scholarly journals Theaflavins Improve Insulin Sensitivity through Regulating Mitochondrial Biosynthesis in Palmitic Acid-Induced HepG2 Cells

2018 ◽  
Author(s):  
Tuantuan Tong ◽  
Ning Ren ◽  
Jiafan Wu ◽  
Na Guo ◽  
Xiaobo Liu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Palmitic Acid ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Mitochondrial Dna Copy Number ◽  
Increase Glucose Uptake

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improvement effects on insulin resistance-associated metabolic abnormalities including obesity and type 2 diebetes. However, the molecular mechanisms of theaflavins improving insulin sensitivity are still not clear. In this study, we investigated the protective effects and mechanisms of theaflavins on palmitic acid-induced insulin resistance in HepG2 cells. Theaflavins could significantly increase glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the glucose transporter 4 protein expression, increasing the phosphorylation of IRS-1 at Ser307, and reduced the phosphor-Akt (Ser473) level. Moreover, theaflavins were found to enhance mitochondrial DNA copy number through down-regulate the PGC-1β mRNA level and up-regulate PRC mRNA expression in insulin-resistant HepG2 cells. These results indicated that theaflavins could improve free fatty acid-induced hepatic insulin resistance by promoting mitochondrial biogenesis, and were promising functional food and medicines for insulin resistance-related disorders.

scholarly journals Theaflavins Improve Insulin Sensitivity through Regulating Mitochondrial Biosynthesis in Palmitic Acid-Induced HepG2 Cells

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3382 ◽  
Author(s):  
Tuantuan Tong ◽  
Ning Ren ◽  
Park Soomi ◽  
Jiafan Wu ◽  
Na Guo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Palmitic Acid ◽  
Glucose Uptake ◽  
Hepg2 Cells ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Mrna Level ◽  
Food Ingredients ◽  
Insulin Resistant ◽  
Mitochondrial Dna Copy Number

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improving effects on insulin resistance-associated metabolic abnormalities, including obesity and type 2 diabetes mellitus. However, the related molecular mechanisms are still unclear. In this research, we investigated the protective effects of theaflavins against insulin resistance in HepG2 cells induced by palmitic acid. Theaflavins significantly increased glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the total and membrane bound glucose transporter 4 protein expressions, increasing the phosphor-Akt (Ser473) level, and decreasing the phosphorylation of IRS-1 at Ser307. Moreover, theaflavins were found to enhance the mitochondrial DNA copy number, down-regulate the PGC-1β mRNA level and increase the PRC mRNA expression. Mdivi-1, a selective mitochondrial division inhibitor, could attenuate TFs-induced promotion of glucose uptake in insulin-resistant HepG2 cells. Taken together, these results suggested that theaflavins could improve hepatocellular insulin resistance induced by free fatty acids, at least partly through promoting mitochondrial biogenesis. Theaflavins are promising functional food ingredients and medicines for improving insulin resistance-related disorders.

scholarly journals Aspalathin-Enriched Green Rooibos Extract Reduces Hepatic Insulin Resistance by Modulating PI3K/AKT and AMPK Pathways

2019 ◽  
Vol 20 (3) ◽  
pp. 633 ◽  
Author(s):  
Sithandiwe Mazibuko-Mbeje ◽  
Phiwayinkosi Dludla ◽  
Candice Roux ◽  
Rabia Johnson ◽  
Samira Ghoor ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Glucose Transporter ◽  
Insulin Signalling ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Glucose Transporter 2

We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.

scholarly journals Sulforaphane Prevents Hepatic Insulin Resistance by Blocking Serine Palmitoyltransferase 3-Mediated Ceramide Biosynthesis

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1185 ◽  
Author(s):  
Wendi Teng ◽  
Yuan Li ◽  
Min Du ◽  
Xingen Lei ◽  
Siyu Xie ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Signaling Pathway ◽  
Glucose Homeostasis ◽  
Hepg2 Cells ◽  
Hepatic Insulin Resistance ◽  
Serine Palmitoyltransferase ◽  
Insulin Resistant ◽  
Ceramide Production

Sulforaphane (SFA), a naturally active isothiocyanate compound from cruciferous vegetables used in clinical trials for cancer treatment, was found to possess potency to alleviate insulin resistance. But its underlying molecular mechanisms are still incompletely understood. In this study, we assessed whether SFA could improve insulin sensitivity and glucose homeostasis both in vitro and in vivo by regulating ceramide production. The effects of SFA on glucose metabolism and expression levels of key proteins in the hepatic insulin signaling pathway were evaluated in insulin-resistant human hepatic carcinoma HepG2 cells. The results showed that SFA dose-dependently increased glucose uptake and intracellular glycogen content by regulating the insulin receptor substrate 1 (IRS-1)/protein kinase B (Akt) signaling pathway in insulin-resistant HepG2 cells. SFA also reduced ceramide contents and downregulated transcription of ceramide-related genes. In addition, knockdown of serine palmitoyltransferase 3 (SPTLC3) in HepG2 cells prevented ceramide accumulation and alleviated insulin resistance. Moreover, SFA treatment improved glucose tolerance and insulin sensitivity, inhibited SPTLC3 expression and hepatic ceramide production and reduced hepatic triglyceride content in vivo. We conclude that SFA recovers glucose homeostasis and improves insulin sensitivity by blocking ceramide biosynthesis through modulating SPTLC3, indicating that SFA may be a potential candidate for prevention and amelioration of hepatic insulin resistance via a ceramide-dependent mechanism.

Investigation of insulin resistance through a multiorgan microfluidic organ-on-chip

2021 ◽  
Author(s):  
Nida Tanataweethum ◽  
Allyson Trang ◽  
Chaeeun Lee ◽  
Jhalak Mehta ◽  
Neha Patel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Lipid Synthesis ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Brown Adipose ◽  
Hepatic Glucose ◽  
On Chip ◽  
Adipose Organ

Abstract The development of hepatic insulin resistance (IR) is a critical factor in developing type 2 diabetes (T2D), where insulin fails to inhibit hepatic glucose production but retains its capacity to promote hepatic lipogenesis. Improving insulin sensitivity can be effective in preventing and treating T2D. However, selective control of glucose and lipid synthesis has been difficult. It is known that excess white adipose tissue is detrimental to insulin sensitivity, whereas brown adipose tissue transplantation can restore it in diabetic mice. However, challenges remain in our understanding of liver-adipose communication because the confounding effects of hypothalamic regulation of metabolic function cannot be ruled out in previous studies. There is a lack of in vitro models that use primary cells to study cellular-crosstalk under insulin resistant conditions. Building upon our previous work on the microfluidic primary liver and adipose organ-on-chips, we report for the first time the development of integrated insulin resistant liver-adipose (white and brown) organ-on-chip. The design of the microfluidic device was carried out using computational fluid dynamics; the experimental studies were conducted by carrying out detailed biochemical analysis RNA-seq analysis on both cell types. Further, we tested the hypothesis that brown adipocytes regulated both hepatic insulin sensitivity and lipogenesis. Our results show effective co-modulation of hepatic glucose and lipid synthesis through a platform for identifying potential therapeutics for IR and diabetes.

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 Palmitic Acid Induces MicroRNA-221 Expression to Decrease Glucose Uptake in HepG2 Cells via the PI3K/AKT/GLUT4 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Fang Huang ◽  
Jie Chen ◽  
Jingwen Wang ◽  
Pingping Zhu ◽  
Wenting Lin
Keyword(s):  
Insulin Resistance ◽  
Palmitic Acid ◽  
Glucose Uptake ◽  
Hepg2 Cells ◽  
Glucose Transporter ◽  
High Fatty Acid ◽  
Luciferase Reporter ◽  
High Concentrations ◽  
Novel Target ◽  
Phosphoinositide 3 Kinase

Obesity-related insulin resistance and high fatty acid concentrations occur during the development of type 2 diabetes mellitus. The role of high concentrations of plasma-free fatty acids is not fully understood. In this study, palmitic acid (PA, 0.8 mM for 24 h) induced the expression of miR-221 that bound to phosphoinositide 3-kinases (PI3K) mRNA to inhibit glucose uptake by HepG2 cells. Compared with controls, PA significantly decreased glucose uptake, increased insulin receptor substrate-2 (IRS-2) and miR-221 expression, and decreased phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and glucose transporter type 4 (GLUT4) mRNA expression. Luciferase reporter assay revealed that miR-221 binding inhibited PI3K expression. Transfection of HepG2 cells with an miR-221 mimic induced miR-221 expression and inhibited the PI3K/AKT pathway. PA decreased glucose uptake in HepG2 cells by inducing the expression of miR-221, which bound to PI3K mRNA and suppressed PI3K/AKT signaling. miR-221 may be a novel target for preventing and treating obesity-induced insulin resistance.

scholarly journals Four sesquiterpene glycosides from loquat (Eriobotrya japonica) leaf ameliorates palmitic acid-induced insulin resistance and lipid accumulation in HepG2 Cells via AMPK signaling pathway

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10413
Author(s):  
Jiawei Li ◽  
Xiaoqin Ding ◽  
Tunyu Jian ◽  
Han Lü ◽  
Lei Zhao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Palmitic Acid ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Eriobotrya Japonica ◽  
Expression Levels ◽  
Ampk Signaling ◽  
Insulin Resistant ◽  
Compound C

Insulin resistance (IR), caused by impaired insulin signal and decreased insulin sensitivity, is generally responsible for the pathophysiology of type 2 diabetes mellitus (T2DM). Sesquiterpene glycosides (SGs), the exclusive natural products from loquat leaf, have been regarded as potential lead compounds owing to their high efficacy in hypoglycemia and hypolipidemia. Here, we evaluated the beneficial effects of four single SGs isolated from loquat leaf, including SG1, SG2, SG3 and one novel compound SG4 against palmitic acid-induced insulin resistance in HepG2 cells. SG1, SG3 and SG4 could significantly enhance glucose uptake of insulin-resistant HepG2 cells at non-cytotoxic concentration. Meanwhile, Oil Red O staining showed the decrease of both total cholesterol and triglyceride content, suggesting the amelioration of lipid accumulation by SGs in insulin-resistant HepG2 cells. Further investigations found that the expression levels of phosphorylated AMPK, ACC, IRS-1, and Akt were significantly up-regulated after SGs treatment, on the contrary, the expression levels of SREBP-1 and FAS were significantly down-regulated. Notably, AMPK inhibitor Compound C (CC) blocked the regulative effects, while AMPK activator AICAR mimicked the effects of SGs in PA-treated insulin-resistant HepG2 cells. In conclusion, SGs (SG4>SG1≈SG3>SG2) improved lipid accumulation in insulin-resistant HepG2 cells through the AMPK signaling pathway.

scholarly journals Resveratrol Counteracts Insulin Resistance—Potential Role of the Circulation

Nutrients ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1160 ◽  
Author(s):  
Rachel Wong ◽  
Peter Howe
Keyword(s):  
Insulin Resistance ◽  
Potential Role ◽  
Glucose Transporter ◽  
Blood Perfusion ◽  
Glut4 Translocation ◽  
Insulin Resistant ◽  
Increase Glucose Uptake ◽  
Glucose Transporter Type 4

Pre-clinical data and human trials indicate that resveratrol supplementation may help to counteract diabetes. Several mechanisms of action have been proposed to explain its metabolic benefits, including activation of sirtuins and estrogen receptors (ER) to promote glucose transporter type-4 (GLUT4) translocation and increase glucose uptake. Resveratrol can also enhance vasodilator function, yet the possibility that this action might help to alleviate insulin resistance in type-2 diabetes mellitus has received little attention. In this brief review we propose that, by restoring impaired endothelium-dependent vasodilatation in insulin resistant individuals resveratrol increases blood perfusion of skeletal muscle, thereby facilitating glucose delivery and utilization with resultant improvement of insulin sensitivity. Thus, circulatory improvements by vasoactive nutrients such as resveratrol may play a role in preventing or alleviating insulin resistance.

scholarly journals Betaine improves nonalcoholic fatty liver and associated hepatic insulin resistance: a potential mechanism for hepatoprotection by betaine

2010 ◽  
Vol 299 (5) ◽  
pp. G1068-G1077 ◽  
Author(s):  
Elango Kathirvel ◽  
Kengathevy Morgan ◽  
Ganesh Nandgiri ◽  
Brian C. Sandoval ◽  
Marie A. Caudill ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Liver ◽  
Signaling Pathways ◽  
Hepg2 Cells ◽  
Fasting Glucose ◽  
Hepatic Insulin Resistance ◽  
Nonalcoholic Fatty Liver ◽  
Downstream Signaling ◽  
Insulin Resistant ◽  
Hepatic Fat

Nonalcoholic fatty liver (NAFL) is a common liver disease, associated with insulin resistance. Betaine has been tested as a treatment for NAFL in animal models and in small clinical trials, with mixed results. The present study aims to determine whether betaine treatment would prevent or treat NAFL in mice and to understand how betaine reverses hepatic insulin resistance. Male mice were fed a moderate high-fat diet (mHF) containing 20% of calories from fat for 7 (mHF) or 8 (mHF8) mo without betaine, with betaine (mHFB), or with betaine for the last 6 wk (mHF8B). Control mice were fed standard chow containing 9% of calories from fat for 7 mo (SF) or 8 mo (SF8). HepG2 cells were made insulin resistant and then studied with or without betaine. mHF mice had higher body weight, fasting glucose, insulin, and triglycerides and greater hepatic fat than SF mice. Betaine reduced fasting glucose, insulin, triglycerides, and hepatic fat. In the mHF8B group, betaine treatment significantly improved insulin resistance and hepatic steatosis. Hepatic betaine content significantly decreased in mHF and increased significantly in mHFB. Betaine treatment reversed the inhibition of hepatic insulin signaling in mHF and in insulin-resistant HepG2 cells, including normalization of insulin receptor substrate 1 (IRS1) phosphorylation and of downstream signaling pathways for gluconeogenesis and glycogen synthesis. Betaine treatment prevents and treats fatty liver in a moderate high-dietary-fat model of NAFL in mice. Betaine also reverses hepatic insulin resistance in part by increasing the activation of IRS1, with resultant improvement in downstream signaling pathways.

scholarly journals Oleanolic Acid Attenuates Insulin Resistance via NF-κB to Regulate the IRS1-GLUT4 Pathway in HepG2 Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Ming Li ◽  
Zongyu Han ◽  
Weijian Bei ◽  
Xianglu Rong ◽  
Jiao Guo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Expression ◽  
Oleanolic Acid ◽  
Hepg2 Cells ◽  
Glucose Transporter ◽  
Underlying Mechanism ◽  
Pyrrolidine Dithiocarbamate ◽  
Glucose Content ◽  
Insulin Resistant

The aim of our study is to elucidate the mechanisms of oleanolic acid (OA) on insulin resistance (IR) in HepG2 cells. HepG2 cells were induced with FFA as the insulin resistance model and were treated with OA. Then the glucose content and the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were analyzed. Moreover, protein expression of nuclear factor kappa B (NF-κB), insulin receptor substrate 1(IRS1), and glucose transporter 4 (GLUT4) in cells treated with OA were measured by Western blot analysis. Additionally, IRS1 protein expression exposed to OA was detected after using pyrrolidine dithiocarbamate (PDTC).Our results revealed that OA decreased the glucose content in HepG2 cells in vitro. Moreover, OA reduced the levels of TNF-α and IL-6 and upregulated IRS1 and GLUT4 protein expression. Furthermore, OA also reduced NF-κB protein expression in insulin-resistant HepG2 cells. After blocking NF-κB, the expression of IRS1 protein had no obvious changes when treated with OA. OA attenuated insulin resistance and decreased the levels of TNF-α and IL-6. Meanwhile, OA decreased NF-κB protein expression and upregulated IRS1 and GLUT4 protein expression. Therefore, regulating the IRS1-GLUT4 pathway via NF-κB was the underlying mechanism of OA on insulin resistance.

Sign in / Sign up

Export Citation Format

Share Document