ER? Negatively Regulates Insulin Signalling In Vivo

2007 ◽  
Vol 32 (05) ◽  
Author(s):  
A Foryst-Ludwig ◽  
M Clemenz ◽  
S Hohmann ◽  
M Hartge ◽  
C Sprang ◽  
...  
Keyword(s):  
Insulin Signalling

scholarly journals Acute elevation of circulating fatty acids impairs downstream insulin signalling in rat skeletal muscle in vivo independent of effects on stress signalling

2008 ◽  
Vol 197 (2) ◽  
pp. 277-285 ◽  
Author(s):  
Georgia Frangioudakis ◽  
Gregory J Cooney
Keyword(s):  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Insulin Signalling ◽  
Plasma Free Fatty Acid ◽  
Nuclear Factor Κb ◽  
Quadriceps Muscle ◽  
Male Wistar Rats ◽  
Gsk 3Β ◽  
Stress Signalling

The aim of this study was to examine the effect of an acute, physiological increase in plasma free fatty acid (FFA) on initial signalling events in rat red quadriceps muscle (RQ). Male Wistar rats received a 7% glycerol (GLYC) or 7% Intralipid/heparin (LIP) infusion for 3 h, after which they were either killed or infused with insulin at a rate of 0.5 U/kg per h for 5 min, before RQ collection. Plasma FFAs were elevated to ∼2 mM in the LIP rats only. Insulin-stimulated insulin receptor (IR) Tyr1162/Tyr1163 phosphorylation and IR substrate (IRS)-1 Tyr612 phosphorylation were increased at least twofold over basal in GLYC rats with insulin and this increase was not significantly impaired in the LIP rats. However, there was no insulin-stimulated protein kinase B (PKB) Ser473 or glycogen synthase kinase (GSK)-3β Ser9 phosphorylation in the LIP rats, compared with at least a twofold increase over basal in GLYC rats for both proteins. c-Jun N-terminal kinase, inhibitor of κ kinase β and inhibitor of nuclear factor-κB phosphorylation and total protein expression, as well as Ser307-IRS-1 phosphorylation, were not altered by lipid infusion compared with GLYC infusion. These data indicate that acute, physiological elevation in FFA has a greater impact on insulin signalling downstream of IR and IRS-1, at the level of PKB and GSK-3β, and that under these conditions stress signalling pathways are not significantly stimulated. Decreased PKB and GSK-3β phosphorylation in RQ may therefore be primary determinants of the reduced insulin action observed in situations of acute FFA oversupply.

scholarly journals GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells

2021 ◽  
Vol 22 (19) ◽  
pp. 10784
Author(s):  
Gemma K. Kinsella ◽  
Stefania Cannito ◽  
Valentina Bordano ◽  
John C. Stephens ◽  
Arianna C. Rosa ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Hepg2 Cells ◽  
Insulin Signalling ◽  
Hepatic Insulin Resistance ◽  
In Vivo Studies ◽  
Negative Effects ◽  
Cellular Models ◽  
Insulin Signalling Pathway ◽  
Novel Strategy

GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT(Ser473)/tot-AKT and phGSK-3β(Ser9)/tot-GSK-3β, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.

Cardiac-specific VEGFB overexpression reduces lipoprotein lipase activity and improves insulin action in rat heart

2021 ◽  
Author(s):  
Rui Shang ◽  
Nathaniel Lal ◽  
ChaeSyng Lee ◽  
Yajie Zhai ◽  
Karanjit Puri ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Lipoprotein Lipase ◽  
Insulin Action ◽  
Insulin Signalling ◽  
Isolated Heart ◽  
Cardiac Metabolism ◽  
Metabolic Reprogramming ◽  
Flux Analysis

Cardiac muscle utilizes multiple sources of energy including glucose and fatty acid (FA). The heart cannot synthesize FA and relies on obtaining it from other sources, with lipoprotein lipase (LPL) breakdown of lipoproteins suggested to be a key source of FA for cardiac use. Recent work has indicated that cardiac vascular endothelial growth factor B (VEGFB) overexpression expands the coronary vasculature and facilitates metabolic reprogramming that favours glucose utilization. We wanted to explore whether this influence of VEGFB on cardiac metabolism involves regulation of LPL activity with consequent effects on lipotoxicity and insulin signalling. The transcriptomes of rats with and without cardiomyocyte-specific overexpression of human VEGFB were compared by using RNA-sequencing. Isolated perfused hearts or cardiomyocytes incubated with heparin were used to enable measurement of LPL activity. Untargeted metabolomic analysis was performed for quantification of cardiac lipid metabolites. Cardiac insulin sensitivity was evaluated using fast-acting insulin. Isolated heart and cardiomyocytes were used to determine transgene-encoded VEGFB isoform secretion patterns and mitochondrial oxidative capacity using high-resolution respirometry and extracellular flux analysis. In vitro, primary transgenic cardiomyocytes incubated overnight and thus exposed to abundantly secreted VEGFB isoforms in the absence of any in vivo confounding regulators of cardiac metabolism demonstrated higher basal oxygen consumption. In the whole heart, VEGFB overexpression induced an angiogenic response that was accompanied by limited cardiac LPL activity through multiple mechanisms. This was associated with a lowered accumulation of lipid intermediates, diacylglycerols and lysophosphatidylcholine, that are known to influence insulin action. In response to exogenous insulin, transgenic hearts demonstrated increased insulin sensitivity. In conclusion, the interrogation of VEGFB function on cardiac metabolism uncovered an intriguing and previously unappreciated effect to lower LPL activity and prevent lipid metabolite accumulation to improve insulin action. VEGFB could be a potential cardioprotective therapy to treat metabolic disorders, for example diabetes.

scholarly journals Short-term infusion of interleukin-6 does not induce insulin resistance in vivo or impair insulin signalling in rats

Diabetologia ◽  
2004 ◽  
Vol 47 (11) ◽  
pp. 1879-1887 ◽  
Author(s):  
V. Rotter Sopasakis ◽  
B.-M. Larsson ◽  
A. Johansson ◽  
A. Holm�ng ◽  
U. Smith
Keyword(s):  
Insulin Resistance ◽  
Interleukin 6 ◽  
Insulin Signalling ◽  
Short Term ◽  
Induce Insulin Resistance

scholarly journals Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Paul M. Titchenell ◽  
Qingwei Chu ◽  
Bobby R. Monks ◽  
Morris J. Birnbaum
Keyword(s):  
Insulin Signalling ◽  
Glucose Output

scholarly journals Toll-like receptor agonist induced changes in clonal rat BRIN-BD11 β-cell insulin secretion and signal transduction

2009 ◽  
Vol 202 (3) ◽  
pp. 365-373 ◽  
Author(s):  
Aoife Kiely ◽  
Aisling Robinson ◽  
Neville H McClenaghan ◽  
Peter R Flatt ◽  
Philip Newsholme
Keyword(s):  
Insulin Secretion ◽  
Insulin Signalling ◽  
Cell Metabolism ◽  
Saturated Fatty Acids ◽  
Insulin Content ◽  
Β Cell ◽  
Akt Phosphorylation ◽  
Tlr4 Ligand ◽  
Induced Changes

Evidence for involvement of toll-like receptors (TLRs) (e.g. TLR4 and TLR2, whose agonists include lipopolysaccharides (LPS) and saturated fatty acids) in altered patterns of signalling in adipose, liver and muscle from animal models of insulin resistance and obesity has been published. We have now extended this area of research and have determined the effects of LPS on cell viability, insulin secretion, insulin signalling and metabolism in a clonal β-cell line. BRIN-BD11 β-cells were treated for 24 h with increasing concentrations of LPS. Chronic (24 h) and acute (20 min) insulin secretion, insulin content and parameters of cell metabolism and insulin signalling were determined. Incubation of BRIN-BD11 cells for 24 h in the presence of increasing concentrations of the TLR4 ligand LPS significantly decreased chronic (24 h) insulin secretion from 1.09±0.19 to 0.76±0.18 μg insulin/mg protein in the presence of 100 ng/ml LPS (P<0.05). There was no change in acute (20 min) stimulated insulin secretion or insulin content. Cell metabolism was not changed. Insulin receptor-β (IRβ) expression levels were increased significantly from 1±0.52 to 8.6±1.83 units (P<0.01), whereas calcineurin activity and Akt phosphorylation were significantly (P<0.01 and P<0.05 respectively) reduced in response to 24 h incubation in the presence of LPS. There was no change in IR substrate-1 protein expression or phosphorylation after 24 h. Further incubation for 24 h in the absence of LPS resulted in the recovery of chronic insulin secretion. The negative β-cell effects of LPS may contribute to hyperglycaemia in vivo.

scholarly journals Mulberry Anthocyanin Extract Ameliorates Oxidative Damage in HepG2 Cells and Prolongs the Lifespan of Caenorhabditis elegans through MAPK and Nrf2 Pathways

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Fujie Yan ◽  
Yushu Chen ◽  
Ramila Azat ◽  
Xiaodong Zheng
Keyword(s):  
Oxidative Stress ◽  
Caenorhabditis Elegans ◽  
Hepg2 Cells ◽  
Insulin Signalling ◽  
Glucose Consumption ◽  
Redox Status ◽  
C Elegans ◽  
Beneficial Effects

Mulberry anthocyanins possess many pharmacological effects including liver protection, anti-inflammation, and anticancer. The aim of this study was to evaluate whether mulberry anthocyanin extract (MAE) exerts beneficial effects against oxidative stress damage in HepG2 cells and Caenorhabditis elegans. In vitro, MAE prevented cytotoxicity, increased glucose consumption and uptake, and eliminated excessive intracellular free radicals in H2O2-induced cells. Moreover, MAE pretreatment maintained Nrf2, HO-1, and p38 MAPK stimulation and abolished upregulation of p-JNK, FOXO1, and PGC-1α that were involved in oxidative stress and insulin signalling modulation. In vivo, extended lifespan was observed in C. elegans damaged by paraquat in the presence of MAE, while these beneficial effects were disappeared in pmk-1 and daf-16 mutants. PMK-1 and SKN-1 were activated after exposure to paraquat and MAE suppressed PMK-1 activation but enhanced SKN-1 stimulation. Our findings suggested that MAE recovered redox status in HepG2 cells and C. elegans that suffered from oxidative stress, which might be by targeting MAPKs and Nrf2.

scholarly journals The Role of TGFβ Ligands and Signalling on Insulin Resistance in Skeletal Muscle in Women With PCOS

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A443-A444
Author(s):  
Alba Moreno-Asso ◽  
Luke C McIlvenna ◽  
Rhiannon K Patten ◽  
Andrew J McAinch ◽  
Raymond J Rodgers ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Insulin Signalling ◽  
Signalling Pathway ◽  
Whole Body ◽  
Insulin Signalling Pathway ◽  
Cultured Myotubes ◽  
Tgfβ Superfamily

Abstract Polycystic ovary syndrome (PCOS) is the most common female endocrinopathy affecting metabolic and reproductive health of 8–13% of reproductive-age women. Insulin resistance (IR) appears to underpin the pathophysiology of PCOS and is present in approximately 38–95% of women with PCOS. This underlying IR has been identified as unique from, but synergistic with, obesity-induced IR (1). Skeletal muscle accounts for up to 85% of whole-body insulin-stimulated glucose uptake; however, in PCOS this is reduced by about 27% when assessed by a euglycaemic-hyperinsulinaemic clamp (2). Interestingly, this reduced insulin-stimulated glucose uptake observed in skeletal muscle tissue is not retained in cultured myotubes (3), suggesting that in vivo environmental factors may play a role in this PCOS-specific IR. Yet, the molecular mechanisms regulating IR remain unclear (4). A potential environmental mechanism contributing to the development of peripheral IR may be the extracellular matrix remodelling and aberrant transforming growth factor beta (TGFβ) signalling. Previous work demonstrated that TGFβ superfamily ligands are involved in the increased collagen deposition and fibrotic tissue in the ovaries, and suggested that these ligands may be involved in the metabolic morbidity associated with PCOS (5). In this study, we investigated the effects of TGFβ1 (1, 5 ng/ml), and the Anti-Müllerian hormone (AMH; 5, 10, 30 ng/ml), a TGFβ superfamily ligand elevated in women with PCOS, as causal factors of IR in cultured myotubes from women with PCOS (n=5) and healthy controls (n=5). TGFβ1 did not have a significant effect on insulin signalling but induced expression of some ECM related genes and proteins, and increased glucose uptake via Smad2/3 signalling in myotubes from both groups. Conversely, AMH did not appear to activate the TGFβ/Smad signalling pathway and had no significant impact on insulin signalling or glucose uptake in any of the groups. In conclusion, these findings suggest that TGFβ1, but not AMH, may play a role in skeletal muscle ECM remodelling/fibrosis and glucose metabolism in PCOS but does not have a direct effect on insulin signalling pathway. Further research is required to elucidate its contribution to the development of in vivo skeletal muscle IR and broader impact in this syndrome. References: (1) Stepto et al., Hum Reprod 2013 Mar;28(3):777–784. (2) Cassar et al., Hum Reprod 2016 Nov;31(11):2619–2631. (3) Corbould et al., Am J Physiol-Endoc 2005 May;88(5):E1047-54. (4) Stepto et al., J Clin Endocrinol Metab, 2019 Nov 1;104(11):5372–5381. (5) Raja-Khan et al., Reprod Sci 2014 Jan;21(1):20–31.

scholarly journals Validating GSK3 as an in vivo target of lithium action

2009 ◽  
Vol 37 (5) ◽  
pp. 1133-1138 ◽  
Author(s):  
W. Timothy O'Brien ◽  
Peter S. Klein
Keyword(s):  
Glycogen Synthase ◽  
Insulin Signalling ◽  
Lithium Treatment ◽  
Glycogen Synthesis ◽  
Model Systems ◽  
Glycogen Synthase Kinase 3 ◽  
Therapeutic Effects ◽  
Inositol Monophosphatase ◽  
Direct Target

Lithium is widely used to treat bipolar disorder, but its mechanism of action in this disorder is unknown. Lithium directly inhibits GSK3 (glycogen synthase kinase 3), a critical regulator of multiple signal transduction pathways. Inhibition of GSK3 provides a compelling explanation for many of the known effects of lithium, including effects on early development and insulin signalling/glycogen synthesis. However, lithium also inhibits inositol monophosphatase, several structurally related phosphomonoesterases, phosphoglucomutase and the scaffolding function of β-arrestin-2. It is not known which of these targets is responsible for the behavioural or therapeutic effects of lithium in vivo. The present review discusses basic criteria that can be applied to model systems to validate a proposed direct target of lithium. In this context, we describe a set of simple behaviours in mice that are robustly affected by chronic lithium treatment and are similarly affected by structurally diverse GSK3 inhibitors and by removing one copy of the Gsk3b gene. These observations, from several independent laboratories, support a central role for GSK3 in mediating behavioural responses to lithium.

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