An interferon-related signature characterizes the whole blood transcriptome profile of insulin-resistant individuals—the CODAM study

Abstract Background Worldwide, the prevalence of obesity and insulin resistance has grown dramatically. Gene expression profiling in blood represents a powerful means to explore disease pathogenesis, but the potential impact of inter-individual differences in a cell-type profile is not always taken into account. The objective of this project was to investigate the whole blood transcriptome profile of insulin-resistant as compared to insulin-sensitive individuals independent of inter-individual differences in white blood cell profile. Results We report a 3% higher relative amount of monocytes in the insulin-resistant individuals. Furthermore, independent of their white blood cell profile, insulin-resistant participants had (i) higher expression of interferon-stimulated genes and (ii) lower expression of genes involved in cellular differentiation and remodeling of the actin cytoskeleton. Conclusions We present an approach to investigate the whole blood transcriptome of insulin-resistant individuals, independent of their DNA methylation-derived white blood cell profile. An interferon-related signature characterizes the whole blood transcriptome profile of the insulin-resistant individuals, independent of their white blood cell profile. The observed signature indicates increased systemic inflammation possibly due to an innate immune response and whole-body insulin resistance, which can be a cause or a consequence of insulin resistance. Altered gene expression in specific organs may be reflected in whole blood; hence, our results may reflect obesity and/or insulin resistance-related organ dysfunction in the insulin-resistant individuals.

Download Full-text

Pseudohyperkalemia in Patients with Chronic Lymphocytic Leukemia

International Journal of Nephrology ◽

10.4061/2011/759749 ◽

2011 ◽

Vol 2011 ◽

pp. 1-3 ◽

Cited By ~ 9

Author(s):

Stephen I. Rifkin

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Blood Cell ◽

Mechanical Stress ◽

White Blood Cell ◽

Whole Blood ◽

Correct Diagnosis ◽

Plasma Potassium ◽

Lymphocytic Leukemia ◽

Blood Potassium

Pseudohyperkalemia occurs occasionally in patients with extreme leukocytosis. Increased white blood cell fragility coupled with mechanical stress is felt to be causal. Serum and plasma potassium levels have been both associated with pseudohyperkalemia. Whole blood potassium determination will usually verify the correct diagnosis. It is important to diagnose this condition early so that patients are not inappropriately treated. Two patients with chronic lymphocytic leukemia and extreme leukocytosis are presented, one with pseudohyperkalemia and one with probable pseudohyperkalemia, and diagnostic considerations are discussed

Download Full-text

THU0003 ALTERED DNA METHYLATION AND DIFFERENTIAL EXPRESSION OF GENES INFLUENCING CARDIOVASCULAR RISK AND IMMUNITY IN CD4+ T CELLS FROM SUBJECTS WITH PSORIATIC ARTHRITIS.

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4492 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 214.1-214

Author(s):

I. Arias de la Rosa ◽

M. D. López Montilla ◽

J. Rodríguez ◽

E. Ballester ◽

C. Torres-Granados ◽

...

Keyword(s):

Gene Expression ◽

Risk Factors ◽

Insulin Resistance ◽

Dna Methylation ◽

T Cells ◽

Cardiovascular Risk ◽

Research Support ◽

Insulin Resistant ◽

Genome Wide ◽

Differentially Methylated Genes

Background:Cardiovascular risk factors are increased in Psoriatic Arthritis (PsA). In fact, around 60% out of PsA patients display insulin resistance (IR), a hallmark of metabolic syndrome, which might significantly contribute to the cardiovascular disease. Latest studies suggested that inflammatory and metabolic disorders may be under epigenetic control, including DNA methylation. DNA methylation is an unexplored area in the field of PsA.Objectives:To study the alterations in the genome-wide DNA methylation profile of CD4+T cells from PsA patients and its relationship with its pathology and the risk of cardiovascular comorbidity.Methods:Twenty healthy controls (HC) and 20 PsA patients were included in the study. PsA patients were classified into insulin resistant and non-insulin resistant according to HOMA-IR index. CD4+T lymphocytes were isolated from peripheral blood by positive immunomagnetic selection. The Illumina Infinium MethylationEPIC Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpGs (TSS1500, TSS200, 5UTR, 3UTR, first exon, gene body). Beta values (β) estimating methylation levels were obtained at each CpG site, and differentially methylated genes (DMG) between PsA and HC were identified. Functional classification of these genes was carried out through gene ontology analysis (PANTHER database). Gene expression analysis of the selected genes was also evaluated by RT-PCR. Vascular parameters including carotid intima-media thickness (cIMT) and endothelial function was analyzed by ecodoppler and periflux respectively.Results:The genome-wide methylation analysis identified 112 DMGs including 41 hypomethylated and 71 hypermethylated. These differentially methylated genes were enriched with several signaling pathways and disease categories including immune response, metabolic processes, oxidative stress, vascular and inflammatory pathways. The altered gene expression of selected genes with altered methylation levels in PsA was also validated. Correlation and association analysis of these DMGs with clinical and analytical variables, cardiovascular risk factors and endothelial microvascular function revealed that the degree of methylation of these genes was significantly associated with cIMT (IGF1R, NDRG3, SMYD3, HLA-DRB1, WDR70), arterial pressure (METT5D1, NRDG3, ADAM17, SMYD3, WNK1, CBX1), insulin resistance (AKAP13, SEMA6D, PLCB1), altered lipid profile and atherogenic index (MYBL1, METT5D1, MAN2A1, SLC1A7, SEMA6D, PLCB1, TLK1, SDK1, CBX1), inflammation (MYBL1, NDUFA5, METT5D1, SEMA6D, PLCB1, TLK1), and endothelial dysfunction (ADAMST10, GPCPD1, CCDC88A). In addition, this analysis also identified 435 DMGs including 280 hypomethylated and 155 hypermethylated in CD4+T cells from IR-PsA vs non IR-PsA patients. Between these two groups of PsA patients, CHUK, SERINC1, RUNX1, TTYH2, TXNDC11, FAF1, BICD1, SCD5, PDE5A, FAS, NFIA and GRP75 displayed the most significantly altered methylation, suggesting the role of these genes in the metabolic complications associated with PsA.Conclusion:These findings help our understanding of the pathogenesis of PsA and advance epigenetic studies in regards to this disease and the cardiometabolic comorbidities associated. Funded by ISCIII (PI17/01316 and RIER RD16/0012/0015) co-funded with FEDER.Disclosure of Interests:Iván Arias de la Rosa: None declared, María Dolores López Montilla Speakers bureau: Celgene, Javier Rodríguez: None declared, Esteban Ballester: None declared, Carmen Torres-Granados: None declared, Carlos Perez-Sanchez: None declared, Maria del Carmen Abalos-Aguilera: None declared, Gómez García Ignacio: None declared, Desiree Ruiz: None declared, Alejandra M. Patiño-Trives: None declared, María Luque-Tévar: None declared, Eduardo Collantes-Estévez Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE, Lilly, Bristol and Celgene., Chary Lopez-Pedrera Grant/research support from: ROCHE and Pfizer., Alejandro Escudero Contreras Grant/research support from: ROCHE and Pfizer, Speakers bureau: ROCHE, Lilly, Bristol and Celgene., Nuria Barbarroja Puerto Grant/research support from: ROCHE and Pfizer., Speakers bureau: ROCHE and Celgene.

Download Full-text

P-141 The contribution of white blood cell gene expression in the prediction of gastrointestinal cancer

Annals of Oncology ◽

10.1016/j.annonc.2020.04.223 ◽

2020 ◽

Vol 31 ◽

pp. S135-S136

Author(s):

P. Apostolou ◽

P. Parsonidis ◽

A. Iliopoulos ◽

I. Papasotiriou

Keyword(s):

Gene Expression ◽

Blood Cell ◽

White Blood Cell ◽

Gastrointestinal Cancer ◽

Cell Gene Expression ◽

Cell Gene

Download Full-text

Diet Modifies Pioglitazone’s Influence on Hepatic PPARγ-Regulated Mitochondrial Gene Expression

PPAR Research ◽

10.1155/2020/3817573 ◽

2020 ◽

Vol 2020 ◽

pp. 1-20

Author(s):

Sakil Kulkarni ◽

Jiansheng Huang ◽

Eric Tycksen ◽

Paul F. Cliften ◽

David A. Rudnick

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Transcriptional Regulation ◽

Mitochondrial Gene ◽

Peroxisome Proliferator ◽

Large Set ◽

Peroxisome Proliferator Activated Receptor ◽

Nonalcoholic Fatty Liver ◽

Hepatic Expression ◽

Insulin Resistant

Pioglitazone (Pio) is a thiazolidinedione (TZD) insulin-sensitizing drug whose effects result predominantly from its modulation of the transcriptional activity of peroxisome proliferator-activated-receptor-gamma (PPARγ). Pio is used to treat human insulin-resistant diabetes and also frequently considered for treatment of nonalcoholic steatohepatitis (NASH). In both settings, Pio’s beneficial effects are believed to result primarily from its actions on adipose PPARγ activity, which improves insulin sensitivity and reduces the delivery of fatty acids to the liver. Nevertheless, a recent clinical trial showed variable efficacy of Pio in human NASH. Hepatocytes also express PPARγ, and such expression increases with insulin resistance and in nonalcoholic fatty liver disease (NAFLD). Furthermore, mice that overexpress hepatocellular PPARγ and Pio-treated mice with extrahepatic PPARγ gene disruption develop features of NAFLD. Thus, Pio’s direct impact on hepatocellular gene expression might also be a determinant of this drug’s ultimate influence on insulin resistance and NAFLD. Previous studies have characterized Pio’s PPARγ-dependent effects on hepatic expression of specific adipogenic, lipogenic, and other metabolic genes. However, such transcriptional regulation has not been comprehensively assessed. The studies reported here address that consideration by genome-wide comparisons of Pio’s hepatic transcriptional effects in wildtype (WT) and liver-specific PPARγ-knockout (KO) mice given either control or high-fat (HFD) diets. The results identify a large set of hepatic genes for which Pio’s liver PPARγ-dependent transcriptional effects are concordant with its effects on RXR-DNA binding in WT mice. These data also show that HFD modifies Pio’s influence on a subset of such transcriptional regulation. Finally, our findings reveal a broader influence of Pio on PPARγ-dependent hepatic expression of nuclear genes encoding mitochondrial proteins than previously recognized. Taken together, these studies provide new insights about the tissue-specific mechanisms by which Pio affects hepatic gene expression and the broad scope of this drug’s influence on such regulation.

Download Full-text

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

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-019-0499-6 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 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.

Download Full-text

Distinct whole-blood transcriptome profile of children with metabolic healthy overweight/obesity compared to metabolic unhealthy overweight/obesity

Pediatric Research ◽

10.1038/s41390-020-01276-7 ◽

2020 ◽

Author(s):

Abel Plaza-Florido ◽

Signe Altmäe ◽

Francisco J. Esteban ◽

Cristina Cadenas-Sanchez ◽

Concepción M. Aguilera ◽

...

Keyword(s):

Whole Blood ◽

Transcriptome Profile ◽

Blood Transcriptome

Download Full-text

A gene expression signature for insulin resistance

Physiological Genomics ◽

10.1152/physiolgenomics.00115.2010 ◽

2011 ◽

Vol 43 (3) ◽

pp. 110-120 ◽

Cited By ~ 17

Author(s):

Nicky Konstantopoulos ◽

Victoria C. Foletta ◽

David H. Segal ◽

Katherine A. Shields ◽

Andrew Sanigorski ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Large Scale ◽

Gene Expression Signature ◽

Channel Blockers ◽

Expression Signature ◽

Insulin Resistant ◽

Novel Strategy

Insulin resistance is a heterogeneous disorder caused by a range of genetic and environmental factors, and we hypothesize that its etiology varies considerably between individuals. This heterogeneity provides significant challenges to the development of effective therapeutic regimes for long-term management of type 2 diabetes. We describe a novel strategy, using large-scale gene expression profiling, to develop a gene expression signature (GES) that reflects the overall state of insulin resistance in cells and patients. The GES was developed from 3T3-L1 adipocytes that were made “insulin resistant” by treatment with tumor necrosis factor-α (TNF-α) and then reversed with aspirin and troglitazone (“resensitized”). The GES consisted of five genes whose expression levels best discriminated between the insulin-resistant and insulin-resensitized states. We then used this GES to screen a compound library for agents that affected the GES genes in 3T3-L1 adipocytes in a way that most closely resembled the changes seen when insulin resistance was successfully reversed with aspirin and troglitazone. This screen identified both known and new insulin-sensitizing compounds including nonsteroidal anti-inflammatory agents, β-adrenergic antagonists, β-lactams, and sodium channel blockers. We tested the biological relevance of this GES in participants in the San Antonio Family Heart Study ( n = 1,240) and showed that patients with the lowest GES scores were more insulin resistant (according to HOMA_IR and fasting plasma insulin levels; P < 0.001). These findings show that GES technology can be used for both the discovery of insulin-sensitizing compounds and the characterization of patients into subtypes of insulin resistance according to GES scores, opening the possibility of developing a personalized medicine approach to type 2 diabetes.

Download Full-text

Dietary fish oil positively regulates plasma leptin and adiponectin levels in sucrose-fed, insulin-resistant rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00846.2004 ◽

2005 ◽

Vol 289 (2) ◽

pp. R486-R494 ◽

Cited By ~ 101

Author(s):

Andrea S. Rossi ◽

Yolanda B. Lombardo ◽

Jean-Marc Lacorte ◽

Adriana G. Chicco ◽

Christine Rouault ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Insulin Sensitivity ◽

Fish Oil ◽

Essential Role ◽

Control Diet ◽

Insulin Resistant ◽

Dietary Fish ◽

Plasma Leptin

Insulin resistance and adiposity induced by a long-term sucrose-rich diet (SRD) in rats could be reversed by fish oil (FO). Regulation of plasma leptin and adiponectin levels, as well as their gene expression, by FO might be implicated in these findings. This study was designed to evaluate the long-term regulation of leptin and adiponectin by dietary FO in a dietary model of insulin resistance induced by long-term SRD in rats and to determine their impact on adiposity and insulin sensitivity. Rats were randomized to consume a control diet (CD; n = 25) or an SRD ( n = 50) for 7 mo. Subsequently, the SRD-fed rats were randomized to consume SRD+FO or to continue on SRD for an additional 2 mo. Long-term SRD induced overweight and decreased both plasma leptin and adiponectin levels without change in gene expression. Dyslipidemia, adiposity, and insulin resistance accompanied these modifications. Shifting the source of fat to FO for 2 mo increased plasma levels of both adipokines, reversed insulin resistance and dyslipidemia, and improved adiposity. These results were not associated with modifications in gene expression. These results suggest that increasing both adipokines by dietary FO might play an essential role in the normalization of insulin resistance and adiposity in dietary-induced, insulin-resistant models.

Download Full-text