within 18 months, whereas the permanent form requires insulin treatment for life. Watson MR, Ward CT, Prabhakar A, Fiza B, Moll V. Case Rep Crit Care. Kir6.2 is the pore-forming subunit of α-cell, muscular, and neuronal KATP channels (34). Molecular basis of KATP channel–induced diabetes. These mice express Kir6.2 subunits with truncated NH2-termini, which causes a 10-fold reduction of ATP sensitivity in heterologously expressed channels. Interestingly, in a subgroup of patients carrying Kir6.2 mutations, permanent neonatal diabetes is part of a larger syndrome that often includes marked developmental delay in motor intellectual and social skills, muscle weakness, dysmorphic features, and epilepsy (27,29,30). Although results from initial studies are conflicting (45,46), large-scale association studies and meta-analyses have now identified the E23K polymorphism in KCNJ11 as a slight, but significant, risk factor in the complex development of type 2 diabetes (42,44,47–50). Insulin secretion is dependent on high blood glucose and ATP may regulate insulin secretion in a … FOIA Republished from Gloyn et al. For a given [MgADP], KATP channel mutations that decrease ATP sensitivity will enhance absolute currents in the physiologic range of ATP, and the net effect of enhanced KATP channel current is a decrease in β-cell excitability. Other mutations (Q52R, I296L I182V, V59G, V59M, Y330C, and F333I) have now been analyzed, demonstrating shifts in ATP sensitivity of up to ∼1,000-fold for homozygous V59G and I296L mutant channels (38,39). E-mail. However, as acknowledged, 1 of 16 of the expressed channels are expected to be pure mutant, and this alone could give rise to significant currents at physiological [ATP]/[ADP] ratios. ATP-sensitive potassium (KATP) channel in the beta-cell membrane and bring about its closure [7]. Fully consistent with the above structural model of the ATP-binding pocket, functional characterization now demonstrates a significant decrease in the ATP sensitivities of these mutants (27,32,38,39). 2006 Dec;32(6):569-80. doi: 10.1016/S1262-3636(07)70311-7. The functional channel consists of SUR1 or SUR2A and Kir6.2 subunits in a 1:1 stoichiometry. Mitochondrial dysfunction is mainly characterized by a decrease in ATP production, which is a central event in the progression of pancreatic β cell dysfunction and diabetes. concentrations correlated well with insulin-stimulated increases in rates of ATP synthesis (r = 0.67; p = 0.008). Structurally, the pancreatic KATP channel consists of two unrelated subunits: a sulfonylurea receptor (the SUR1 isoform) that is a member of the ABC transporter family and a potassium channel subunit (Kir6.2) that forms the central ion-conducting pathway (Fig. The ATP-sensitive K+ channel (K ATP channel) senses metabolic changes in the pancreatic beta-cell, thereby coupling metabolism to electrical activity and ultimately to insulin secretion. But note that insulin exocytosis in SLC17A9 knockout is accelerated. B: Predicted octameric structure of KATP channel. Decreased blood glucose leads to decrease in β-cell [glucose] and hence decreased [ATP]: [ADP]. ATP is energy to be used anywhere in the body. 8600 Rockville Pike Numerous studies have now examined the association of KATP channel polymorphisms with late-onset type 2 diabetes (40–44). 1988; Q52R, I296L, R50P, F33I, and E322K have all been found in one proband each (28,29,31). The role of pancreatic KATP channel in insulin secretion. In each case, overactive KATP channel activity, with a failure to switch on insulin secretion, is the logical underlying mechanism; this is due to altered metabolic signal in the former (12) and insensitivity to the normal metabolic signal in the latter (11). Glucose is transported thorough the glucose transporter into the pancreatic beta cell. However, when ATP and insulin were added in combination, ATP dramatically reduced the insulin-stimulated Akt activation (2-fold above basal).

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