scholarly journals Synthesis, Characterization, and Preclinical Evaluation of New Thiazolidin-4-ones Substituted with p-Chlorophenoxy Acetic Acid and Clofibric Acid against Insulin Resistance and Metabolic Disorder

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Vasantharaju S. Gowdra ◽  
Jayesh Mudgal ◽  
Punit Bansal ◽  
Pawan G. Nayak ◽  
Seethappa A. Manohara Reddy ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Uptake ◽  
Metabolic Disorders ◽  
Insulin Resistant ◽  
Insulin Sensitizers ◽  
Uptake Assay ◽  
Glucose Uptake Assay ◽  
Plasma Leptin

We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From thein vitroglucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound3areduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.

scholarly journals Reducing effect of insulin resistance on alpha-synuclein gene expression in skeletal muscle

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Amirhosein Khoshi ◽  
Golnaz Goodarzi ◽  
Rezvan Mohammadi ◽  
Roghaye Arezumand ◽  
Meysam Moghbeli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Glucose Uptake ◽  
Alpha Synuclein ◽  
C2c12 Cells ◽  
Diabetic Mice ◽  
Insulin Metabolism ◽  
Insulin Resistant ◽  
Type 2 Diabetic

Abstract Background Alpha-synuclein (SNCA) as the presynaptic protein is expressed in different tissues and prevents insulin-resistance (IR) through increasing glucose-uptake by adipocytes and muscles. However, the effect of insulin metabolism on SNCA expression has scarcely elucidated. In present study we assessed the probable effect of insulin resistance on SNCA expression in muscle C2C12 cells and also skeletal muscle tissues of type 2 diabetic mice. Materials and methods Sixteen male C57BL/6 mice were divided into two experimental groups, including control and type 2 diabetic mice with IR (induced by high-fat diet + low-dose streptozotocin). The animals of the study involved the measurements of fasting blood glucose, oral-glucose-tolerance-test, as well as fasting plasma insulin. Moreover, insulin-resistant and insulin-sensitive muscle C2C12 cells were prepared. The insulin-resistance was confirmed by the glucose-uptake assay. Comparative quantitative real time PCR was used to assess the SNCA expression. Results The obtained results have showed a significant ~ 27% decrease in SNCA expression level in muscle tissue of diabetic mice (P = 0.022). Moreover, there was a significant change of SNCA expression in insulin-resistant C2C12 cells (P < 0.001). Conclusion Type 2 diabetes due to insulin-resistance can decrease SNCA gene expression in muscles. In addition to the role of SNCA in cell susceptibility to insulin and glucose uptake, the SNCA expression can also be affected by insulin metabolism.

A novel small molecule A2A adenosine receptor agonist, indirubin-3′-monoxime, alleviates lipid-induced inflammation and insulin resistance in 3T3-L1 adipocytes

2019 ◽  
Vol 476 (16) ◽  
pp. 2371-2391 ◽  
Author(s):  
Saynaz A. Choudhary ◽  
Nikita Bora ◽  
Dipanjan Banerjee ◽  
Leena Arora ◽  
Anindhya Sundar Das ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adenosine Receptor ◽  
In Vitro Study ◽  
A2a Adenosine Receptor ◽  
Insulin Resistant ◽  
Adenosine Receptor Agonist ◽  
Inflammatory State

Abstract Saturated free fatty acid-induced adipocyte inflammation plays a pivotal role in implementing insulin resistance and type 2 diabetes. Recent reports suggest A2A adenosine receptor (A2AAR) could be an attractive choice to counteract adipocyte inflammation and insulin resistance. Thus, an effective A2AAR agonist devoid of any toxicity is highly appealing. Here, we report that indirubin-3′-monoxime (I3M), a derivative of the bisindole alkaloid indirubin, efficiently binds and activates A2AAR which leads to the attenuation of lipid-induced adipocyte inflammation and insulin resistance. Using a combination of in silico virtual screening of potential anti-diabetic candidates and in vitro study on insulin-resistant model of 3T3-L1 adipocytes, we determined I3M through A2AAR activation markedly prevents lipid-induced impairment of the insulin signaling pathway in adipocytes without any toxic effects. While I3M restrains lipid-induced adipocyte inflammation by inhibiting NF-κB dependent pro-inflammatory cytokines expression, it also augments cAMP-mediated CREB activation and anti-inflammatory state in adipocytes. However, these attributes were compromised when cells were pretreated with the A2AAR antagonist, SCH 58261 or siRNA mediated knockdown of A2AAR. I3M, therefore, could be a valuable option to intervene adipocyte inflammation and thus showing promise for the management of insulin resistance and type 2 diabetes.

Normal Akt/PKB with reduced PI3K activation in insulin-resistant mice

2001 ◽  
Vol 281 (6) ◽  
pp. E1249-E1254 ◽  
Author(s):  
Samuel T. Nadler ◽  
Jonathan P. Stoehr ◽  
Mary E. Rabaglia ◽  
Kathryn L. Schueler ◽  
Morris J. Birnbaum ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Resistant ◽  
Experimental Systems ◽  
Pi3k Activity ◽  
Pi3k Activation

Insulin stimulates muscle and adipose tissue to absorb glucose through a signaling cascade that is incompletely understood. Insulin resistance, the inability of insulin to appropriately stimulate glucose uptake, is a hallmark of type 2 diabetes mellitus. The development of experimental systems that model human insulin resistance is important in elucidating the defects responsible for the development of type 2 diabetes. When two strains of mice, BTBR and C57BL/6J (B6), are crossed, the resultant male offspring (BtB6) demonstrate insulin resistance in muscle tissue. Here, we report an insulin resistance phenotype in adipose tissue from lean, nondiabetic BtB6 mice similar to that observed in human muscle. Adipocytes isolated from insulin-resistant male mice display 65% less insulin-stimulated glucose uptake compared with insulin-sensitive female mice. Similarly, adipocytes from insulin-resistant mice have diminished insulin-stimulated IRS-1 phosphorylation and phosphatidylinositol 3-kinase (PI3K) activation. However, normal activation of protein kinase B (Akt/PKB) by insulin is observed. Thus BtB6 mice demonstrate the dissociation of insulin-stimulated PI3K activity and Akt/PKB activation and represent a useful model to investigate the causes of insulin resistance in humans.

scholarly journals STUDIES ON IN VITRO ANTIDIABETIC ACTIVITIES OF HOPEA PONGA AND VITEX LEUCOXYLON

2017 ◽  
Vol 9 (2) ◽  
pp. 263 ◽  
Author(s):  
Arun Kashivishwanath Shettar ◽  
Ankala Basappa Vedamurthy
Keyword(s):  
Glucose Uptake ◽  
Aqueous Extract ◽  
Yeast Cells ◽  
Antidiabetic Activity ◽  
Significant Activity ◽  
Soxhlet Apparatus ◽  
Ic50 Value ◽  
Uptake Assay ◽  
Glucose Uptake Assay

<p><strong>Objective: </strong>Evaluating antidiabetic property of <em>Hopea ponga</em> and <em>Vitex leucoxylon</em> extracts by using <em>in vitro</em> assays.</p><p><strong>Methods: </strong>The exhaustive serial extraction was carried out with a series of solvents: chloroform, ethyl acetate, methanol, ethanol and water with increasing polarity using Soxhlet apparatus. The concentrated and dried extracts were evaluated for antidiabetic activity by employing standard <em>in vitro</em> techniques (α-amylase and glucose uptake assay using yeast model in which the effects of extracts on α-amylase and glucose uptake was tested by considering the percentage of inhibition of α-amylase and increase in glucose uptake in yeast cells).</p><p><strong>Results: </strong><em>In vitro</em> antidiabetic studies show that in case of <em>Hopea ponga</em> methanol extract showed comparable antidiabetic activity with percentage of α-amylase inhibition 51.7925±0.92794 % and with IC50 value 96.53 µg and it was less on comparison with standard i.e. 71.0907±0.67796% with IC50 value 70.33 µg and in case of glucose uptake assay aqueous extract showed higher activity over all remaining extracts with percentage of inhibition 49.8100±0.62476% and with IC50 value 250.95 µg. whereas in case of <em>Vitex leucoxylon</em> aqueous extract exhibited significant activity in both performed assays i. e α-amylase inhibition and glucose uptake assay with percentage 54.6147±0.46397% and 57.1337±0.44201% respectively when compared to other solvent extracts.</p><p><strong>Conclusion: </strong>Results confirm that aqueous extract of <em>Vitex leucoxylon</em> exhibited highest antidiabetic activity among all extracts. Additional studies are needed for purification, characterization and structural elucidation of bioactive compounds from aqueous extract and also confirm its antidiabetic property by <em>in vivo</em> studies. The present study provides scientific evidence that the leaves of <em>Hopea ponga and Vitex leucoxylon</em> possess anti-diabetic efficacy. Thus, considering its relative antidiabetic potency, these extracts are the useful therapeutic agents for treating and management of diabetes.</p>

scholarly journals Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng

2009 ◽  
Vol 203 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Yun Wang ◽  
Patsy M Nishina ◽  
Jürgen K Naggert
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Insulin Resistant

The TALLYHO/Jng (TH) mouse strain is a polygenic model for type 2 diabetes (T2D) characterized by moderate obesity, impaired glucose tolerance and uptake, insulin resistance, and hyperinsulinemia. The goal of this study was to elucidate the molecular mechanisms responsible for the reduced glucose uptake and insulin resistance in the adipose tissue of this model. The translocation and localization of glucose transporter 4 (GLUT4) to the adipocyte plasma membrane were impaired in TH mice compared to control C57BL6/J (B6) mice. These defects were associated with decreased GLUT4 protein, reduced phosphatidylinositol 3-kinase activity, and alterations in the phosphorylation status of insulin receptor substrate 1 (IRS1). Activation of c-Jun N-terminal kinase 1/2, which can phosphorylate IRS1 on Ser307, was significantly higher in TH mice compared with B6 controls. IRS1 protein but not mRNA levels was found to be lower in TH mice than controls. Immunoprecipitation with anti-ubiquitin and western blot analysis of IRS1 protein revealed increased total IRS1 ubiquitination in adipose tissue of TH mice. Suppressor of cytokine signaling 1, known to promote IRS1 ubiquitination and subsequent degradation, was found at significantly higher levels in TH mice compared with B6. Immunohistochemistry showed that IRS1 colocalized with the 20S proteasome in proteasomal structures in TH adipocytes, supporting the notion that IRS1 is actively degraded. Our findings suggest that increased IRS1 degradation and subsequent impaired GLUT4 mobilization play a role in the reduced glucose uptake in insulin resistant TH mice. Since low-IRS1 levels are often observed in human T2D, the TH mouse is an attractive model to investigate mechanisms of insulin resistance and explore new treatments.

scholarly journals IN VITRO EVALUATION OF ANTIDIABETIC AND CYTOTOXICITY POTENTIALS OF THE RHIZOME EXTRACT OF DRYNARIA QUERCIFOLIA (L.) J. SMITH

2019 ◽  
pp. 72-76
Author(s):  
PRASANNA G ◽  
DEVI R ◽  
ISHWARYA G
Keyword(s):  
Liver Cancer ◽  
Glucose Uptake ◽  
Cell Line ◽  
Hepg2 Cell ◽  
Plant Extract ◽  
Mtt Assay ◽  
Hepg2 Cell Line ◽  
Uptake Assay ◽  
Glucose Uptake Assay

Objective: In the present study, an attempt has been made to evaluate the in vitro antidiabetic and cytotoxic potentials of the rhizome extract of Drynaria quercifolia (L.) J. Smith. Methods: In vitro antidiabetic activity was determined by two different assays such as alpha-amylase inhibition assay and glucose uptake assay. The plant extract with three different concentrations was used for this assay. L6 rat myogenic cells were selected and subjected to glucose uptake assay. The cytotoxic activity of the different concentrations of the plant extract on HepG2 cell line was also investigated in vitro through 3-(4,5, dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Results: The findings of the study provide evidence that the rhizome extract of D. quercifolia possesses significant anti-diabetic activity. In MTT assay, the significant cytotoxic effect of plant extract was observed by measuring the percentage of cell viability on the HepG2 cell line. Conclusion: The findings indicated that rhizome extracts of D. quercifolia have potential as a medicinal drug against diabetes mellitus (DM) and liver cancer. Further, studies with in vivo and clinical trials need to be conducted to establish rhizome extract as a safe agent for DM and liver cancer therapy.

scholarly journals Attenuation of Free Fatty Acid (FFA)-Induced Skeletal Muscle Cell Insulin Resistance by Resveratrol is Linked to Activation of AMPK and Inhibition of mTOR and p70 S6K

2020 ◽  
Vol 21 (14) ◽  
pp. 4900
Author(s):  
Danja J. Den Hartogh ◽  
Filip Vlavcheski ◽  
Adria Giacca ◽  
Evangelia Tsiani
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Muscle Insulin Resistance ◽  
Skeletal Muscle Insulin Resistance ◽  
Specific Proteins ◽  
P70 S6k

Insulin resistance, a main characteristic of type 2 diabetes mellitus (T2DM), is linked to obesity and excessive levels of plasma free fatty acids (FFA). Studies indicated that significantly elevated levels of FFAs lead to skeletal muscle insulin resistance, by dysregulating the steps in the insulin signaling cascade. The polyphenol resveratrol (RSV) was shown to have antidiabetic properties but the exact mechanism(s) involved are not clearly understood. In the present study, we examined the effect of RSV on FFA-induced insulin resistance in skeletal muscle cells in vitro and investigated the mechanisms involved. Parental and GLUT4myc-overexpressing L6 rat skeletal myotubes were used. [3H]2-deoxyglucose (2DG) uptake was measured, and total and phosphorylated levels of specific proteins were examined by immunoblotting. Exposure of L6 cells to FFA palmitate decreased the insulin-stimulated glucose uptake, indicating insulin resistance. Palmitate increased ser307 (131% ± 1.84% of control, p < 0.001) and ser636/639 (148% ± 10.1% of control, p < 0.01) phosphorylation of IRS-1, and increased the phosphorylation levels of mTOR (174% ± 15.4% of control, p < 0.01) and p70 S6K (162% ± 20.2% of control, p < 0.05). Treatment with RSV completely abolished these palmitate-induced responses. In addition, RSV increased the activation of AMPK and restored the insulin-mediated increase in (a) plasma membrane GLUT4 glucose transporter levels and (b) glucose uptake. These data suggest that RSV has the potential to counteract the FFA-induced muscle insulin resistance.

scholarly journals Dibenzocyclooctadiene Lignans from Fructus Schisandrae Chinensis Improve Glucose Uptake in vitro

2010 ◽  
Vol 5 (2) ◽  
pp. 1934578X1000500 ◽  
Author(s):  
Jing Zhang ◽  
Lei Ling Shi ◽  
Yi Nan Zheng
Keyword(s):  
Glucose Uptake ◽  
Methanol Extract ◽  
Antidiabetic Activity ◽  
Traditional Use ◽  
Gomisin A ◽  
Uptake Assay ◽  
Glucose Uptake Assay ◽  
Gomisin N ◽  
Fructus Schisandrae Chinensis

Glucose uptake assay-guided fractionations of the methanol extract of Schisandra chinensis led to the isolation of the dibenzocyclooctadiene lignans: gomisin J (1), gomisin N (2), wuweizisu B (3), wuweizisu C (4), gomisin C (5), gomisin D (6), (+)-schisandrin A (7), schisandrin C (8), schisandrol A (9), gomisin H (10), angeloylgomisin H (11), gomisin A (12), and schizandrin (13). Among these, 1, 2, 7, and 8 significantly improved basal glucose uptake in HepG2 cells. Their improving effects were concentration-dependent. Compound 2 exhibited a stronger effect than that of rosiglitazone, which has been used as an antidiabetic drug. The results suggest that these lignans may partially contribute to the antidiabetic activity of Fructus Schisandrae Chinensis in traditional use by stimulating the glucose uptake into peripheral tissue, which may be responsible for reducing the level of blood glucose in circulation. Thus, these findings show the potential of these lignans for development as hypoglycemic drugs.

Increased glucose uptake promotes oxidative stress and PKC-δ activation in adipocytes of obese, insulin-resistant mice

2003 ◽  
Vol 285 (2) ◽  
pp. E295-E302 ◽  
Author(s):  
Ilana Talior ◽  
Merav Yarkoni ◽  
Nava Bashan ◽  
Hagit Eldar-Finkelman
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Glucose Uptake ◽  
Glucose Deprivation ◽  
Insulin Resistant ◽  
Glucose Intake ◽  
Glut1 Expression ◽  
And Oxidative Stress ◽  
Type 2 Diabetic

Increased oxidative stress is believed to be one of the mechanisms responsible for hyperglycemia-induced tissue damage and diabetic complications. In these studies, we undertook to characterize glucose uptake and oxidative stress in adipocytes of type 2 diabetic animals and to determine whether these promote the activation of PKC-δ. The adipocytes used were isolated either from C57Bl/6J mice that were raised on a high-fat diet (HF) and developed obesity and insulin resistance or from control animals. Basal glucose uptake significantly increased (8-fold) in HF adipocytes, and this was accompanied with upregulation of GLUT1 expression levels. Insulin-induced glucose uptake was inhibited in HF adipocytes and GLUT4 content reduced by 20% in these adipocytes. Reactive oxygen species (ROS) increased twofold in HF adipocytes compared with control adipocytes and were largely reduced with decreased glucose concentrations. At zero glucose, ROS levels were reduced to the normal levels seen in control adipocytes. The activity of PKC-δ increased twofold in HF adipocytes compared with control adipocytes and was further activated by H2O2. Moreover, PKC-δ activity was inhibited in HF adipocytes either by glucose deprivation or by treatment with the antioxidant N-acetyl-l-cysteine. In summary, we propose that increased glucose intake in HF adipocytes increases oxidative stress, which in turn promotes the activation of PKC-δ. These consequential events may be responsible, at least in part, for development of HF diet-induced insulin resistance in the fat tissue.

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