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transporter
kecurian
Last Update: 2020-02-11
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ground transporter truck
lori pengangkut tanah
Last Update: 2022-11-28
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ace2 also regulates the membrane trafficking of the neutral amino acid transporter slc6a19 and has been implicated in hartnup's disease.
ace2 juga mengawal selia pengedaran membran pengangkut asid amino neutral slc6a19 dan ditunjukkan dalam penyakit hartnup.
Last Update: 2020-08-25
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ace2 protein contains an n-terminal peptidase m2 domain and a c-terminal collectrin renal amino acid transporter domain.
protein ace2 mengandungi domain m2 peptidase n-terminal dan domain pengangkut asid amino renal kolektrin c-terminal.
Last Update: 2020-08-25
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insulin receptors and insulin binding insulin mediates its actions through binding to insulin receptors. the insulin receptor was fi rst characterised in 1971. it consists of a heterotetramer consisting of 2 α and 2 β glycoprotein subunits linked by disulphide bonds and is located on the cell membrane.25 the gene coding for the insulin receptor is located on the short arm of chromosome 19.17 insulin binds to the extracellular α subunit, resulting in conformational change enabling atp to bind to the intracellular component of the β subunit.23 atp binding in turn triggers phosphorylation of the β subunit conferring tyrosine kinase activity. this enables tyrosine phosphorylation of intracellular substrate proteins known as insulin responsive substrates (irs). the irs can then bind other signalling molecules which mediate further cellular actions of insulin.25 there are four known specifi cally-named irs proteins. irs 1 and 2 have widely overlapping tissue distribution. irs 1 is phosphorylated by both the insulin receptor and insulinlike growth factor 1 (igf-1 see below) receptor, mediates the mitogenic effects of insulin and couples glucose sensing to insulin secretion with irs 1 proposed to be the major irs in skeletal muscle. irs 2, proposed to be the main irs in liver, mediates peripheral actions of insulin and growth of pancreatic β cells.25 irs 3 and 4 are less well characterised. irs 3 is found only in adipose tissue, β cells and liver and irs 4 in thymus, brain and kidney.26,27 phosphorylated irs proteins bind specifi c src-homology-2 domain proteins (sh2), which include important enzymes such as phosphatidylinositol 3-kinase (pi 3-kinase) and phosphotyrosine phosphatase shptp2 (or syp), and other proteins that lack enzymatic activity but which link irs-1 and other intracellular signalling systems, e.g. the adaptor protein grb2 which connects with the ras (rat sarcoma protein) pathway. pi 3-kinase promotes the translocation of glucose transporter proteins, glycogen, lipid and protein synthesis, anti-lipolysis and the control of hepatic gluconeogenesis.27 pi 3-kinase acts via serine and threonine kinases such as akt/protein kinase b (pkb), protein kinase c (pkc) and pi dependent protein kinases1& 2 (pipd 1&2). the ras pathway activates transcription factors and stimulates the growth promoting actions of insulin.25 thus broadly, pi 3-kinase mediates insulin’s metabolic effects, e.g. cellular glucose uptake, while ras signifi cantly mediates insulin’s mitogenic effects17,25 clin biochem rev vol 26 may 2005 i 23 insulin and insulin resistance together with other less well described actions. these pathways are presented schematically in figure 2. glucose transporter proteins glucose enters cells in an atp-independent manner by means of glucose transporter proteins (glut), of which at least 5 subtypes have been identifi ed28,29 (table 2). differing in characteristics such as km for maximal glucose transport and insulin dependency, they enable different cell types to utilise glucose according to their specifi c functions. for example, most brain cells, having glut 1 as the principal transporter protein, are able to move glucose intracellularly at very low blood glucose blood concentrations without the need for insulin. thus these neurons, which are principally dependent on glucose for intracellular energy, are able to extract it from the circulation and function despite the low glucose and insulin levels seen during the fasting state. on the other hand, adipose cells and muscle cells have glut 4 as the major glucose transporter protein, which requires insulin for its action and has a much higher km for glucose. this enables adipose tissue cells, whose function is to store excess energy, to respond to the higher glucose levels characteristic of the fed state, and allows glucose to enter the cells where fatty acid and glycerol synthesis is stimulated and lipolysis suppressed. however, where glucose and insulin levels fall to fasting values, glucose no longer enters the cells, promoting lipolysis. in muscle cells, intracellular glucose transport facilitates glycogen synthesis in the fed state.27 pi 3-kinase appears to be essential for the translocation of glut 4 to the cell membrane in muscle cells and adipocytes; this facilitates the downstream actions of this key intracellular enzyme.25 actions of insulin at the cellular level insulin’s actions at the cellular level encompass carbohydrate, lipid and amino acid metabolism and mrna transcription and translation. carbohydrate metabolism insulin acts at multiple steps in carbohydrate metabolism. its effect on facilitated diffusion of glucose into fat and muscle cells via modulation of glut 4 translocation has been discussed. glycogen synthesis is increased, and glycogen breakdown decreased, by dephosphorylation of glycogen synthase and glycogen phosphorylase kinase respectively. glycolysis is stimulated and gluconeogenesis inhibited by dephosphorylation of pyruvate kinase (pk) and 2,6 biphosphate kinase. signalling intracellular energy abundance, insulin enhances the irreversible conversion of pyruvate to 24 i clin biochem rev vol 26 may 2005 wilcox g table 1. mediators of insulin secretion. stimulus nutrient hormone neural stimulatory glucose growth hormone β-adrenergic amino acids glucagon vagal (ketones) glp-1 (parasympathetic) gip secretin cholecystokinin gastrin vip gastrin releasing peptide inhibitory adrenocorticosteroids α-adrenergic somatostatin adrenalin noradrenalin galanin neuropeptide y calcitonin gene-related peptide (cgrp) prostaglandin e reference: adapted from reference 17. acetyl co-a by activation of the intra-mitochondrial enzyme complex pyruvate dehydrogenase. acetyl-coa may then be directly oxidised via the krebs’ cycle, or used for fatty acid synthesis.30 lipid metabolism insulin stimulates fatty acid synthesis in adipose tissue, liver and lactating mammary glands along with formation and storage of triglycerides in adipose tissue and liver. fatty acid synthesis is increased by activation and increased phosphorylation of acetyl-coa carboxylase, while fat oxidation is suppressed by inhibition of carnitine acyltransferase. triglyceride synthesis is stimulated by esterifi cation of glycerol phosphate, while triglyceride breakdown is suppressed by dephosphorylation of hormone sensitive lipase. cholesterol synthesis is increased by activation and dephosphorylation of hmg co-a reductase while cholesterol ester breakdown appears to be inhibited by dephosphorylation of cholesterol esterase. phospholipid metabolism is also infl uenced by insulin.28 protein synthesis insulin promotes protein synthesis in a range of tissues. there are effects on transcription of specifi c mrna, as well as translation of mrna into proteins in the ribosomes. examples of enhanced mrna transcription include the mrna for glucokinase, pk, fatty acid synthase and albumin in the liver, pyruvate carboxylase in the adipose tissue, casein in the mammary gland and amylase in the pancreas. insulin action decreases mrna for liver enzymes such as carbamoyl phosphate synthetase, a key enzyme in the urea cycle. effects on translation are widespread and infl uenced by both insulin itself and by various growth factors, e.g. igf-1.19,28 other ligands for the insulin receptor insulin-like growth factors (igf) are so-called because they have signifi cant structural homology with proinsulin but mainly mitogenic effects, signifi cantly regulated by growth hormone.31 igf-1 and 2 are coded for on the long arm of chromosome 12 and short arm of chromosome 11 respectively.32 they have specifi c receptors and bind with clin biochem rev vol 26 may 2005 i 25 insulin and insulin resistance figure 2. schematic presentation of insulin signalling pathways. adapted from references: 25, 28 & 35. see footnotes on page 22 for figure abbreviations. different affi nities to the various igf binding proteins. insulin can bind to the receptors for igf-1 and 2 but with much lower affi nity (10-2 and 5x10-3) respectively. igf-1 binds weakly to the insulin receptor, with only 1.25x10-3 the affi nity for the igf-1 receptor; it binds the igf-2 receptor with 1/4 the affi nity for the igf-2 receptor. igf-2 does not bind to the insulin receptor; it does bind the igf-1 receptor but with 1/3 the affi nity for the igf-2 receptor.29 therefore overlap in physiological functions is more limited in vivo. physiological role of insulin insulin is the pivotal hormone regulating cellular energy supply and macronutrient balance, directing anabolic processes of the fed state.27 insulin is essential for the intra-cellular transport of glucose into insulin-dependent tissues such as muscle and adipose tissue. signalling abundance of exogenous energy, adipose tissue fat breakdown is suppressed and its synthesis promoted. in muscle cells, glucose entry enables glycogen to be synthesised and stored, and for carbohydrates, rather than fatty acids (or amino acids) to be utilised as the immediately available energy source for muscle contraction. insulin therefore promotes glycogen and lipid synthesis in muscle cells, while suppressing lipolysis and gluconeogenesis from muscle amino acids. in the presence of an adequate supply of amino acids, insulin is anabolic in muscle.29 mechanisms of insulin resistance physiologically, at the whole body level, the actions of insulin are infl uenced by the interplay of other hormones. insulin, though the dominant hormone driving metabolic processes in the fed state, acts in concert with growth hormone and igf1; growth hormone is secreted in response to insulin, among other stimuli, preventing insulin-induced hypoglycaemia. other counter-regulatory hormones include glucagon, glucocorticoids and catecholamines. these hormones drive metabolic processes in the fasting state. glucagon promotes glycogenolysis, gluconeogenesis and ketogenesis. the ratio of insulin to glucagon determines the degree of phosphorylation or dephosphorylation of the relevant enzymes.29 catecholamines promote lipolysis and glycogenolysis; glucocorticoids promote muscle catabolism, gluconeogenesis and lipolysis. excess secretion of these hormones may contribute to insulin resistance in particular settings, but does not account for the vast majority of insulin resistant states. 26 i clin biochem rev vol 26 may 2005 wilcox g table 2. glucose transporter proteins.26,27 isoform tissue distribution affi nity for glucose km characteristics gene location glut 1 brain microvessels, red blood cells placenta kidney all tissues high 1 mmol/l ubiquitous basal transporter chr 1 glut 2 liver kidney β cell small intestine low 15-20 mmol/l high km transporter insulin-independent chr 3 glut 3 brain neurons placenta foetal muscle all tissues high <1 mmol/l low km transporter found in glucosedependent tissues chr 12 glut 4 muscle cells fat cells heart medium 2.5-5 mmol/l sequestered intracellularly and translocates to cell surface in response to insulin chr 17 glut 5 small intestine testes medium 6 mmol/l high affi nity for fructose chr 1 insulin resistance in most cases is believed to be manifest at the cellular level via post-receptor defects in insulin signalling. despite promising fi ndings in experimental animals with respect to a range of insulin signalling defects, their relevance to human insulin resistance is presently unclear. possible mechanisms include down-regulation, defi ciencies or genetic polymorphisms of tyrosine phosphorylation of the insulin receptor, irs proteins or pip-3 kinase, or may involve abnormalities of glut 4 function.33 sites of insulin action and manifestations of insulin resistance the effects of insulin, insulin defi ciency and insulin resistance vary according to the physiological function of the tissues and organs concerned, and their dependence on insulin for metabolic processes. those tissues defi ned as insulin dependent, based on intracellular glucose transport, are principally adipose tissue and muscle. however, insulin’s actions are pleotropic and widespread, as are the manifestations of insulin resistance and the associated compensatory hyperinsulinaemia.3 muscle glucose uptake into muscle is essentially insulin dependent via glut 4, and muscle accounts for about 60-70% of whole-body insulin mediated uptake.34 in the fed state insulin promotes glycogen synthesis via activation of glycogen synthase. this enables energy to be released anaerobically via glycolysis, e.g. during intense muscular activity. muscle cells do not rely on glucose (or glycogen) for energy during the basal state, when insulin levels are low. insulin suppresses protein catabolism while insulin defi ciency promotes it, releasing amino acids for gluconeogenesis. in starvation, protein synthesis is reduced by 50%.35 whilst data regarding a direct anabolic effect of insulin are inconsistent, it is clearly permissive, modulating the phosphorylation status of intermediates in the protein synthetic pathway. in experimental studies, the insulin dose promoting protein synthesis is signifi cantly greater than the dose required to suppress proteolysis. insulin is anabolic in conjunction with growth hormone, igf-1 and suffi cient amino acids.35 in insulin resistance, muscle glycogen synthesis is impaired; this appears largely mediated by reduced intracellular glucose translocation.28 in regard to protein turnover, one study reported no difference between insulin resistant type 2 diabetics and controls, though this was at the expense of hyperinsulinaemia in this hyperinsulinemic euglycemic clamp study.36 adipose tissue intracellular glucose transport into adipocytes in the postprandial state is insulin-dependent via glut 4; it is estimated that adipose tissue accounts for about 10% of insulin stimulated whole body glucose uptake.34 insulin stimulates glucose uptake, promotes lipogenesis while suppressing lipolysis, and hence free fatty acid fl ux into the bloodstream. as adipocytes are not dependent on glucose in the basal state, intracellular energy may be supplied by fatty acid oxidation in insulin-defi cient states, whilst liberating free fatty acids into the circulation for direct utilization by other organs e.g. the heart, or in the liver where they are converted to ketone bodies. ketone bodies provide an alternative energy substrate for the brain during prolonged starvation.30 in insulin resistance the effects on adipose tissue are similar, but in the liver the increased free fatty acid fl ux tends to promote hepatic very low density lipoprotein (vldl) production37 whilst ketogenesis typically remains suppressed by the compensatory hyperinsulinaemia. furthermore, since lipoprotein lipase activity is insulin-dependent and impaired by insulin resistance, peripheral uptake of triglycerides from vldl is also diminished. these mechanisms contribute to the observed hypertriglyceridaemia of insulin resistance.38 in addition to free fatty acids, adipose tissue secretes a number of cytokines which have systemic effects on insulin resistance. these include il-6, tnfα, plasminogen activator inhibitor 1 (pai-1), angiotensinogen and leptin which are associated with increased insulin resistance, and adiponectin with reduced insulin resistance.39 tnfα and il-6 impair insulin signalling, lipolysis and endothelial function. il-6 production is enhanced by sympathetic nervous system activation, e.g. stress.39 adipose tissue depots differ in their response to insulin.35 adipocytes from diabetic and insulin resistant individuals have reduced glut 4 translocation, impaired intracellular signalling via reduced irs-1 gene and protein expression, impaired insulin-stimulated pip-3 kinase and akt (protein kinase b).34 liver while glucose uptake into the liver is not insulin-dependent, it accounts for about 30% of whole body insulin-mediated glucose disposal,34 with insulin being needed to facilitate key metabolic processes. through intracellular signalling described above, glycogen synthesis is stimulated while protein synthesis and lipoprotein metabolism are modulated.30 gluconeogenesis and ketone body production are inhibited. mitogenic effects of insulin (and growth hormone) are mediated via hepatic production of insulin-like growth factors and potentially via suppression of sex-hormone binding globulin (shbg) production.28 whilst in insulin defi ciency, e.g. starvation, these processes are more uniformly affected, this is not necessarily the case with insulin resistance. compensatory hyperinsulinaemia, differential insulin resistance and differential tissue requirements may dissociate these processes.3 resistance to clin biochem rev vol 26 may 2005 i 27 insulin and insulin resistance insulin’s metabolic effects results in increased glucose output via increased gluconeogenesis (as in starvation), however, unlike starvation, compensatory hyperinsulinaemia depresses shbg production and promotes insulin’s mitogenic effects. alterations in lipoprotein metabolism represent a major hepatic manifestation of insulin resistance. increased free fatty acid delivery, and reduced vldl catabolism by insulin resistant adipocytes, results in increased hepatic triglyceride content and vldl secretion.38 hepatic synthesis of creactive protein, fi brinogen and pai-1 is induced in response to adipocyte-derived pro-infl ammatory cytokines such as tnfα and il-6. insulin may also increase factor vii gene expression.39 endothelium and vasculature insulin and its actions play an important role in various aspects of endothelial function, e.g. nitric oxide production, while insulin resistance is strongly associated with endothelial dysfunction. whether these associations are causal, or mediated by common mechanisms, awaits clarifi cation. the functions of vascular endothelial cells are critical to many aspects of cardiovascular biology, with endothelial dysfunction being seen at a very early stage of atherosclerosis and its associated clinical risk factors. endothelial cells not only provide the physical lining of the blood vessels but secrete various factors infl uencing vessel tone, platelet function, coagulation and fi brinolysis. clinical problems develop when these processes are in imbalance. nitric oxide (no) is the major factor in large arteries mediating endothelial dependent relaxation. it also inhibits platelet aggregation, cell adhesion and smooth muscle cell proliferation. no is synthesised from l-arginine, molecular oxygen and nadph, via the activity of endothelial enzyme nitric oxide synthase (enos), and its cofactors tetrahydrobiopterin, fl avin adenine dinucleotide and fl avin mononucleotide. interestingly, arginine is a potent secretatogue for insulin and there is a fi nal common pathway for the intracellular signalling of both enos and insulin. insulin enhances tetrahydrobiopterin production by stimulating its biosynthetic enzyme gtp cyclohydrolase, and stimulates enos by calcium-independent phosphorylation of enos at serine and threonine residues via pip-3 kinase and akt (protein kinase b). thus nitric oxide production is enhanced. insulin also promotes release of the vasoconstrictor endothelin while tnfα decreases enos expression and induces von willebrand factor release. in insulin resistance tetrahydrobiopterin levels are reduced, the pathways for enos stimulation are downregulated, and vasodilator responses to insulin and cholinergic agonists are impaired. insulin’s ability to counteract the tnfαmediated akt dephosphorylation in endothelial cells is also lost. free fatty acids, elevated in insulin resistant states, also inhibit enos activity, decreasing no production. the compensatory hyperinsulinaemia that accompanies insulin resistance is associated with increased levels of procoagulant factors such as pai-1. these factors are thought to contribute to the enhanced platelet aggregation seen in insulin resistant states. endothelin 1 secret
Last Update: 2021-04-26
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