What is the role of the glucose transporter GLUT4 in diabetes?
The glucose transporter GLUT4 facilitates insulin-stimulated glucose uptake into muscle and adipose tissue. Defects in glucose uptake represent an early step in the development of type 2 diabetes mellitus.
What does GLUT-4 stand for?
Glucose transporter type 4 (GLUT-4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac).
How does insulin stimulate exocytosis of GLUT4?
Treatment of muscle or adipose cells with insulin stimulates exocytosis of GLUT4 from multiple intracellular compartments, which results in increased GLUT4 levels at the plasma membrane for shuttling of glucose into the cell. In the absence of insulin, at least 50% of GLUT4 is sequestered in specialized immobile GSVs.
How is GLUT4 released from adipose cells?
In muscle and adipose cells, GLUT4 is packaged in vesicles that are released upon stimulation of the insulin receptor and, in the case of muscle, also in response to exercise (Bryant et al., 2002 ).
How does GLUT4 affect glucose?
Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction.
Why is GLUT4 important?
GLUT4 is one of the most important downstream sites of the insulin receptor because it sits at the rate-limiting step in the insulin transduction signal pathway. It has been reported that GLUT4 protein and mRNA are reduced in type 2 diabetes (Chen et al., 2003).
What does GLUT4 do without insulin?
In the absence of insulin, Glut4 slowly recycles between the plasma membrane and vesicular compartments within the cell, where most of the Glut4 resides.
What does GLUT4 mean?
Glucose transporter type 4Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac).
What is the function of glucose transporter?
Glucose transporters are proteins, which facilitate glucose (and related substance) transport across cell membrane. As glucose is vital to all cells of body, so are glucose transporters.
What happens to glucose without insulin?
Without enough insulin, glucose builds up in the bloodstream instead of going into the cells. This buildup of glucose in the blood is called hyperglycemia. The body is unable to use the glucose for energy. This leads to the symptoms of type 1 diabetes.
What triggers GLUT4?
Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway. Diabetes.
What is GLUT4 in biology?
GLUT4. GLUT4 (509aa) is insulin-responsive transporter, restricted to striated muscle and adipose tissue, and defects may be associated with some forms of diabetes. From: The Dictionary of Cell & Molecular Biology (Fifth Edition), 2013. Download as PDF.
What is the role of GLUT4 in the postprandial process?
GLUT4 is the insulin-responsive glucose transporter responsible for postprandial glucose clear ance. In muscle and adipose cells, GLUT4 is packaged in vesicles that are released upon stimulation of the insulin receptor and, in the case of muscle, also in response to exercise (Bryant et al., 2002). The formation of intracellular GLUT4 storage vesicles provides a reservoir of transporters that, when delivered to the PM, can generate a rapid metabolic response resulting in tissue uptake of glucose. From well-studied murine adipocyte and rat myoblast models, it has been established that CHC17 clathrin plays a role in formation of the GLUT4 storage compartment through membrane traffic from late endosomes and the TGN (Bogan, 2012 ). In humans, this pathway is mediated by CHC22 clathrin instead of CHC17 ( Vassilopoulos et al., 2009). CHC17 in human GLUT4 membrane traffic controls only endocytosis and not intracellular sequestration. CHC22 sorting functions have been mapped to retrograde transport from late endosomes to the TGN (Esk et al., 2010) and CHC22 expression levels are highest in human muscle, where this pathway contributes to GLUT4 sequestration. In muscle of insulin-resistant type 2 diabetic patients, CHC22 accumulates at the expanded GLUT4 storage compartment that results from an impaired insulin response (Vassilopoulos et al., 2009). The different biochemical properties of CHC22 clathrin compared to CHC17 define specialized features of human glucose metabolism.
What is the role of AS160 in insulin?
AS160 was initially demonstrated to regulate insulin-stimulated GLUT4 translocation in 3T3LI adipocytes.78–80 AS160 has numerous phosphorylation sites, and Rab GAP activity is controlled by phosphorylation. The best-studied phosphorylation sites are a group of six distinct sites that were identified as substrates for Akt. These are collectively referred to as phospho-Akt-substrate (PAS) sites and both insulin and exercise increase AS160 PAS phosphorylation in skeletal muscle. 78,81,82 Prolonged exercise in humans 82–84 and rats, 78 as well as AICAR, are also known to cause AS160 PAS phosphorylation. Therefore, in addition to Akt, AMPK has been shown to phosphorylate AS160. 81 Mutation of four PAS sites significantly inhibits both insulin- and exercise-induced glucose uptake.85 AS160 also contains a calmodulin-binding domain, and mutation of this domain inhibits exercise-, but not insulin-stimulated glucose uptake.86 These data show that both phosphorylation and calmodulin binding on AS160 are involved in the regulation of exercise-stimulated glucose uptake. These data also suggest that while AS160 may serve as a point of convergence for both insulin- and exercise-dependent signaling in the regulation of glucose uptake, other proteins may be involved in this regulation of glucose uptake.
What is impaired GLUT4 translocation?
Impaired GLUT4 regulation results in insulin resistance and impaired IRAP translocation may contribute to altered vasopressin dynamics in insulin-resistant individuals. The impaired regulation of these proteins can reflect a combination of increased abundance at the cell surface during the basal, unstimulated state, as well as decreased abundance at the cell surface in the presence of insulin. A highly significant, 4.3-fold increase in cell surface abundance of IRAP was observed in unstimulated adipocytes obtained from individuals with type 2 diabetes, as compared to healthy controls ( Maianu et al., 2001 ). A similar trend was observed in skeletal muscle where increased IRAP is present in membrane fractions containing sarcolemma and T-tubule markers in patients with insulin resistance or diabetes, compared with healthy controls, in both basal and insulin-stimulated states ( Garvey et al., 1998 ). The interesting implication of this data is that increased copeptin concentrations in insulin-resistant individuals may result, at least in part, from accelerated vasopressin degradation triggering a compensatory increase in vasopressin secretion.
What is the role of glucose transport in insulin sensitive tissues?
The transport step is rate limiting for glucose uptake into fat and muscle under most conditions. 76,77 A central role for GLUT4 in whole-body metabolism is strongly supported by a variety of genetically engineered mouse models. Heterozygous GLUT4+/- mice that display decreased GLUT4 protein in muscle and adipose tissue are insulin resistant and develop diabetes later in life. 78,79
Where does glucose go in the body?
Figure 4.10. The flow of glucose in the body and its regulation by insulin. Glucose absorbed in the digestive system goes directly to muscle and to adipose tissue, where it is stored, and also to the pancreas. The pancreas, in response to the signal of an elevated blood glucose level, secretes insulin into the blood circulation and this, in turn, stimulates glucose uptake via GLUT4 into the adipose stores and into muscle, and diminishes flow into the liver, but does not impinge upon the brain which is continuously supplied by glucose entering via GLUT1.
Where is GLUT4 found?
GLUT4 (SLC2A4) is the insulin-responding glucose transporter, found predominantly in muscle cells and adipocytes (fat cells). After a meal, glucose that is absorbed from the digestive system and circulates in the blood now stimulates the release of insulin from the pancreas ( Figure 4.10). This insulin is the signal for a rapid transfer ...
What is the role of GLUT4 in insulin?
The translocation of GLUT4 to the plasma membrane following insulin stimulation represents the convergence of two complex systems: signal transduction and vesicular transport. GLUT4 itself has a central role in whole-body glucose homeostasis and defective GLUT4 trafficking might represent one of the earliest defects contributing to insulin resistance in humans (Box 1). Hence, pinpointing the major deterministic nodes for this process could yield important translational benefits for people with metabolic disease. In this Commentary we provide a cell biological perspective of GLUT4 trafficking that focuses on GLUT4 vesicles, their exocytosis and the molecules that control their exocytosis. Several recent reviews have covered other aspects of insulin-regulated glucose transport, including insulin signalling, GLUT4 endocytosis and formation of GLUT4 vesicles. We will not discuss these aspects in detail and direct the reader to these reviews for further information (Bryant and Gould, 2011; Foley et al., 2011; Hoffman and Elmendorf, 2011; Kandror and Pilch, 2011; Rowland et al., 2011). Our review focuses to a large extent on studies carried out in 3T3-L1 adipocytes because this model system has been used extensively for many years and there is an emerging consensus on mechanisms of GLUT4 trafficking in these cells. Important observations about GLUT4 trafficking have been made in other systems such as muscle cells (for a review, see Chiu et al., 2011) and for the most part the overall regulation of this process seems to be conserved between these different systems.
What is GLUT4 in the body?
GLUT4 is an insulin-regulated glucose transporter that is responsible for insulin-regulated glucose uptake into fat and muscle cells. In the absence of insulin, GLUT4 is mainly found in intracellular vesicles referred to as GLUT4 storage vesicles (GSVs). Here, we summarise evidence for the existence of these specific vesicles, how they are sequestered inside the cell and how they undergo exocytosis in the presence of insulin. In response to insulin stimulation, GSVs fuse with the plasma membrane in a rapid burst and in the continued presence of insulin GLUT4 molecules are internalised and recycled back to the plasma membrane in vesicles that are distinct from GSVs and probably of endosomal origin. In this Commentary we discuss evidence that this delivery process is tightly regulated and involves numerous molecules. Key components include the actin cytoskeleton, myosin motors, several Rab GTPases, the exocyst, SNARE proteins and SNARE regulators. Each step in this process is carefully orchestrated in a sequential and coupled manner and we are beginning to dissect key nodes within this network that determine vesicle–membrane fusion in response to insulin. This regulatory process clearly involves the Ser/Thr kinase AKT and the exquisite manner in which this single metabolic process is regulated makes it a likely target for lesions that might contribute to metabolic disease.
How do GSVs retain their vesicles?
Retention of GSVs could involve a mechanism that anchors the vesicles in the interior of the cell or restricts their access to the (cytoskeletal) tracks that shuttle them to the plasma membrane. In adipocytes, static pools of GLUT4 that become more mobile with insulin have been reported using live cell fluorescence microscopy (Fujita et al., 2010). However, in this study no distinction was made between GSVs and other GLUT4-containing compartments such as endosomes and the TGN. Taking into account the resolution limits of light microscopy (Box 2), these studies might selectively visualise the larger GLUT4-positive structures. It is possibly not surprising that these structures also undergo insulin-dependent changes, because insulin regulates numerous vesicle transport pathways in adipocytes (Tanner and Lienhard, 1987) and has a significant effect on endosomal morphology (Slot et al., 1991b). Therefore, the initially static structures might represent GLUT4 in TGN and/or endosomes, possibly en route to GSVs.
How does insulin transport glucose?
Insulin stimulates glucose transport into muscle and adipose tissue 10- to 30-fold with a half time of 2–5 minutes. The major glucose transporter expressed in these tissues is GLUT4. In the absence of insulin, the majority of GLUT4 is stored in small intracellular vesicles [referred to as GLUT4 storage vesicles (GSVs) (Martin et al., 1998) or insulin responsive vesicles (IRVs) (Kupriyanova et al., 2002)]. Following a meal, insulin is secreted by the pancreas and engages its receptor on the surface of myocytes and adipocytes, thereby activating the canonical PI3K–AKT pathway. Activation of this pathway is necessary and sufficient to trigger exocytosis of GSVs to the plasma membrane. This process involves microtubules and actin to navigate GSVs toward the plasma membrane, a tethering apparatus at the plasma membrane (the exocyst complex) to engage and capture GSVs at the cell surface, and fusion machinery (SNARE proteins and SNARE-associated proteins) that merges the GSV lipid bilayer with that of the plasma membrane.
What is the mechanism of glucose transport in muscle?
The mechanisms that govern insulin-stimulated glucose transport in muscle and fat cells have captured the imagination of researchers for decades (see Fig. 1). It all began with Einar Lundsgaard, who observed that insulin increased glucose uptake into muscle of eviscerated cats, whereas the intracellular glucose concentration remained negligible (Lundsgaard, 1939). He concluded that glucose is transported into muscle and that this process, rather than any subsequent step, is rate limiting in the overall glucose clearance process. This was probably the first ‘Eureka’ moment in the field. Since then, many important discoveries have been made (Fig. 1), of which the formulation of the translocation hypothesis (Cushman and Wardzala, 1980; Suzuki and Kono, 1980) and the identification (James et al., 1988) and cloning of the GLUT4 glucose transporter (Birnbaum, 1989; Charron et al., 1989; Fukumoto et al., 1989; James et al., 1989; Kaestner et al., 1989) were possibly the most important, because they put aside other theories that proposed that insulin regulates the intrinsic activity of a transporter.
Where is GLUT4 found?
GLUT4 expression is highest in adipose tissue and skeletal muscle, but GLUT4 is also found in other organs such as brain, kidney and intestine (Brosius et al., 1992; Rayner et al., 1994; Stöckli and James, 2009) and its possible role as a glucose sensor in these and other organs is worthy of future investigation.
Does GLUT4 cause diabetes?
A global reduction in GLUT4 (as occurs in mice heterozygous for GLUT4) results in diabetes (Stenbit et al., 1997), whereas selective disruption of GLUT4 expression in muscle or adipose tissue induces global insulin resistance (Abel et al., 2001; Zisman et al., 2000). The mechanism for intra-tissue communication is unclear, although it has been proposed that insulin signalling in other tissues might be attenuated by an adipokine in adipose-specific GLUT4-knockout mice (Yang et al., 2005). Despite this, it is of interest that genetic ablation of GLUT4 in adipose tissue and/or skeletal muscle does not lead to diabetes (Abel et al., 2001; Kotani et al., 2004; Zisman et al., 2000).
What is GLUT4 in mice?
GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes Nature Medicine volume 3, pages 10961101 (1997) GLUT4, the insulin-responsive glucose transporter , plays an important role in postprandial glucose disposal. Altered GLUT4 activity is suggested to be one of the factors responsible for decreased glucose uptake in muscle and adipose tissue in obesity and diabetes. To assess the effect of GLUT4 expression on whole-body glucose homeostasis, we disrupted the murine GLUT4 gene by homologous recombination. Male mice heterozygous for the mutation (GLUT+/) exhibited a decrease in GLUT4 expression in adipose tissue and skeletal muscle. This decrease in GLUT4 expression did not result in obesity but led to increased serum glucose and insulin, reduced muscle glucose uptake, hypertension, and diabetic histopathologies in the heart and liver similar to those of humans with non-insulin-dependent diabetes mellitus (NIDDM). The male GLUT4+/ mice represent a good model for studying the development of NIDDM without the complications associated with obesity. Subscribe to Nature Medicine for full access: The triumvirate: -cell, muscle, liver: A collusion responsible for NIDDM (Lilly Lecture 1987) Continue reading >>
What is the PTP1B inhibitor?
A novel PTP1B inhibitor extracted from Ganoderma lucidum ameliorates insulin resistance by regulating IRS1-GLUT4 cascades in the insulin signaling pathway a State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, Fudan University, Shanghai 200433, P. R. China b Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. China c Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, Australia Insulin resistance caused by the overexpression of protein tyrosine phosphatase 1 B (PTP1B) as well as the dephosphorylation of its target is one of the main causes of type 2 diabetes (T2D). A newly discovered proteoglycan, Fudan-Yueyang Ganoderma lucidum (FYGL) extracted from Ganoderma lucidum, was first reported to be capable of competitively inhibiting PTP1B activity in vitro in our previous work. In the present study, we sought to reveal the mechanism of PTP1B inhibition by FYGL at the animal and cellular levels. We found that FYGL can decrease blood glucose, reduce body weight and ameliorate insulin resistance in ob/ob mice. Decrease of PTP1B expression and increase of the phosphorylation of PTP1B targets in the insulin signaling pathway of skeletal muscles were observed. In order to clearly reveal the underlying mechanism of the hypoglycemic effect caused by FYGL, we further investigated the effects of FYGL on the PTP1B-involved insulin signaling pathway in rat myoblast L6 cells. We demonstrated that FYGL had excellent cell permeability by using a confocal laser scanning microscope and a flow cytometer. We found that FYGL had a positive effect on insulin-stimulated glucose uptake by using the 2-deoxyglucose (2-DG) method. Continue reading >>
Does GLUT4 increase insulin sensitivity?
Moderat e GLUT4 Overexpression Improves Insulin Sensitivity and Fasting Triglyceridemia in High-Fat DietFed Transgenic Mice Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Corresponding author: Ann Louise Olson, ude.cshuo@noslo-nna . Received 2012 Aug 23; Accepted 2013 Feb 28. Copyright 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details. This article has been cited by other articles in PMC. The GLUT4 facilitative glucose transporter mediates insulin-dependent glucose uptake. 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. Transgenic mice engineered to express the human GLUT4 gene and promoter (hGLUT4 TG) and their nontransgenic counterparts (NT) were fed either a control diet (CD) or a high-fat diet (HFD) for up to 10 weeks. Homeostasis model assessment of insulin resistance scores revealed that hGLUT4 TG mice fed an HFD remained highly insulin sensitive. The presence of the GLUT4 transgene did not completely prevent the metabolic adaptations to HFD. For example, HFD resulted in loss of dynamic regulation of the expression of several metabolic genes in the livers of fasted and refed NT and hGLUT4 TG mice. The hGLUT4 TG mice fed a CD showed no feeding-dependent regulation of SREBP-1c and fatty acid synthase (FAS) mRNA expression in the transition from the fasted to the fed state. Similarly, HFD altered the response of SREBP-1c and FAS mRNA expression to feeding in both strains. These changes in hepatic gene expressio Continue reading >>
Does GLUT4 cause insulin resistance?
Impaired Translocation of GLUT4 Results in Insulin Resistance of Atrophic Soleus Muscle Department of Aerospace Physiology, Fourth Military Medical University, No. 169 Changlexi Road, Xian 710032, China Received 20 August 2014; Revised 15 January 2015; Accepted 15 January 2015 Copyright 2015 Peng-Tao Xu et al. This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin res Continue reading >>
