Glucose Transporter 4 (GLUT4) and Diabetes

Glucose Transporter 4 (GLUT4) and DiabetesInsulin and AMP- activated protein kinase (AMPK) signal pathways ar know to be involved in glucose phthisis regulation, still the integ dirty dogion of signals amongst these two pathways in maintaining glucose homeostasis remains mysterious (1). Insulin stimulates glucose use into skeletal pass mainly via the translocation of glucose header 4 (GLUT4) to the germ plasm membrane (2). Also the take up mechanism involved is not yet fully understood, however, in insulin-induced glucose transport cascade it seems that insulin activates specific protein kinase C (PKC) isoforms (2).In Liu L. Z. et al work, stimulation of insulin conferred a glucose intake or translocation of surface glucose transporter 4 (GLUT4).Using specific inhibitors to rudimentary kinases of both pathways and PKCzeta small meddlence RNA, it was found that protein kinase C zeta (PKCzeta) regulate insulin- affected protein kinase B (PKB) energizing and inhibit AMPK leg al action on dorsal jail prison cell surface, whereas in the front end of berberine, PKCzeta controlled AMPK activation and AMPK blocked PKB activity in perinuclear region. The inhibitory frame exerted by PKCzeta on AMPK activation or the arrestment of PKB activity by AMPK gloss over existed in basal condition. Overall, these results are suggestive for an antagonistic regulation amongst insulin and AMPK signal pathways, which is mediated by the switch habits of PKCzeta.The protein kinase Akt is associated with different cellular processes, including cell proliferation, offset, metabolism and importantly, insulin-regulated transport of glucose into vigor and fat cells. Activation of Akt involves binding of an extracellular ligand to its cognate tyrosine kinase receptor, which lead to activation of PI3K (phosphoinositide 3-kinase) and divisorration of PtdIns(3,4,5)P3. This in turn enables the translocation of Akt to the blood germ plasm membrane where it is phosphorylated at Thr308 and Ser473 by PDK1 (phosphoinositide-dependent kinase 1) and the mTOR (mammalian target of rapamycin)/rictor (rapamycin-insensitive companion of mTOR) complex respectively. erst activated, Akt phosphorylates a range of substrates that regulate a variety of key biologic processes (3). There are several Akt isoforms, Akt1 function is mainly related to growth and proliferation. On the other hand, Akt2 is more involved in metabolism, and loss-of function mutations in Akt2 have been linked to Type 2 diabetes (3). Akt has been involved in the insulin-induced sort of GLUT1 in hepatoma cells and GLUT3 in skeletal muscle (4).Insulin-regulated transport of glucose into muscle and fat cells is thought to be mediated by Akt-dependent movement of GLUT4 glucose transporters to the plasma membrane (3). It was found after burning S. X. study that non-ATP-competitive allosteric Akt inhibitors in 3T3-L1 adipocytes caused a decrease in the Akt signalize pathway simultaneously with reduce d glucose uptake, notwithstanding, no such lessening in GLUT4 translocation to the plasma membrane was seen. This is explained by the point that minimal amount of Akt phosphorylation is prerequisite for robust GLUT4 translocation, thus a marked reduction in Akt phosphorylation may not necessarily translate into a similar reduction in GLUT4 translocation to the plasma membrane (3, 5). Additional investigating revealed that the inhibitory gists on glucose uptake in 3T3-L1 adipocytes of these compounds were breakaway of the Akt signaling pathway. Moreover, crushing of glucose transport was as hale noticed in other cell types such as human erythrocytes that are rich in GLUT1 and T-47D embrace cancer cells, proposing that these effects are not specific to GLUT4, and that the Akt inhibitors affect glucose uptake in different cell types (3).Alternatively, the phosphatidylinositol 3-kinase (PI3K) signal transduction pathway is a well-known(a) mediator of cell growth, proliferatio n, and survival signals. Riley J. K. et al studied the Inhibition of the PI3K pathway, and results indicated that inhibition of this pathway cause an induction of apoptosis in both murine blastocysts and trophoblast stem cells. Moreover, the apoptosis induced correlates with a decrease in the grimace of the glucose transporter GLUT1 at the plasma membrane (6). Additionally, blastocysts cultured in the presence of the PI3K inhibitor LY-294002 exhibited a reduction in 2-deoxyglucose uptake and hexokinase activity.In rat primary winding brown adipocytes, insulin acutely stimulated glucose uptake in a PI3-kinase-dependent but p70S6-kinase-independent manner, and Akt represents an intermediate step between these kinases. Therefore, the goal of Hernandez R. et al study was to ask the contribution of Akt to insulin-induced glucose uptake in brown adipocytes victimisation ML-9, a belatedly proposed chemical inhibitor of Akt activity (7) and by using Akt protein with dominant-negative a ctivity to block (4). ML-9 preaching of primary brown adipocytes showed a complete inhibition of insulin-stimulated glucose uptake and also impaired GLUT4 redistribution from internal membrane to plasma membrane in answer to insulin. It was found that ML-9 inhibited Akt activity and Akt phosphorylation at Ser473. Furthermore, results showed that long-term treatment with ML-9 produced down-regulation of the GLUT4 messenger RNA accumulation, inactivation of Akt, and possibly its translocation to the nucleus (8). Co-transfection with Akt prevented insulin stimulation of GLUT4 promoter activity, suggesting that PI3-kinase/Akt pathway is regulation GLUT4 gene organisation by insulin (4).It is well known that phosphatidylinositol (PI)3-kinase activation mediates GLUT4 redistribution to the plasma membrane, and over thoughtfulness of the catalytic subunit of p110 produced GLUT4 translocation and increased glucose uptake (9). Alternatively, inhibition of PI3-kinase (by chemical inhibito rs or by microinjection of blocking p85 protein, or by transfection with a dominant-negative mutant of p85) prohibits insulin-induced GLUT4 translocation (10).deuce classes of Ser/Thr kinases have been suggested to act downstream of PI3-kinase, and they are Akt/PKB and the atypical protein kinase (PK) C isoforms and (PKC /). It well established that structure of a constitutively active, membrane-bound form of Akt cause a glum localization of GLUT4 at the plasma membrane and increased glucose uptake in 3T3-L1 adipocytes, yet, it did not promote GLUT4 translocation or glucose transport in L6 myotube(4, 11).Despite the concomitant proved by in vivo studies that GLUT4 expression in insulin-responsive tissues is under insulin and/or metabolic control (12), experiments performed with cultured fat cells had failed to establish a stimulatory role of insulin in GLUT4 expression (13), and the positive effect of insulin seen on GLUT4 gene expression had only been noticed in the presence o f dexamethasone (14). Nevertheless, rat cardiomyocytes showed a direct effect of insulin on GLUT4 transcription (15).Different studies have pass that insulin-stimulated glucose uptake is separated from GLUT4 translocation based on using phosphatidylinositol 3-kinase inhibitor wortmannin .Therefore, it can be concluded that GLUT4 translocation and the intrinsic activity of GLUT4 are differentially regulated.Insulin is known to activate p38MAPK, and using SB203580 p38MAPK and p38MAPK inhibitors reduce insulin- stimulated glucose uptake without affecting GLUT4 translocation. p38MAPKs are serine/threonine kinases that are activated by several factors such as environmental stressors, instigative cytokines, protein synthesis inhibitors, growth factors like insulin and muscle contraction. It has four isoforms p38 and p38 that are ubiquitously expressed, p38 that is super expressed in skeletal muscle and p38 in the lung and kidney (16). Full activation of p38MAPK necessitates dual phospho rylation on residues corresponding to threonine-180 and tyrosine-182 on p38 catalyzed by dual-specificity MAPK kinases 3 and 6 (MKK3 and 6).p38MAPK inhibitors like pyridinyl imidazole derivatives (SB203580 and SB202190) or azaazulene pharmacophores (A291077 and A304000) have the potential to inhibit insulin-mediated glucose uptake without producing any effect on GLUT4 translocation. As a conclusion, insulin increases the intrinsic activity of GLUT4 via p38MAPK (16).Antonescu, C. N. et al aimed to determine whether p38MAPK is required for insulin- stimulated glucose uptake in L6-GLUT4myc myotubes using a mutant of p38 (DR-p38) resistant to SB203580, dominant-inhibitory mutants of p38 and p38 and siRNA against p38 and p38. The results obtained by these independent molecular methods to interfere with p38MAPK signaling did not interfere with stimulated glucose uptake. Nonetheless, SB220025 was found to inhibit p38MAPK as strongly as SB203580, but again, had no effect on insulin stimulat ed glucose uptake. So, collectively, it can anticipated that p38MAPK is not involved in insulin-stimulated glucose uptake and that the SB203580-mediated reduction in glucose uptake is a result of SB203580 action on another(prenominal) protein (16).References1. Liu LZ, Cheung SC, Lan LL, Ho SK, Chan JC, Tong PC. The pivotal role of protein kinase C zeta (PKCzeta) in insulin- and AMP-activated protein kinase (AMPK)-mediated glucose uptake in muscle cells. Cellular signalling. 201022(10)1513-22. Epub 2010/06/24.2. Braiman L, Alt A, Kuroki T, Ohba M, Bak A, Tennenbaum T, et al. Activation of protein kinase C zeta induces serine phosphorylation of VAMP2 in the GLUT4 compartment and increases glucose transport in skeletal muscle. molecular and cellular biology. 200121(22)7852-61. Epub 2001/10/18.3. Tan SX, Ng Y, James DE. 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