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How Does Insulin Stimulate Uptake Of Glucose Into Cells?

Insulin's Effects On Metabolism

Insulin's Effects On Metabolism

Sort - vesicles carry multiple molecules of glucose transport proteins in their own membrane - transport proteins bind with the cell membrane and facilitate glucose uptake into the cells - when there is no more insulin available, the vesicles seperate from the cell membrane (within 3-5 mins) - then move back to the interior of the cell to be used again How do the intracellular vesicles operate to increase glucose transport? - blood glucose concentration begins to fall - insulin secreation decreases rapidly - liver glycogen is split back into glucose - glucose is released back into the blood - keeping the glucose concentration from falling too low What happens with insulin and glucose (all forms) inbetween meals when food is not available? - decrease secreation of insulin by pancreas - therefore, stops further synthesis of glycogen by the liver and prevents further uptake of glucose by liver -activates phosphorylase, causing the splitting of glycogen into glucose phosphate -activates glucose phosphatase, causing phosphate to split from glucose = free glucose in the blood After a meal, blood glucose begins to fall to a low level; what are the events that cause the liver to release glucose back into the circulation? - (mainly) by decreasing the quantities and activities of the liver enzymes required for gluconeogenesis - (partly) by decreasing the release of amino acids from muscle (and other extrahepatic tissues) - thereby decreasing the availability of necessary precursors required for gluconeogenesis How does insulin inhibit gluconeogenesis? - stimulates the transport of many amino acids into cells - increases the translation of mRNA, forming new proteins - stimulates protein synthesis, especially of enzymes - inhibits protein catabolism - inhibits gluconeogenesis in th Continue reading >>

Glucose Uptake - An Overview | Sciencedirect Topics

Glucose Uptake - An Overview | Sciencedirect Topics

Benny Kwong Huat Tan, Khang Wei Ong, in Polyphenols in Human Health and Disease , 2014 Polyphenols and Peripheral Glucose Uptake Glucose uptake in cells, from the simplest single-cell bacterium to the highly specialized mammalian neuron, is facilitated by GLUTs in the plasma membrane. Upon entering the cells, glucose is rapidly phosphorylated by GK and further metabolized via storage and/or oxidation (Figure 9.1). The mammalian GLUT is a superfamily of genes, encoding homologous proteins with different functional properties and tissue-specific expressions.179 The first GLUT cloned and studied was GLUT1, which is ubiquitous in most fetal and adult tissues.180 Subsequent searches successfully identified 11 other GLUTs, namely GLUT2 to GLUT12.181 GLUT1 and GLUT4 are the major contributors for glucose disposal in peripheral tissues. The broad distribution of GLUT1 makes it an important transporter to regulate the basal glucose disposal. Its expression has been shown to be altered by sulfonylureas,182 insulin,183 hypoxia,184 insulin-like growth factor-1185 and a number of other factors. On the other hand, GLUT4 is exclusively expressed in peripheral insulin-sensitive tissues like fat, and skeletal and cardiac muscles. It is the only insulin-responsive GLUT identified so far, with the observation that its level of expression in various muscles and fat cells generally corresponded to the magnitude of insulin-stimulated glucose disposal in the tissues.186 Later on, it was established that this insulin-stimulated glucose transport was mediated through the redistribution of GLUT4 from the intracellular membrane compartment to the cell surface.187 In T2DM, desensitization of peripheral target tissues to insulin action is one of the main pathophysiological characteristics. This is Continue reading >>

Insulin And Glucagon

Insulin And Glucagon

Acrobat PDF file can be downloaded here. The islets of Langerhans The pancreatic Islets of Langerhans are the sites of production of insulin, glucagon and somatostatin. The figure below shows an immunofluorescence image in which antibodies specific for these hormones have been coupled to differing fluorescence markers. We can therefore identify those cells that produce each of these three peptide hormones. You can see that most of the tissue, around 80 %, is comprised of the insulin-secreting red-colored beta cells (ß-cells). The green cells are the α-cells (alpha cells) which produce glucagon. We see also some blue cells; these are the somatostatin secreting γ-cells (gamma cells). Note that all of these differing cells are in close proximity with one another. While they primarily produce hormones to be circulated in blood (endocrine effects), they also have marked paracrine effects. That is, the secretion products of each cell type exert actions on adjacent cells within the Islet. An Introduction to secretion of insulin and glucagon The nutrient-regulated control of the release of these hormones manages tissue metabolism and the blood levels of glucose, fatty acids, triglycerides and amino acids. They are responsible for homeostasis; the minute-to-minute regulation of the body's integrated metabolism and, thereby, stabilize our inner milieu. The mechanisms involved are extremely complex. Modern medical treatment of diabetes (rapidly becoming "public enemy number one") is based on insight into these mechanisms, some of which are not completely understood. I will attempt to give an introduction to this complicated biological picture in the following section. Somewhat deeper insight will come later. The Basics: secretion Let us begin with two extremely simplified figur Continue reading >>

Glucose Transport

Glucose Transport

The oxidation of glucose represents a major source of metabolic energy for mammalian cells. Because the plasma membrane is impermeable to polar molecules such as glucose, the cellular uptake of this important nutrient is accomplished by special carrier proteins called glucose transporters[1][2][3][4][5][6][7]. These are integral membrane proteins located in the plasma membrane that bind glucose and transfer it across the lipid bilayer. The rate of glucose transport is limited by the number of glucose transporters on the cell surface and the affinity of the transporters for glucose. There are two classes of glucose carriers described in mammalian cells: the Na+-glucose cotransporters (SGLTs) and the facilitative glucose transporters (GLUTs)[1-7]. There are two families of glucose transporters The Na+-glucose cotransporter or symporter is expressed by specialized epithelial (brush border) cells of the small intestine and the proximal tubule of the kidney and mediates an active, Na+-linked transport process against an electrochemical gradient[1-3] . It actively transports glucose from the lumen of the intestine or the nephron against its concentration gradient by coupling glucose uptake with that of Na+, which is being transported down its concentration gradient. The Na+ gradient is maintained by the active transport of Na+ across the basolateral (antiluminal) surface of the brush border cells by membrane-bound Na+-K+- ATPase[1-3,7]. The second class of glucose carriers is the facilitative glucose transporters (GLUTs) of which there are 14 genes in the human genome[1,4-7] . These proteins mediate a bidirectional and energy-independent process of glucose transport in most tissues and cells where glucose is transported down its concentration gradient by facilitative diffusio Continue reading >>

Hypothesis Insulin-independent Glucose Transport Regulates Insulin Sensitivity

Hypothesis Insulin-independent Glucose Transport Regulates Insulin Sensitivity

1. Phylogeny and structure of glucose transport proteins Glucose is a vital fuel for microorganisms and nearly all cell types in humans. Glucose transport into the cell is catalyzed by transport proteins. Even Escherichia coli, which does not have insulin, has two proton-sugar symporters, proton-xylose and proton-arabinose. They share 20–25% amino acid sequence identity with mammalian glucose transporters [1]. In mammalian cells there are at least six facilitative glucose transporters, which are products of a gene family and have specific functions and sites of expression [2]. Glucose transporter 1 (GLUT1) is the predominant facilitative glucose transporter and it is widely distributed in different tissues. GLUT1 is highly conserved with 98% identity in the amino acid sequence between humans and the rat [2]. GLUT4 is insulin-sensitive and it is the predominant glucose transporter in the muscle and adipose tissue. There is 95% sequence identity between human and rat GLUT4 [2], whereas human GLUT1 and GLUT4 have 65% identity. GLUT1 seems to be coupled with hexokinase I, and GLUT4 with hexokinase II (Fig. 1). Fetal muscle expresses GLUT1 and hexokinase I [3, 4], whereas GLUT4 and hexokinase II become predominant in the muscle postnatally [3, 4]. The appearances of GLUT4 and hexokinase II in skeletal muscle are coordinated and concomitant with insulin sensitivity in young rats [3, 4]. Insulin increases the transcription of muscle hexokinase II, but has no effect on hexokinase I [4–6], which is ubiquitous and is found in almost all cells [5]. Fig. 1. Glucose transport into muscle cell is mediated by two glucose transport proteins: insulin-independent GLUT1 and insulin-dependent GLUT4. If glucose is transported though the GLUT1 pathway, it is further metabolized by hexoki Continue reading >>

Physiologic Effects Of Insulin

Physiologic Effects Of Insulin

Stand on a streetcorner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?" Insulin is a key player in the control of intermediary metabolism, and the big picture is that it organizes the use of fuels for either storage or oxidation. Through these activities, insulin has profound effects on both carbohydrate and lipid metabolism, and significant influences on protein and mineral metabolism. Consequently, derangements in insulin signalling have widespread and devastating effects on many organs and tissues. The Insulin Receptor and Mechanism of Action Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane. The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response. Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activa Continue reading >>

C2006/f2402 '11 Outline Of Lecture #16

C2006/f2402 '11 Outline Of Lecture #16

Handouts: 15A -- Lining of the GI Tract & Typical Circuit 15B -- Homeostasis -- Seesaw view for Glucose and Temperature Regulation; 16 -- Absorptive vs Postabsorptive state I. Homeostasis, cont. See handouts 15A & B & notes of last time, topic VI. A. Regulation of Blood Glucose Levels -- Seesaw View #1 (Handout 15B) B. Regulation of Human Body Temperature -- Seesaw #2 (Handout 15B) C. The Circuit View (Handout 15A) II. Matching circuits and signaling -- an example: How the glucose circuit works at molecular/signaling level Re-consider the circuit or seesaw diagram for homeostatic control of blood glucose levels -- what happens in the boxes on 15A? It may help to refer to the table below. A. How do Effectors Take Up Glucose? 1. Major Effectors: Liver, skeletal muscle, adipose tissue 2. Overall: In response to insulin, effectors increase both uptake & utilization of glucose. Insulin triggers one or more of the following in the effectors: a. Causes direct increase of glucose uptake by membrane transporters b. Increases breakdown of glucose to provide energy c. Increases conversion of glucose to 'stores' (1). Glucose is converted to storage forms (fat, glycogen), AND (2). Breakdown of storage fuel molecules (stores) is inhibited. d. Causes indirect increase of glucose uptake by increasing phosphorylation of glucose to G-P, trapping it inside cells 3. How does Insulin Work? a. Receptor: (1). Insulin works through a special type of cell surface receptor, a tyrosine kinase linked receptor; See Sadava fig. 7.7 (15.6). Insulin has many affects on cells and the mechanism of signal transduction is complex (activating multiple pathways). (2). In many ways, insulin acts more like a typical growth factor than like a typical endocrine. (Insulin has GF-like effects on other cells; is i Continue reading >>

Insulin And Glucose Regulation

Insulin And Glucose Regulation

INTRODUCTION Glucose in the blood provides a source of fuel for all tissues of the body. Blood glucose levels are highest during the absorptive period after a meal, during which the stomach and small intestine are breaking down food and circulating glucose to the bloodstream. Blood glucose levels are the lowest during the postabsorptive period, when the stomach and small intestines are empty. Despite having food only periodically in the digestive tract, the body works to maintain relatively stable levels of circulatory glucose throughout the day. The body maintains blood glucose homeostasis mainly through the action of two hormones secreted by the pancreas. These hormones are insulin, which is released when glucose levels are high, and glucagon, which is released when glucose levels are low. The accompanying animation depicts the functions of these hormones in blood glucose regulation. EFFECTS OF INSULIN 1 After a high carbohydrate lunch, like a plate of spaghetti, polysaccharides are digested into monosaccharides. Monosaccharides such as glucose are absorbed by the small intestine and released into the blood. 2 Increased levels of blood glucose signal the pancreas to secrete insulin into the bloodstream. 3 Insulin promotes the uptake of glucose by most cells of the body. Many cells, like muscle, burn glucose for their metabolic fuel. Fat cells in adipose tissue use glucose to make fat. Liver cells convert glucose to glycogen and fat. 4 As the afternoon passes, the cells continue to take up glucose, and blood glucose levels decrease. 5 By 6:00, all the glucose from the spaghetti lunch has been absorbed, and blood glucose levels have fallen further. 6 The low blood glucose puts a brake on insulin release from the pancreas. 7 Without a glucose supply, cells switch to usin Continue reading >>

Insulin Signaling And The Regulation Of Glucose Transport

Insulin Signaling And The Regulation Of Glucose Transport

Go to: GLUT4 TRANSLOCATION OCCURS IN MULTIPLE STAGES In the absence of insulin, Glut4 slowly recycles between the plasma membrane and vesicular compartments within the cell, where most of the Glut4 resides. Insulin stimulates the translocation of a pool of Glut4 to the plasma membrane, through a process of targeted exocytosis (4,5) (Figure 1). At the same time, Glut4 endocytosis is attenuated (6,7). Thus, the rate of glucose transport into fat and muscle cells is governed by the concentration of Glut4 at the cell surface and the duration for which the protein is maintained at this site. There is substantial evidence that Glut4 exists in specialized vesicles sequestered within the cell, but the precise intracellular location and trafficking pathways of these vesicles are unclear. Following internalization, Glut4 is localized into tubulovesicular and vesicular structures that are biochemically distinct from but possibly interacting with the recycling endosomal network (8). In adipocytes, these vesicles are retained in a perinuclear region in the cell via an unknown mechanism that might involve a tethering protein (9) or continuous futile recycling (10). The Glut4 compartment is enriched in the v-SNARE (soluble N-ethylmaleimide sensitive factor attachment protein) protein VAMP2 (vesicle-associated membrane protein 2) but not the related VAMP3/cellubrevin isoform that is present in recycling endosome (11). Consistent with these data, ablation of transferrin receptor containing endosomes does not impair insulin-stimulated Glut4 translocation (12). The microtubule network and actin cytoskeleton play a role in Glut4 trafficking, either by linking signaling components or by directing movement of vesicles from the perinuclear region to the plasma membrane in response to insulin. Continue reading >>

Glucose Metabolism

Glucose Metabolism

Energy is required for the normal functioning of the organs in the body. Many tissues can also use fat or protein as an energy source but others, such as the brain and red blood cells, can only use glucose. Glucose is stored in the body as glycogen. The liver is an important storage site for glycogen. Glycogen is mobilized and converted to glucose by gluconeogenesis when the blood glucose concentration is low. Glucose may also be produced from non-carbohydrate precursors, such as pyruvate, amino acids and glycerol, by gluconeogenesis. It is gluconeogenesis that maintains blood glucose concentrations, for example during starvation and intense exercise. The endocrine pancreas The pancreas has both endocrine and exocrine functions. The endocrine tissue is grouped together in the islets of Langerhans and consists of four different cell types each with its own function. Alpha cells produce glucagon. Beta cells produce proinsulin. Proinsulin is the inactive form of insulin that is converted to insulin in the circulation. Delta cells produce somatostatin. F or PP cells produce pancreatic polypeptide. Regulation of insulin secretion Insulin secretion is increased by elevated blood glucose concentrations, gastrointestinal hormones and Beta adrenergic stimulation. Insulin secretion is inhibited by catecholamines and somatostatin. The role of insulin and glucagon in glucose metabolism Insulin and glucagon work synergistically to keep blood glucose concentrations normal. Insulin: An elevated blood glucose concentration results in the secretion of insulin: glucose is transported into body cells. The uptake of glucose by liver, kidney and brain cells is by diffusion and does not require insulin. Click on the thumbnail for details of the effect of insulin: Glucagon: The effects of glu Continue reading >>

How Does Insulin Signal A Cell To Take In Glucose From The Blood?

How Does Insulin Signal A Cell To Take In Glucose From The Blood?

Just as we receive and act on signals from our environment, our cells also receive and act on signals from their environment, our bodies. This is a necessary biological occurrence that keeps cells alive and functioning. Insulin is a hormone released by our pancreas that signals cells in a specific way in order to stimulate them to take in, use and store glucose. Function of Insulin After ingesting food, your meal is broken down and digested. As a result, glucose is released into your bloodstream. High concentrations of glucose in the blood are a signal for the beta cells of the pancreas to release insulin. This hormone works like a key to unlock the protective cell membranes and allow the passage of glucose into the cell to be used for energy. Mechanism of Insulin Insulin works to decrease the concentration of glucose in the blood and facilitate transport into the cells by binding to special receptors embedded in their membranes. Although there are some tissues such as the brain and the liver that do not require insulin for glucose uptake, most of our cells would not be able to access blood glucose without it. Glucose is the energy source for all cells and is required for their, and ultimately our, survival. The insulin signaling pathway includes an insulin receptor that is made up of two receptor subunits that are located on the outside of the cell membrane and two subunits that penetrate through the membrane. These subunits are chemically bonded together. The extracellular (outside the cell) subunits contain a binding site for insulin. When insulin binds to the extracellular subunits, it activates a chemical reaction that travels through the linked subunits into the cell. This mechanism sends chemical signals to proteins within the cell and causes them to alter their Continue reading >>

High Leptin Levels Acutely Inhibit Insulin-stimulated Glucose Uptake Without Affecting Glucose Transporter 4 Translocation In L6 Rat Skeletal Muscle Cells

High Leptin Levels Acutely Inhibit Insulin-stimulated Glucose Uptake Without Affecting Glucose Transporter 4 Translocation In L6 Rat Skeletal Muscle Cells

High Leptin Levels Acutely Inhibit Insulin-Stimulated Glucose Uptake without Affecting Glucose Transporter 4 Translocation in L6 Rat Skeletal Muscle Cells Programme in Cell Biology (G.S., J.K., R.S., D.K., R.G., A.K.), University of Toronto, Toronto, Ontario, M5G 1X8, Canada Search for other works by this author on: Programme in Cell Biology (G.S., J.K., R.S., D.K., R.G., A.K.), University of Toronto, Toronto, Ontario, M5G 1X8, Canada Search for other works by this author on: Programme in Cell Biology (G.S., J.K., R.S., D.K., R.G., A.K.), University of Toronto, Toronto, Ontario, M5G 1X8, Canada The Hospital for Sick Children, Department of Biochemistry (R.S., A.K.), University of Toronto, Toronto, Ontario, M5G 1X8, Canada Search for other works by this author on: Programme in Cell Biology (G.S., J.K., R.S., D.K., R.G., A.K.), University of Toronto, Toronto, Ontario, M5G 1X8, Canada Institute of Medical Science (D.K.), University of Toronto, Toronto, Ontario, M5G 1X8, Canada Search for other works by this author on: Programme in Cell Biology (G.S., J.K., R.S., D.K., R.G., A.K.), University of Toronto, Toronto, Ontario, M5G 1X8, Canada Search for other works by this author on: Programme in Cell Biology (G.S., J.K., R.S., D.K., R.G., A.K.), University of Toronto, Toronto, Ontario, M5G 1X8, Canada The Hospital for Sick Children, Department of Biochemistry (R.S., A.K.), University of Toronto, Toronto, Ontario, M5G 1X8, Canada Address all correspondence and requests for reprints to: Amira Klip, Program in Cell Biology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada. Search for other works by this author on: Endocrinology, Volume 142, Issue 11, 1 November 2001, Pages 48064812, Gary Sweeney, Jessica Keen, Romel Somwar, Daniel Konrad, Rami Continue reading >>

Myth: Insulin Is Needed For Glucose Uptake

Myth: Insulin Is Needed For Glucose Uptake

Abstract: Despite evidence to the contrary, there is a widespread misconception that cells cannot take up glucose without insulin. It is believed that these starving cells, by their inability to absorb glucose, cause hyperglycemia (high blood sugar). This brief review of the available scientific literature intends simply to show that 1) considerable glucose uptake occurs independently of insulin, 2) that hyperglycemia is not caused by cells unable to import glucose, 3) AND lastly THAT CELLS ARE NOT STARVING DURING HYPERGLYCEMIA. Important: this text discusses the underlying mechanisms of glucose uptake. It has little clinical significance. Diabetics should continue to use insulin as prescribed by their doctor. As a medical student, i’ve been taught that cells need insulin to absorb glucose. Insulin causes a glucose transporter (glut) to rise to the cell surface. This transporter creates a channel for glucose to flow through. There are about 13 different gluts, and the one that needs insulin is glut4 (possibly 12, also). According to the misconception, glut4 is required for glucose uptake, and that is why insulin is necessary. Without insulin, there will be no glut4, and so we’re told that the cell cannot consume glucose, which causes glucose to build up in the blood – hyperglycemia. This is demonstrably false, as many experiments have shown. While insulin does impact absorption by doubling the glucose uptake speed, we’ll see that it is not required. 1 While it is true that glut4 is largely insulin dependent, it has almost a dozen brothers that function quite well without insulin. 2 take, for example, glut1. It’s nearly everywhere in the body, all the time, and it’s as powerful as the glut4. Glut1 is the day-to-day glucose transporter responsible for basal gl Continue reading >>

Introduction

Introduction

INTRODUCTION Glucose in the blood provides a source of fuel for all tissues of the body. Blood glucose levels are highest during the absorptive period after a meal, during which the stomach and small intestine are breaking down food and circulating glucose to the bloodstream. Blood glucose levels are the lowest during the postabsorptive period, when the stomach and small intestines are empty. Despite having food only periodically in the digestive tract, the body works to maintain relatively stable levels of circulatory glucose throughout the day. The body maintains blood glucose homeostasis mainly through the action of two hormones secreted by the pancreas. These hormones are insulin, which is released when glucose levels are high, and glucagon, which is released when glucose levels are low. The accompanying animation depicts the functions of these hormones in blood glucose regulation. CONCLUSION Throughout the day, the release of insulin and glucagon by the pancreas maintains relatively stable levels of glucose in the blood. During the absorptive period blood glucose levels tend to increase, and this increase stimulates the pancreas to release insulin into the bloodstream. Insulin promotes the uptake and utilization of glucose by most cells of the body. Thus, as long as the circulating glucose supply is high, cells preferentially use glucose as fuel and also use glucose to build energy storage molecules glycogen and fats. In the liver, insulin promotes conversion of glucose into glycogen and into fat. In muscle insulin promotes the use of glucose as fuel and its storage as glycogen. In fat cells insulin promotes the uptake of glucose and its conversion into fats. The nervous system does not require insulin to enable its cells to take up and utilize glucose. If glucose Continue reading >>

The Molecular Basis Of Insulin-stimulated Glucose Uptake: Signalling, Trafficking And Potential Drug Targets

The Molecular Basis Of Insulin-stimulated Glucose Uptake: Signalling, Trafficking And Potential Drug Targets

Abstract The search for the underlying mechanism through which insulin regulates glucose uptake into peripheral tissues has unveiled a highly intricate network of molecules that function in concert to elicit the redistribution or ‘translocation’ of the glucose transporter isoform GLUT4 from intracellular membranes to the cell surface. Following recent technological advances within this field, this review aims to bring together the key molecular players that are thought to be involved in GLUT4 translocation and will attempt to address the spatial relationship between the signalling and trafficking components of this event. We will also explore the degree to which components of the insulin signalling and GLUT4 trafficking machinery may serve as potential targets for the development of orally available insulin mimics for the treatment of diabetes mellitus. Introduction Glucose homeostasis and diabetes mellitus The ability of insulin to stimulate glucose uptake into muscle and adipose tissue is central to the maintenance of whole-body glucose homeostasis. Autoimmune destruction of the pancreatic β-cells results in a lack of insulin production and the development of type I diabetes mellitus (T1DM). Deregulation of insulin action manifests itself as insulin resistance, a key component of type II diabetes mellitus (T2DM). Both forms of diabetes confer an increased risk of major lifelong complications. In the case of insulin resistance, this includes a fivefold increased risk of coronary vascular disease. The need for an effective treatment for both forms of diabetes as well as for the development of early detection methodologies has, therefore, become increasingly important. Yet for this to be possible, we must first understand the mechanism through which insulin regulate Continue reading >>

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