scholarly journals PGC1A regulates the IRS1:IRS2 ratio during fasting to influence hepatic metabolism downstream of insulin

2019 ◽  
Vol 116 (10) ◽  
pp. 4285-4290 ◽  
Author(s):  
Aurèle Besse-Patin ◽  
Stewart Jeromson ◽  
Philipa Levesque-Damphousse ◽  
Blandine Secco ◽  
Mathieu Laplante ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Ex Vivo ◽  
Insulin Response ◽  
Glucose Production ◽  
Insulin Signaling Pathway ◽  
Peroxisome Proliferator ◽  
Loss Of Function ◽  
Gene And Protein Expression

Precise modulation of hepatic glucose metabolism is crucial during the fasting and feeding cycle and is controlled by the actions of circulating insulin and glucagon. The insulin-signaling pathway requires insulin receptor substrate 1 (IRS1) and IRS2, which are found to be dysregulated in diabetes and obesity. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1A) is a fasting-induced transcriptional coactivator. In nonalcoholic fatty liver disease and in patients with type 2 diabetes, low hepatic PGC1A levels are associated with insulin resistance. However, how PGC1A activity impacts the hepatic insulin-signaling pathway is still unclear. We used gain- and loss-of-function models in mouse primary hepatocytes and measured hepatocyte insulin response by gene and protein expression and ex vivo glucose production. We found that the PGC1A level determines the relative ratio of IRS1 and IRS2 in hepatocytes, impacting insulin receptor signaling via protein kinase B/AKT (AKT). PGC1A drove the expression of IRS2 downstream of glucagon signaling while simultaneously reducing IRS1 expression. We illustrate that glucagon- or PGC1A-induced IRS2 expression was dependent on cAMP Response Element Binding Protein activity and that this was essential for suppression of hepatocyte gluconeogenesis in response to insulin in vitro. We also show that increased hepatic PGC1A improves glucose homeostasis in vivo, revealing a counterregulatory role for PGC1A in repressing uncontrolled glucose production in response to insulin signaling. These data highlight a mechanism by which PGC1A plays dual roles in the control of gluconeogenesis during the fasting-to-fed transition through regulated balance between IRS1 and IRS2 expression.

scholarly journals MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle

2020 ◽  
Author(s):  
Clothilde Philouze ◽  
Sophie Turban ◽  
Béatrice Cremers ◽  
Audrey Caliez ◽  
Gwladys Lamarche ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Insulin Response ◽  
Muscle Cells ◽  
Insulin Signaling Pathway ◽  
Akt Phosphorylation ◽  
Impaired Insulin

AbstractIn type 2 diabetes (T2D), both muscle and liver are severely resistant to insulin action. Muscle insulin resistance accounts for more than 80% of the impairment in total body glucose disposal in T2D patients and is often characterized by an impaired insulin signaling. Mitsugumin 53 (MG53), a muscle-specific TRIM family protein initially identified as a key regulator of cell membrane repair machinery has been suggested to be a critical regulator of muscle insulin signaling pathway by acting as ubiquitin E3 ligase targeting both the insulin receptor and insulin receptor substrate 1 (IRS1). Here, we show using in vitro and in vivo approaches that MG53 is not a critical regulator of insulin signaling and glucose homeostasis. First, MG53 expression is not consistently regulated in skeletal muscle from various preclinical models of insulin resistance. Second, MG53 gene knock-down in muscle cells does not lead to impaired insulin response as measured by Akt phosphorylation on Serine 473 and glucose uptake. Third, recombinant human MG53 does not alter insulin response in both differentiated C2C12 and human skeletal muscle cells. Fourth, ectopic expression of MG53 in HEK293 cells lacking endogenous MG53 expression fails to alter insulin response as measured by Akt phosphorylation. Finally, both male and female mg53 −/− mice were not resistant to high fat induced obesity and glucose intolerance compared to wild-type mice. Taken together, these results strongly suggest that MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.

scholarly journals MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0245179
Author(s):  
Clothilde Philouze ◽  
Sophie Turban ◽  
Beatrice Cremers ◽  
Audrey Caliez ◽  
Gwladys Lamarche ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Insulin Response ◽  
Muscle Cells ◽  
Insulin Signaling Pathway ◽  
Akt Phosphorylation ◽  
Impaired Insulin

In type 2 diabetes (T2D), both muscle and liver are severely resistant to insulin action. Muscle insulin resistance accounts for more than 80% of the impairment in total body glucose disposal in T2D patients and is often characterized by an impaired insulin signaling. Mitsugumin 53 (MG53), a muscle-specific TRIM family protein initially identified as a key regulator of cell membrane repair machinery has been suggested to be a critical regulator of muscle insulin signaling pathway by acting as ubiquitin E3 ligase targeting both the insulin receptor and insulin receptor substrate 1 (IRS1). Here, we show using in vitro and in vivo approaches that MG53 is not a critical regulator of insulin signaling and glucose homeostasis. First, MG53 expression is not consistently regulated in skeletal muscle from various preclinical models of insulin resistance. Second, MG53 gene knock-down in muscle cells does not lead to impaired insulin response as measured by Akt phosphorylation on Serine 473 and glucose uptake. Third, recombinant human MG53 does not alter insulin response in both differentiated C2C12 and human skeletal muscle cells. Fourth, ectopic expression of MG53 in HEK293 cells lacking endogenous MG53 expression fails to alter insulin response as measured by Akt phosphorylation. Finally, both male and female mg53 -/- mice were not resistant to high fat induced obesity and glucose intolerance compared to wild-type mice. Taken together, these results strongly suggest that MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.

scholarly journals Activation of PI3K/Akt Signaling Pathway in Rat Hypothalamus Induced by an Acute Oral Administration of D-Pinitol

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2268
Author(s):  
Dina Medina-Vera ◽  
Juan Antonio Navarro ◽  
Rubén Tovar ◽  
Cristina Rosell-Valle ◽  
Alfonso Gutiérrez-Adan ◽  
...  
Keyword(s):  
Oral Administration ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Insulin Response ◽  
Pharmacological Action ◽  
Akt Signaling ◽  
Insulin Signaling Pathway ◽  
Acute Administration ◽  
Insulin Sensitizer ◽  
Peripheral Tissues

D-Pinitol (DPIN) is a natural occurring inositol capable of activating the insulin pathway in peripheral tissues, whereas this has not been thoroughly studied in the central nervous system. The present study assessed the potential regulatory effects of DPIN on the hypothalamic insulin signaling pathway. To this end we investigated the Phosphatidylinositol-3-kinase (PI3K)/Protein Kinase B (Akt) signaling cascade in a rat model following oral administration of DPIN. The PI3K/Akt-associated proteins were quantified by Western blot in terms of phosphorylation and total expression. Results indicate that the acute administration of DPIN induced time-dependent phosphorylation of PI3K/Akt and its related substrates within the hypothalamus, indicating an activation of the insulin signaling pathway. This profile is consistent with DPIN as an insulin sensitizer since we also found a decrease in the circulating concentration of this hormone. Overall, the present study shows the pharmacological action of DPIN in the hypothalamus through the PI3K/Akt pathway when giving in fasted animals. These findings suggest that DPIN might be a candidate to treat brain insulin-resistance associated disorders by activating insulin response beyond the insulin receptor.

scholarly journals Altered Insulin Receptor Substrate 1 Phosphorylation in Blood Neuron-Derived Extracellular Vesicles From Patients With Parkinson’s Disease

2020 ◽  
Vol 8 ◽  
Author(s):  
Szu-Yi Chou ◽  
Lung Chan ◽  
Chen-Chih Chung ◽  
Jing-Yuan Chiu ◽  
Yi-Chen Hsieh ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Extracellular Vesicles ◽  
Insulin Signaling ◽  
Clinical Manifestations ◽  
Insulin Signaling Pathway ◽  
Insulin Receptor Substrate ◽  
Neuronal Markers

IntroductionDiabetes increases the risk of Parkinson’s disease (PD). The phosphorylation of type 1 insulin receptor substrate (IRS-1) determines the function of insulin signaling pathway. Extracellular vesicles (EVs) are emerging as biomarkers of human diseases. The present study investigated whether PD patients exert altered phosphorylation IRS-1 (p-IRS-1) inside the blood neuron-derived extracellular vesicles (NDEVs).Research Design and MethodsIn total, there were 94 patients with PD and 63 healthy controls recruited and their clinical manifestations were evaluated. Blood NDEVs were isolated using the immunoprecipitation method, and Western blot analysis was conducted to assess total IRS-1, p-IRS-1, and downstream substrates level in blood NDEVs. Statistical analysis was performed using SPSS 19.0, and p < 0.05 was considered significant.ResultsThe isolated blood EVs were validated according to the presence of CD63 and HSP70, nanoparticle tracking analysis and transmission electron microscopy. NDEVs were positive with neuronal markers. PD patients exerted significantly higher level of p-IRS-1S312 in blood NDEVs than controls. In addition, the p-IRS-1S312 levels in blood NDEVs was positively associated with the severity of tremor in PD patients after adjusting of age, sex, hemoglobin A1c, and body mass index (BMI).ConclusionPD patients exerted altered p-IRS-1S312 in the blood NDEVs, and also correlated with the severity of tremor. These findings suggested the association between dysfunctional insulin signaling pathway with PD. The role of altered p-IRS-1S312 in blood NDEVs as a segregating biomarker of PD required further cohort study to assess the association with the progression of PD.

268 THE EFFECTS OF METFORMIN ON THE INSULIN SIGNALING PATHWAY ON PORCINE GRANULOSA LUTEIN CELLS IN A PRIMARY CULTURE SYSTEM

2007 ◽  
Vol 19 (1) ◽  
pp. 250
Author(s):  
M. S. Hossein ◽  
M. S. Lee ◽  
W. S. Hwang
Keyword(s):  
Insulin Receptor ◽  
Signaling Pathway ◽  
Granulosa Cells ◽  
Insulin Signaling ◽  
Luciferase Activity ◽  
Insulin Signaling Pathway ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Activator Protein ◽  
Nuclear Factor Kb

Metformin (N,N22-dimethylbiguanide) is an oral antihyperglycaemic drug which increases insulin-stimulated glucose uptake as an insulin sensitizing agent (ISA) and has direct effects on ovarian steroidogenesis in human. To investigate the effects of metformin on the insulin signaling pathway on porcine granulosa lutein cells in a primary culture system, we examined mRNA expressions of porcine insulin receptor, insulin-like growth factor-1 receptor, and insulin receptor substrate-1; expressions of downstream targets (Raf, MEK1/2, ERK, PDK1, mTOR, p70, and nuclear factor kB) of the insulin receptor signaling pathway; the luciferase activity of transcription factors activator protein 1; and nuclear factor kB. Granulosa cells were plated in DMEM and 10% fetal bovine serum at a density of 3.5 � 107 in a T-25 tissue culture flask and cultured for 48 h at 37�C in a humidified atmosphere of 5% CO2 and 95% air. Then, porcine granulosa lutein cells (pGLs) were cultured in a serum-free DMEM as a control group or supplemented with 10-5 M metformin, 100 ng mL-1 of insulin, or both for 24 h. The monolayer was collected for RT-PCR and western blot analysis. For transient transfections, porcine granulosa cells were plated in DMEM and 10% FBS at a concentration of 2.5 � 106/well in 24-well culture dishes for 16 h and then transfected with plasmid constructs using FuGene6 Transfection Reagent. Reporter vectors used in these studies were AP-1-luc and NF-κ B-luc. Cells were treated post-transfection with 10-5 M metformin, 100 ng mL-1 insulin, or both for 48 h. The luciferase activity was assayed using the dual luciferase assay kit with a Microlumat LB 96 P luminometer. Metformin with insulin significantly increased mRNA expressions of insulin receptor, insulin-like growth factor-1 receptor, and insulin receptor substrate-1, whereas metformin alone had no significant effect on the expression of genes. Metformin alone and with insulin significantly increased expressions of downstream targets of the insulin receptor signaling pathway except MEK2. Metformin with insulin significantly elicited an induction of luciferase activity in the transfection of activator protein 1 and nuclear factor kB reporter, whereas metformin alone did not. Metformin induced expressions of target molecules in the insulin signaling pathway but had no effect on the luciferase activity of activator protein 1 and nuclear factor kB in porcine granulosa lutein cells. Metformin with insulin increased the luciferase activity of activator protein 1. These results suggest that metformin with insulin could change the function of ovarian granulosa cells induced by activator protein 1 activity.

scholarly journals Sphingomyelinase has an insulin-like effect on glucose transporter translocation in adipocytes

1998 ◽  
Vol 274 (5) ◽  
pp. R1446-R1453 ◽  
Author(s):  
T. S. David ◽  
P. A. Ortiz ◽  
T. R. Smith ◽  
J. Turinsky
Keyword(s):  
Plasma Membrane ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Insulin Signaling Pathway ◽  
Glut 1 ◽  
Glut 4 ◽  
Glut 4 Translocation

Rat epididymal adipocytes were incubated with 0, 0.1, and 1 mU sphingomyelinase/ml for 30 or 60 min, and glucose uptake and GLUT-1 and GLUT-4 translocation were assessed. Adipocytes exposed to 1 mU sphingomyelinase/ml exhibited a 173% increase in glucose uptake. Sphingomyelinase had no effect on the abundance of GLUT-1 in the plasma membrane of adipocytes. In contrast, 1 mU sphingomyelinase/ml increased plasma membrane content of GLUT-4 by 120% and produced a simultaneous decrease in GLUT-4 abundance in the low-density microsomal fraction. Sphingomyelinase had no effect on tyrosine phosphorylation of either the insulin receptor β-subunit or the insulin receptor substrate-1, a signaling molecule in the insulin signaling pathway. It is concluded that the incubation of adipocytes with sphingomyelinase results in insulin-like translocation of GLUT-4 to the plasma membrane and that this translocation does not occur via the activation of the initial components of the insulin signaling pathway.

scholarly journals Modulation of Renal Insulin Signaling Pathway and Antioxidant Enzymes with Streptozotocin-Induced Diabetes: Effects of Resveratrol

Medicina ◽  
2018 ◽  
Vol 55 (1) ◽  
pp. 3 ◽  
Author(s):  
Gökhan Sadi ◽  
Gamze Şahin ◽  
Aykut Bostanci
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Antioxidant Enzymes ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Diabetic Rats ◽  
Insulin Signaling Pathway ◽  
Enzymatic Antioxidants ◽  
Gene And Protein Expression ◽  
Male Wistar Rats

Background and objectives: Diabetes mellitus is a disease of insulin deficiency or its inability of usage by the target tissues leading to impairment of carbohydrate, lipid, and protein metabolisms. Resveratrol, having robust anti-inflammatory and anti-oxidant properties, has a high potential to treat or prevent the pathogenesis of diseases. This study was conducted to reveal the relationship between diabetes-induced oxidative stress and tissue inflammation with changes in main enzymatic antioxidants (cat, sod, gpx, and gst) and the components of the insulin signaling pathway (insulin Rβ, irs-1, pi3k, akt, mtor) in kidney tissues. Additionally, the effects of resveratrol on these parameters were evaluated. Materials and Methods: Male Wistar rats were randomly divided into four groups; (1) control/vehicle; (2) control/20 mg/kg resveratrol; (3) diabetic/vehicle; (4) diabetic/20 mg/kg resveratrol. Gene and protein expressions of antioxidant enzymes and insulin signaling elements were evaluated in renal tissues. Results: Downregulation of antioxidant enzymes’ gene expression in the kidney tissues of diabetic rats was demonstrated and this situation was devoted partially to the reduced gene expression of nfκb. Moreover, the components of renal insulin signaling elements were upregulated at both gene and protein expression levels in diabetic rats, and resveratrol treatment decreased this sensitization towards the control state. Conclusion: Resveratrol partially improved diabetes-induced renal oxidative stress and inflammation due to healing action on renal antioxidant enzymes and insulin signaling pathway components.

scholarly journals Glucose Effects on Beta-Cell Growth and Survival Require Activation of Insulin Receptors and Insulin Receptor Substrate 2

2009 ◽  
Vol 29 (11) ◽  
pp. 3219-3228 ◽  
Author(s):  
Anke Assmann ◽  
Kohjiro Ueki ◽  
Jonathon N. Winnay ◽  
Takahashi Kadowaki ◽  
Rohit N. Kulkarni
Keyword(s):  
Insulin Receptor ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Insulin Signaling ◽  
Insulin Receptors ◽  
Insulin Signaling Pathway ◽  
Insulin Receptor Substrate ◽  
Β Cells ◽  
Β Cell ◽  
Growth And Survival

ABSTRACT Insulin and insulin-like growth factor I (IGF-I) are ubiquitous hormones that regulate growth and metabolism of most mammalian cells, including pancreatic β-cells. In addition to being an insulin secretagogue, glucose regulates proliferation and survival of β-cells. However, it is unclear whether the latter effects of glucose occur secondary to autocrine activation of insulin signaling proteins by secreted insulin. To examine this possibility we studied the effects of exogenous glucose or insulin in β-cell lines completely lacking either insulin receptors (βIRKO) or insulin receptor substrate 2 (βIRS2KO). Exogenous addition of either insulin or glucose activated proteins in the insulin signaling pathway in control β-cell lines with the effects of insulin peaking earlier than glucose. Insulin stimulation of βIRKO and βIRS2KO cells led to blunted activation of phosphatidylinositol 3-kinase and Akt kinase, while surprisingly, glucose failed to activate either kinase but phosphorylated extracellular signal-regulated kinase. Control β-cells exhibited low expression of IGF-1 receptors compared to compensatory upregulation in βIRKO cells. The signaling data support the slow growth and reduced DNA and protein synthesis in βIRKO and βIRS2KO cells in response to glucose stimulation. Together, these studies provide compelling evidence that the growth and survival effects of glucose on β-cells require activation of proteins in the insulin signaling pathway.

scholarly journals Blood Orange Juice Intake Modulates the Expression of miR-126–3p and let-7f-5p in PBMC of Overweight and Insulin Resistance Women

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 936-936
Author(s):  
Vinícius Cooper Capetini ◽  
Bruna Jardim Quintanilha ◽  
Geni Rodrigues Sampaio ◽  
Frederico Moraes Ferreira ◽  
Marcelo Rogero
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Orange Juice ◽  
Target Genes ◽  
Mononuclear Cells ◽  
Insulin Signaling Pathway ◽  
Model Assessment ◽  
Blood Orange

Abstract Objectives To investigate the effect of chronic blood orange juice intake on the microRNA profile in peripheral blood mononuclear cells (PBMC) of overweight and insulin resistance women. Methods Interventional and chronic study with women (n = 8) aged 18 to 40 years, diagnosed with overweight [body mass index (BMI) 25–29.9 kg/m2] and insulin resistance [homeostatic model assessment insulin resistance (HOMA-IR) index >2,71]. For four weeks, the volunteers ingested 500 mL/day of blood orange juice (Moro variety), with blood samples collected at baseline and four weeks after the beginning of drink ingestion. Evaluation of the expression of 137 microRNAs in PBMC was performed by real-time polymerase chain reaction (PCR). Results Blood orange juice intake decreased the expression of miR-126-3p (p = 0.004) and let-7f-5p (p = 0.005) in PBMC. These microRNAs are involved in suppressing the synthesis of several proteins of the insulin signaling pathway. Insulin receptor substrates (IRS) 1 and 2 were identified as target genes of mir-126. Insulin-like growth factor 1 receptor (IGF1R), insulin receptor (INSR), IRS2, phosphatidylinositol-3-kinase interacting protein 1 (PIK3IP1), and protein kinase B/Akt 2 (AKT2) were identified as target genes of let-7f. Conclusions Blood orange juice, rich in vitamin C, flavonoids, and anthocyanins, downregulates the expression of microRNA involved in impairing the insulin signaling pathway. Funding Sources Food Research Center (FoRC), São Paulo Research Foundation (FAPESP)

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