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1
Bevan, Paul. "Insulin signalling." Journal of Cell Science 114, no. 8 (January 1, 2001): 1429–30. http://dx.doi.org/10.1242/jcs.114.8.1429.
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Nystrom, Fredrik H., and Michael J. Quon. "Insulin Signalling." Cellular Signalling 11, no. 8 (August 1999): 563–74. http://dx.doi.org/10.1016/s0898-6568(99)00025-x.
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SHEPHERD, Peter R., Dominic J. WITHERS, and Kenneth SIDDLE. "Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling." Biochemical Journal 333, no. 3 (August 1, 1998): 471–90. http://dx.doi.org/10.1042/bj3330471.
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Insulin plays a key role in regulating a wide range of cellular processes. However, until recently little was known about the signalling pathways that are involved in linking the insulin receptor with downstream responses. It is now apparent that the activation of class 1a phosphoinositide 3-kinase (PI 3-kinase) is necessary and in some cases sufficient to elicit many of insulin's effects on glucose and lipid metabolism. The lipid products of PI 3-kinase act as both membrane anchors and allosteric regulators, serving to localize and activate downstream enzymes and their protein substrates. One of the major ways these lipid products of PI 3-kinase act in insulin signalling is by binding to pleckstrin homology (PH) domains of phosphoinositide-dependent protein kinase (PDK) and protein kinase B (PKB) and in the process regulating the phosphorylation of PKB by PDK. Using mechanisms such as this, PI 3-kinase is able to act as a molecular switch to regulate the activity of serine/threonine-specific kinase cascades important in mediating insulin's effects on endpoint responses.
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Persaud, Shanta J., Dany Muller, and Peter M. Jones. "Insulin signalling in islets." Biochemical Society Transactions 36, no. 3 (May 21, 2008): 290–93. http://dx.doi.org/10.1042/bst0360290.
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Studies in transgenic animals, rodent insulin-secreting cell lines and rodent islets suggest that insulin acts in an autocrine manner to regulate β-cell mass and gene expression. Very little is known about the in vitro roles played by insulin in human islets, and the regulatory role of insulin in protecting against β-cell apoptosis. We have identified mRNAs encoding IRs (insulin receptors) and downstream signalling elements in dissociated human islet β-cells by single-cell RT (reverse transcription)–PCR, and perifusion studies have indicated that insulin does not have an autocrine role to regulate insulin secretion from human islets, but activation of the closely related IGF-1 (insulin-like growth factor 1) receptors is linked to inhibition of insulin secretion. Knockdown of IR mRNA by siRNAs (small interfering RNAs) decreased IR protein expression without affecting IGF-1 receptor levels, and blocked glucose stimulation of preproinsulin gene expression. Similar results were obtained when human islet IRS (IR substrate)-2 was knocked down, whereas depletion of IRS-1 caused an increase in preproinsulin mRNA levels. Studies using the mouse MIN6 β-cell line indicated that glucose protected β-cells from undergoing apoptosis and that this was a consequence, at least in part, of insulin release in response to elevated glucose. IGF-1 also exerted anti-apoptotic effects. These data indicate that insulin can exert autocrine effects in human islets through receptors on β-cells. It protects β-cells against apoptosis and increases preproinsulin mRNA synthesis, but does not affect insulin secretion.
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Pathak, Himani, and Jishy Varghese. "Edem1 activity in the fat body regulates insulin signalling and metabolic homeostasis in Drosophila." Life Science Alliance 4, no. 8 (June 17, 2021): e202101079. http://dx.doi.org/10.26508/lsa.202101079.
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In Drosophila, nutrient status is sensed by the fat body, a functional homolog of mammalian liver and white adipocytes. The fat body conveys nutrient information to insulin-producing cells through humoral factors which regulate Drosophila insulin-like peptide levels and insulin signalling. Insulin signalling has pleiotropic functions, which include the management of growth and metabolic pathways. Here, we report that Edem1 (endoplasmic reticulum degradation–enhancing α-mannosidase–like protein 1), an endoplasmic reticulum–resident protein involved in protein quality control, acts in the fat body to regulate insulin signalling and thereby the metabolic status in Drosophila. Edem1 limits the fat body–derived Drosophila tumor necrosis factor-α Eiger activity on insulin-producing cells and maintains systemic insulin signalling in fed conditions. During food deprivation, edem1 gene expression levels drop, which aids in the reduction of systemic insulin signalling crucial for survival. Overall, we demonstrate that Edem1 plays a vital role in helping the organism to endure a fluctuating nutrient environment by managing insulin signalling and metabolic homeostasis.
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Villalobos-Labra, Roberto, Luis Silva, Mario Subiabre, Joaquín Araos, Rocío Salsoso, Bárbara Fuenzalida, Tamara Sáez, et al. "Akt/mTOR Role in Human Foetoplacental Vascular Insulin Resistance in Diseases of Pregnancy." Journal of Diabetes Research 2017 (2017): 1–13. http://dx.doi.org/10.1155/2017/5947859.
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Insulin resistance is characteristic of pregnancies where the mother shows metabolic alterations, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), or abnormal maternal conditions such as pregestational maternal obesity (PGMO). Insulin signalling includes activation of insulin receptor substrates 1 and 2 (IRS1/2) as well as Src homology 2 domain-containing transforming protein 1, leading to activation of 44 and 42 kDa mitogen-activated protein kinases and protein kinase B/Akt (Akt) signalling cascades in the human foetoplacental vasculature. PE, GDM, and PGMO are abnormal conditions coursing with reduced insulin signalling, but the possibility of the involvement of similar cell signalling mechanisms is not addressed. This review aimed to determine whether reduced insulin signalling in PE, GDM, and PGMO shares a common mechanism in the human foetoplacental vasculature. Insulin resistance in these pathological conditions results from reduced Akt activation mainly due to inhibition of IRS1/2, likely due to the increased activity of the mammalian target of rapamycin (mTOR) resulting from lower activity of adenosine monophosphate kinase. Thus, a defective signalling via Akt/mTOR in response to insulin is a central and common mechanism of insulin resistance in these diseases of pregnancy. In this review, we summarise the cell signalling mechanisms behind the insulin resistance state in PE, GDM, and PGMO focused in the Akt/mTOR signalling pathway in the human foetoplacental endothelium.
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Heinrichs, Arianne. "PTEN and insulin signalling." Trends in Molecular Medicine 7, no. 5 (May 2001): 200. http://dx.doi.org/10.1016/s1471-4914(01)02037-8.
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Lizcano, Jose M., and Dario R. Alessi. "The insulin signalling pathway." Current Biology 12, no. 7 (April 2002): R236—R238. http://dx.doi.org/10.1016/s0960-9822(02)00777-7.
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Buren, J., HX Liu, J. Lauritz, and JW Eriksson. "High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes: possible implications for insulin resistance in type 2 diabetes." European Journal of Endocrinology 148, no. 1 (January 1, 2003): 157–67. http://dx.doi.org/10.1530/eje.0.1480157.
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OBJECTIVE: The purpose of this study was to investigate the cellular effects of long-term exposure to high insulin and glucose levels on glucose transport and insulin signalling proteins. DESIGN AND METHODS: Rat adipocytes were cultured for 24 h in different glucose concentrations with 10(4) microU/ml of insulin or without insulin. After washing, (125)I-insulin binding, basal and acutely insulin-stimulated d-[(14)C]glucose uptake, and insulin signalling proteins and glucose transporter 4 (GLUT4) were assessed. RESULTS: High glucose (15 and 25 mmol/l) for 24 h induced a decrease in basal and insulin-stimulated glucose uptake compared with control cells incubated in low glucose (5 or 10 mmol/l). Twenty-four hours of insulin treatment decreased insulin binding capacity by approximately 40%, and shifted the dose-response curve for insulin's acute effect on glucose uptake 2- to 3-fold to the right. Twenty-four hours of insulin treatment reduced basal and insulin-stimulated glucose uptake only in the presence of high glucose (by approximately 30-50%). At high glucose, insulin receptor substrate-1 (IRS-1) expression was downregulated by approximately 20-50%, whereas IRS-2 was strongly upregulated by glucose levels of 10 mmol/l or more (by 100-400%). Insulin treatment amplified the suppression of IRS-1 when combined with high glucose and also IRS-2 expression was almost abolished. Twenty-four hours of treatment with high glucose or insulin, alone or in combination, shifted the dose-response curve for insulin's effect to acutely phosphorylate protein kinase B (PKB) to the right. Fifteen mmol/l glucose increased GLUT4 in cellular membranes (by approximately 140%) compared with 5 mmol/l but this was prevented by a high insulin concentration. CONCLUSIONS: Long-term exposure to high glucose per se decreases IRS-1 but increases IRS-2 content in rat adipocytes and it impairs glucose transport capacity. Treatment with high insulin downregulates insulin binding capacity and, when combined with high glucose, it produces a marked depletion of IRS-1 and -2 content together with an impaired sensitivity to insulin stimulation of PKB activity. These mechanisms may potentially contribute to insulin resistance in type 2 diabetes.
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Bergantin, Leandro B. "A Link Between Brain Insulin Resistance and Cognitive Dysfunctions: Targeting Ca2+/cAMP Signalling." Central Nervous System Agents in Medicinal Chemistry 20, no. 2 (September 29, 2020): 103–9. http://dx.doi.org/10.2174/1871524920666200129121232.
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Background: A correlation between cognitive dysfunctions and brain insulin resistance has been established by several clinical and experimental studies. Consistent data support that people diagnosed with brain insulin resistance, resulted from diabetes, have shown an increased risk of presenting cognitive dysfunctions, clinical signs of dementia and depression, then speculating a role of dysregulations related to insulin signalling in these diseases. Furthermore, it is currently discussed that Ca2+ signalling, and its dysregulations, may be a factor which could correlate with brain insulin resistance and cognitive dysfunctions. Objective: Following this, revealing this interplay between these diseases may provide novel insights into the pathogenesis of such diseases. Methods: Publications covering topics such as Ca2+ signalling, diabetes, depression and dementia (alone or combined) were collected by searching PubMed and EMBASE. Results: The controlling of both neurotransmitters/hormones release and neuronal death could be achieved through modulating Ca2+ and cAMP signalling pathways (Ca2+/cAMP signalling). Conclusion: Taking into account our previous reports on Ca2+/cAMP signalling, and considering a limited discussion in the literature on the role of Ca2+/cAMP signalling in the link between cognitive dysfunctions and brain insulin resistance, this article has comprehensively discussed the role of these signalling pathways in this link (between cognitive dysfunctions and brain insulin resistance).
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Ruiz-Alcaraz, Antonio J., Hui-Kang Liu, Daniel J. Cuthbertson, Edward J. Mcmanus, Simeen Akhtar, Christopher Lipina, Andrew D. Morris, John R. Petrie, Hari S. Hundal, and Calum Sutherland. "A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration." Biochemical Journal 392, no. 2 (November 22, 2005): 345–52. http://dx.doi.org/10.1042/bj20051194.
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Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM.
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Teleman, Aurelio A. "Molecular mechanisms of metabolic regulation by insulin in Drosophila." Biochemical Journal 425, no. 1 (December 14, 2009): 13–26. http://dx.doi.org/10.1042/bj20091181.
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The insulin signalling pathway is highly conserved from mammals to Drosophila. Insulin signalling in the fly, as in mammals, regulates a number of physiological functions, including carbohydrate and lipid metabolism, tissue growth and longevity. In the present review, I discuss the molecular mechanisms by which insulin signalling regulates metabolism in Drosophila, comparing and contrasting with the mammalian system. I discuss both the intracellular signalling network, as well as the communication between organs in the fly.
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Kang, Gideon Gatluak, Nidhish Francis, Rodney Hill, Daniel Waters, Christopher Blanchard, and Abishek Bommannan Santhakumar. "Dietary Polyphenols and Gene Expression in Molecular Pathways Associated with Type 2 Diabetes Mellitus: A Review." International Journal of Molecular Sciences 21, no. 1 (December 24, 2019): 140. http://dx.doi.org/10.3390/ijms21010140.
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Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder with various contributing factors including genetics, epigenetics, environment and lifestyle such as diet. The hallmarks of T2DM are insulin deficiency (also referred to as β-cell dysfunction) and insulin resistance. Robust evidence suggests that the major mechanism driving impaired β-cell function and insulin signalling is through the action of intracellular reactive oxygen species (ROS)-induced stress. Chronic high blood glucose (hyperglycaemia) and hyperlipidaemia appear to be the primary activators of these pathways. Reactive oxygen species can disrupt intracellular signalling pathways, thereby dysregulating the expression of genes associated with insulin secretion and signalling. Plant-based diets, containing phenolic compounds, have been shown to exhibit remedial benefits by ameliorating insulin secretion and insulin resistance. The literature also provides evidence that polyphenol-rich diets can modulate the expression of genes involved in insulin secretion, insulin signalling, and liver gluconeogenesis pathways. However, whether various polyphenols and phenolic compounds can target specific cellular signalling pathways involved in the pathogenesis of T2DM has not been elucidated. This review aims to evaluate the modulating effects of various polyphenols and phenolic compounds on genes involved in cellular signalling pathways (both in vitro and in vivo from human, animal and cell models) leading to the pathogenesis of T2DM.
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Jiang, G., and B. B. Zhang. "Modulation of insulin signalling by insulin sensitizers." Biochemical Society Transactions 33, no. 2 (April 1, 2005): 358–61. http://dx.doi.org/10.1042/bst0330358.
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Insulin resistance is a hallmark of Type II diabetes. It is well documented that insulin sensitizers such as peroxisome-proliferator-activated receptor γ agonists and aspirin improve insulin action in vivo. The detailed mechanisms by which the insulin sensitizers promote insulin signalling, however, are not completely understood and remain somewhat controversial. In the present review, we summarize our studies attempting to explore the molecular mechanisms underlying the effects of insulin sensitizers in cells and in animal models of insulin resistance. In 3T3-L1 adipocytes and/or in HEK-293 cells stably expressing recombinant IRS1 protein (insulin receptor substrate protein 1), the peroxisome-proliferator-activated receptor γ agonist rosiglitazone and aspirin promote insulin signalling by decreasing inhibitory IRS1 serine phosphorylation. Increased IRS1 Ser-307 phosphorylation and concomitant decreased insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation and Akt threonine phosphorylation were observed in adipose tissues of Zucker obese rats compared with lean control rats. Treatment with rosiglitazone for 24 and 48 h increased insulin signalling and decreased IRS1 Ser-307 phosphorylation concomitantly. Treatment of the Zucker obese rats with rosiglitazone for 24 h also reversed the high circulating levels of free fatty acids, which have been shown to correlate with increased IRS1 serine phosphorylation. Taken together, the results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal may be physiologically relevant to insulin sensitization in vivo.
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SHYMKO, Ronald M., Erik DUMONT, Pierre DE MEYTS, and Jacques E. DUMONT. "Timing-dependence of insulin-receptor mitogenic versus metabolic signalling: a plausible model based on coincidence of hormone and effector binding." Biochemical Journal 339, no. 3 (April 26, 1999): 675–83. http://dx.doi.org/10.1042/bj3390675.
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Mitogenic signalling through the insulin receptor is enhanced compared with metabolic signalling for insulin analogues having slower dissociation kinetics than insulin itself. A plausible explanation in molecular terms of this timing-dependent specificity is lacking. We show here that if signalling is transmitted through a single effector, binding coincidentally with hormone to the insulin receptor and whose association and dissociation kinetics are slow relative to the hormone dissociation rate, the resulting biological effect is predicted to be dependent on hormone-binding kinetics. However, known primary effector molecules associating with the insulin receptor bind and interact rapidly with the receptor, contrary to the assumptions of the single-effector model. A model with two effectors which must bind coincidentally with hormone for signalling to occur also gives the required dependence of signalling on hormone-binding kinetics, provided that at least one of the effectors has slow binding kinetics relative to hormone binding. In this case, the other effector can have rapid kinetics, which is consistent with the properties of the major known substrates of the insulin receptor, such as the insulin receptor substrate (IRS) molecules.
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Javed, Kiran, and Stephen J. Fairweather. "Amino acid transporters in the regulation of insulin secretion and signalling." Biochemical Society Transactions 47, no. 2 (April 1, 2019): 571–90. http://dx.doi.org/10.1042/bst20180250.
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Abstract Amino acids are increasingly recognised as modulators of nutrient disposal, including their role in regulating blood glucose through interactions with insulin signalling. More recently, cellular membrane transporters of amino acids have been shown to form a pivotal part of this regulation as they are primarily responsible for controlling cellular and circulating amino acid concentrations. The availability of amino acids regulated by transporters can amplify insulin secretion and modulate insulin signalling in various tissues. In addition, insulin itself can regulate the expression of numerous amino acid transporters. This review focuses on amino acid transporters linked to the regulation of insulin secretion and signalling with a focus on those of the small intestine, pancreatic β-islet cells and insulin-responsive tissues, liver and skeletal muscle. We summarise the role of the amino acid transporter B0AT1 (SLC6A19) and peptide transporter PEPT1 (SLC15A1) in the modulation of global insulin signalling via the liver-secreted hormone fibroblast growth factor 21 (FGF21). The role of vesicular vGLUT (SLC17) and mitochondrial SLC25 transporters in providing glutamate for the potentiation of insulin secretion is covered. We also survey the roles SNAT (SLC38) family and LAT1 (SLC7A5) amino acid transporters play in the regulation of and by insulin in numerous affective tissues. We hypothesise the small intestine amino acid transporter B0AT1 represents a crucial nexus between insulin, FGF21 and incretin hormone signalling pathways. The aim is to give an integrated overview of the important role amino acid transporters have been found to play in insulin-regulated nutrient signalling.
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Avenatti, R. C. "The intersection of inflammation, insulin resistance and ageing: implications for the study of molecular signalling pathways in horses." Comparative Exercise Physiology 8, no. 3-4 (January 1, 2012): 153–71. http://dx.doi.org/10.3920/cep12018.
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Inflammation-associated insulin resistance contributes to chronic disease in humans and other long-lived species, such as horses. Insulin resistance arises due to an imbalance among molecular signalling mediators in response to pro-inflammatory cytokines in the aged and obese. The mammalian heat shock protein response has received much attention as an avenue for attenuating inflammatory mediator signalling and for contributing to preservation and restoration of insulin signalling in metabolically important tissues. Data on heat shock proteins and inflammatory signalling mediators in untrained and aged horses are lacking, and horses represent an untapped resource for studying the mediator imbalance contributing to insulin resistance in a comparative model.
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Shepherd, P. R., B. T. Navé, and K. Siddle. "Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-L1 adipocytes: evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-S6 kinase." Biochemical Journal 305, no. 1 (January 1, 1995): 25–28. http://dx.doi.org/10.1042/bj3050025.
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We have investigated the involvement of phosphoinositide (PI) 3-kinase and p70 ribosomal protein-S6 kinase (p70s6k) in mediating insulin stimulation of glycogen synthesis in 3T3-L1 adipocytes using specific inhibitors. Wortmannin inhibited PI 3-kinase activity (IC50 approximately 10 nM), inhibition being complete at 100 nm. Wortmannin (100 nM) completely blocked the ability of insulin to activate glycogen synthase in 3T3-L1 adipocytes and the ability of insulin to stimulate glucose incorporation into glycogen in 3T3-L1 fibroblasts. Rapamycin, which blocks insulin-stimulated activation of p70s6k, decreased insulin activation of glycogen synthase in a dose-dependent manner (IC50 approximately 0.8 ng/ml), with a maximum approx. 75% inhibition of insulin's stimulatory effect. Rapamycin inhibited insulin-stimulated glucose incorporation into glycogen to a similar extent and with similar dose-dependency, while having no effect on insulin-stimulated glucose transport. We conclude that PI 3-kinase and p70s6k are involved in the signalling pathways by which insulin stimulates glycogen synthase in 3T3-L1 adipocytes.
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Qiu, Beiying, Xiaohe Shi, Qiling Zhou, Hui Shan Chen, Joy Lim, Weiping Han, and Vinay Tergaonkar. "Hypothalamic NUCKS regulates peripheral glucose homoeostasis." Biochemical Journal 469, no. 3 (July 23, 2015): 391–98. http://dx.doi.org/10.1042/bj20150450.
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NUCKS regulates genes involved in insulin signalling and loss of NUCKS in vivo leads to insulin resistance and obesity. We report here the specificity of NUCKS in hypothalamus to regulate hypothalamic insulin signalling and peripheral glucose homoeostasis.
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Kirwan, J. P., and L. F. del Aguila. "Insulin signalling, exercise and cellular integrity." Biochemical Society Transactions 31, no. 6 (December 1, 2003): 1281–85. http://dx.doi.org/10.1042/bst0311281.
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Although the effects of exercise on insulin sensitivity are generally positive, eccentric exercise presents a paradox because it induces a transient state of insulin resistance that persists for up to 48 h after the exercise bout. Excessive eccentric contractions, such as prolonged downhill running, or marathon running, causes muscle damage and disruption of the integrity of the cell. Down-regulation of insulin receptor tyrosine phosphorylation and subsequent steps in the insulin signalling pathway, including insulin receptor substrate-1 (IRS-1)-associated phosphoinositide 3-kinase (PI3K), Akt kinase serine phosphorylation and activity and glucose transporter (GLUT-4) protein content, are evident in skeletal muscle after eccentric exercise. Furthermore, increased tumour necrosis factor α (TNF-α) secretion from monocytes is associated with the decrease in PI3K activity after this type of exercise. Recent studies have shown that TNF-α can increase IRS-1 serine/threonine phosphorylation, which impairs IRS-1 docking to the insulin receptor, and this inhibits insulin signalling. Thus a unifying hypothesis to explain insulin resistance after eccentric exercise may include inflammation arising from the disruption of muscle-cell integrity, leading to an acute-phase response that includes TNF-α, with the latter inhibiting insulin signalling and subsequent metabolic events. In contrast, exercise training increases insulin signalling and GLUT-4 expression, decreases TNF-α expression in skeletal muscle, and is associated with enhanced insulin sensitivity. These observations highlight the complexity of the cellular and molecular adaptations to exercise. Understanding these adaptations is essential in order to establish a sound theoretical basis for recommending exercise as a therapeutic intervention for insulin resistance and type 2 diabetes.
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Chaussade, Claire, Gordon W. Rewcastle, Jackie D. Kendall, William A. Denny, Kitty Cho, Line M. Grønning, Mei Ling Chong, et al. "Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling." Biochemical Journal 404, no. 3 (May 29, 2007): 449–58. http://dx.doi.org/10.1042/bj20070003.
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Recent genetic knock-in and pharmacological approaches have suggested that, of class IA PI3Ks (phosphatidylinositol 3-kinases), it is the p110α isoform (PIK3CA) that plays the predominant role in insulin signalling. We have used isoform-selective inhibitors of class IA PI3K to dissect further the roles of individual p110 isoforms in insulin signalling. These include a p110α-specific inhibitor (PIK-75), a p110α-selective inhibitor (PI-103), a p110β-specific inhibitor (TGX-221) and a p110δ-specific inhibitor (IC87114). Although we find that p110α is necessary for insulin-stimulated phosphorylation of PKB (protein kinase B) in several cell lines, we find that this is not the case in HepG2 hepatoma cells. Inhibition of p110β or p110δ alone was also not sufficient to block insulin signalling to PKB in these cells, but, when added in combination with p110α inhibitors, they are able to significantly attenuate insulin signalling. Surprisingly, in J774.2 macrophage cells, insulin signalling to PKB was inhibited to a similar extent by inhibitors of p110α, p110β or p110δ. These results provide evidence that p110β and p110δ can play a role in insulin signalling and also provide the first evidence that there can be functional redundancy between p110 isoforms. Further, our results indicate that the degree of functional redundancy is linked to the relative levels of expression of each isoform in the target cells.
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Stepto, N. K., D. Hiam, M. Gibson-Helm, S. Cassar, C. L. Harrison, S. K. Hutchison, A. E. Joham, et al. "Exercise and insulin resistance in PCOS: muscle insulin signalling and fibrosis." Endocrine Connections 9, no. 4 (April 2020): 346–59. http://dx.doi.org/10.1530/ec-19-0551.
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Objective Mechanisms of insulin resistance in polycystic ovary syndrome (PCOS) remain ill defined, contributing to sub-optimal therapies. Recognising skeletal muscle plays a key role in glucose homeostasis we investigated early insulin signalling, its association with aberrant transforming growth factor β (TGFβ)-regulated tissue fibrosis. We also explored the impact of aerobic exercise on these molecular pathways. Methods A secondary analysis from a cross-sectional study was undertaken in women with (n = 30) or without (n = 29) PCOS across lean and overweight BMIs. A subset of participants with (n = 8) or without (n = 8) PCOS who were overweight completed 12 weeks of aerobic exercise training. Muscle was sampled before and 30 min into a euglycaemic-hyperinsulinaemic clamp pre and post training. Results We found reduced signalling in PCOS of mechanistic target of rapamycin (mTOR). Exercise training augmented but did not completely rescue this signalling defect in women with PCOS. Genes in the TGFβ signalling network were upregulated in skeletal muscle in the overweight women with PCOS but were unresponsive to exercise training except for genes encoding LOX, collagen 1 and 3. Conclusions We provide new insights into defects in early insulin signalling, tissue fibrosis, and hyperandrogenism in PCOS-specific insulin resistance in lean and overweight women. PCOS-specific insulin signalling defects were isolated to mTOR, while gene expression implicated TGFβ ligand regulating a fibrosis in the PCOS-obesity synergy in insulin resistance and altered responses to exercise. Interestingly, there was little evidence for hyperandrogenism as a mechanism for insulin resistance.
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MORA, Alfonso, Christopher LIPINA, François TRONCHE, Calum SUTHERLAND, and Dario R. ALESSI. "Deficiency of PDK1 in liver results in glucose intolerance, impairment of insulin-regulated gene expression and liver failure." Biochemical Journal 385, no. 3 (January 24, 2005): 639–48. http://dx.doi.org/10.1042/bj20041782.
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The liver plays an important role in insulin-regulated glucose homoeostasis. To study the function of the PDK1 (3-phosphoinositide-dependent protein kinase-1) signalling pathway in mediating insulin's actions in the liver, we employed CRE recombinase/loxP technology to generate L(liver)-PDK1−/− mice, which lack expression of PDK1 in hepatocytes and in which insulin failed to induce activation of PKB in liver. The L-PDK1−/− mice were not insulin-intolerant, possessed normal levels of blood glucose and insulin under normal feeding conditions, but were markedly glucose-intolerant when injected with glucose. The L-PDK1−/− mice also possessed 10-fold lower levels of hepatic glycogen compared with control littermates, and were unable to normalize their blood glucose levels within 2 h after injection of insulin. The glucose intolerance of the L-PDK1−/− mice may be due to an inability of glucose to suppress hepatic glucose output through the gluconeogenic pathway, since the mRNA encoding hepatic PEPCK (phosphoenolpyruvate carboxykinase), G6Pase (glucose-6-phosphatase) and SREBP1 (sterol-regulatory-element-binding protein 1), which regulate gluconeogenesis, are no longer controlled by feeding. Furthermore, three other insulin-controlled genes, namely IGFBP1 (insulin-like-growth-factor-binding protein-1), IRS2 (insulin receptor substrate 2) and glucokinase, were regulated abnormally by feeding in the liver of PDK1-deficient mice. Finally, the L-PDK1−/− mice died between 4–16 weeks of age due to liver failure. These results establish that the PDK1 signalling pathway plays an important role in regulating glucose homoeostasis and controlling expression of insulin-regulated genes. They suggest that a deficiency of the PDK1 pathway in the liver could contribute to development of diabetes, as well as to liver failure.
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MALBON, Craig C. "Insulin signalling: putting the G- in protein-protein interactions." Biochemical Journal 380, no. 1 (May 15, 2004): e11-e12. http://dx.doi.org/10.1042/bj20040619.
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Cell signalling via receptor tyrosine kinases, such as the insulin receptor, and via heterotrimeric G-proteins, such as Gαi, Gαs and Gαq family members, constitute two of most avidly studied paradigms in cell biology. That elements of these two populous signalling pathways must cross-talk to achieve proper signalling in the regulation of cell proliferation, differentiation and metabolism has been anticipated, but the evolution of our thinking and the analysis of such cross-talk have lagged behind the ever-expanding troupe of players and the recognition of multivalency as the rule, rather than the exception, in signalling biology. New insights have been provided by Kreuzer et al. in this issue of the Biochemical Journal, in which insulin is shown to provoke recruitment of Gαi-proteins to insulin-receptor-based complexes that can regulate the gain of insulin-receptor-catalysed autophosphorylation, a proximal point in the insulin-sensitive cascade of signalling. Understanding the convergence and cross-talk of signals from the receptor tyrosine kinases and G-protein-coupled receptor pathways in physical, spatial and temporal contexts will remain a major challenge of cell biology.
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Bertrand, L., S. Horman, C. Beauloye, and J. L. Vanoverschelde. "Insulin signalling in the heart." Cardiovascular Research 79, no. 2 (April 30, 2008): 238–48. http://dx.doi.org/10.1093/cvr/cvn093.
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Levy, Jonathan C. "Insulin signalling through ultradian oscillations." Growth Hormone & IGF Research 11 (June 2001): S17—S23. http://dx.doi.org/10.1016/s1096-6374(01)80004-6.
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James, David, Sean J. Humphrey, Guang Yang, Pengyi Yang, Daniel Fazakerley, Jacqueline Stoeckli, and Jean Yang. "Mapping the insulin signalling network." Obesity Research & Clinical Practice 7 (December 2013): e4-e5. http://dx.doi.org/10.1016/j.orcp.2013.12.506.
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Silva, Luis, Mario Subiabre, Joaquín Araos, Tamara Sáez, Rocío Salsoso, Fabián Pardo, Andrea Leiva, Rody San Martín, Fernando Toledo, and Luis Sobrevia. "Insulin/adenosine axis linked signalling." Molecular Aspects of Medicine 55 (June 2017): 45–61. http://dx.doi.org/10.1016/j.mam.2016.11.002.
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Whitehead, Jonathan P., Sharon F. Clark, Birgitte Ursø, and David E. James. "Signalling through the insulin receptor." Current Opinion in Cell Biology 12, no. 2 (April 2000): 222–28. http://dx.doi.org/10.1016/s0955-0674(99)00079-4.
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Posner, Barry I. "Insulin Signalling: The Inside Story." Canadian Journal of Diabetes 41, no. 1 (February 2017): 108–13. http://dx.doi.org/10.1016/j.jcjd.2016.07.002.
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Bateman, J. M., and H. McNeill. "Insulin/IGF signalling in neurogenesis." Cellular and Molecular Life Sciences 63, no. 15 (June 19, 2006): 1701–5. http://dx.doi.org/10.1007/s00018-006-6036-4.
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Schliess, Freimut, and Dieter Häussinger. "Cell Hydration and Insulin Signalling." Cellular Physiology and Biochemistry 10, no. 5-6 (2000): 403–8. http://dx.doi.org/10.1159/000016378.
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Besse-Patin, Aurèle, and Jennifer L. Estall. "An Intimate Relationship between ROS and Insulin Signalling: Implications for Antioxidant Treatment of Fatty Liver Disease." International Journal of Cell Biology 2014 (2014): 1–9. http://dx.doi.org/10.1155/2014/519153.
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Oxidative stress damages multiple cellular components including DNA, lipids, and proteins and has been linked to pathological alterations in nonalcoholic fatty liver disease (NAFLD). Reactive oxygen species (ROS) emission, resulting from nutrient overload and mitochondrial dysfunction, is thought to be a principal mediator in NAFLD progression, particularly toward the development of hepatic insulin resistance. In the context of insulin signalling, ROS has a dual role, as both a facilitator and inhibitor of the insulin signalling cascade. ROS mediate these effects through redox modifications of cysteine residues affecting phosphatase enzyme activity, stress-sensitive kinases, and metabolic sensors. This review highlights the intricate relationship between redox-sensitive proteins and insulin signalling in the context of fatty liver disease, and to a larger extent, the importance of reactive oxygen species as primary signalling molecules in metabolically active cells.
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Dupont, Joëlle, and Rex J. Scaramuzzi. "Insulin signalling and glucose transport in the ovary and ovarian function during the ovarian cycle." Biochemical Journal 473, no. 11 (May 27, 2016): 1483–501. http://dx.doi.org/10.1042/bcj20160124.
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Data derived principally from peripheral tissues (fat, muscle and liver) show that insulin signals via diverse interconnecting intracellular pathways and that some of the major intersecting points (known as critical nodes) are the IRSs (insulin receptor substrates), PI3K (phosphoinositide kinase)/Akt and MAPK (mitogen-activated protein kinase). Most of these insulin pathways are probably also active in the ovary and their ability to interact with each other and also with follicle-stimulating hormone (FSH) and luteinizing hormone (LH) signalling pathways enables insulin to exert direct modulating influences on ovarian function. The present paper reviews the intracellular actions of insulin and the uptake of glucose by ovarian tissues (granulosa, theca and oocyte) during the oestrous/menstrual cycle of some rodent, primate and ruminant species. Insulin signals through diverse pathways and these are discussed with specific reference to follicular cell types (granulosa, theca and oocyte). The signalling pathways for FSH in granulosa cells and LH in granulosa and theca cells are summarized. The roles of glucose and of insulin-mediated uptake of glucose in folliculogenesis are discussed. It is suggested that glucose in addition to its well-established role of providing energy for cellular function may also have insulin-mediated signalling functions in ovarian cells, involving AMPK (AMP-dependent protein kinase) and/or hexosamine. Potential interactions of insulin signalling with FSH or LH signalling at critical nodes are identified and the available evidence for such interactions in ovarian cells is discussed. Finally the action of the insulin-sensitizing drugs metformin and the thiazolidinedione rosiglitazone on follicular cells is reviewed.
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TILL, Martin, D. Margriet OUWENS, Alexandra KESSLER, and Jürgen ECKEL. "Molecular mechanisms of contraction-regulated cardiac glucose transport." Biochemical Journal 346, no. 3 (March 7, 2000): 841–47. http://dx.doi.org/10.1042/bj3460841.
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Insulin and contraction are the most important regulators of glucose utilization in cardiac muscle. In contrast with insulin, the intracellular signalling elements of contraction have remained unexplored. In the present studies, adult rat ventricular cardiomyocytes were electrically stimulated to perform rhythmic contractions to permit the determination of potential sites of convergence of contraction and insulin signalling to glucose transport. The participation of phosphoinositide 3-kinase (PI-3K) in Ca2+- and contraction-stimulated 3-O-methylglucose transport was suggested by the great sensitivity of this process towards the PI-3K inhibitors wortmannin and LY294002 and by the presence of PI-3K activity in anti-phosphotyrosine immunoprecipitates from contracted cells. Initial signalling events of insulin action, including receptor kinase activation, the tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 and the recruitment of PI-3K to IRS-1 and IRS-2, were found not to be involved in contraction-mediated signalling. However, immunoprecipitation of p85α revealed a markedly enhanced tyrosine phosphorylation of an unknown co-precipitated 200 kDa protein in response to both stimuli. It is concluded that contraction-regulated cardiac glucose transport involves the activation of PI-3K in response to upstream signalling pathways different from that of insulin.
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Zhang, Jiandi. "Resveratrol inhibits insulin responses in a SirT1-independent pathway." Biochemical Journal 397, no. 3 (July 13, 2006): 519–27. http://dx.doi.org/10.1042/bj20050977.
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Resveratrol mimics calorie restriction to extend lifespan of Caenorhabditis elegans, yeast and Drosophila, possibly through activation of Sir2 (silent information regulator 2), a NAD+-dependent histone deacetylase. In the present study, resveratrol is shown to inhibit the insulin signalling pathway in several cell lines and rat primary hepatocytes in addition to its broad-spectrum inhibition of several signalling pathways. Resveratrol effectively inhibits insulin-induced Akt and MAPK (mitogen-activated protein kinase) activation mainly through disruption of the interactions between insulin receptor substrates and its downstream binding proteins including p85 regulatory subunit of phosphoinositide 3-kinase and Grb2 (growth factor receptor-bound protein 2). The inhibitory effect of resveratrol on insulin signalling is also demonstrated at mRNA level, where resveratrol reverses insulin effects on phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, fatty acid synthase and glucokinase. In addition, RNA interference experiment shows that the inhibitory effect of resveratrol on insulin signalling pathway is not weakened in cells with reduced expression of SirT1, the mammalian counterpart of Sir2. These observations raise the possibility that resveratrol may additionally modulate lifespan through inhibition of insulin signalling pathway, independently of its activation of SirT1 histone deacetylase. Furthermore, the present study may help to explain a wide range of biological effects of resveratrol, and provides further insight into the molecular basis of calorie restriction.
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Bolukbasi, Ekin, Sharron Vass, Neville Cobbe, Bryce Nelson, Victor Simossis, Donald R. Dunbar, and Margarete M. S. Heck. "Drosophila poly suggests a novel role for the Elongator complex in insulin receptor–target of rapamycin signalling." Open Biology 2, no. 1 (January 2012): 110031. http://dx.doi.org/10.1098/rsob.110031.
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Multi-cellular organisms need to successfully link cell growth and metabolism to environmental cues during development. Insulin receptor–target of rapamycin (InR–TOR) signalling is a highly conserved pathway that mediates this link. Herein, we describe poly , an essential gene in Drosophila that mediates InR–TOR signalling. Loss of poly results in lethality at the third instar larval stage, but only after a stage of extreme larval longevity. Analysis in Drosophila demonstrates that Poly and InR interact and that poly mutants show an overall decrease in InR–TOR signalling, as evidenced by decreased phosphorylation of Akt, S6K and 4E-BP. Metabolism is altered in poly mutants, as revealed by microarray expression analysis and a decreased triglyceride : protein ratio in mutant animals. Intriguingly, the cellular distribution of Poly is dependent on insulin stimulation in both Drosophila and human cells, moving to the nucleus with insulin treatment, consistent with a role in InR–TOR signalling. Together, these data reveal that Poly is a novel, conserved (from flies to humans) mediator of InR signalling that promotes an increase in cell growth and metabolism. Furthermore, homology to small subunits of Elongator demonstrates a novel, unexpected role for this complex in insulin signalling.
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Lancaster, Graeme I., Beata Skiba, Christine Yang, Hayley T. Nicholls, Katherine G. Langley, M. H. Stanley Chan, Clinton R. Bruce, et al. "IκB kinase β (IKKβ) does not mediate feedback inhibition of the insulin signalling cascade." Biochemical Journal 442, no. 3 (February 24, 2012): 723–32. http://dx.doi.org/10.1042/bj20112037.
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In the present study, we have examined whether IKKβ [IκB (inhibitor of nuclear factor κB) kinase β] plays a role in feedback inhibition of the insulin signalling cascade. Insulin induces the phosphorylation of IKKβ, in vitro and in vivo, and this effect is dependent on intact signalling via PI3K (phosphoinositide 3-kinase), but not PKB (protein kinase B). To test the hypothesis that insulin activates IKKβ as a means of negative feedback, we employed a variety of experimental approaches. First, pharmacological inhibition of IKKβ via BMS-345541 did not potentiate insulin-induced IRS1 (insulin receptor substrate 1) tyrosine phosphorylation, PKB phosphorylation or 2-deoxyglucose uptake in differentiated 3T3-L1 adipocytes. BMS-345541 did not prevent insulin-induced IRS1 serine phosphorylation on known IKKβ target sites. Secondly, adenovirus-mediated overexpression of wild-type IKKβ in differentiated 3T3-L1 adipocytes did not suppress insulin-stimulated 2-deoxyglucose uptake, IRS1 tyrosine phosphorylation, IRS1 association with the p85 regulatory subunit of PI3K or PKB phosphorylation. Thirdly, insulin signalling was not potentiated in mouse embryonic fibroblasts lacking IKKβ. Finally, insulin treatment of 3T3-L1 adipocytes did not promote the recruitment of IKKβ to IRS1, supporting our findings that IKKβ, although activated by insulin, does not promote direct serine phosphorylation of IRS1 and does not contribute to the feedback inhibition of the insulin signalling cascade.
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Sharma, P. M., K. Egawa, T. A. Gustafson, J. L. Martin, and J. M. Olefsky. "Adenovirus-mediated overexpression of IRS-1 interacting domains abolishes insulin-stimulated mitogenesis without affecting glucose transport in 3T3-L1 adipocytes." Molecular and Cellular Biology 17, no. 12 (December 1997): 7386–97. http://dx.doi.org/10.1128/mcb.17.12.7386.
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Activated insulin receptor (IR) interacts with its substrates, IRS-1, IRS-2, and Shc via the NPXY motif centered at Y960. This interaction is important for IRS-1 phosphorylation. Studies using the yeast two-hybrid system and sequence identity analysis between IRS-1 and IRS-2 have identified two putative elements, the PTB and SAIN domains, between amino acids 108 and 516 of IRS-1 that are sufficient for receptor interaction. However, their precise function in mediating insulin's bioeffects is not understood. We expressed the PTB and SAIN domains of IRS-1 in HIRcB fibroblasts and 3T3-L1 adipocytes utilizing replication-defective adenoviral infection to investigate their role in insulin signalling. In both cell types, overexpression of either the PTB or the SAIN protein caused a significant decrease in insulin-induced tyrosine phosphorylation of IRS-1 and Shc proteins, IRS-1-associated phosphatidylinositol 3-kinase (PI 3-K) enzymatic activity, p70s6k activation, and p44 and p42 mitogen-activated protein kinase (MAPK) phosphorylation. However, epidermal growth factor-induced Shc and MAPK phosphorylation was unaffected by the overexpressed proteins. These findings were associated with a complete inhibition of insulin-stimulated cell cycle progression. In 3T3-L1 adipocytes, PTB or SAIN expression extinguished IRS-1 phosphorylation with a corresponding 90% decrease in IRS-1-associated PI 3-K activity. p70s6k is a downstream target of PI 3-K, and insulin-stimulated p70s6k was inhibited by PTB or SAIN expression. Interestingly, overexpression of either PTB or SAIN protein did not affect insulin-induced AKT activation or insulin-stimulated 2-deoxyglucose transport, even though both of these bioeffects are inhibited by wortmannin. Thus, interference with the IRS-1-IR interaction inhibits insulin-stimulated IRS-1 and Shc phosphorylation, PI 3-K enzymatic activity, p70s6k activation, MAPK phosphorylation and cell cycle progression. In 3T3-L1 adipocytes, interference with the IR-IRS-1 interaction did not cause inhibition of insulin-stimulated AKT activation or glucose transport. These results indicate a bifurcation or subcompartmentalization of the insulin signalling pathway whereby some targets of PI 3-K (i.e., p70s6k) are dependent on IRS-1-associated PI 3-K and other targets (i.e., AKT and glucose transport) are not. IR-IRS-1 interaction is not essential for insulin's effect on glucose transport, and alternate, or redundant, pathways exist in these cells.
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Wang, Pengwen, Caixin Su, Huili Feng, Xiaopei Chen, Yunfang Dong, Yingxue Rao, Ying Ren, et al. "Curcumin regulates insulin pathways and glucose metabolism in the brains of APPswe/PS1dE9 mice." International Journal of Immunopathology and Pharmacology 30, no. 1 (January 26, 2017): 25–43. http://dx.doi.org/10.1177/0394632016688025.
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Recent studies have shown the therapeutic potential of curcumin in Alzheimer’s disease (AD). In 2014, our lab found that curcumin reduced Aβ40, Aβ42 and Aβ-derived diffusible ligands in the mouse hippocampus, and improved learning and memory. However, the mechanisms underlying this biological effect are only partially known. There is considerable evidence in brain metabolism studies indicating that AD might be a brain-specific type of diabetes with progressive impairment of glucose utilisation and insulin signalling. We hypothesised that curcumin might target both the glucose metabolism and insulin signalling pathways. In this study, we monitored brain glucose metabolism in living APPswe/PS1dE9 double transgenic mice using a micro-positron emission tomography (PET) technique. The study showed an improvement in cerebral glucose uptake in AD mice. For a more in-depth study, we used immunohistochemical (IHC) staining and western blot techniques to examine key factors in both glucose metabolism and brain insulin signalling pathways. The results showed that curcumin ameliorated the defective insulin signalling pathway by upregulating insulin-like growth factor (IGF)-1R, IRS-2, PI3K, p-PI3K, Akt and p-Akt protein expression while downregulating IR and IRS-1. Our study found that curcumin improved spatial learning and memory, at least in part, by increasing glucose metabolism and ameliorating the impaired insulin signalling pathways in the brain.
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Rajkhowa, Madhurima, Sandra Brett, Daniel J. Cuthbertson, Christopher Lipina, Antonio J. Ruiz-Alcaraz, Giles E. Thomas, Lisa Logie, John R. Petrie, and Calum Sutherland. "Insulin resistance in polycystic ovary syndrome is associated with defective regulation of ERK1/2 by insulin in skeletal muscle in vivo." Biochemical Journal 418, no. 3 (February 25, 2009): 665–71. http://dx.doi.org/10.1042/bj20082176.
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Insulin resistance is a recognized feature of PCOS (polycystic ovary syndrome). However, the molecular reason(s) underlying this reduced cellular insulin sensitivity is not clear. The present study compares the major insulin signalling pathways in skeletal muscle isolated from PCOS and controls. We measured whole-body insulin sensitivity and insulin signalling in skeletal muscle biopsies taken before and after acute exposure to hyperinsulinaemia in nine women diagnosed with PCOS and seven controls. We examined the expression, basal activity and response to in vivo insulin stimulation of three signalling molecules within these human muscle samples, namely IRS-1 (insulin receptor substrate-1), PKB (protein kinase B) and ERK (extracellular-signal-regulated kinase) 1/2. There was no significant difference in the expression, basal activity or activation of IRS-1 or PKB between PCOS and control subjects. However, there was a severe attenuation of insulin stimulation of the ERK pathway in muscle from all but two of the women with PCOS (the two most obese), and an accompanying trend towards higher basal phosphorylation of ERK1/2 in PCOS. These results are striking in that the metabolic actions of insulin are widely believed to require the IRS-1/PKB pathway rather than ERK, and the former has been reported as defective in some previous PCOS studies. Most importantly, the molecular defect identified was independent of adiposity. The altered response of ERK to insulin in PCOS was the most obvious signalling defect associated with insulin resistance in muscle from these patients.
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Rajan, Meenu R., Elin Nyman, Cecilia Brännmark, Charlotta S. Olofsson, and Peter Strålfors. "Inhibition of FOXO1 transcription factor in primary human adipocytes mimics the insulin-resistant state of type 2 diabetes." Biochemical Journal 475, no. 10 (May 31, 2018): 1807–20. http://dx.doi.org/10.1042/bcj20180144.
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Type 2 diabetes is characterized by insulin resistance in the expanding adipose tissue of obesity. The insulin resistance manifests in human adipocytes as system-wide impairment of insulin signalling. An exception is the regulation of transcription factor FOXO1 (forkhead box protein O1), which is phosphorylated downstream of mTORC2 (mammalian/mechanistic target of rapamycin in complex with raptor) and is therefore not exhibiting impaired response to insulin. However, the abundance, and activity, of FOXO1 is reduced by half in adipocytes from patients with diabetes. To elucidate the effect of reduced FOXO1 activity, we here transduced human adipocytes with a dominant-negative construct of FOXO1 (DN-FOXO1). Inhibition of FOXO1 reduced the abundance of insulin receptor, glucose transporter-4, ribosomal protein S6, mTOR and raptor. Functionally, inhibition of FOXO1 induced an insulin-resistant state network-wide, a state that qualitatively and quantitatively mimicked adipocytes from patients with type 2 diabetes. In contrast, and in accordance with these effects of DN-FOXO1, overexpression of wild-type FOXO1 appeared to augment insulin signalling. We combined experimental data with mathematical modelling to show that the impaired insulin signalling in FOXO1-inhibited cells to a large extent can be explained by reduced mTORC1 activity — a mechanism that defines much of the diabetic state in human adipocytes. Our findings demonstrate that FOXO1 is critical for maintaining normal insulin signalling of human adipocytes.
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DADKE, Shrikrishna, and Jonathan CHERNOFF. "Interaction of protein tyrosine phosphatase (PTP) 1B with its substrates is influenced by two distinct binding domains." Biochemical Journal 364, no. 2 (June 1, 2002): 377–83. http://dx.doi.org/10.1042/bj20011372.
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We have shown previously that protein tyrosine phosphatase (PTP) 1B interacts with insulin receptor and negatively regulates insulin signalling by an N-terminal binding domain [Dadke, Kusari and Chernoff (2000) J. Biol. Chem. 275, 23642–23647] and it also negatively regulates integrin signalling through a proline-rich region present in the C-terminus [Liu, Hill and Chernoff (1996) J. Biol. Chem. 271, 31290–31295; Liu, Sells and Chernoff (1998) Curr. Biol. 8, 173–176]. Here we show that PTP1B mutants that are defective in Src homology 3 domain binding fully retain the ability to inhibit insulin signalling, whereas mutants defective in insulin-receptor binding fully retain the ability to inhibit integrin signalling. In contrast, both the C-terminal proline-rich region and the tandem tyrosine residues present in the N-terminal region are required for the activation of Src family kinases. These data show that PTP1B can independently regulate insulin and integrin signals, and that Src might represent a convergence point for regulating signal transduction by this phosphatase.
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Jensen, Maja, Jane Palsgaard, Rehannah Borup, Pierre de Meyts, and Lauge Schäffer. "Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts." Biochemical Journal 412, no. 3 (May 28, 2008): 435–45. http://dx.doi.org/10.1042/bj20080279.
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Single-chain peptides have been recently produced that display either mimetic or antagonistic properties against the insulin and IGF-1 (insulin-like growth factor 1) receptors. We have shown previously that the insulin mimetic peptide S597 leads to significant differences in receptor activation and initiation of downstream signalling cascades despite similar binding affinity and in vivo hypoglycaemic potency. It is still unclear how two ligands can initiate different signalling responses through the IR (insulin receptor). To investigate further how the activation of the IR by insulin and S597 differentially activates post-receptor signalling, we studied the gene expression profile in response to IR activation by either insulin or S597 using microarray technology. We found striking differences between the patterns induced by these two ligands. Most remarkable was that almost half of the genes differentially regulated by insulin and S597 were involved in cell proliferation and growth. Insulin either selectively regulated the expression of these genes or was a more potent regulator. Furthermore, we found that half of the differentially regulated genes interact with the genes involved with the MAPK (mitogen-activated protein kinase) pathway. These findings support our signalling results obtained previously and confirm that the main difference between S597 and insulin stimulation resides in the activation of the MAPK pathway. In conclusion, we show that insulin and S597 acting via the same receptor differentially affect gene expression in cells, resulting in a different mitogenicity of the two ligands, a finding which has critical therapeutic implications.
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Dongre, Utpal Jagdish. "Adipokines in Insulin Resistance: Current Updates." Biosciences Biotechnology Research Asia 18, no. 2 (August 30, 2021): 357–66. http://dx.doi.org/10.13005/bbra/2922.
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Obesity is a chronic metabolic disease that affects both the pediatric and adult populations. Adipose tissue acts as an endocrine organ which secretes various adipokines involved in fat mass regulation and energy balance via modulating the metabolic signalling pathways. Altered secretion of adipokines promotes multiple complications, including insulin resistance. The primary mechanism of action that underlines the involvement of adipokines in the development of insulin resistance includes phosphorylation/de-phosphorylation of insulin receptor substrate-1 (IRS-1) facilitate by other signalling molecules like a suppressor of cytokine signalling 1 (SOCS-1). Adipokines mediated insulin resistance further contribute to the development of atherosclerosis, dyslipidemia, fatty liver disease, cancer etc. Thus, this review provides recent updates on the role of resistin, lipocalin-2, RBP-4, chemerin, TNF-alpha and IL-6 adipokines in the progression of insulin resistance.
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Bartke, Andrzej. "Single-gene mutations and healthy ageing in mammals." Philosophical Transactions of the Royal Society B: Biological Sciences 366, no. 1561 (January 12, 2011): 28–34. http://dx.doi.org/10.1098/rstb.2010.0281.
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Studies of the effects of single-gene mutations on longevity in Caenorhabditis elegans, Drosophila melanogaster and Mus musculus identified homologous, highly conserved signalling pathways that influence ageing. In each of these very distantly related species, single mutations which lead—directly or indirectly—to reduced insulin, insulin-like growth factor (IGF) or insulin/IGF-like signalling (IIS) can produce significant increases in both average and maximal lifespan. In mice, most of the life-extending mutations described to date reduce somatotropic (growth hormone (GH) and IGF-1) signalling. The reported extensions of longevity are most robust in GH-deficient and GH-resistant mice, while suppression of somatotropic signalling ‘downstream’ of the GH receptor produces effects that are generally smaller and often limited to female animals. This could be due to GH influencing ageing by both IGF-1-mediated and IGF-1-independent mechanisms. In mutants that have been examined in some detail, increased longevity is associated with various indices of delayed ageing and extended ‘healthspan’. The mechanisms that probably underlie the extension of both lifespan and healthspan of these animals include increased stress resistance, improved antioxidant defences, alterations in insulin signalling (e.g. hypoinsulinaemia combined with improved insulin sensitivity in some mutants and insulin resistance in others), a shift from pro- to anti-inflammatory profile of circulating adipokines, reduced mammalian target of rapamycin-mediated translation and altered mitochondrial function including greater utilization of lipids when compared with carbohydrates.
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Strembitska, Anastasiya, Sarah Mancini, Jonathan Gamwell, Timothy Palmer, George Baillie, and Ian Salt. "A769662 Inhibits Insulin-Stimulated Akt Activation in Human Macrovascular Endothelial Cells Independent of AMP-Activated Protein Kinase." International Journal of Molecular Sciences 19, no. 12 (December 5, 2018): 3886. http://dx.doi.org/10.3390/ijms19123886.
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Protein kinase B (Akt) is a key enzyme in the insulin signalling cascade, required for insulin-stimulated NO production in endothelial cells (ECs). Previous studies have suggested that AMP-activated protein kinase (AMPK) activation stimulates NO synthesis and enhances insulin-stimulated Akt activation, yet these studies have largely used indirect activators of AMPK. The effects of the allosteric AMPK activator A769662 on insulin signalling and endothelial function was therefore examined in cultured human macrovascular ECs. Surprisingly, A769662 inhibited insulin-stimulated NO synthesis and Akt phosphorylation in human ECs from umbilical veins (HUVECs) and aorta (HAECs). In contrast, the AMPK activators compound 991 and AICAR had no substantial inhibitory effect on insulin-stimulated Akt phosphorylation in ECs. Inhibition of AMPK with SBI-0206965 had no effect on the inhibition of insulin-stimulated Akt phosphorylation by A769662, suggesting the inhibitory action of A769662 is AMPK-independent. A769662 decreased IGF1-stimulated Akt phosphorylation yet had no effect on VEGF-stimulated Akt signalling in HUVECs, suggesting that A769662 attenuates early insulin/IGF1 signalling. The effects of A769662 on insulin-stimulated Akt phosphorylation were specific to human ECs, as no effect was observed in the human cancer cell lines HepG2 or HeLa, as well as in mouse embryonic fibroblasts (MEFs). A769662 inhibited insulin-stimulated Erk1/2 phosphorylation in HAECs and MEFs, an effect that was independent of AMPK in MEFs. Therefore, despite being a potent AMPK activator, A769662 has effects unlikely to be mediated by AMPK in human macrovascular ECs that reduce insulin sensitivity and eNOS activation.
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PRYOR, Paul R., Simon C. H. LIU, Avril E. CLARK, Jing YANG, Geoffrey D. HOLMAN, and David TOSH. "Chronic insulin effects on insulin signalling and GLUT4 endocytosis are reversed by metformin." Biochemical Journal 348, no. 1 (May 9, 2000): 83–91. http://dx.doi.org/10.1042/bj3480083.
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Decreases in insulin-responsive glucose transport and associated levels of cell surface GLUT4 occur in rat adipocytes maintained in culture for 20 h under hyperinsulinaemic and hyperglycaemic conditions. We have investigated whether this defect is due to reduced signalling from the insulin receptor, GLUT4 expression or impaired GLUT4 trafficking. The effects of chronic insulin treatment on glucose transport and GLUT4 trafficking were ameliorated by inclusion of metformin in the culture medium. In comparison with the acute effects of insulin, chronic insulin treatment attenuated changes in signalling processes leading to glucose transport. These included insulin receptor tyrosine phosphorylation, phosphoinositide 3-kinase activity and Akt activity, which were all reduced by 60-70%. Inclusion of metformin in the culture medium prevented the effects of the chronic insulin treatment on these signalling processes. In comparison with cells maintained in culture without insulin, the total expression of GLUT4 protein was not significantly altered by chronic insulin treatment, although the level of GLUT1 expression was increased. Trafficking rate constants for wortmannin-induced cell-surface loss of GLUT4 and GLUT1 were assessed by 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis(D-mannose-4-yloxy)-2-propylamine (ATB-BMPA) photolabelling. In comparison with cells acutely treated with insulin, chronic insulin treatment resulted in a doubling of the rate constants for GLUT4 endocytosis. These results suggest that the GLUT4 endocytosis process is very sensitive to the perturbations in signalling that occur under hyperinsulinaemic and hyperglycaemic conditions, and that the resulting elevation of endocytosis accounts for the reduced levels of net GLUT4 translocation observed.
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Oliver, Elizabeth, Fiona McGillicuddy, Catherine Phillips, Sinead Toomey, and Helen M. Roche. "The role of inflammation and macrophage accumulation in the development of obesity-induced type 2 diabetes mellitus and the possible therapeutic effects of long-chainn-3 PUFA." Proceedings of the Nutrition Society 69, no. 2 (February 17, 2010): 232–43. http://dx.doi.org/10.1017/s0029665110000042.
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The WHO estimate that >1×106deaths in Europe annually can be attributed to diseases related to excess body weight, and with the rising global obesity levels this death rate is set to drastically increase. Obesity plays a central role in the metabolic syndrome, a state of insulin resistance that predisposes patients to the development of CVD and type 2 diabetes mellitus. Obesity is associated with low-grade chronic inflammation characterised by inflamed adipose tissue with increased macrophage infiltration. This inflammation is now widely believed to be the key link between obesity and development of insulin resistance. In recent years it has been established that activation of pro-inflammatory pathways can cross talk with insulin signalling pathways via a number of mechanisms including (a) down-regulation of insulin signalling pathway proteins (e.g. GLUT4 and insulin receptor substrate (IRS)-1), (b) serine phosphorylation of IRS-1 blocking its tyrosine phosphorylation in response to insulin and (c) induction of cytokine signalling molecules that sterically hinder insulin signalling by blocking coupling of the insulin receptor to IRS-1. Long-chain (LC)n-3 PUFA regulate gene expression (a) through transcription factors such as PPAR and NF-κB and (b) via eicosanoid production, reducing pro-inflammatory cytokine production from many different cells including the macrophage. LCn-3 PUFA may therefore offer a useful anti-inflammatory strategy to decrease obesity-induced insulin resistance, which will be examined in the present review.
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Woodfield, Amy, Tatiana Gonzales, Erik Helmerhorst, Simon Laws, Philip Newsholme, Tenielle Porter, and Giuseppe Verdile. "Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer’s Disease." International Journal of Molecular Sciences 23, no. 24 (December 13, 2022): 15811. http://dx.doi.org/10.3390/ijms232415811.
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Alzheimer’s disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of consistent outcomes. This narrative review provided insight into how targeting insulin signalling in the brain has potential as a therapeutic target for AD and provided a detailed update on the efficacy of insulin, its analogues and the outcomes of human clinical trials. We also discussed the current evidence that warrants the further investigation of the use of the mimetics of insulin for AD. These small molecules may provide a modifiable alternative to insulin, aiding in developing drugs that selectively target insulin signalling in the brain with the aim to attenuate cognitive dysfunction and AD pathologies.