Glucose Transporter 4 (GLUT4) and Diabetes

Glucose Transporter 4 (GLUT4) and Diabetes Insulin and AMP-activated 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 (1). Insulin stimulates glucose uptake into skeletal muscle mainly via the translocation of glucose transporter 4 (GLUT4) to the plasma membrane (2). Also the exact 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 uptake or translocation of surface glucose transporter 4 (GLUT4).Using specific inhibitors to key kinases of both pathways and PKCzeta small interference RNA, it was found that protein kinase C zeta (PKCzeta) regulate insulin-stimulated protein kinase B (PKB) activation and inhibit AMPK activity on dorsal cell surface, whereas in the presence of berberine, PKCzeta controlled AMPK activation and AMPK blocked PKB activity in perinuclear region. The inhibitory effect exerted by PKCzeta on AMPK activation or the arrestment of PKB activity by AMPK still existed in basal condition. Overall, these results are suggestive for an antagonistic regulation between insulin and AMPK signal pathways, which is mediated by the switch roles of PKCzeta. The protein kinase Akt is associated with different cellular processes, including cell proliferation, growth, metabolism and importantly, insulin-regulated transport of glucose into muscle 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 generation of PtdIns(3,4,5)P3. This in turn enables the translocation of Akt to the plasma 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. Once activated, Akt phosphorylates a range of substrates that regulate a variety of key biological 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 link ed to Type 2 diabetes (3). Akt has been involved in the insulin-induced expression 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 Tan S. X. study that non-ATP-competitive allosteric Akt inhibitors in 3T3-L1 adipocytes caused a decrease in the Akt signaling pathway simultaneously with reduced glucose uptake, notwithstanding, no such reduction in GLUT4 translocation to the plasma membrane was seen. This is explained by the fact 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 investigation revealed that the inhibitory effects on glucose uptake in 3T3-L1 adipocytes of these compounds were independent of the Akt signaling pathway. Moreover, inhibition of glucose transport was also noticed in other cell types such as hum an erythrocytes that are rich in GLUT1 and T-47D breast 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 mediator of cell growth, proliferation, 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 expression 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 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 investigate the contribution of Akt to insulin-induced glucose uptake in brown adipocytes using ML-9, a recently proposed chemical inhibitor of Akt activity (7) and by using Akt protein with dominant-negative activity to block (4). ML-9 treatment 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 response 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 mRNA accumulation, inactivation of Akt, and possibly its translocation to the nucleus (8). Co-transfection with à Ã‚ ªAkt prevented insulin stimulation of GLUT4 promoter activity, suggesting that PI3-kinase/Akt pathway is regulating GLUT4 gene transcription by insulin (4). It is well known that phosphatidylinositol (PI)3-kinase activation mediates GLUT4 redistribution to the plasma membrane, and overexpression of the catalytic subunit of p110 produced GLUT4 translocation and increased glucose uptake (9). Alternatively, inhibition of PI3-kinase (by chemical inhibitors or by microinjection of blocking p85 protein, or by transfection with a dominant-negative mutant of p85) prohibits insulin-induced GLUT4 translocation (10). Two 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 ÃŽ ¶ and ÃŽ » (PKC ÃŽ ¶/ÃŽ »). It well established that expression of a constitutively active, membrane-bound form of Akt cause a persistent 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 fact 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 of dexamethasone (14). Nevertheless, rat cardiomyocytes showed a direct effect of insulin on GLUT4 transcription (15). Different studies have validated 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; p38MAPKÃŽ ± and p38MAPKÃŽ ² 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, inflammatory cytokines, protein synthesis inhibitors, growth factors like insulin and muscle contraction. It has four isoforms; p38ÃŽ ± and p38ÃŽ ² that are ubiquitously expressed, p38ÃŽ ³ that is highly expressed in skeletal muscle and p38ÃŽ ´ in the lung and kidney (16). Full activation of p38MAPK necessitates dual phosphorylation on residues corresponding to threonine-180 and tyrosine-182 on p38ÃŽ ± 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 p38ÃŽ ± (DR-p38ÃŽ ±) resistant to SB203580, dominant-inhibitory mutants of p38ÃŽ ± and p38ÃŽ ² and siRNA against p38ÃŽ ± and p38ÃŽ ². 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 stimulated 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 protein (16). References 1. 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. 2010;22(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. 2001;21(22):7852-61. Epub 2001/10/18. 3. Tan SX, Ng Y, James DE. Akt inhibitors reduce glucose uptake independently of their effects on Akt. The Biochemical journal. 2010;432(1):191-7. Epub 2010/09/08. 4. Hernandez R, Teruel T, Lorenzo M. Akt mediates insulin induction of glucose uptake and up-regulation of GLUT4 gene expression in brown adipocytes. FEBS letters. 2001;494(3):225-31. Epub 2001/04/20. 5. Ng Y, Ramm G, Burchfield JG, Coster AC, Stockli J, James DE. Cluster analysis of insulin action in adipocytes reveals a key role for Akt at the plasma membrane. The Journal of biological chemistry. 2010;285(4):2245-57. Epub 2009/11/10. 6. Riley JK, Carayannopoulos MO, Wyman AH, Chi M, Moley KH. Phosphatidylinositol 3-kinase activity is critical for glucose metabolism and embryo survival in murine blastocysts. The Journal of biological chemistry. 2006;281(9):6010-9. Epub 2005/11/08. 7. Smith U, Carvalho E, Mosialou E, Beguinot F, Formisano P, Rondinone C. PKB inhibition prevents the stimulatory effect of insulin on glucose transport and protein translocation but not the antilipolytic effect in rat adipocytes. Biochemical and biophysical research communications. 2000;268(2):315-20. Epub 2000/02/19. 8. Salinas M, Lopez-Valdaliso R, Martin D, Alvarez A, Cuadrado A. Inhibition of PKB/Akt1 by C2-ceramide involves activation of ceramide-activated protein phosphatase in PC12 cells. Molecular and cellular neurosciences. 2000;15(2):156-69. Epub 2000/02/16. 9. Martin SS, Haruta T, Morris AJ, Klippel A, Williams LT, Olefsky JM. Activated phosphatidylinositol 3-kinase is sufficient to mediate actin rearrangement and GLUT4 translocation in 3T3-L1 adipocytes. The Journal of biological chemistry. 1996;271(30):17605-8. Epub 1996/07/26. 10. Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J, Kahn CR. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Molecular and cellular biology. 1994;14(7):4902-11. Epub 1994/07/01. 11. Kohn AD, Summers SA, Birnbaum MJ, Roth RA. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. The Journal of biological chemistry. 1996;271(49):31372-8. Epub 1996/12/06. 12. Berger J, Biswas C, Vicario PP, Strout HV, Saperstein R, Pilch PF. Decreased expression of the insulin-responsive glucose transporter in diabetes and fasting. Nature. 1989;340(6228):70-2. Epub 1989/07/06. 13. Flores-Riveros JR, McLenithan JC, Ezaki O, Lane MD. Insulin down-regulates expression of the insulin-responsive glucose transporter (GLUT4) gene: effects on transcription and mRNA turnover. Proceedings of the National Academy of Sciences of the United States of America. 1993;90(2):512-6. Epub 1993/01/15. 14. Hajduch E, Hainault I, Meunier C, Jardel C, Hainque B, Guerre-Millo M, et al. Regulation of glucose transporters in cultured rat adipocytes: synergistic effect of insulin and dexamethasone on GLUT4 gene expression through promoter activation. Endocrinology. 1995;136(11):4782-9. Epub 1995/11/01. 15. Petersen S, Bahr M, Eckel J. Insulin-dependent regulation of Glut4 gene expression in ventricular cardiomyocytes: evidence for a direct effect on Glut4 transcription. Biochemical and biophysical research communications. 1995;213(2):533-40. Epub 1995/08/15. 16. Antonescu CN, Huang C, Niu W, Liu Z, Eyers PA, Heidenreich KA, et al. Reduction of insulin-stimulated glucose uptake in L6 myotubes by the protein kinase inhibitor SB203580 is independent of p38MAPK activity. Endocrinology. 2005;146(9):3773-81. Epub 2005/06/11.

Prison Term Policy Recommendation Essay

Abstract The purpose of this paper is to advise members of the state legislature with recommendations for new prison term policies to double the maximum prison term for any individual convicted of armed robbery. Although the state legislature concedes the bill is popular the concern is whether the bill will deter arm robberies. Prison Term Policy Recommendation In a few days the state legislature will be voting on a new bill to determine if the maximum prison term for anyone convicted of armed robbery should affect anyone convicted of armed robbery be given a double maximum sentence. However, the effectiveness of double prison sentences as deterrence to first time and re-offenders is quite difficult to estimate. Many states define robbery as larceny or theft of money or property through the use of intimidation, physical force, or violence against a victim by the offender(s). When a weapon is used or the victim suffers injury, whereby the offender may be charged as aggravated or armed robbery. Robbery is differentiated between armed robbery that involves the use of some type of weapon, and aggravated robbery that involves the use of a deadly weapon. Armed robbery is one of the most committed crimes in the United States that concerns legislatures, the entire criminal justice system, and society. All states punish armed robbery as a major or capital offense, whereas sentencing depending on many factors such as state laws and procedures, prior criminal history, whether there are any sentencing improvements, or whether the state has a diversion program. For example a person (victim) is walking down the street a man (the robber) approaches and ask for the time when the victim looks at his watch and looks back up the robber has a gun in the victims face demanding money if the victim fails to give the robber his or her money the robber may shoot or hit the victim with the gun to obtain the money. In the early 1990s, legislation of many states (with the exception of Michigan) enacted mandatory sentencing for repeat offenders. These laws became known as the three strikes laws, were invoked when an offender committed his or her third offense. The three strike law requires the courts to hand down an extended mandatory sentence of confinement. The belief behind the three strikes law was to target repeat or career offenders who repeatedly commit felonies posing a serious threat to society. Under the new law by 2001 California had more than 50,000 offenders sentenced than any other state with one fourth facing a minimum of 25 years in prison. Although critics, maintained that these sentences are disproportionate to the crime perpetrated and would increase correctional costs, in March 2003 the United States Supreme Court rejected the argument of cruel and unusual punishment and upheld the three strikes laws. Michigan’s prisons population since 1973 has grown 474% faster than other states. In 1998 the Michigan legislatures enacted the Truth-in-Sentencing law, to be tougher on crime. During this time the violent crime rate in Michigan did not decrease and has continued to grow, and has spent more on correctional facilities than any of its surrounding states.

What Does Term Paper Custom Mean?

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Comparing The Strange Case Of Dr. Jekyll And Mr. Hyde

Comparative Task Comparing ‘The Strange Case Of Dr. Jekyll And Mr. Hyde’ And ‘Frankenstein’ When comparing the similarities and differences between Mary Shelley’s story of ‘Frankenstein’ and Robert Louis Stevenson’s story of ‘The Strange Case Of Dr. Jekyll And Mr. Hyde’, it was found that although the characters in both stories suffer an unhealthy obsession/addiction to their scientific work and even though both Frankenstein and Dr. Jekyll had good intentions for their creations, the outcome of the Monster and Mr. Hyde were practically opposites of one another. The characters in both ‘Frankenstein’ and ‘The Strange Case Of Dr. Jekyll And Mr. Hyde’ suffer an unhealthy obsession/addiction to their scientific work and revenge. In Stevenson’s story of ‘The Strange Case Of Dr. Jekyll And Mr. Hyde’, the character Dr. Jekyll is dominated by his narcotic and relentless need to settle his unhealthy craving for larger quantities of the potion which turns him into the evil and cruel Mr. Hyde. The main protagonist states his fail when he says â€Å"†¦and it was as an ordinary secret sinner that I at last fell before the assaults of temptation.† Throughout the novel and movies produced, there are detailed events in which Mr. Hyde is portrayed as a raving addict. Dr. Jekyll not greeting his friend Utterson, showed the audience that Dr. Jekyll’s lack of the substance sent him spiralling into a sort of depression and ‘down’ period. Like any drug or alcohol addicted person, this w as due to hisShow MoreRelatedDr. Jekyll And Mr. Hyde Case Study1621 Words   |  7 Pages1 Inner Demons Although Dr. Jekyll struggled with the noticeable inner demon that was Mr. Hyde, many tend to overlook the true inner demon that initially provoked Dr. Jekyll to create the potion which ultimately lead to his downfall. In Stevenson’s The Strange Case of Dr. Jekyll and Mr. Hyde, Henry Jekyll was not satisfied with his life, even though he had everything he could ever ask for, and this is when his inner demon took over as he stated, â€Å"Hence it came about that I concealed my pleasures;Read More The Gothic Novel Dr. Jekyll and Mr. Hyde Essay examples1403 Words   |  6 PagesTo what extent can The strange case of Dr Jekyll and Mr Hyde be viewed as a gothic novel? Jekyll and Hyde is a gothic novel. It was written by Robert Louis Stevenson, he got the idea for the story after a dream he had. The word ‘Goth’ is originally from a German tribe and has come to mean ‘barbarian’ and later know as ‘Gothic’. In Gothic Literature certain features are expected. These are supernatural events, have villains and hero characters, strange weather, horror, mystery and deathsRead MoreEssay on Dual Personalities in Dr. Jekyll and Mr. Hyde by Stevenson1313 Words   |  6 PagesDual Personalities in Dr. Jekyll and Mr. Hyde by Stevenson INTRO The Strange Case of Dr Jekyll and Mr Hyde is a classic mystery story, enticing to all audiences merely upon it’s suspense alone. When Stevenson first wrote the story (after recalling a dream he had) he had only the intentions of writing such an entertaining tale. Yet at the suggestion of his wife, he decided to revamp the mystery to comment on the dual nature of man and of society in general. I believe that Stevenson is suggestingRead More Personality and the Beast Within in The Strange Case of Dr. Jekyll and Mr. Hyde981 Words   |  4 PagesPersonality and the Beast Within in The Strange Case of Dr. Jekyll and Mr. Hyde Everyone has a dual personality, two sides, good and evil. Robert Louis Stephenson uses the book to explain this, he wanted people to realise that not only Dr Jekyll carries a double personality, but the other characters in the book too. Also the people reading it must see that they too, are a part of this frightening uncontrollable fact, that there is â€Å"the beast within† us all. Stephenson suggests that allRead MoreComparing Human Nature in Macbeth and Dr Jekyll and Mr Hyde1596 Words   |  7 PagesDr Jekyll and Mr Hyde CA The strange case of Dr Jekyll and Mr Hyde was written in the Victorian Era by Robert Louis Stevenson, this novella dwells into the concept of the duality of human nature. The narrative is extremely fragmented structure due to the use of multiple narrators and through the use of mixed media, in the form of letters and accounts. The inconsistent structure conveys that of a gothic detective story; which were very popular in the Victorian era. Victorian London at the time wasRead MoreThe Strange Case Of Dr. Jekyll And Mr. Hyde1474 Words   |  6 Pagesinterpretation to their existence? In the Strange Case of Dr. Jekyll and Mr. Hyde, Hyde is without a doubt a monster. His appearance is strange, his behavior erratic, and his morals nonexistent. The respectable Dr. Jekyll morphs into Mr. Hyde by consuming an odd potion. In the form of Mr. Hyde, Dr. Jekyll fulfills the dark needs that he has. Yet, that is not really the reason that he appears to be scary to other people. Throughout the book many people describe Hyde as being deformed and creepy in a wayRead MoreHow Does Stevenson Portray the Duality of Man in the Opening Chapters of ‘the Strange Case of Dr. Jekyll and Mr. Hyde’?1845 Words   |  8 Pagesopening chapters of ‘The Strange Case of Dr. Jekyll and Mr. Hyde’? Stevenson writes ‘The Strange Case of Dr. Jekyll and Mr. Hyde’ with the intention of showing the reader the duality of man and explores this through the juxtaposition of Dr. Jekyll and Mr. Hyde. In this novella, Stevenson also uses the environment and setting of the story to represent the contrast between Dr. Jekyll and Mr. Hyde. In the opening chapters of ‘The Strange Case of Dr. Jekyll and Mr. Hyde’, the Soho area of VictorianRead MoreThe Strange Case Of Dr. Jekyll And Mr. Hyde1126 Words   |  5 Pagesbetween outer and inner worlds, between the rush of experience and the immobility of awareness†. Robert Louis Stevenson’s 1886 novel, The Strange Case of Dr. Jekyll and Mr. Hyde, brilliantly exemplifies the philosophical phenomenon that is the duality of human nature through the 2 main characters that coexist interdependently together, Henry Jekyll and Edward Hyde. According to Webster’s dictionary, the duplicity of human beings is based on the contradictory doubleness of thought, speech, or action;Read MoreDr. Jekyll And Mr. Hyde1887 Words   |  8 Pagesperson† when he consumes his particular poison. â€Å"Strange Case of Dr. Jekyll and Mr. Hyde† is the story of an addict whose inebriated self just happens to have a different name. It does not matter what the solution he drinks for his transformation is supposed to represent, whether alcohol, opium, heroin, or some other substance—he checks off every box for addictive and self destructive behavior. There can be no clearer interpretation of â€Å"Dr. Jekyll and Mr. Hyde† than that it is a polemic against the prevalentRead MoreA Comparison of Dr. Jekyll and Mr. Hyde and Fight Club3130 Words   |  13 PagesIntroduction The purpose of my essay is to compare and contrast the novel titled Fight Club, written by Chuck Palahniuk, and the story, dated back to the Victorian age, known as The Strange Case of Dr. Jekyll and Mr. Hyde, written by Robert Louis Stevenson. I will compare these two works by evaluating how these two authors represent the theme of dual/split personalities within a specific character found in within each of their respective stories. Each author portrays the idea of dual personalities