GLUT4 Goes Abnormal: Disregulation of the Insulin-Responsive Glucose Transporter in Abnormal Metabolic States (original) (raw)
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AJP: Endocrinology and Metabolism, 2008
Karnieli E, Armoni M. Transcriptional regulation of the insulinresponsive glucose transporter GLUT4 gene: from physiology to pathology. Am J Physiol Endocrinol Metab 295: E38 -E45, 2008. The insulin-responsive glucose transporter 4 (GLUT4) plays a key role in glucose uptake and metabolism in insulin target tissues. Being a rate-limiting step in glucose metabolism, the expression and function of the GLUT4 isoform has been extensively studied and found to be tightly regulated at both mRNA and protein levels. Adaptation to states of enhanced metabolic demand is associated with increased glucose metabolism and GLUT4 gene expression, whereas states of insulin resistance such as type 2 diabetes mellitus (DM2), obesity, and aging are associated with impaired regulation of GLUT4 gene expression and function. The present review focuses on the interplay among hormonal, nutritional, and transcription factors in the regulation of GLUT4 transcription in health and sickness.
Hormonal regulation of the insulin-responsive glucose transporter, GLUT4: some recent advances
Proceedings of the Nutrition Society, 1996
A ce jour, quatre transporteurs facilitants du glucose ont CtC clBnCs et caracterisis dans leur fonction. Ces proteines qui sont les produits de gknes distincts, s'expriment specifiquement selon le tissu, et catalysent le mouvement facilitant du glucose dans son gradient chimique a travers la membrane de la cellule. I1 est possible de proposer une explication cette diversit6 d'expression basee sur l'analyse des proprietes cinetiques et fonctionnelles de ces diffirents isoformes. Ainsi, on pense que GLUT1 est impliquC dans le transport du glucose 2 travers les barrikres entre le sang et les organes tels que la rCtine, et a travers la barrih-e entre le sang et le cerveau; il est aussi impliquC dans le maintien de niveaux basals ou d'entretien de I'activitC de transport du glucose dans beaucoup de types de cellules, sinon dans tous. GLUT;! est un transporteur a haute capacitC et B faible affinitC qui convient idkalement a cet isoforme dans son r6le dans les flux d'entrCe et de sortie du foie; de plus, il joue potentiellement un r6le-clC dans la reconnaissance du glucose dans le pancreas. GLUT 3 est un transporteur haute affinitk qui s'exprime essentiellement dans le cerveau et les nerfs, qui dCpendent presqu'entikrement du glucose pour leur Cnergie. Ainsi, on peut postuler la presence d'un transporteur a haute affinitC dans ces cellules pour leur confCrer la capacitC de rechercher le glucose avec efficacitk, mCme dans des conditions d'hypoglyckmie. Nous prCsentons ici les nouvelles avancees dans les connaisances de la regulation du dit transporteur du glucose rCpondant a l'insuline, GLUT4, dont les principaux sites d'expression sont le muscle, le coeur et le tissu adipeux.
Expression of human GLUT4 in mice results in increased insulin action
Diabetologia, 1994
Glucose metabolism was evaluated in transgenic mice expressing the human GLUT 4 glucose transporter. Fed GLUT 4 transgenic mice exhibited a 32 % and 56 % reduction in serum glucose and insulin and a 69 % and 33 % increase in non-esterified fatty acid and lactate levels, respectively. Transgenic mice exhibited a significant increase in whole-body glucose disposal during a euglycaemic-hyperinsulinaemic clamp. Insulin-stin'mlated glucose uptake in isolated soleus muscles and adipocytes was greater in transgenic compared to control mice due to increased basal glucose uptake. Transgenic mice displayed increased glycogen levels in liver and gastrocnemius muscle, and increased insulin-stimulated 14C-glycogen accumulation in isolated soleus muscle. We conclude that over-expression of the GLUT 4 glucose transporter in mice results in 1) an increase in whole-body glucose disposal and storage, and 2) an increase in both basal and insulin-stimulated glucose uptake and disposal in vitro. These changes resulted in the reduction of serum glucose and insulin levels. These results provide direct evidence that glucose transport (and GLUT 4 per se) plays a significant role in regulating wholebody glucose homeostasis. Additionally, these data support the idea that pharmacological strategies directed at increasing the expression of GLUT 4 protein may have beneficial (hypoglycaemic) effects in the diabetic state. [Diabetologia (1994[Diabetologia ( ) 37: 1097[Diabetologia ( -1104
The facilitative glucose transporter GLUT12: what do we know and what would we like to know?
Journal of Physiology and Biochemistry, 2013
Human GLUT12 was isolated from the breast cancer cell line MCF-7 by its homology with GLUT4. Glucose has been described as its main substrate, but it also can transport other sugars. In humans, GLUT12 protein is expressed mainly in insulin sensitive tissues. Functional analysis has showed that GLUT12 transports sugars down its concentration gradient, but it can also work as a proton-coupled symporter. Studies from our laboratory, performed in Xenopus laevis oocytes expressing GLUT12, show that glucose uptake increases in the presence of Na + and induces inward current. These findings suggest a transport mechanism never described for other GLUTs, which would indicate a distinct functional role for GLUT12. In relation with its physiological and pathophysiological function, GLUT12 has been mainly studied due to its role as a secondary insulin-sensitive glucose transporter and its possible implication in impaired insulin signalling pathologies. Its expression in some tumour tissues has been described and recently, it has been proposed as one of the key proteins in the glucose supply to malignant cells. Overall, even though a lot of information about GLUT12 has been released during the last years, its functional characteristics, physiological role or implication in the development of some diseases is still unclear. Therefore, this review of the literature can help to address further investigations needed to elucidate these issues that, in our view, are of great interest mainly due to the direct GLUT12 relation with cancer and probably with diabetes development.
Regulation of GLUT4 and Insulin-Dependent Glucose Flux
ISRN Molecular Biology, 2012
GLUT4 has long been known to be an insulin responsive glucose transporter. Regulation of GLUT4 has been a major focus of research on the cause and prevention of type 2 diabetes. 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 the current rise in diabetes and metabolic disease.
GLUT4 Gene Regulation and Manipulation
Journal of Biological Chemistry, 1999
A decade has passed since the cloning of the insulin-responsive glucose transporter, GLUT4. Numerous studies have demonstrated the complex hormonal and metabolic regulation of GLUT4 gene expression in adipose tissue and muscle. Careful dissection of the regulatory elements in the GLUT4 promoter has provided insight into the intricate control of this central gene of glucose homeostasis. Genetic manipulation of mice has provided further insight into the role of GLUT4 in carbohydrate and lipid metabolism at the whole body and tissue-specific levels. Analysis of GLUT4ϩ/Ϫ, GLUT4 null, and muscle-complemented GLUT4 knockout mice has furthered our understanding of peripheral insulin sensitivity. Additional studies on GLUT4 gene regulation and GLUT4 knockout models are likely to lead to novel therapies for type II diabetes and other diseases of insulin resistance. Regulation of GLUT4 mRNA Expression in Vivo and in Vitro Proof that the facilitative glucose transporter, GLUT4, is the primary effector molecule for insulin-mediated glucose disposal comes from the use of transgenic animals. Mice that are genetically engineered to generally overexpress an exogenous GLUT4 gene, or specifically in skeletal muscle or adipose tissue, display enhanced insulin responsiveness and peripheral glucose utilization (for review see Ref. 1). The high levels of transporters are able to enhance insulin responsiveness in genetic and experimental models of diabetes. Thus, expression of the GLUT4 gene is a clinically relevant molecule to target for treatment of insulin-resistant disease states. Expression of GLUT4 mRNA is subject to tissue-specific, hormonal, and metabolic regulation (for review see Ref. 2). GLUT4 mRNA expression is largely restricted to both brown and white adipose tissue, skeletal and cardiac muscle, although GLUT4 mRNA have been detected in specialized cell types of other tissues. Changes in GLUT4 gene expression are observed in physiologic states of altered glucose homeostasis and vary in a tissue-specific manner, occurring much more rapidly in adipose tissue than skeletal muscle (3). In general, GLUT4 mRNA expression is down-regulated in states of relative insulin deficiency such as streptozotocin (STZ) 1induced diabetes and chronic fasting (for review see Ref. 2). Chronic fasting markedly reduces GLUT4 mRNA levels in adipose tissue, while having either no effect or slightly increasing GLUT4 mRNA in skeletal muscle (4). Changes in steady state levels of GLUT4 mRNA result from changes in the rate of synthesis of GLUT4 mRNA (gene transcription) and changes in degradation of * This minireview will be reprinted in the 1999 Minireview Compendium, which will be available in December, 1999. This is the third article of three in the "Insulin-stimulated Glucose Transport Minireview Series." This work was supported by National Institutes of Health Grants DK47425 and HL58119 (to M. J. C.
Glucose transporters and diabetes
Seminars in Cell & Developmental Biology, 1996
Peripheral insulin resistance is a characteristic feature of obesity and non-insulin-dependent diabetes mellitus (NIDDM), and the cause can be localized in part to a defect in glucose transport. GLUT4, the predominant glucose transporter in insulin sensitive tissues, undergoes striking tissue specific metabolic regulation; GLUT4 gene expression is reduced in adipocytes, and generally unchanged in muscle from insulin resistant humans and rodents. In adipocytes, lower levels of GLUT4 account for the glucose transport defect, whereas in muscle, impaired traffic or decreased function of GLUT4 at the plasma membrane may account for the defect. Future studies of GLUT4 translocation, fusion and exposure/activation will unravel the molecular mechanism(s) behind the development of insulin resistance.
Journal of Clinical Investigation, 1997
Glucose transporter type 4 (GLUT4) is insulin responsive and is expressed in striated muscle and adipose tissue. To investigate the impact of a partial deficiency in the level of GLUT4 on in vivo insulin action, we examined glucose disposal and hepatic glucose production (HGP) during hyperinsulinemic clamp studies in 4-5-mo-old conscious mice with one disrupted GLUT4 allele [GLUT4 ( ϩ / Ϫ )], compared with wild-type control mice [WT ( ϩ / ϩ )]. GLUT4 ( ϩ / Ϫ ) mice were studied before the onset of hyperglycemia and had normal plasma glucose levels and a 50% increase in the fasting (6 h) plasma insulin concentrations. GLUT4 protein in muscle was ف 45% less in GLUT4 ( ϩ / Ϫ ) than in WT ( ϩ / ϩ ). Euglycemic hyperinsulinemic clamp studies were performed in combination with [3-3 H]glucose to measure the rate of appearance of glucose and HGP, with [U-14 C]-2-deoxyglucose to estimate muscle glucose transport in vivo, and with [U-14 C]lactate to assess hepatic glucose fluxes.