Mitochondrial dysfunction in insulin resistance: differential contributions of chronic insulin and saturated fatty acid exposure in muscle cells

Yang, Chenjing; Aye, Cho Cho; Li, Xiaoxin; Ramos, Angels Diaz; Zorzano, António; Mora, Sílvia

doi:10.1042/bsr20120034

Cited by 45 publications

(47 citation statements)

References 51 publications

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“…The above hypothesis is supported by the observation that the exposure to saturated fatty acids of isolated mitochondria (Abdul-Ghani et al 2008) or cells (Hirabara et al 2010, Jheng et al 2012, Yang et al 2012, Teodoro et al 2014 clearly elicits mitochondrial dysfunction, which in the cells is accompanied by IR. However, in more complex systems, such as in men and experimental animal models, the link between plasma NEFA delivery to skeletal muscle, mitochondrial impairment and insulin resistance is less strong.…”

Section: Mitochondrial Dysfunction In Insulin Resistancesupporting

confidence: 60%

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

Meo

Iossa

Venditti

2017

Journal of Endocrinology

228

103

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At present, obesity is one of the most important public health problems in the world because it causes several diseases and reduces life expectancy. Although it is well known that insulin resistance plays a pivotal role in the development of type 2 diabetes mellitus (the more frequent disease in obese people) the link between obesity and insulin resistance is yet a matter of debate. One of the most deleterious effects of obesity is the deposition of lipids in non-adipose tissues when the capacity of adipose tissue is overwhelmed. During the last decade, reduced mitochondrial function has been considered as an important contributor to 'toxic' lipid metabolite accumulation and consequent insulin resistance. More recent reports suggest that mitochondrial dysfunction is not an early event in the development of insulin resistance, but rather a complication of the hyperlipidemia-induced reactive oxygen species (ROS) production in skeletal muscle, which might promote mitochondrial alterations, lipid accumulation and inhibition of insulin action. Here, we review the literature dealing with the mitochondria-centered mechanisms proposed to explain the onset of obesity-linked IR in skeletal muscle. We conclude that the different pathways leading to insulin resistance may act synergistically because ROS production by mitochondria and other sources can result in mitochondrial dysfunction, which in turn can further increase ROS production leading to the establishment of a harmful positive feedback loop.

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Section: Mitochondrial Dysfunction In Insulin Resistancesupporting

confidence: 60%

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

Meo

Iossa

Venditti

2017

Journal of Endocrinology

228

103

View full text Add to dashboard Cite

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“…Saturated nonesterified fatty acids such as palmitic acid are involved in the process of insulin resistance. Indeed, it was demonstrated that palmitic acidinduced insulin resistance by inhibiting PGC-1 alpha (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) expression in skeletal muscle cells [18] and by reducing phosphatidylinositol 3 kinase inhibiting mitochondrial respiration [19]. In the present study, we used palmitic acid as a tool to induce insulin resistance in primary rat skeletal muscle cells to study the in vitro effects of melatonin treatment, and we used PNX rats to study the in vivo effects of melatonin.…”

Section: Introductionmentioning

confidence: 99%

Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle

Teodoro

Baraldi

Sampaio

et al. 2014

Journal of Pineal Research

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Melatonin has a number of beneficial metabolic actions and reduced levels of melatonin may contribute to type 2 diabetes. The present study investigated the metabolic pathways involved in the effects of melatonin on mitochondrial function and insulin resistance in rat skeletal muscle. The effect of melatonin was tested both in vitro in isolated rats skeletal muscle cells and in vivo using pinealectomized rats (PNX). Insulin resistance was induced in vitro by treating primary rat skeletal muscle cells with palmitic acid for 24 hr. Insulin-stimulated glucose uptake was reduced by palmitic acid followed by decreased phosphorylation of AKT which was prevented my melatonin. Palmitic acid reduced mitochondrial respiration, genes involved in mitochondrial biogenesis and the levels of tricarboxylic acid cycle intermediates whereas melatonin counteracted all these parameters in insulin-resistant cells. Melatonin treatment increases CAMKII and p-CREB but had no effect on p-AMPK. Silencing of CREB protein by siRNA reduced mitochondrial respiration mimicking the effect of palmitic acid and prevented melatonin-induced increase in p-AKT in palmitic acid-treated cells. PNX rats exhibited mild glucose intolerance, decreased energy expenditure and decreased p-AKT, mitochondrial respiration, and p-CREB and PGC-1 alpha levels in skeletal muscle which were restored by melatonin treatment in PNX rats. In summary, we showed that melatonin could prevent mitochondrial dysfunction and insulin resistance via activation of CREB-PGC-1 alpha pathway. Thus, the present work shows that melatonin play an important role in skeletal muscle mitochondrial function which could explain some of the beneficial effects of melatonin in insulin resistance states.

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“…This treatment resulted in the downregulation of the insulin receptor and subsequently significantly reduced insulin signaling cascades [26]. We used the gene set enrichment analysis method (GSEA, [25]) to look for enrichment of differential expression using our set of internode, mitochondria, and insulin genes as molecular signatures.…”

Section: Resultsmentioning

confidence: 99%

Identification of Novel Type 2 Diabetes Candidate Genes Involved in the Crosstalk between the Mitochondrial and the Insulin Signaling Systems

et al. 2012

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Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein–protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12×10−5). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases.

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Mitochondrial dysfunction in insulin resistance: differential contributions of chronic insulin and saturated fatty acid exposure in muscle cells

Cited by 45 publications

References 51 publications

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

Skeletal muscle insulin resistance: role of mitochondria and other ROS sources

Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle

Identification of Novel Type 2 Diabetes Candidate Genes Involved in the Crosstalk between the Mitochondrial and the Insulin Signaling Systems

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