There is 95% sequence identity between human and rat glut4, whereas human glut1 and glut4 have 65% identity. In pancreatic beta cells, glut2 is required for glucosestimulated insulin secretion. Insulin receptor definition of insulin receptor by. The glucose transporter which is sensitive to insulin is a. Also, 75% of patients with diabetes show an elevated blood pressure. Cleavage of polysaccharides by alphaamylase results in which three possible molecules. Insulin and ampactivated protein kinase ampk signal pathways are known to be involved in glucose uptake regulation, but the integration of signals between these two pathways in maintaining glucose homeostasis remains mysterious.
Glut4 is expressed in glucosesensing neurons 29, but it is not known. Regulated membrane trafficking of the insulinresponsive glucose. Glut4 trafficking in insulinsensitive cells springerlink. In fa 20, it says, glut1 insulin independent glucose uptake, glut2 bidirectional, glut4insulin dependent. Insulin resistance of glucose in skeletal muscle is seen in both obesity and type 2. How insulin regulates blood glucose with the glut4 glucose. Glut3 is the primary glucose carrier for neurons or nerve cells. Jci insulin resistance and the disruption of glut4.
In the liver, however, glucose moves freely across the plasma membrane, so this process is not rate limiting at this point. Insulin is a hormone that regulates the uptake of glucose into fat and skeletal muscle cells. Intriguingly, fully differentiated 3t3l1 adipocytes display patches of. Insulin sensitivity an overview sciencedirect topics. Structure of, and functional insight into the glut family of membrane transporters wentong long, chris i cheeseman department of physiology, faculty of medicine and dentistry, university of alberta, edmonton, ab, canada abstract. Using western blotting with polyclonal antibodies and then confirmed by northern analysis, tilapia peripheral tissues appear to be devoid of glut4, the insulinsensitive glucose transporter, but not glut1, the insulin independent glucose transporter wright et al. 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.
However, anatomic and functional mapping of insulins cns action is not nearly as detailed. In previous studies, we showed that glut4 neurons are indeed insulinsensitive neurons and that they may play a role in integrating olfactosensory responses with metabolic cues. Which of the following transports cholesterol that has been absorbed from the small intestine after a meal. Insulin stimulated glut4 translocation in cho glut4egfp. Ampa receptors regulate exocytosis and insulin release in. The classic pathway for insulin release is that when the blood glucose level increases, glucose enters. Altered central nutrient sensing in male mice lacking. Glucose transporters, insulin, and diabetes flashcards. Glucoseresponsive insulin analogs or delivery systems are desirable for enhancing health and improving quality of life of people with diabetes. The insulinresponsive glucose transporter glut4 was first described in 1988 as a result of studies on the regulation of glucose metabolism by insulin.
Structural and functional evolution of glucose transporter. Glut4 expression defines an insulinsensitive hypothalamic. One system to which these advances have been profitably applied is the regulation of the trafficking of a glucose transporter, glut4, from intracellular. Glut4 glucosetransporter protein and mrna levels were assessed in heart, red muscle and white muscle, as well as in brown and white adipose tissue from 7day streptozotocininduced diabetic and 48 hfasted rats. Insulin, stored in secretory granules of pancreatic. For patchclamp recording in acute slices, we sectioned. We describe here a simple strategy to engineer a longacting insulin analog, which can establish an endogenous glutassociated delivery reservoir of insulin that can modulate glucose metabolism in a blood glucosedependent manner. Glut4credriven insulin receptor knockout mice with a combined ablation of ir in. Glut4 content decreases along with insulin resistance and.
The addition of wortmannin or ml9 on incubation with insulin decreased the glut4 protein content in 70% plt0,01. In 1979, researchers showed that the level of insulin in the brain determined how much food a group of monkeys consumed, but they could not produce a direct link to how insulin worked in the brain. Being a type 1 diabetic means you make very little of you own insulin so the insulin you inject is very important to stimulate transport of this protein to the surface of cells so they can take on glucose from the bloodstream. Glut4 neurons in the hypothalamus were glucose responsive.
Although the content in intracellular glucose transporters did not differ in the. Wholecell patch recordings were performed using borosilicate glass electrodes. Glut4 expression defines an insulinsensitive hypothalamic neuronal. Akt3 is not expressed in insulinresponsive tissues 55. Glucose transporter inhibitorconjugated insulin mitigates. However, the leptin receptor oligomerizes with itself but not with its closely. Secretion of insulin in response to diet and hormones. Then the brick l mnemonic includes the liver and intestine as insulinindependent glucose uptake, but not the beta islet cells. Low affinity for glucose high km, b cells of pancreas have glut 2 receptors for recognition of glucose therefore release insulin. The glucose transporter that is placed on the surface of fat and muscle cells has a. In this study the scientists used mice with vegf expression knocked out in cardiac and skeletal muscle at day sixteen of development. Role of glut4 in type ii diabetes by weini low on prezi. Altered central nutrient sensing in male mice lacking insulin.
The glucose transporter system glut4 across the membrane is rate limiting in peripheral tissues that are sensitive to insulin muscle, fat. However, the benefits of insulin therapy are often not fully realized, due to the. Diabetes is the 7th leading cause of death in the united states. Soon after the discovery of glut4, several groups cloned glut4 in the human, rat 3,4 and mouse. Diabetes about 8% of the population have diabetes and about 19% are in a prediabetic state. 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. Glucoseresponsive microneedle patches for diabetes treatment. In this study we have shown that the insulinsensitive glucose transporter glut4 interacts physically with daxx, the adaptor protein whose function has been associated with apoptosis 1, 2, 10,2729.
Glucoseresponsive insulin analogs or delivery systems are. Although glp1 receptors are not classically thought to be widely expressed in peripheral insulinsensitive tissues such as muscle, fat, or liver, several studies have suggested that sustained treatment with glp1 receptor agonists is associated with improvements in insulin sensitivity glp1, insulin sensitivity, and human studies. These results showed that insulin modulate glut4 protein content in soleus muscleitalic,italic probably via pi3k and akt. The glucose transporter isoform glut2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for glut2 in several regulatory mechanisms. Insulin stimulates glucose uptake into skeletal muscle mainly via the translocation of glucose transporter 4 glut4 to the plasma membrane. Glucoseresponsive insulin patch for the regulation of blood glucose. Lipoic acid insulin resistance illustration omitted when insulin docks in the receptors on cell membranes, that should signal glucose transporters to let glucose blood sugar into the cell. This condition prevents the receptors from allowing. Glucoseresponsive mnarray patch systems for diabetes treatment. Rapamycin did not induce any change in glut4 protein content.
Receptors for cholecystokinin and insulin in isolated pancreatic acini. Glut 4 is a insulin regulated glucose transporter which is found in fatty and muscle cell. Allowing all tissues to have only glut3 or all glut4 would mean they would all respond to changes in glucose availability in the same way a totally inappropriate situation for the organism, with potentially disastrous consequences. The glucose transporter which is sensitive to insulin is a glut2 b glut4 c from nutrition 111 at university of california, davis. Glut4 has long been known to be an insulin responsive glucose transporter. Studies of mice with inactivation of glut4 or of the insulin receptor.
Insulinresponsive 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. Insulin signaling in the cns modulates satiety and glucose metabolism, but insulin target neurons are poorly defined. In nonequilibrium fractions, insulin led to small glut4 decrements in the 25 and 28% sucrose fractions and increased glut4 in the 32% sucrose fraction by 2. Shortterm effect of insulin on glut4 expression in soleus. Glut2, glucose sensing and glucose homeostasis springerlink. Indeed, it was recently demonstrated that in cellattached patch measurements of obob. Glut4 glut4 is an insulin responsive glucose transporter that. Glucose transporter an overview sciencedirect topics. This is further evidence that glucose transport by glut2 is not a. Spontaneously hypertensive neonate rats 18group were treated with monosodium glutamate mets during 9 days. Later studies found large amounts of both the glut1 transporter, which carries glucose from the blood steam to brain tissue, and the glut3.
Thus, we evaluated the glut4 expression, insulin resistance and inflammation, characteristics of the metabolic syndrome, in an experimental model. Glut4 is insulinsensitive and it is the predominant glucose transporter in the muscle and adipose tissue. Since its discovery, glut4 has received, together with glut1, more experimental attention than any other single membrane transport protein. Regulation of glut4 and insulindependent glucose flux ncbi. Glut1 seems to be coupled with hexokinase i, and glut4 with hexokinase ii. Because glucose is a vital source of energy for all life, these transporters are present in all phyla. The glucose transporter isoform glut2 is expressed in liver, intestine, kidney. Because glucose would be, at best, a minimal component of the natural. Regulation of glut4 and insulindependent glucose flux.
Surprisingly, blood glucose levels in glut4 null mice are normal under fasted and fed conditions. A single removable transdermal patch bearing microneedles loaded with insulin and a nondegradable glucoseresponsive polymeric matrix regulates blood. Therefore, it is not surprising that glucose is the primary energy source used in the. Recently, another insulinregulatable glucose transporter, glut12, has been. In recent years, there have been major advances in the understanding of both the cell biology of vesicle trafficking between intracellular compartments and the molecular targeting signals intrinsic to the trafficking proteins themselves. Associated with diabetes are 24 fold higher risk of stroke and heart disease. Endosomal sorting of glut4 morphological studies in both muscle and fat cells indicate that,although there is some overlap of glut4 with markers of the endocytic system such as the tfr,a. Insulinindependent glucose transport regulates insulin. Regulation of glut4 has been a major focus of research on the cause and prevention of type 2 diabetes. Generation of pip3 patches in the plasma membrane can act as docking sites for. The role of exercise on insulin sensitivity exercise.
Glut3 has a high affinity for glucose, and is also able to transport galactose, but is unable to carry fructose. The coimmunoprecipitation of daxx and glut4 from extracts of 3t3l1 fibroblasts stably transfected with glut4 and from 3t3l1 adipocytes. Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion. Glut4 is the only known insulinresponsive glut highly and. We have previously shown that ablation of insulin receptors insr in glut4expressing tissues results in systemic abnormalities of insulin action. Metabolic syndrome is characterized by insulin resistance, which is closely related to glut4 content in insulinsensitive tissues. Molecular pathology defects of insr cause rabsonmendenhall syndrome, leprechaunism and hyperinsulinaemic hypoglycaemia type 5. Moreover, in cell ablation experiments, we showed that hypothalamic glut4 neurons regulate satiety, glucose homeostasis, and cns sensing of hormones and nutrients 15. We propose that glut4 neurons constitute an insulinsensitive neuronal subset. Insulin stimulated glut4 translocation in chohircmycglut4egfp cells. Structure of, and functional insight into the glut family. 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.
581 336 377 549 1045 148 610 1550 495 701 639 661 813 920 1460 70 503 223 481 429 1028 1149 1423 156 1367 1182 492 1179 611 959 398 10 715 1334 793 76 1116 461 544 1495 1126 736 1438 770 765 1162 1423 1082 351