Role of Neu-p11/luzindole in the regulation of insulin signaling pathways and insulin resistance

Background. It has been suggested that visfatin, which is an adipocytokine, exhibits proinflammatory properties and is associated with insulin resistance. Insulin resistance and inflammation are the principal pathogeneses of nonalcoholic fatty liver disease (NAFLD), but the relationship, if any, between visfatin and NAFLD remains unclear. Here, we evaluated the effects of visfatin on hepatic inflammation and insulin resistance in HepG2 cells and examined the molecular mechanisms involved. Methods. After treatment with visfatin, the inflammatory cytokines IL-6, TNF-α, and IL-1β were assessed by real-time polymerase chain reaction (RT-PCR) and immunocytochemical staining in HepG2 cells. To investigate the effects of visfatin on insulin resistance, we evaluated insulin-signaling pathways, such as IR, IRS-1, GSK, and AKT using immunoblotting. We assessed the intracellular signaling molecules including STAT3, NF-κB, IKK, p38, JNK, and ERK by western blotting. We treated HepG2 cells with both visfatin and either AG490 (a JAK2 inhibitor) or Bay 7082 (an NF-κB inhibitor); we examined proinflammatory cytokine mRNA levels using RT-PCR and insulin signaling using western blotting. Results. In HepG2 cells, visfatin significantly increased the levels of proinflammatory cytokines, reduced the levels of proteins (e.g., phospho-IR, phospho-IRS-1 (Tyr612), phospho-AKT, and phospho-GSK-3α/β) involved in insulin signaling, and increased IRS-1 S307 phosphorylation compared to controls. Interestingly, visfatin increased the activities of the JAK2/STAT3 and IKK/NF-κB signaling pathways but not those of the JNK, p38, and ERK pathways. Visfatin-induced inflammation and insulin resistance were regulated by JAK2/STAT3 and IKK/NF-κB signaling; together with AG490 or Bay 7082, visfatin significantly reduced mRNA levels of IL-6, TNF-α and IL-1β and rescued insulin signaling. Conclusion. Visfatin induced proinflammatory cytokine production and inhibited insulin signaling via the STAT3 and NF-κB pathways in HepG2 cells.

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Crosstalk between the AMP-activated kinase and insulin signaling pathways rescues murine blastocyst cells from insulin resistance

Reproduction ◽

10.1530/rep-08-0161 ◽

2008 ◽

Vol 136 (3) ◽

pp. 335-344 ◽

Cited By ~ 24

Author(s):

Erica Louden ◽

Maggie M Chi ◽

Kelle H Moley

Keyword(s):

Insulin Resistance ◽

Signaling Pathways ◽

Insulin Signaling ◽

Kinase Activity ◽

Pi3 Kinase ◽

Ampk Activation ◽

Embryonic Cells ◽

Insulin Resistant

Maternal insulin resistance results in poor pregnancy outcomes. In vivo and in vitro exposure of the murine blastocyst to high insulin or IGF1 results in the down-regulation of the IGF1 receptor (IGF1R). This in turn leads to decreased glucose uptake, increased apoptosis, as well as pregnancy resorption and growth restriction. Recent studies have shown that blastocyst activation of AMP-activated protein kinase (AMPK) reverses these detrimental effects; however, the mechanism was not clear. The objective of this study was to determine how AMPK activation rescues the insulin-resistant blastocyst. Using trophoblast stem (TS) cells derived from the blastocyst, insulin resistance was recreated by transfecting with siRNA to Igf1r and down-regulating expression of the protein. These cells were then exposed to AMPK activators 5-aminoimidazole-4-carboxamide riboside and phenformin, and evaluated for apoptosis, insulin-stimulated 2-deoxyglucose uptake, PI3-kinase activity, and levels of phospho-AKT, phospho-mTor, and phospho-70S6K. Surprisingly, disrupted insulin signaling led to decreased AMPK activity in TS cells. Activators reversed these effects by increasing the AMP/ATP ratio. Moreover, this treatment increased insulin-stimulated 2-deoxyglucose transport and cell survival, and led to an increase in PI3-kinase activity, as well as increased P-mTOR and p70S6K levels. This study is the first to demonstrate significant crosstalk between the AMPK and insulin signaling pathways in embryonic cells, specifically the enhanced response of PI3K/AKT/mTOR to AMPK activation. Decreased insulin signaling also resulted in decreased AMPK activation. These findings provide mechanistic targets in the AMPK signaling pathway that may be essential for improved pregnancy success in insulin-resistant states.

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Putative Key Role of Inositol Messengers in Endothelial Cells in Preeclampsia

International Journal of Endocrinology ◽

10.1155/2016/7695648 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Sirilaksana Kunjara ◽

Patricia McLean ◽

Laurens Rademacher ◽

Thomas W. Rademacher ◽

Fabiana Fascilla ◽

...

Keyword(s):

Insulin Resistance ◽

Endothelial Cells ◽

Endothelial Dysfunction ◽

Signaling Pathways ◽

Second Messengers ◽

Intracellular Pathways ◽

Intracellular Action ◽

Cell Signaling Pathways ◽

Immunological Alterations

Immunological alterations, endothelial dysfunction, and insulin resistance characterize preeclampsia. Endothelial cells hold the key role in the pathogenesis of this disease. The signaling pathways mediating these biological abnormalities converge on PKB/Akt, an intracellular kinase regulating cell survival, proliferation, and metabolism. Inositol second messengers are involved in metabolic and cell signaling pathways and are highly expressed during preeclampsia. Intracellular action of these molecules is deeply affected by zinc, manganese, and calcium. To evaluate the pathophysiological significance, we present the response of the intracellular pathways of inositol phosphoglycans involved in cellular metabolism and propose a link with the disease.

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Role of protein tyrosine phosphatases in the modulation of insulin signaling and their implication in the pathogenesis of obesity-linked insulin resistance

Reviews in Endocrine and Metabolic Disorders ◽

10.1007/s11154-013-9282-4 ◽

2013 ◽

Vol 15 (1) ◽

pp. 79-97 ◽

Cited By ~ 37

Author(s):

Elaine Xu ◽

Michael Schwab ◽

André Marette

Keyword(s):

Insulin Resistance ◽

Insulin Signaling ◽

Protein Tyrosine Phosphatases ◽

Tyrosine Phosphatases ◽

Protein Tyrosine

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OR08-04 Differences in Advanced Lipoprotein Profile Between Rabson-Mendenhall Syndrome and Lipodystrophy

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.170 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Mohammad Al-Jundi ◽

Marissa Lightbourne ◽

Megan Startzell ◽

Robert D Shamburek ◽

Rebecca J Brown

Keyword(s):

Insulin Resistance ◽

Signaling Pathways ◽

Insulin Signaling ◽

Lipoprotein Profile ◽

Cvd Risk ◽

Lipoprotein Particles ◽

Lipoprotein Particle ◽

Ldl Particles ◽

Low Hdl ◽

Artery Disease

Abstract Insulin resistance (IR) is associated with metabolic dyslipidemia (high triglycerides [TG] and low HDL) and increased cardiovascular disease (CVD) risk. In obesity-associated IR, dyslipidemia is thought to be caused by increased insulin-mediated stimulation of hepatic lipogenesis, whereas IR in glucoregulatory pathways leads to hyperglycemia. This dichotomy in insulin signaling pathways is termed selective insulin resistance. Rare human conditions exist in which there is extreme, non-selective, IR impairing all insulin signaling pathways (e.g. mutations of the insulin receptor, INSR) or extreme IR affecting only selected intracellular insulin signaling pathways analogous to obesity (e.g. lipodystrophy). Lipodystrophy leads to very high TG, low HDL, and increased CVD, while INSR mutation leads to low TG and high HDL, with unknown CVD risk. We sought to further characterize the lipid phenotype and atherogenicity in these conditions in order to understand effects of different insulin signaling pathways on CVD risk. We studied 7 patients with INSR mutation (42% female; 5 homozygous; 2 heterozygous) and 21 with lipodystrophy (85% female; 5 generalized; 16 partial). Fasting lipoprotein profiles were assessed by NMR using the LP4 deconvolution algorithm. The major lipoprotein particle categories defined by this method are small, medium, and large HDL and LDL particles (HDLP and LDLP) and very small, small, medium, large, and very large TG rich lipoprotein particles (TRLP). Very small TRLP (median 189.6 [68.7, 315.0] vs 4.5 [0.00, 9.4], p=0.0001), small LDLP (mean 1425.0 ± 636.2 vs 612.8 ± 233.9, p=0.003), small HDLP (mean 14.0 ± 4.7 vs 9.0 ± 3.2, p=0.014) were more elevated in patients with lipodystrophy vs INSR mutation. This lipoprotein profile has been associated with increased atherosclerotic coronary artery disease. GlycA, a marker of inflammation was also more elevated in lipodystrophy vs INSR mutation (435.9 ± 107.2 vs 315.7 ± 74.4, p=0.01). Insulin resistance assessed by HOMA-IR was higher in patients with INSR mutation vs lipodystrophy (mean 93.5 ± 94.4 vs 15.6 ± 14.7, p=0. 00085).) Lipoprotein insulin resistance (LPIR), an index of IR based on lipoprotein particles, was lower in patients with INSR mutation (25.0 ± 19.0 vs 84.0 ± 9.0, p < 0.0001) despite their higher HOMA-IR. In conclusion, severe, selective insulin resistance in patients with lipodystrophy was associated with a more atherogenic lipoprotein particle profile and increased inflammation compared to severe, non-selective insulin resistance caused by INSR mutations. Patients with INSR mutations had a striking discrepancy between a glucose/insulin-based index of insulin resistance (HOMA-IR) and a lipid-based marker of insulin resistance (LPIR). These findings point toward a key role of selective insulin resistance in the development of an atherogenic lipid profile, which should lead to increased CVD risk.

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Potential Roles of Adipocyte Extracellular Vesicle–Derived miRNAs in Obesity-Mediated Insulin Resistance

Advances in Nutrition ◽

10.1093/advances/nmaa105 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yujeong Kim ◽

Ok-Kyung Kim

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Signaling Pathway ◽

Insulin Signaling ◽

Metabolic Disorders ◽

Extracellular Vesicle ◽

Extracellular Mirnas

ABSTRACT Recently, extracellular microRNAs (miRNAs) from adipose tissue have been shown to be involved in the development of insulin resistance. Here, we summarize several mechanisms explaining the pathogenesis of obesity-induced insulin resistance and associated changes in the expression of obesity-associated extracellular miRNAs. We discuss how miRNAs, particularly miR-27a, miR-34a, miR-141-3p, miR-155, miR210, and miR-222, in extracellular vesicles secreted from the adipose tissue can affect the insulin signaling pathway in metabolic tissue. Understanding the role of these miRNAs will further support the development of therapeutics for obesity and metabolic disorders such as type 2 diabetes.

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Abstract 15225: Post-ischemic Myocardial Insulin Resistance Induced by Tnf-α Overproduction Precipitates the Development of Heart Failure After Myocardial Infarction

Circulation ◽

10.1161/circ.130.suppl_2.15225 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Feng Fu ◽

Jia Li ◽

Jie Xu ◽

Yuan Zhang ◽

Chao Gao ◽

...

Keyword(s):

Myocardial Infarction ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Insulin Signaling ◽

Left Ventricular ◽

Separate Experiment ◽

Tnf Α ◽

Lv Remodeling ◽

Myocardial Insulin Resistance

Objectives: Clinical evidence has demonstrated a decreased myocardial insulin response in HF patients. However, the role of myocardial insulin resistance and the underlying mechanisms in HF are largely unclear. Methods and Results: Sprague Dawley rats subjected to myocardial infarction (MI) resulted in a progressive left ventricular (LV) remodeling and dysfunction. Echocardiographic assessment showed preserved LV end-systolic dimension (LVESD 0.453 ± 0.027 cm) and ejection fraction (EF 57.03 ± 2.35%) at 1 wk after MI, and evident LV dilation (LVESD 0.612 ± 0.026 cm) and dysfunction (EF 40.21 ± 3.09%) at 4 wk after MI. Myocardial insulin sensitivity decreased significantly at 1 wk after MI as evidenced by reduced insulin-stimulated myocardial fluorodeoxyglucose uptake (Standardized Uptake Value: 2.71 ± 0.42 vs. 5.13 ± 0.51 of sham+insulin, n=6, P <0.01) and GLUT-4 translocation and altered insulin signaling, whereas systemic insulin sensitivity remained unchanged. Mechanistically, myocardial TNF-α production was increased following MI. Treatment with etanercept (a TNF-α inhibitor) post-MI improved myocardial insulin sensitivity, while adenovirus-mediated overexpression of TNF-α resulted in myocardial insulin resistance in non-MI hearts. In addition, TNF-α overexpressed rat hearts exhibited LV dysfunction (EF 41.32 ± 4.21%) and LV dilation as early as 1 wk after MI. Moreover, insulin treatment during the first week following MI suppressed myocardial TNF-α production and increased myocardial insulin sensitivity, resulting in alleviated cardiac dysfunction and remodeling at 4 wk after MI. Importantly, in a separate experiment, cardiomyocyte-specific insulin receptor knockout mice exhibited aggravated post-ischemic LV remodeling and dysfunction compared with littermate controls. Conclusions: Our data provide novel insights that myocardial insulin resistance, independently of systemic insulin resistance, precipitates the development of post-ischemic HF. Myocardial insulin resistance is an early event partly attributed to myocardial TNF-α overproduction following MI. This finding indicates the essential role of myocardial insulin signaling in protection against ischemic HF.

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Abstract 1185: Role Of Sphingosine-1-Phosphate (S1P) In Insulin Signaling.

Circulation ◽

10.1161/circ.116.suppl_16.ii_239-d ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Suzanne M Nicholl ◽

Elisa Roztocil ◽

Mark G Davies

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Insulin Signaling ◽

Receptor Expression ◽

Serine Phosphorylation ◽

Glucose Disposal ◽

Sphingosine 1 Phosphate ◽

Low Glucose

A failure to increase glucose disposal into peripheral tissues in response to insulin leads to impaired insulin signaling and an inability to uptake glucose leading to the onset of insulin resistance, a major contributing factor to diabetes. We examined the role of sphingosine-1-phosphate (S1P) in insulin signaling and its ability to regulate glucose uptake in skeletal muscle cells. S1P, a sphingolipid found in abundance in the circulation, has been implicated in not only mediating crosstalk with other signaling pathways but has also been implicated in insulin resistance. We hypothesize that S1P interacts with post-receptor insulin signaling to increase glucose disposal in an in vitro model of insulin resistance using differentiated mouse skeletal C2C12 myotubes. Our data demonstrates that S1P (10μM) increases basal glucose levels similar to that observed in response to insulin (100nM) under conditions of low glucose (** p < 0.005: n = 3). Conversely, high glucose conditions completely inhibit both insulin and S1P stimulated glucose uptake (*p < 0.01:n = 3). Pre-incubation with S1P does not augment insulin-induced glucose uptake (***p < 0.001:n = 3), suggesting that S1P does not act via a separate signaling pathway. This is confirmed by our data demonstrating that S1P-induced glucose uptake is abrogated by Cytochalasin B (*p < 0.001:n = 3). In addition, the PI3-K inhibitors, LY294002 and Wortmannin, the Akt inhibitor, AKT2 and the p38MAPK inhibitor, SB203580 significantly inhibited glucose uptake in response to S1P, demonstrating their importance in S1P-induced glucose uptake (*p < 0.05:n = 3). S1P2 and S1P3 receptor expression were upregulated in response to insulin (~2-fold over basal) under low glucose conditions suggesting that insulin may regulate S1P signaling via one or both of these receptors. S1P increased serine phosphorylation of IRS1, both at serine 307 and serines 636/639 maximally after 15 minutes of stimulation. This data has important clinical implications in patients with metabolic syndrome who have impaired skeletal muscle glucose disposal due to insulin resistance and will help guide present and future therapy for patients who have this rapidly growing disease.

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Growth Hormone Signaling in Vivo in Human Muscle and Adipose Tissue: Impact of Insulin, Substrate Background, and Growth Hormone Receptor Blockade

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-2414 ◽

2008 ◽

Vol 93 (7) ◽

pp. 2842-2850 ◽

Cited By ~ 40

Author(s):

Charlotte Nielsen ◽

Lars C. Gormsen ◽

Niels Jessen ◽

Steen Bønløkke Pedersen ◽

Niels Møller ◽

...

Keyword(s):

Insulin Resistance ◽

Growth Hormone ◽

Signaling Pathways ◽

Cross Talk ◽

Insulin Signaling ◽

Human Muscle ◽

Receptor Blockade ◽

Gh Receptor ◽

Igf I

Abstract Context: GH induces insulin resistance in muscle and fat, and in vitro data indicate that this may involve cross-talk between the signaling pathways of the two hormones. Objective: Our objective was to investigate GH and insulin signaling in vivo in human muscle and fat tissue in response to GH, GH receptor blockade, and insulin stimulation. Design: We conducted two randomized crossover studies. Participants: Sixteen healthy males participated. Intervention: GH was administered as a bolus (n = 8) and constant infusion (n = 8). The bolus study included three arms: 1) control (saline), 2) GH (0.5 mg iv), and 3) GH blockade (pegvisomant 30 mg sc), each combined with a hyperinsulinemic glucose clamp. The infusion study included two arms: 1) GH infusion (45 ng/·kg·min, 5.5 h) and 2) saline infusion (5.5 h) combined with a hyperinsulinemic glucose clamp during the final 2.5 h. Main Outcome Measures: Muscle and fat biopsies were subjected to Western blotting for expression of Stat5/p-Stat5, Akt/p-Akt, and ERK1/2/p-ERK1/2 and to real-time RT-PCR for expression of SOCS1–3 and IGF-I mRNA. Results: GH significantly reduced insulin sensitivity. The GH bolus as well as GH infusion induced phosphorylation of Stat5 in muscle and fat, and SOCS3 and IGF-I mRNA expression increased after GH infusion. Hyperinsulinemia induced Akt phosphorylation in both tissues, irrespective of GH status. In muscle, ERK1/2 phosphorylation was increased by insulin, but insulin per se did not induce phosphorylation of Stat5. Conclusions: GH exposure associated with insulin resistance acutely translates into GH receptor signaling in human muscle and fat without evidence of cross-talk with insulin signaling pathways. The molecular mechanisms subserving GH-induced insulin resistance in humans remain unclarified.

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Mechanisms Linking Inflammation to Insulin Resistance

International Journal of Endocrinology ◽

10.1155/2015/508409 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 159

Author(s):

Li Chen ◽

Rui Chen ◽

Hua Wang ◽

Fengxia Liang

Keyword(s):

Insulin Resistance ◽

Signaling Pathways ◽

Insulin Signaling ◽

Experimental Studies ◽

Low Grade ◽

The World ◽

The Status ◽

Specific Factors ◽

Low Grade Inflammation

Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies.

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