An animation intended for physical therapy students, explaining through cellular processes why daily exercise is important for patients with type 2 diabetes. Below is an animation giving an overview of diabetes type 2. Our results suggest that insulin stimulated glucose transport in skeletal muscle from patients with niddm is downregulated in the presence of hyperglycaemia. Insulin action on glucose transport and plasma membrane. Regulated transport of the glucose transporter glut4 nia j. Insulinstimulated delivery of glucose transporter4 glut4 to the. Insulin signaling bifurcates into the rac and akt pathways. Adiposeselective targeting of the glut4 gene impairs. Mar 08, 2011 milwaukee school of engineerings center for biomolecular modeling discusses the role of the protein insulin in the regulation of glucose in the bloodstream.
The fruit fly drosophila melanogaster is an excellent model system for studies of genes controlling development and disease. Understanding how insulin signaling alters the intracellular trafficking of glut4 as well as understanding the fate of glucose transported into the cell by glut4 will be critically important for seeking solutions to. Jci glucose toxicity and the development of diabetes in. Production of insulin and glucagon video khan academy. Impaired translocation of glut4 results in insulin resistance.
When high levels of glucose are detected by beta cells in the pancreas, insulin is released by the cells. Ppt insulin signaling powerpoint presentation free to. Expressed in adipose tissues and striated muscle skeletal muscle and cardiac muscle. Exercise and insulin stimulated glucose uptake by skeletal. Diabetes about 8% of the population have diabetes and about 19% are in a prediabetic state. For this reason, mutations in glut4 have been associated with type 2 diabetes 4. This indicates that insulin had an enhanced inhibitory effect on lipolysis after intermittent fasting compared with before. When glucose levels rise in these tissues, the glucose transporter 4 or glut4 protein is mobilized from the cytoplasm and deposited in the plasma membrane. I am asked to deduce the mechanism by which glucose. Zinc stimulates glucose oxidation and glycemic control by. Insulin stimulates translocation of human glut4 to.
To determine the mechanism, we examined insulinstimulated glucose uptake and metabolism during hyperinsulinemiceuglycemic clamp in control and muscle glut4 ko mice before and after development of diabetes. Pdf role for the cytoskeleton in glut4 vesicle trafficking. It has been reported that glut4 protein and mrna are reduced in type 2 diabetes chen et al. Glucose uptake through translocation and activation of. Insulin receptor and type 2 diabetes walter and eliza hall institute. Insulinregulated trafficking of glut4 requires ubiquitination.
Western blot protein band intensities were quantified by densitometry using image studio software. The first evidence for this distinct glucose transport protein was provided by david james in 1988. However, its applicability to physiological systems is less clear because of metabolic differences between insects and mammals. Although pi3k and pip3 are promising targets for therapeutic purpose to improve insulin sensitivity, current data of alterations in pi3k pathway in insulin resistance conditions are related to the immunoprecipitates to irs12 or. In adipocytes, vesicles containing glucose transporter4 glut4 redistribute from intracellular stores to the cell periphery in response to insulin stimulation. Quantitative measurement of glut4 translocation to the. When high levels of glucose enter the blood stream, insulin is released by beta cells in the pancreas. Search, discover and share your favorite insulin gifs.
Cartoon representation of the insulin dependent glut4. To gain insight into the details of microtubule involvement, we examined the spatial organization and dynamics of microtubules in relation to. Symptoms role of glut4 in type 2 diabetes important consequences bladder, kidney, skin, or other infections are more frequent or heal slowly fatigue hunger and thirst frequent urination blurred vision erectile dysfunction pain or numbness in the feet or hands key to understand. Expressed mostly in neurons where it is believed to be the main glucose transporter isoform, and in the placenta. Total glut4 content was unaltered by exercise and we were unable to detect any glut4 in glycogen fractions, either with or without amylase treatment. The software signal rac, a molecular switch, controls the actin cytoskeletal hardware to provide a tetheringdocking zone beneath the plasma membrane. Glut4 has long been known to be an insulin responsive glucose transporter. Effect of intermittent fasting and refeeding on insulin. Prolonged exposure to insulin with insufficient glucose. The membrane bound glut4 proteins are needed to transport even the low level of glucose into the cell. Glut4containing transport vesicles are postulated to bud from an insulinsensitive intracellular membrane compartment and to fuse with the plasma membrane. Insulin and glut 4 scientific video and animation site. Glut4 content decreases along with insulin resistance and. Furthermore, ablation of the transferrin receptorcontaining endosomes does not prevent insulin stimulated glut4 translocation.
Our new crystalgraphics chart and diagram slides for powerpoint is a collection of over impressively designed datadriven chart and editable diagram s guaranteed to impress any audience. Oct 05, 2004 the presence of insulin increases the activity of the glut4 glucose transporters and not the actual number of the transporters. Insulin signaling virtual cell animation collection. The role of phytochemicals and their action on insulin signaling pathways through stimulation of glut4 translocation is crucial to understand the pathogenesis. May 15, 2001 insulin resistance is an extremely prevalent condition in many human populations, being closely associated with obesity and niddm. The simulation platform was implemented in matlab software and all the results. The gene that encodes glut4 was cloned and mapped in 1989. Insulin regulated glucose transporter type 4 glut4, an insulin sensitive transporter characteristic of adipose tissue and skeletal muscle, is responsible for isgu, a key process for the normalization of postprandial blood glucose levels. Here you can see a few glucose molecules moving into the cell. Insulin and the regulation of glucose in the blood youtube. Glucose transporter type 4 glut4 is the major transporter that mediates glucose uptake by insulin sensitive tissues, such as the skeletal muscle. Glut4 is insulin dependent and is responsible for the majority of glucose transport into muscle and adipose cells in anabolic conditions.
A lot of factors inhibit glut4 expression at the basic or insulin stimulated conditions. James in muscle and fat cells, insulin stimulates the delivery of the glucose transporter glut4 from an intracellular location to the cell surface, where it facilitates the reduction of plasma glucose levels. Vesicles then fuse with the plasma membrane, facilitating glucose transport into the cell. Visualize and record the selected cell samples immediately. James1,2, 1diabetes and obesity program, garvan institute of medical research, sydney, new south wales 2010, australia 2school of biotechnology and biomolecular sciences, university of new south wales, sydney, new south wales 2052, australia.
Insulin and glut4 glucose transporters physics forums. Zinc stimulates glucose oxidation and glycemic control by modulating the insulin signaling pathway in human and mouse skeletal muscle cell lines shaghayegh norouzi, roles conceptualization, data curation, formal analysis, methodology, project administration, writing. The insulin circulates through the blood stream until it binds to an insulin receptor embedded in the cell membrane of a muscle, fat, or brain cell. Insulin stimulates glut4 translocation to the plasma membrane predominantly by releasing glut4 from this specialised intracellular pool resulting in a. Glut4 is the insulinsensitive glucose transporter which main role is to provide the insulinstimulated glucose uptake by adipose tissue, skeletal muscle and the heart, tissues that specifically express this protein 12. Then the brick l mnemonic includes the liver and intestine as insulin independent glucose uptake, but not the beta islet cells. When insulin is low, glut4 is stored in vesicles in the cytoplasm of cells but when insulin binds to receptors on the cellsurface membrane, it causes glut4 to move to membrane where glucose can then be transported into cell through the protiens by facilitated diffusion. Molecular basis of insulinstimulated glut4 vesicle trafficking. Insulin resistance and the disruption of glut4 trafficking. Quantitative measurement of glut4 translocation to the plasma. Is a highaffinity isoform, allowing it to transport even in times of low glucose concentrations. The physiology behind exercises role in controlling diabetes.
The effects of high ht and low lt intensity exercise training were therefore examined on insulin stimulated 3omethyldglucose 3 omg transport and the concentration of glucose transporter isoform glut4 in the red fasttwitch oxidative and white fast. Stacks of images were deconvolved and later analyzed with the help of the respective software velocity from perkinelmer in this case. Insulin signaling has been studied in mammals because of relevance to diabetes and other diseases but there are many parallels between. Glut4 is one of the most important downstream sites of the insulin receptor because it sits at the ratelimiting step in the insulin transduction signal pathway. However, when the blood sugar levels are normal and muscle needs more energy the glut4 translocation during exercise is induced by 5 ampactivated kinase in response to increased amp. Glut4 is the insulin regulated glucose transporter found in adipose tissues and striated muscle skeletal and cardiac that is responsible for insulin regulated glucose translocation into the cell. Atp ratio which is independent of insulin since there is not much. This fusion is mediated by vesicleassociated snare proteins vsnares present in transport vesicles, which interact specifically with targetmembrane snare proteins tsnares in the plasma membrane.
These data demonstrate that insulin stimulated glut4 trafficking can occur independent of the recycling endosome system, at least the endosome population defined by the transferrin receptor. Review article pi3kakt pathway in modulating glucose. A study that was released late last year found that exercise increases insulin sensitivity through capillary proliferation in the muscle musclespecific vegf deletion induces muscle capillary rarefaction creating muscle insulin resistance, 2012. Role of glut4 in type ii diabetes by weini low on prezi. Impaired translocation of glut4 results in insulin. Insulin responsive glucose transport has been exhaustively studied in the adipocyte since 1980, when evidence came to light that insulin stimulates the recruitment or translocation of glucose transporters from intracellular membrane compartments to the plasma membrane, increasing the number of functional cell surface glucose transporters and thus the rate of sugar uptake 5, 6. A a cartoon representation of the glut4 homology model used for. The stimulation of exocytosis by insulin is probably the major step for glut4 translocation because complete inhibition of glut4 endocytosis only modestly increases plasma membraneassociated glut4 protein without affecting the extent of insulin stimulated glut4 translocation. Glucose transporter type 4, also known as glut4, is a protein that in humans is encoded by the glut4 gene. Insulin regulates glut4 confinement in plasma membrane clusters. This process was associated with inactivation of glut4, a major insulin facilitated glucose transporter, suggesting a potential approach for the development of. Diabetes in mice with selective impairment of insulin.
Metabolic syndrome is characterized by insulin resistance, which is closely related to glut4 content in insulin sensitive tissues. The channel pore was monitored during the simulations using the hole program. Figure 2 in the other hand shows a reduced level of expression in muscle from a mouse line overexpressing pparalpha, which is a gene that presumably induces insulin resistant diabetes. Glut4 is the insulin regulated glucose transporter found primarily in adipose tissues and striated muscle skeletal and cardiac. Glut4 is a protein that facilitates the movement of glucose into the cell. Objective impaired insulin dependent glucose disposal in muscle and fat is a harbinger of type 2 diabetes, but murine models of selective insulin resistance at these two sites are conspicuous by their failure to cause hyperglycemia.
There is a program called firecracker, its really fun, they made. Effects of glut4 expression on insulin resistance in. Insulin action on glucose transport and plasma membrane glut4. Skeletal and cardiac muscle cells contain a transporter called glut4.
Sites of glucose transporter4 vesicle fusion with the plasma. This animation describes the role of the insulin receptor in type 2. Shortterm effect of insulin on glut4 expression in soleus muscle skeletal muscle is a target ti skeletal muscle is a target tissue for approaches that can improve insulin sensitivity in insulin resistant states such as diabetes. James in muscle and fat cells, insulin stimulates the delivery of the glucose transporter glut4 from an intracellular location to the cell surface, where it. Cell biology program, the hospital for sick children, toronto. The translocation of glut4 to the pm of insulin induced wild type cells was significantly higher than that in irs2deficient cells, which exhibited only a 1. Insulinindependent glucose transport regulates insulin.
In contrast to glut4, glut1 is localized both to the plasma. Thus, we evaluated the glut4 expression, insulin resistance and inflammation, characteristics of the metabolic syndrome, in an experimental model. Here, we discuss the known molecular and cellular regulatory mechanisms for glut4, its gene regulation, its trafficking pathways and their integration with insulin signaling, and the profound. Glut1 is insulin independent and is widely distributed in different tissues. If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. When the signal that was originally sent by insulin reaches the gsv pool, the vesicles are released from their holding pattern and move toward the plasma membrane. Insulin infusion can increase glut4 expression in the health persons, obese one with insulin resistance and type 1 diabetic patients, but not in type 2 diabetic.
No evidence of direct association between glut4 and. Arsenic induces insulin resistance in mouse adipocytes and. Glut4 is the insulinregulated glucose transporter found in adipose tissues and striated muscle skeletal and cardiac that is responsible for insulinregulated glucose translocation into the cell. Excessive caloric intake acutely causes oxidative stress. Lauritzen, section on integrative physiology and metabolism, joslin diabetes center, harvard medical school, boston, ma 02215, usa. We tested the hypothesis that moderate overexpression of human glut4 in mice, under the regulation of the human glut4 promoter, can prevent the hyperinsulinemia that results from obesity. Spontaneously hypertensive neonate rats 18group were treated with monosodium glutamate mets during 9 days, and. The earliest defect in developing type 2 diabetes is insulin resistance1,2, characterized by decreased glucose transport and metabolism in muscle and adipocytes3,4. When the insulin signal pathway is inactive, glut4 storage vesicles gsvs are held in a recycling state, a short distance from the cell membrane.
Regulation of glut4 and insulindependent glucose flux. Glut4 is in the family of solute carriers and is responsible for facilitating the transport glucose into the cells in response to insulin 3. Shortterm effect of insulin on glut4 expression in soleus. In a freeze fracture, it appeared that the glut4s moved from the internal membrane into the plasma membrane. Insulin and contractioninduced glut4 traffic in muscle. In skinned muscle fiber segments, there was very little, if any, glut4 detected in wash solutions, except following exposure to 1% triton x. Glucose transporter trafficking flashcards quizlet. Learn vocabulary, terms, and more with flashcards, games, and other study tools.
To investigate the contribution of ccr5 to insulin mediated glut4 membrane trafficking, gfp glut4 transfected neurons were treated with insulin or recombinant ccl5. Associated with diabetes are 24 fold higher risk of stroke and heart disease. Live images of glut4 protein trafficking in mouse primary. This makes sense since it is known that glucose transport takes place as a result of translocation of glut4, and not as a result of new biosynthesis of glut4. The magnitude of glut4 membrane translocation was influenced by the protein level of glut4. The insulin circulates through the blood stream until it binds to an insulin receptor embedded in the cell membrane of a. Insulin resistance and the disruption of glut4 trafficking in skeletal muscle mike mueckler department of cell biology and physiology, washington university school. Jan 11, 2012 this feature is not available right now. Role for the cytoskeleton in glut4 vesicle trafficking and in the regulation of insulinstimulated glucose uptake. Transgenic mice engineered to express the human glut4 gene and promoter hglut4 tg and their nontransgenic. Insulin dependent glut4 trafficking is not regulated by protein sumoylation in l6 myocytes.
Essential role of insulin receptor substrate2 in insulin. Decreased glucose tolerance and diabetes are frequently observed in advanced liver cirrhosis patients and may be related to insulin resistance. The increased flux of glucose as a consequence of hyperglycaemia may result in resistance to any further insulin induced gain of glut4 at the level of the plasma membrane. Thus, lack of irs2 impairs insulin induced glut4 translocation, as well as. The role of exercise on insulin sensitivity exercise medicine. Insulindependent glut4 trafficking is not regulated by. Also, 75% of patients with diabetes show an elevated blood pressure. Using creloxp gene targeting, transgenic mice with musclespecific inactivation of the glut4 gene muscle glut4 ko were generated and shown to develop a diabetes phenotype. Glut 4 ia the only glucose transporter that is insulin dependent, thats why. The glut4 facilitative glucose transporter mediates insulin dependent glucose uptake. The glucose transport proteins glut1 and glut4 facilitate glucose transport into insulin sensitive cells. Insulin then initiates a number of signal pathways in. The glut4 glucose transporter is thus a major mediator of glucose removal from the circulation and a key regulator of wholebody glucose homeostasis.
So insulin and glucagon from the pancreas will have four times greater effect in the liver than in the rest of the body. The vast majority about 90% is found in glut4 storage vesicles or gsvs. Simply select your manager software from the list below and click on download. In fa 20, it says, glut1 insulin independent glucose uptake, glut2 bidirectional, glut4 insulin dependent. This differential function of insulin to glut4 and other recycling protein is most probably due to separation of glut4 from normal endosomal trafficking pathways to form separate compartment which readily transfer to cell membrane in response to insulin. Molecular basis of insulinstimulated glut4 vesicle. There is a steady recycling of the plasma membrane glut4 protein pool. Protein recycling signal pathways virtual cell animation. Abstracta major consequence of insulin binding its receptor on fat and muscle cells is. This article is from traffic copenhagen, denmark, volume 11. But now the thing about the pancreas is that it doesnt just contain insulin and glucagon hanging out in random cells, theyre organized. Insulin resistance and the disruption of glut4 trafficking in. This protocol describes a technique for observation of realtime green fluorescence protein gfp tagged glucose transporter 4 glut4 protein trafficking upon insulin stimulation and characterization of the biological role of ccr5 in the insulinglut4 signaling pathway with deconvolution microscopy.
Because the molecular basis of insulin resistance is likely to be heterogeneous, any new animal model of insulin resistance can be of considerable experimental value. Milwaukee school of engineerings center for biomolecular modeling discusses the role of the protein insulin in the regulation of glucose in the bloodstream. Insulin induced akt activity and downstream signaling are not altered in irs2deficient adipocytes. Upon binding of insulin to its receptor, vesicles containing glut4 translocate from the cytoplasm to the plasma membrane, inducing glucose uptake. Regulation of glut4 has been a major focus of research on the cause and prevention of type 2 diabetes. In the absence of insulin, this integral membrane protein is sequestered within the.
Background glucose transporter 4 glut4 is an insulin facilitated. Molecules free fulltext action of phytochemicals on insulin. Moderate glut4 overexpression improves insulin sensitivity. Insulin action on glucose transport and plasma membrane glut4 content in skeletal muscle from patients with niddm springerlink. Dec 24, 1996 a major physiological role of insulin is the regulation of glucose uptake into skeletal and cardiac muscle and adipose tissue, mediated by an insulin stimulated translocation of glut4 glucose transporters from an intracellular vesicular pool to the plasma membrane. This gene is a member of the solute carrier family 2 facilitated glucose transporter family and encodes a protein that functions as an insulin regulated facilitative glucose transporter. With support from autodesks academy award winning 3d animation and effects software. Glucose transporter4 glut4, one of the most important glucose transporters, plays a key role in the development of type 2 diabetes. Diabetes is the 7th leading cause of death in the united states. Chart and diagram slides for powerpoint beautifully designed chart and diagram s for powerpoint with visually stunning graphics and animation effects. The serinethreonine kinase akt is a downstream target of pi 3kinase and has been implicated in insulin stimulated glut4 translocation and glucose transport. Consolidated view on the software and hardware molecules that drive insulin stimulated glut4 translocation in muscle cells. A novel method for simulating insulin mediated glut4 translocation.
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