Turning Signals On and Off: GLUT4 Traffic in the Insulin-Signaling Highway

Thong, Farah S. L.; Dugani, Chandrasagar B.; Klip, Amira

doi:10.1152/physiol.00017.2005

Cited by 183 publications

(146 citation statements)

References 163 publications

(135 reference statements)

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“…When cells are treated with insulin, AS160 is rapidly phosphorylated at multiple Akt phospho-motifs (Kane et al 2002). When 3T3-L1 adipocytes and L6 GLUT4-myc myoblasts were transfected with a constitutively active mutant AS160 (incapable of being phosphorylated at these regulatory sites), a significantly reduced insulin-induced GLUT4 translocation was observed (Sano et al 2003, Thong et al 2005). In addition, previous studies have reported increased AS160 phosphorylation with in vitro contractions in rat epitrochlearis muscles (Bruss et al 2005).…”

Section: Convergent Mechanisms Of Glucose Uptake: Role Of As160 and Tmentioning

confidence: 99%

General aspects of muscle glucose uptake

Alvim

Cheuhen

Machado

et al. 2015

An. Acad. Bras. Ciênc.

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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.

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Section: Convergent Mechanisms Of Glucose Uptake: Role Of As160 and Tmentioning

confidence: 99%

General aspects of muscle glucose uptake

Alvim

Cheuhen

Machado

et al. 2015

An. Acad. Bras. Ciênc.

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“…GLUT4 has drawn intense attention in the context of type 2 diabetes development, and several studies have found an association between impaired translocation/recycling of GLUT4 and insulin resistance (4,11,12). Clarification of the molecular events involved in insulin-stimulated GLUT4 translocation is therefore of medical importance.…”

Section: Glucose Transporters (Gluts)mentioning

confidence: 99%

N-Glycosylation Is Critical for the Stability and Intracellular Trafficking of Glucose Transporter GLUT4

Haga

Ishii

Suzuki

2011

Journal of Biological Chemistry

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The facilitative glucose transporter GLUT4 plays a key role in regulating whole body glucose homeostasis. GLUT4 dramatically changes its distribution upon insulin stimulation, and insulin-resistant diabetes is often linked with compromised translocation of GLUT4 under insulin stimulation. To elucidate the functional significance of the sole N-glycan chain on GLUT4, wild-type GLUT4 and a GLUT4 glycosylation mutant conjugated with enhanced GFP were stably expressed in HeLa cells. The N-glycan contributed to the overall stability of newly synthesized GLUT4. Moreover, cell surface expression of wildtype GLUT4 in HeLa cells was elevated upon insulin treatment, whereas the glycosylation mutant lost the ability to respond to insulin. Subcellular distribution of the mutant was distinct from that of wild-type GLUT4, implying that the subcellular localization required for insulin-mediated translocation was impaired in the mutant protein. Interestingly, kifunensine-treated cells also lost sensitivity to insulin, suggesting the functional importance of the N-glycan structure for GLUT4 trafficking. The K m or turnover rates of wild-type and mutant GLUT4, however, were similar, suggesting that the N-glycan had little effect on transporter activity. These findings underscore the critical roles of the N-glycan chain in quality control as well as intracellular trafficking of GLUT4.

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“…Signaling mediated by active PKB/Akt is crucial for promoting cell survival: PKB/ Akt not only phosphorylates and inhibits the pro-apoptotic factor BCL2-antagonist of cell death (BAD) but also phosphorylates murine double minute2 (Mdm2) leading to p53 degradation (Engelman et al 2006). On the other hand, PKB/Akt controls metabolism by promoting glucose transporter 4 (Glut4) membrane targeting (Thong et al 2005). Similarly, metabolic control is achieved by the FoxOmediated inhibition of genes involved in liver gluconeogenesis (Barthel et al 2005).…”

Section: Pi3k Downstream Effectorsmentioning

confidence: 99%

Phosphoinositide 3-kinases as a common platform for multi-hormone signaling

Hirsch

Costa²,

Ciraolo³

2007

Journal of Endocrinology

121

128

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In multicellular organisms, concerted actions of different tissues are regulated inside single cells by signal transduction mechanisms that, subsequently to hormones sensing, trigger intracellular responses. In recent years, increasing evidence indicates phosphoinositide 3-kinases (PI3K) as crucial signal transducing elements that regulate communication across the plasma membrane. PI3K generate lipid secondary messengers that trigger a plethora of intracellular responses ranging from metabolic regulation to cell proliferation, survival, and migration. The growing number of hormones that relay signals by activating PI3K suggests not only multiple roles of these enzymes in the regulation of different physiological responses but also a way by which common reactions can be stimulated by different inputs. This review will thus focus on the different pathways that converge on PI3K activation, with particular attention to the paradigmatic PI3K involvement in insulin signaling.

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Turning Signals On and Off: GLUT4 Traffic in the Insulin-Signaling Highway

Cited by 183 publications

References 163 publications

General aspects of muscle glucose uptake

General aspects of muscle glucose uptake

N-Glycosylation Is Critical for the Stability and Intracellular Trafficking of Glucose Transporter GLUT4

Phosphoinositide 3-kinases as a common platform for multi-hormone signaling

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