Impairment of cardiac insulin signaling and myocardial contractile performance in high-cholesterol/fructose-fed rats

Although insulin resistance is recognized as a potent and prevalent risk factor for coronary heart disease, less is known as to whether insulin resistance causes an altered cardiac phenotype independent of coronary atherosclerosis. In this study, we investigated the relationship between insulin resistance and cardiac contractile dysfunctions by generating a new insulin resistance animal model with rats on high cholesterol-fructose diet. Male Sprague-Dawley rats were given high cholesterol-fructose (HCF) diet for 15 wk; the rats developed insulin resistance syndrome characterized by elevated blood pressure, hyperlipidemia, hyperinsulinemia, impaired glucose tolerance, and insulin resistance. The results show that HCF induced insulin resistance not only in metabolic-response tissues (i.e., liver and muscle) but also in the heart as well. Insulin-stimulated cardiac glucose uptake was significantly reduced after 15 wk of HCF feeding, and cardiac insulin resistance was associated with blunted Akt-mediated insulin signaling along with glucose transporter GLUT4 translocation. Basal fatty acid transporter FATP1 levels were increased in HCF rat hearts. The cardiac performance of the HCF rats exhibited a marked reduction in cardiac output, ejection fraction, stroke volume, and end-diastolic volume. It also showed decreases in left ventricular end-systolic elasticity, whereas the effective arterial elasticity was increased. In addition, the relaxation time constant of left ventricular pressure was prolonged in the HCF group. Overall, these results indicate that insulin resistance reduction of cardiac glucose uptake is associated with defects in insulin signaling. The cardiac metabolic alterations that impair contractile functions may lead to the development of cardiomyopathy.

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Alleviative Effect of Ruellia tuberosa L. on Insulin Resistance and Abnormal Lipid Accumulation in TNF-α-Treated FL83B Mouse Hepatocytes

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/9967910 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Hong-Jie Chen ◽

Chih-Yuan Ko ◽

Jian-Hua Xu ◽

Yu-Chu Huang ◽

James Swi-Bea Wu ◽

...

Keyword(s):

Insulin Resistance ◽

Ethyl Acetate ◽

Glucose Uptake ◽

Insulin Signaling ◽

Lipid Accumulation ◽

Glucose Transporter ◽

Peroxisome Proliferator ◽

Glucose Transporter 2 ◽

Tnf Α ◽

Mouse Hepatocytes

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease, and most patients with T2DM develop nonalcoholic fatty liver disease (NAFLD). Both diseases are closely linked to insulin resistance (IR). Our previous studies demonstrated that Ruellia tuberosa L. (RTL) extract significantly enhanced glucose uptake in the skeletal muscles and ameliorated hyperglycemia and IR in T2DM rats. We proposed that RTL might be via enhancing hepatic antioxidant capacity. However, the potent RTL bioactivity remains unidentified. In this study, we investigated the effects of RTL on glucose uptake, IR, and lipid accumulation in vitro to mimic the T2DM accompanied by the NAFLD paradigm. FL83B mouse hepatocytes were treated with tumor necrosis factor-α (TNF-α) to induce IR, coincubated with oleic acid (OA) to induce lipid accumulation, and then, treated with RTL fractions, fractionated with n-hexane or ethyl acetate (EA), from column chromatography, and analyzed by thin-layer chromatography. Our results showed that the ethyl acetate fraction (EAf2) from RTL significantly increased glucose uptake and suppressed lipid accumulation in TNF-α plus OA-treated FL83B cells. Western blot analysis showed that EAf2 from RTL ameliorated IR by upregulating the expression of insulin-signaling-related proteins, including protein kinase B, glucose transporter-2, and peroxisome proliferator-activated receptor alpha in TNF-α plus OA-treated FL83B cells. The results of this study suggest that EAf2 from RTL may improve hepatic glucose uptake and alleviate lipid accumulation by ameliorating and suppressing the hepatic insulin signaling and lipogenesis pathways, respectively, in hepatocytes.

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Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01185.2009 ◽

2011 ◽

Vol 300 (5) ◽

pp. H1637-H1644 ◽

Cited By ~ 34

Author(s):

Yukihiro Ohta ◽

Shintaro Kinugawa ◽

Shouji Matsushima ◽

Taisuke Ono ◽

Mochamad A. Sobirin ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Glucose Transporter ◽

Diastolic Pressure ◽

Left Ventricular ◽

Serine Phosphorylation ◽

Glucose Transporter 4

Insulin resistance has been shown to occur as a consequence of heart failure. However, its exact mechanisms in this setting remain unknown. We have previously reported that oxidative stress is enhanced in the skeletal muscle from mice with heart failure after myocardial infarction (MI) ( 30 ). This study is aimed to investigate whether insulin resistance in postinfarct heart failure is due to the impairment of insulin signaling in the skeletal muscle caused by oxidative stress. Mice were divided into four groups: sham operated (sham); sham treated with apocynin, an inhibitor of NAD(P)H oxidase activation (10 mmol/l in drinking water); MI; and MI treated with apocynin. After 4 wk, intraperitoneal insulin tolerance tests were performed, and skeletal muscle samples were obtained for insulin signaling measurements. MI mice showed left ventricular dilation and dysfunction by echocardiography and increased left ventricular end-diastolic pressure and lung weight. The decrease in glucose level after insulin load significantly attenuated in MI compared with sham. Insulin-stimulated serine phosphorylation of Akt and glucose transporter-4 translocation were decreased in MI mice by 61 and 23%, respectively. Apocynin ameliorated the increase in oxidative stress and NAD(P)H oxidase activities measured by the lucigenin assay in the skeletal muscle after MI. It also improved insulin resistance and inhibited the decrease of Akt phosphorylation and glucose transporter-4 translocation. Insulin resistance was induced by the direct impairment of insulin signaling in the skeletal muscle from postinfarct heart failure, which was associated with the enhanced oxidative stress via NAD(P)H oxidase.

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(Pro)renin receptor in skeletal muscle is involved in the development of insulin resistance associated with postinfarct heart failure in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00449.2013 ◽

2014 ◽

Vol 307 (6) ◽

pp. E503-E514 ◽

Cited By ~ 23

Author(s):

Arata Fukushima ◽

Shintaro Kinugawa ◽

Shingo Takada ◽

Shouji Matsushima ◽

Mochamad Ali Sobirin ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Signaling ◽

Glucose Transporter ◽

Renin Angiotensin System ◽

Left Ventricular ◽

Serine Phosphorylation ◽

Superoxide Production

We previously reported that insulin resistance was induced by the impairment of insulin signaling in the skeletal muscle from heart failure (HF) via NAD(P)H oxidase-dependent oxidative stress. (Pro)renin receptor [(P)RR] is involved in the activation of local renin-angiotensin system and subsequent oxidative stress. We thus examined whether (P)RR inhibitor, handle region peptide (HRP), could ameliorate insulin resistance in HF after myocardial infarction (MI) by improving oxidative stress and insulin signaling in the skeletal muscle. C57BL6J mice were divided into four groups: sham operated (Sham, n = 10), Sham treated with HRP (Sham+HRP, 0.1 mg·kg−1·day−1, n = 10), MI operated (MI, n = 10), and MI treated with HRP (MI+HRP, 0.1 mg/kg/day, n = 10). After 4 wk, MI mice showed left ventricular dysfunction, which was not affected by HRP. (P)RR was upregulated in the skeletal muscle after MI (149% of sham, P < 0.05). The decrease in plasma glucose after insulin load was smaller in MI than in Sham (21 ± 2 vs. 44 ± 3%, P < 0.05), and was greater in MI+HRP (38 ± 2%, P < 0.05) than in MI. Insulin-stimulated serine phosphorylation of Akt and glucose transporter 4 translocation were decreased in the skeletal muscle from MI by 48 and 49% of Sham, both of which were ameliorated in MI+HRP. Superoxide production and NAD(P)H oxidase activities were increased in MI, which was inhibited in MI+HRP. HRP ameliorated insulin resistance associated with HF by improving insulin signaling via the inhibition of NAD(P)H oxidase-induced superoxide production in the skeletal muscle. The (P)RR pathway is involved in the development of insulin resistance, at least in part, via the impairment of insulin signaling in the skeletal muscle from HF.

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Pulmonary vascular effect of insulin in a rodent model of pulmonary arterial hypertension

Pulmonary Circulation ◽

10.1086/689908 ◽

2017 ◽

Vol 7 (3) ◽

pp. 624-634 ◽

Cited By ~ 11

Author(s):

Aaron W. Trammell ◽

Megha Talati ◽

Thomas R. Blackwell ◽

Niki L. Fortune ◽

Kevin D. Niswender ◽

...

Keyword(s):

Insulin Resistance ◽

Endothelial Cells ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Glucose Uptake ◽

Insulin Signaling ◽

Glucose Transporter ◽

Western Diet ◽

Mutant Mice ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is associated with metabolic derangements including insulin resistance, although their effects on the cardiopulmonary disease are unclear. We hypothesized that insulin resistance promotes pulmonary hypertension (PH) development and mutations in type 2 bone morphogenetic protein receptor (BMPR2) cause cellular insulin resistance. Using a BMPR2 transgenic murine model of PAH and two models of inducible diabetes mellitus, we explored the impact of hyperglycemia and/or hyperinsulinemia on development and severity of PH. We assessed insulin signaling and insulin-mediated glucose uptake in human endothelial cells with and without mutations in BMPR2. PH developed in control mice fed a Western diet and PH in BMPR2 mutant mice was increased by Western diet. Pulmonary artery pressure correlated strongly with fasting plasma insulin but not glucose. Reactive oxygen species were increased in lungs of insulin-resistant animals. BMPR2 mutation impaired insulin-mediated endothelial glucose uptake via reduced glucose transporter translocation despite intact insulin signaling. Experimental hyperinsulinemia is strongly associated with PH in both control and BMPR2-mutant mice, though to a greater degree in those with BMPR2 mutation. Human pulmonary endothelial cells with BMPR2 mutation have evidence of reduced glucose uptake due to impaired glucose transporter translocation. These experiments support a role for hyperinsulinemia in pulmonary vascular disease.

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Abstract 1651: Exercise Improves Aging-associated Myocardial Insulin Resistance by Enhancing Mitochondrial Function in an eNOS Dependent Mechanism

Circulation ◽

10.1161/circ.116.suppl_16.ii_346-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Qiu X Li ◽

Quan J Zhang ◽

Hai F Zhang ◽

Kun R Zhang ◽

Jia Li ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Uptake ◽

Mitochondrial Function ◽

Left Ventricular ◽

Sprague Dawley ◽

Enos Expression ◽

Adult Heart ◽

Aging Heart ◽

Myocardial Insulin Resistance

Objective . This study sought to determine whether exercise reduces aging-associated myocardial insulin resistance, with a specific focus on the role of eNOS and its relation to mitochondria. Methods . Aging male Sprague-Dawley rats (24 months) were subjected to swim training (60 min/d, 5 d/wk, 9 wk) or assigned as sedentary control. The myocardial contraction, myocardial glucose uptake, mitochondrial function, and eNOS signaling were determined. Results. Aging rats had myocardial insulin resistance as shown by decreased insulin-induced glucose uptake (0.22±0.05 μmol/min/g in aging heart vs.1.29 ± 0.13 μmol/min/g in adult heart, n=8, P <0.01) and attenuated insulin’s positive inotropic role as evidenced by reduced left ventricular developed pressure (90±12 mmHg in aging heart vs. 155±14 mmHg in adult heart, P <0.01). Mitochondrial function was decreased in aging hearts as manifested by the attenuated maximum O 2 consumption by FCCP (1.85±0.39 μmol/min/g in aging hearts vs. 3.72±0.40 μmol/min/g in adult hearts, P <0.01). This was accompanied with the reduced insulin-induced O 2 consumption (1.37±0.31 μmol/min/g in aging heart vs. 2.35±0.31 μmol/min/g in adult heart, P <0.01). In addition, eNOS expression and its phosphorylation by insulin were reduced by 1.2- and 2.3-fold in aging heart, respectively ( P <0.01). Swim training upregulated eNOS expression by 72% ( P <0.01), facilitated eNOS phosphorylation by insulin ( P <0.01), and improved myocardial insulin sensitivity as shown by enhanced glucose uptake by insulin ( P <0.01). Moreover, mitochondrial function was facilitated as manifested by the enhanced O 2 consumption by insulin ( P <0.05), and maximum O 2 consumption ( P <0.01) following swim training. Pretreatment with Cavtratin, an eNOS inhibitor, abolished exercise-improved mitochondrial response to insulin, blocked exercise-improved myocardial insulin sensitivity and the positive inotropic response to insulin in aging heart. Conclusion . These results demonstrate that impaired eNOS signaling and subsequent mitochondrial depression is a major mechanism contributes to aging-associated myocardial insulin resistance, and that exercise improves insulin sensitivity by restoring eNOS signaling and enhancing mitochondrial function.

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Local Cortisol Elevation Contributes to Endometrial Insulin Resistance in Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-02459 ◽

2018 ◽

Vol 103 (7) ◽

pp. 2457-2467 ◽

Cited By ~ 5

Author(s):

Jia Qi ◽

Wangsheng Wang ◽

Qinling Zhu ◽

Yaqiong He ◽

Yao Lu ◽

...

Keyword(s):

Insulin Resistance ◽

Polycystic Ovary Syndrome ◽

Glucose Uptake ◽

Signaling Pathway ◽

Insulin Signaling ◽

Glucose Transporter ◽

Polycystic Ovary ◽

Implantation Rate ◽

Insulin Signaling Pathway ◽

Ovary Syndrome

Abstract Context Endometrial insulin resistance (IR) may account for the endometrial dysfunction in polycystic ovary syndrome (PCOS). The underlying mechanism remains to be elucidated. Objective To investigate whether the abundance of 11β-hydroxysteroid dehydrogenases (11β-HSDs) 1 and 2 and cortisol as well as the insulin signaling pathway are altered in PCOS endometrium and to clarify the relationship between endometrial IR and local cortisol. Design We measured cortisol and cortisone concentrations, 11β-HSD1 and 11β-HSD2, and core insulin signaling molecules in endometrial biopsies collected from non-PCOS and PCOS with or without IR patients on the seventh day after human chorionic gonadotropin injection. We also studied the effects of cortisol on glucose uptake and the insulin signaling pathway in primary cultured endometrial epithelial cells (EECs). Results The cortisol concentration was elevated, whereas 11β-HSD2 expression was diminished in endometrial biopsies obtained from PCOS with IR patients compared with those from non-PCOS and PCOS without IR patients. The implantation rate was relatively impaired and the endometrial insulin signaling pathway was defective in PCOS with IR patients. In addition, cortisol attenuated insulin-stimulated glucose uptake in EECs, which was mediated by inhibition of Akt phosphorylation and glucose transporter type 4 translocation via induction of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Conclusions Decreased oxidation of cortisol and defects of insulin signaling in endometrium were observed in PCOS with IR patients. The excessive cortisol level, derived from the reduction of 11β-HSD2, might contribute to the development of endometrial IR by inhibiting the insulin signaling pathway via induction of PTEN expression in EECs.

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Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

Molecules ◽

10.3390/molecules24101992 ◽

2019 ◽

Vol 24 (10) ◽

pp. 1992 ◽

Cited By ~ 10

Author(s):

Firas H. Bazzari ◽

Dalaal M. Abdallah ◽

Hanan S. El-Abhar

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Chenodeoxycholic Acid ◽

Insulin Signaling ◽

Glucose Transporter ◽

Farnesoid X Receptor ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Significant Difference

Insulin resistance is a major risk factor for Alzheimer’s disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (Aβ42). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl3-treated rats, which highlights its potential in AD management.

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Phenylalanine Impairs Insulin Signaling and Inhibits Glucose Uptake by Modifying IRβ

10.21203/rs.3.rs-483980/v1 ◽

2021 ◽

Author(s):

Qian Zhou ◽

Wan-Wan Sun ◽

Jia-Cong Chen ◽

Huilu Zhang ◽

Jie Liu ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Amino Acids ◽

Insulin Receptor ◽

Glucose Uptake ◽

Insulin Signaling ◽

Trna Synthetase ◽

Blood Samples ◽

Receptor Beta

Abstract Although elevated circulating amino acids are associated with the onset of type 2 diabetes (T2D), how amino acids act on cell insulin signaling and glucose uptake remains unclear. Herein, we report that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake. Mice fed phenylalanine-rich chow or overexpressing human phenylalanyl-tRNA synthetase (hFARS) developed insulin resistance and symptoms of T2D. Mechanistically, FARS phenylalanylated lysine 1057/1079 of IRβ (F-K1057/1079) inactivated IRβ and prevented insulin from generating insulin signaling to promote glucose uptake by cells. SIRT1 reversed F-K1057/1079 and counteracted the insulin-inactivating effects of hFARS and phenylalanine. F-K1057/1079 and SIRT1 levels of white cells of T2D patients’ blood samples were positively and negatively correlated with T2D onset, respectively. Blocking F-K1057/1079 with phenylalaninol sensitized insulin signaling and relieved T2D symptoms in hFARS-transgenic and db/db mice. We revealed mechanisms of how phenylalanylation inactivates insulin signaling that may be employed to control T2D.

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Effect of Subtoxic DDT Exposure on Glucose Uptake and Insulin Signaling in Rat L6 Myoblast-Derived Myotubes

International Journal of Toxicology ◽

10.1177/1091581819850577 ◽

2019 ◽

Vol 38 (4) ◽

pp. 303-311 ◽

Cited By ~ 2

Author(s):

Vijay Kumar Singh ◽

Sajib Kumar Sarkar ◽

Alpana Saxena ◽

Bidhan Chandra Koner

Keyword(s):

Insulin Resistance ◽

Glucose Uptake ◽

Tyrosine Phosphorylation ◽

Insulin Signaling ◽

Messenger Rna ◽

Insulin Receptors ◽

Serine Phosphorylation ◽

Enzyme Linked Immunosorbent Assay ◽

Antioxidant Content ◽

L6 Myoblast

Exposure to persistent organic pollutants including dichlorodiphenyltrichloroethane (DDT) induces insulin resistance. But the mechanism is not clearly known. The present study was designed to explore the effect of subtoxic DDT exposure on (1) insulin-stimulated glucose uptake, (2) malondialdehyde (MDA) level and total antioxidant content, (3) activation of redox sensitive kinases (RSKs), and (4) insulin signaling in rat L6 myoblast-derived myotubes. Exposure to 30 mg/L and 60 mg/L of DDT for 18 hours dose dependently decreased glucose uptake and antioxidant content in myotubes and increased MDA levels. The exposures did not alter tumor necrosis factor α (TNF-α) level as determined by enzyme-linked immunosorbent assay, despite decreased messenger RNA expression following DDT exposures. Phosphorylation of c-Jun N-terminal kinases and IκBα, an inhibitory component of nuclear factor κB (NFκB), was increased, suggesting activation of RSKs. The level of tyrosine phosphorylation of insulin receptor substrate 1 and serine phosphorylation of protein kinase B (Akt) on insulin stimulation decreased in myotubes with exposure to subtoxic concentrations of DDT, but there was no change in tyrosine phosphorylation level of insulin receptors. We conclude that subtoxic DDT exposure impairs insulin signaling and thereby induces insulin resistance in muscle cells. Data show that oxidative stress-induced activation of RSKs is responsible for impairment of insulin signaling on DDT exposure.

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Wu-Mei-Wan Reduces Insulin Resistance via Inhibition of NLRP3 Inflammasome Activation in HepG2 Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/7283241 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Xueping Yang ◽

Lingli Li ◽

Ke Fang ◽

Ruolan Dong ◽

Jingbin Li ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Receptor ◽

Insulin Signaling ◽

Nlrp3 Inflammasome ◽

Hepg2 Cells ◽

Glucose Transporter ◽

Interleukin 1 ◽

Serine Phosphorylation ◽

Inflammasome Activation ◽

Glucose Consumption Rate

Wu-Mei-Wan (WMW) is a Chinese herbal formula used to treat type 2 diabetes. In this study, we aimed to explore the effects and mechanisms of WMW on insulin resistance in HepG2 cells. HepG2 cells were pretreated with palmitate (0.25 mM) to impair the insulin signaling pathway. Then, they were treated with different doses of WMW-containing medicated serum and stimulated with 100 nM insulin. Results showed that palmitate could reduce the glucose consumption rate in HepG2 cells and impair insulin signaling related to phosphorylation of insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), thereby regulating the downstream signaling pathways. However, medicated serum of WMW restored impaired insulin signaling, upregulated the expression of phospho-IR (pIR), phosphatidylinositol 3-kinase p85 subunit, phosphoprotein kinase B, and glucose transporter 4, and decreased IRS serine phosphorylation. In addition, it decreased the expression of interleukin-1β and tumor necrosis factor-α, which are the key proinflammatory cytokines involved in insulin resistance; besides, it reduced the expression of NLRP3 inflammasome. These results suggested that WMW could alleviate palmitate-induced insulin resistance in HepG2 cells via inhibition of NLRP3 inflammasome and reduction of proinflammatory cytokine production.

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