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How Does Insulin Promote Uptake Of Glucose?

Insulin And Glucose Uptake By The Liver

Insulin And Glucose Uptake By The Liver

The full text of this article hosted at iucr.org is unavailable due to technical difficulties. Please review our Terms and Conditions of Use and check box below to share full-text version of article. I have read and accept the Wiley Online Library Terms and Conditions of Use. Use the link below to share a full-text version of this article with your friends and colleagues. Learn more. The rate of glucose uptake by the tissues after a large insulin dose has heen determined in normal, hepatectoniized and eviscerated cats. No difference in the rate of uptake, or in the dependence of the rate of uptake on the glucose concentration, was found among the three groups of experiments. Apparently in the cat the liver takes no part in the glucose uptake by the tissues under the influence of insulin. The inahility to induce a net glucose uptake in the isolated cat liver by means of insulin is consequently scarcely due to an impairment of the liver caused by the perfusion technique. Christian De Duve, The Hepatic Action of Insulin, Ciba Foundation Symposium Internal Secretions of the Pancreas (Colloquia on Endocrinology), (203-226), (2008). Continue reading >>

What Is Insulin?

What Is Insulin?

Insulin is a hormone; a chemical messenger produced in one part of the body to have an action on another. It is a protein responsible for regulating blood glucose levels as part of metabolism.1 The body manufactures insulin in the pancreas, and the hormone is secreted by its beta cells, primarily in response to glucose.1 The beta cells of the pancreas are perfectly designed "fuel sensors" stimulated by glucose.2 As glucose levels rise in the plasma of the blood, uptake and metabolism by the pancreas beta cells are enhanced, leading to insulin secretion.1 Insulin has two modes of action on the body - an excitatory one and an inhibitory one:3 Insulin stimulates glucose uptake and lipid synthesis It inhibits the breakdown of lipids, proteins and glycogen, and inhibits the glucose pathway (gluconeogenesis) and production of ketone bodies (ketogenesis). What is the pancreas? The pancreas is the organ responsible for controlling sugar levels. It is part of the digestive system and located in the abdomen, behind the stomach and next to the duodenum - the first part of the small intestine.4 The pancreas has two main functional components:4,5 Exocrine cells - cells that release digestive enzymes into the gut via the pancreatic duct The endocrine pancreas - islands of cells known as the islets of Langerhans within the "sea" of exocrine tissue; islets release hormones such as insulin and glucagon into the blood to control blood sugar levels. Islets are highly vascularized (supplied by blood vessels) and specialized to monitor nutrients in the blood.2 The alpha cells of the islets secrete glucagon while the beta cells - the most abundant of the islet cells - release insulin.5 The release of insulin in response to elevated glucose has two phases - a first around 5-10 minutes after g 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-stimulated Glucose Transport Minireview Series*

Insulin-stimulated Glucose Transport Minireview Series*

Regulation of glucose metabolism is a key aspect of metabolic homeostasis, and insulin is the dominant hormone influencing this regulatory system. One of the major effects of insulin is to enhance overall glucose disposal, and this is achieved by stimulation of glucose uptake into target tissues. In mammalian systems there are currently five distinct hexose transport proteins that have been identified, each derived from a separate gene. The mammalian glucose transporters are quite similar in sequence and overall structure but are unique in their tissue distribution. One of them, GLUT4 or the insulin-sensitive glucose transporter, is uniquely expressed in skeletal muscle, cardiac muscle, and adipose tissue. Insulin stimulates glucose transport into these tissues by causing the recruitment, or translocation, of GLUT4 proteins from an intracellular vesicular compartment to the plasma membrane. Once GLUT4 recruitment occurs, the transporter inserts into the plasma membrane, allowing uptake of glucose into the cell. However, tissue-specific expression of GLUT4 is not the only factor conferring insulin-stimulated glucose transport into these tissues because heterologous expression of GLUT4 in other tissues by various transfection strategies does not confer insulin-stimulated GLUT4 translocation to non-muscle, non-adipocyte cells. Therefore, it follows that additional factors in muscle and adipose tissue, related to insulin signaling or vesicle trafficking, must exist. Thus, the genetic program endowing the cell with the ability to exhibit insulin-stimulated GLUT4 translocation is complex and most likely involves a number of specific components. Skeletal muscle accounts for the bulk of insulin-stimulated glucose disposalin vivo (70–80%), with adipose tissue and other organs 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 >>

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 >>

Overview Of Insulin Signaling Pathways

Overview Of Insulin Signaling Pathways

​Introduction Insulin is a hormone released by pancreatic beta cells in response to elevated levels of nutrients in the blood. Insulin triggers the uptake of glucose, fatty acids and amino acids into liver, adipose tissue and muscle and promotes the storage of these nutrients in the form of glycogen, lipids and protein respectively. Failure to uptake and store nutrients results in diabetes. Type-1 diabetes is characterized by the inability to synthesize insulin, whereas in type-2 diabetes the body becomes resistant to the effects of insulin, presumably because of defects in the insulin signaling pathway. A. Glucose storage and uptake ​​​The insulin receptor is composed of two extracellular α subunits and two transmembrane β subunits linked together by disulphide bonds (Figure 1). Binding of insulin to the α subunit induces a conformational change resulting in the autophosphorylation of a number of tyrosine residues present in the β subunit (Van Obberghen et al., 2001). These residues are recognized by phosphotyrosine-binding (PTB) domains of adaptor proteins such as members of the insulin receptor substrate family (IRS) (Saltiel and Kahn 2001; Lizcano and Alessi 2002). Receptor activation leads to the phosphorylation of key tyrosine residues on IRS proteins, some of which are recognized by the Src homology 2 (SH2) domain of the p85 regulatory subunit of PI3-kinase (a lipid kinase). The catalytic subunit of PI3-kinase, p110, then phosphorylatesphosphatidylinositol (4,5) bisphosphate [PtdIns(4,5)P2​] leading to the formation of Ptd(3,4,5)P3. A key downstream effector of Ptd(3,4,5)P3 is AKT, which is recruited to the plasma membrane. Activation of AKT also requires the protein kinase 3-phosphoinositide dependent protein kinase-1 (PDK1), which in combination w 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 >>

General Aspects Of Muscle Glucose Uptake

General Aspects Of Muscle Glucose Uptake

Glucose uptake in peripheral tissues is dependent on the translocation of GLUT4 glucose transporters to the plasma membrane. Studies have shown the existence of two major signaling pathways that lead to the translocation of GLUT4. The first, and widely investigated, is the insulin activated signaling pathway through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. The second is the insulin-independent signaling pathway, which is activated by contractions. Individuals with type 2 diabetes mellitus have reduced insulin-stimulated glucose uptake in skeletal muscle due to the phenomenon of insulin resistance. However, those individuals have normal glucose uptake during exercise. In this context, physical exercise is one of the most important interventions that stimulates glucose uptake by insulin-independent pathways, and the main molecules involved are adenosine monophosphate-activated protein kinase, nitric oxide, bradykinin, AKT, reactive oxygen species and calcium. In this review, our main aims were to highlight the different glucose uptake pathways and to report the effects of physical exercise, diet and drugs on their functioning. Lastly, with the better understanding of these pathways, it would be possible to assess, exactly and molecularly, the importance of physical exercise and diet on glucose homeostasis. Furthermore, it would be possible to assess the action of drugs that might optimize glucose uptake and consequently be an important step in controlling the blood glucose levels in diabetic patients, in addition to being important to clarify some pathways that justify the development of drugs capable of mimicking the contraction pathway. Key words: diabetes; exercise; glucose uptake; diet; hypoglycemic drugs A captação de glicose nos tecidos peri Continue reading >>

Effects Of Insulin And Glucagon On The Uptake Of Amino Acids From Arterial Blood By Canine Ileum

Effects Of Insulin And Glucagon On The Uptake Of Amino Acids From Arterial Blood By Canine Ileum

Abstract Insulin and glucagon have variable effects in altering arteriovenous differences for amino acids and glucose in liver and muscle. It has not been determined whether these hormones may similarly affect intestine. Acute effects of intraarterial insulin and glucagon were evaluated inin situ, luminally cleansed ileal segments in anesthetized, fasted dogs. Insulin significantly increased the ileal uptake of valine, isoleucine, leucine, tyrosine, threonine, and serine from arterial blood: uptake of these amino acids was approximately doubled 45 min after the end of the insulin infusion. Insulin had no effect on glucose uptake or release. Glucagon decreased ileal glutamate release into mesenteric venous blood 45 min after the end of infusion but the uptake or release of other amino acids and ammonia was not changed. Glucagon did increase mesenteric blood flow acutely and caused a net release of glucose into mesenteric venous blood. The results indicate that insulin and glucagon directly alter metabolism of the ileumin vivo. 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 >>

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 >>

Molecular Mechanisms Of Insulin-stimulated Glucose Uptake In Adipocytes - Em|consulte

Molecular Mechanisms Of Insulin-stimulated Glucose Uptake In Adipocytes - Em|consulte

Molecular mechanisms of insulin-stimulated glucose uptake in adipocytes P.-H. Ducluzeau[1 et 2], L.M. Fletcher[1], H. Vidal[2], M. Laville[2], J.M. Tavar[1] [1]Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, BS8 1TD, U.K. [2]Unit INSERM U449, Facult de Mdecine RTH Laennec, rue Guillaume Paradin, 69372 Lyon Cedex 08, France. [1]Unit INSERM U449, Facult de Mdecine RTH Laennec, rue Guillaume Paradin 69372 Lyon Cedex 08, France. E-mail: The stimulation of muscle and adipose tissue glucose metabolism, which is ultimately responsible for bringing about post-absorptive blood glucose clearance, is the primary clinically relevant action of insulin. Insulin acts on many steps of glucose metabolism, but one of the most important effects is its ability to increase the rate of cellular glucose transport. This results from the translocation of the insulin-responsive transporter isoform, GLUT4, from intra-cellular vesicular storage sites to the plasma membrane. In adipocytes, a substantial amount of cellular GLUT4 is located in a specific highly insulin-responsive storage pool, termed GLUT4 Storage Vesicles (GSVs). GLUT4 can also translocate to the plasma membrane from the recycling endosomal pool which also additionally contains the GLUT1 isoform of glucose transporter and the transferrin receptor. In this article we review the molecular mechanism by which insulin stimulates GLUT4 translocation in adipose cells, including the nature of the signaling pathways involved and the role of the cytoskeleton. Transport du glucose induit par l'insuline dans le tissu adipeux: de la localisation la translocation. La principale action de l'insuline est de stimuler l'utilisation post-absorptive du glucose par les muscles et le tissu adipeux. L'insuline modi Continue reading >>

Glucose Uptake

Glucose Uptake

Method of glucose uptake differs throughout tissues depending on two factors; the metabolic needs of the tissue and availability of glucose. The two ways in which glucose uptake can take place are facilitated diffusion (a passive process) and secondary active transport (an active process which depends on the ion-gradient which is established through the hydrolysis of ATP, known as primary active transport). Facilitated diffusion[edit] There are over 10 different types of glucose transporters; however, the most significant for study are GLUT1-4. GLUT1 and GLUT3 are located in the plasma membrane of cells throughout the body, as they are responsible for maintaining a basal rate of glucose uptake. Basal blood glucose level is approximately 5mM (5 millimolar). The Km value (an indicator of the affinity of the transporter protein for glucose molecules; a low Km value suggests a high affinity) of the GLUT1 and GLUT3 proteins is 1mM; therefore GLUT1 and GLUT3 have a high affinity for glucose and uptake from the bloodstream is constant. GLUT2 in contrast has a high Km value (15-20mM) and therefore a low affinity for glucose. They are located in the plasma membranes of hepatocytes and pancreatic beta cells (in mice, but GLUT1 in human beta cells; see Reference 1). The high Km of GLUT2 allows for glucose sensing; rate of glucose entry is proportional to blood glucose levels. GLUT4 transporters are insulin sensitive, and are found in muscle and adipose tissue. As muscle is a principal storage site for glucose and adipose tissue for triglyceride (into which glucose can be converted for storage), GLUT4 is important in post-prandial uptake of excess glucose from the bloodstream. Moreover, several recent papers show that GLUT 4 is present in the brain also. The drug Metformin phosphor 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 >>

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