scholarly journals Low-Grade Chronic Inflammation in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) Population: Associations with insulin resistance and cardiometabolic risk profile

Diabetes Care ◽  
2009 ◽  
Vol 32 (7) ◽  
pp. 1295-1301 ◽  
Author(s):  
S. R. de Rooij ◽  
G. Nijpels ◽  
P. M. Nilsson ◽  
J. J. Nolan ◽  
R. Gabriel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Insulin Sensitivity ◽  
Chronic Inflammation ◽  
Cardiometabolic Risk ◽  
Risk Profile ◽  
Low Grade ◽  
The Relationship

scholarly journals Insulin resistance and liver histopathology in metabolically unhealthy subjects do not correlate with the hepatic abundance of NLRP3 inflammasome nor circulating IL-1β levels

2021 ◽  
Vol 9 (1) ◽  
pp. e001975
Author(s):  
Nicolas Quezada ◽  
Ilse Valencia ◽  
Javiera Torres ◽  
Gregorio Maturana ◽  
Jaime Cerda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Liver Damage ◽  
Nlrp3 Inflammasome ◽  
Low Grade ◽  
Model Assessment ◽  
Alcoholic Fatty Liver ◽  
Protein Levels ◽  
Liver Histopathology ◽  
Inflammatory Status

IntroductionSystemic chronic low-grade inflammation has been linked to insulin resistance (IR) and non-alcoholic steatohepatitis (NASH). NOD-like receptor protein 3 (NLRP3) inflammasome and its final product, interleukin (IL)-1β, exert detrimental effects on insulin sensitivity and promote liver inflammation in murine models. Evidence linking hepatic NLRP3 inflammasome, systemic IR and NASH has been scarcely explored in humans. Herein, we correlated the hepatic abundance of NLRP3 inflammasome components and IR and NASH in humans.Research design and methodsMetabolically healthy (MH) (n=11) and metabolically unhealthy (MUH) (metabolic syndrome, n=21, and type 2 diabetes, n=14) subjects were recruited. Insulin sensitivity (homeostatic model assessment of IR (HOMA-IR) and Oral Glucose Sensitivity (OGIS120)), glycemic (glycated hemoglobin), and lipid parameters were determined by standard methods. Plasma cytokines were quantified by Magpix. Hepatic NLRP3 inflammasome components were determined at the mRNA and protein levels by reverse transcription–quantitative PCR and western blot, respectively. Liver damage was assessed by histological analysis (Non-alcoholic Fatty Liver Disease Activity Score (NAS) and Steatosis, Inflammatory Activity, and Fibrosis (SAF) scores). IR and liver histopathology were correlated with NLRP3 inflammasome components as well as with liver and plasma IL-1β levels.ResultsBody Mass Index, waist circumference, and arterial hypertension frequency were significantly higher in MUH subjects. These patients also had increased high-sensitivity C reactive protein levels compared with MH subjects. No differences in the plasma levels of IL-1β nor the hepatic content of Nlrp3, apoptosis-associated speck-like (Asc), Caspase-1, and IL-1β were detected between MUH and MH individuals. MUH subjects had significantly higher NAS and SAF scores, indicating more severe liver damage. However, histological severity did not correlate with the hepatic content of NLRP3 inflammasome components nor IL-1β levels.ConclusionOur results suggest that NLRP3 inflammasome activation is linked neither to IR nor to the inflammatory status of the liver in MUH patients.

scholarly journals The Relationship between Insulin Resistance and the Cardiovascular Biomarker Growth Differentiation Factor-15 in Obese Patients

2011 ◽  
Vol 57 (2) ◽  
pp. 309-316 ◽  
Author(s):  
Greisa Vila ◽  
Michaela Riedl ◽  
Christian Anderwald ◽  
Michael Resl ◽  
Ammon Handisurya ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Gastric Bypass ◽  
Insulin Sensitivity ◽  
Oral Glucose ◽  
Model Assessment ◽  
Obese Patients ◽  
Growth Differentiation Factor 15 ◽  
Homeostatic Model Assessment ◽  
Homeostatic Model ◽  
The Relationship

BACKGROUND Growth differentiation factor-15 (GDF-15) is a stress-responsive cytokine linked to obesity comorbidities such as cardiovascular disease, inflammation, and cancer. GDF-15 also has adipokine properties and recently emerged as a prognostic biomarker for cardiovascular events. METHODS We evaluated the relationship of plasma GDF-15 concentrations with parameters of obesity, inflammation, and glucose and lipid metabolism in a cohort of 118 morbidly obese patients [mean (SD) age 37.2 (12) years, 89 females, 29 males] and 30 age- and sex-matched healthy lean individuals. All study participants underwent a 75-g oral glucose tolerance test; 28 patients were studied before and 1 year after Roux-en-Y gastric bypass surgery. RESULTS Obese individuals displayed increased plasma GDF-15 concentrations (P < 0.001), with highest concentrations observed in patients with type 2 diabetes. GDF-15 was positively correlated with age, waist-to-height ratio, mean arterial blood pressure, triglycerides, creatinine, glucose, insulin, C-peptide, hemoglobin A1c, and homeostatic model assessment insulin resistance index and negatively correlated with oral glucose insulin sensitivity. Age, homeostatic model assessment index, oral glucose insulin sensitivity, and creatinine were independent predictors of GDF-15 concentrations. Roux-en-Y gastric bypass led to a significant reduction in weight, leptin, insulin, and insulin resistance, but further increased GDF-15 concentrations (P < 0.001). CONCLUSIONS The associations between circulating GDF-15 concentrations and age, insulin resistance, and creatinine might account for the additional cardiovascular predictive information of GDF-15 compared to traditional risk factors. Nevertheless, GDF-15 changes following bariatric surgery suggest an indirect relationship between GDF-15 and insulin resistance. The clinical utility of GDF-15 as a biomarker might be limited until the pathways directly controlling GDF-15 concentrations are better understood.

Insulin resistance and risk of vascular events, interventions and mortality in type 1 diabetes

2021 ◽  
Author(s):  
Marga A.g. Helmink ◽  
Marieke de Vries ◽  
Frank L.j. Visseren ◽  
Wendela L. de Ranitz ◽  
Harold W. de Valk ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Type 1 Diabetes ◽  
Insulin Sensitivity ◽  
Lower Risk ◽  
Cardiovascular Events ◽  
Additional Risk Factor ◽  
Vascular Events ◽  
All Cause Mortality

Objective: To identify determinants associated with insulin resistance and to assess the association between insulin resistance and cardiovascular events, vascular interventions and mortality in people with type 1 diabetes at high risk of cardiovascular disease . Design: Prospective cohort study. Methods: 195 people with type 1 diabetes from the Secondary Manifestations of ARTerial disease (SMART) cohort were included. Insulin resistance was quantified by the estimated glucose disposal rate (eGDR) with higher eGDR levels indicating higher insulin sensitivity (i.e. lower eGDR levels indicating higher insulin resistance). Linear regression models were used to evaluate determinants associated with eGDR. The effect of eGDR on cardiovascular events, cardiovascular events or vascular interventions (combined endpoint) and on all-cause mortality was analysed using Cox proportional hazards models adjusted for confounders. Results: In 195 individuals (median follow-up 12.9 years, IQR 6.7-17.0), a total of 25 cardiovascular events, 26 vascular interventions and 27 deaths were observed. High eGDR as a marker for preserved insulin sensitivity was independently associated with a lower risk of cardiovascular events (HR 0.75; 95%CI 0.61-0.91), a lower risk of cardiovascular events and vascular interventions (HR 0.74; 95%CI 0.63-0.87), and a lower risk of all-cause mortality (HR 0.81; 95%CI 0.67-0.98). Conclusions: Insulin resistance as measured by eGDR is an additional risk factor for cardiovascular disease in individuals with type 1 diabetes. Modification of insulin resistance by lifestyle interventions or pharmacological treatment could be a viable therapeutic target to lower the risk of cardiovascular disease.

Disturbed Tumor Necrosis Factor System is Linked with Lower eGFR and Chronic Inflammation in Hypertension

2014 ◽  
Vol 29 (1) ◽  
pp. e69-e77 ◽  
Author(s):  
Takashi Eguchi ◽  
Tatsuya Maruyama ◽  
Yoichi Ohno ◽  
Toshiyuki Morii ◽  
Hiroshi Hirose ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Tumor Necrosis Factor ◽  
Chronic Inflammation ◽  
Tumor Necrosis ◽  
Renin Angiotensin System ◽  
Metabolic Factors ◽  
Lower Egfr ◽  
Soluble Tnf Receptor ◽  
The Relationship ◽  
Necrosis Factor

Background The relationship between tumor necrosis factor (TNF)-related parameters and cardiorenal metabolic factors is still controversial in clinical hypertension. Methods Normotensive men (NT, n=60) and treated stage 2 and 3 essential hypertensive men (HT, n=89) were enrolled in this study. The relationship between TNF-related parameters and cardiorenal metabolic factors was examined in NT and HT, separately. Results HT showed higher rates of insulin resistance and enhanced chronic inflammation compared with NT. The levels of soluble TNF receptor 1 and 2 were significantly higher in HT than in NT, although TNF-α levels were unexpectedly lower in HT than in NT. Regression analysis indicated that the TNF-related parameters were closely linked with mild renal dysfunction both in NT and HT, and moderately related to chronic inflammation only in HT. HT taking inhibitors of the renin-angiotensin system showed improved insulin resistance, but no difference in the TNF-related parameters. Conclusion These results suggest that the disturbed TNF system is closely linked with chronic inflammation rather than with insulin resistance in HT.

Differential DNA Methylation and Cardiometabolic Risk in African American Mother-Adolescent Dyads

2021 ◽  
pp. 109980042110390
Author(s):  
Amanda Elswick Gentry ◽  
Jo Robins ◽  
Mat Makowski ◽  
Wendy Kliewer
Keyword(s):  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Dna Methylation ◽  
African American ◽  
African Americans ◽  
Waist Circumference ◽  
Low Income ◽  
Cardiometabolic Risk ◽  
Disease Risk ◽  
Cardiovascular Disease Risk

Background: Cardiovascular disease disproportionately affects African Americans as the leading cause of morbidity and mortality. Among African Americans, compared to other racial groups, cardiovascular disease onset occurs at an earlier age due to a higher prevalence of cardiometabolic risk factors, particularly obesity, hypertension and type 2 diabetes. Emerging evidence suggests that heritable epigenetic processes are related to increased cardiovascular disease risk, but this is largely unexplored in adolescents or across generations. Materials and Methods: In a cross-sectional descriptive pilot study in low-income African American mother-adolescent dyads, we examined associations between DNA methylation and the cardiometabolic indicators of body mass index, waist circumference, and insulin resistance. Results: Four adjacent cytosine and guanine nucleotides (CpG) sites were significantly differentially methylated and associated with C-reactive protein (CRP), 62 with waist circumference, and none to insulin resistance in models for both mothers and adolescents. Conclusion: Further study of the relations among psychological and environmental stressors, indicators of cardiovascular disease, risk, and epigenetic factors will improve understanding of cardiovascular disease risk so that preventive measures can be instituted earlier and more effectively. To our knowledge this work is the first to examine DNA methylation and cardiometabolic risk outcomes in mother-adolescent dyads.

scholarly journals Empagliflozin reverses obesity and insulin resistance through fat browning and alternative macrophage activation in mice fed a high-fat diet

2019 ◽  
Vol 7 (1) ◽  
pp. e000783 ◽  
Author(s):  
Liang Xu ◽  
Naoto Nagata ◽  
Guanliang Chen ◽  
Mayumi Nagashimada ◽  
Fen Zhuge ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Energy Expenditure ◽  
Chronic Inflammation ◽  
Plasma Levels ◽  
High Fat Diet ◽  
Macrophage Activation ◽  
Low Grade ◽  
Obese Mice ◽  
High Fat

ObjectiveWe reported previously that empagliflozin—a sodium-glucose cotransporter (SGLT) 2 inhibitor—exhibited preventive effects against obesity. However, it was difficult to extrapolate these results to human subjects. Here, we performed a therapeutic study, which is more relevant to clinical situations in humans, to investigate antiobesity effects of empagliflozin and illustrate the mechanism underlying empagliflozin-mediated enhanced fat browning in obese mice.Research design and methodsAfter 8 weeks on a high-fat diet (HFD), C57BL/6J mice exhibited obesity, accompanied by insulin resistance and low-grade chronic inflammation. Cohorts of obese mice were continued on the HFD for an additional 8-week treatment period with or without empagliflozin.ResultsTreatment with empagliflozin for 8 weeks markedly increased glucose excretion in urine, and suppressed HFD-induced weight gain, insulin resistance and hepatic steatosis. Notably, empagliflozin enhanced oxygen consumption and carbon dioxide production, leading to increased energy expenditure. Consistently, the level of uncoupling protein 1 expression was increased in both brown and white (WAT) adipose tissues of empagliflozin-treated mice. Furthermore, empagliflozin decreased plasma levels of interleukin (IL)-6 and monocyte chemoattractant protein-1, but increased plasma levels of IL-33 and adiponectin in obese mice. Finally, we found that empagliflozin reduced M1-polarized macrophage accumulation, while inducing the anti-inflammatory M2 phenotype of macrophages in the WAT and liver, thereby attenuating obesity-related chronic inflammation.ConclusionsTreatment with empagliflozin attenuated weight gain by increasing energy expenditure and adipose tissue browning, and alleviated obesity-associated inflammation and insulin resistance by alternative macrophage activation in the WAT and liver of obese mice.

scholarly journals Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality

Diabetologia ◽  
2019 ◽  
Vol 63 (2) ◽  
pp. 253-260 ◽  
Author(s):  
Martijn C. G. J. Brouwers ◽  
Nynke Simons ◽  
Coen D. A. Stehouwer ◽  
Aaron Isaacs
Keyword(s):  
Cardiovascular Disease ◽  
Liver Disease ◽  
Fatty Liver Disease ◽  
Plasma Lipids ◽  
Low Grade ◽  
Alcoholic Fatty Liver ◽  
Important Mediator ◽  
Low Grade Inflammation ◽  
The Relationship ◽  
Alcoholic Fatty Liver Disease

Abstract Non-alcoholic fatty liver disease (NAFLD) is highly prevalent among individuals with type 2 diabetes. Although epidemiological studies have shown that NAFLD is associated with cardiovascular disease (CVD), it remains unknown whether NAFLD is an active contributor or an innocent bystander. Plasma lipids, low-grade inflammation, impaired fibrinolysis and hepatokines are potential mediators of the relationship between NAFLD and CVD. The Mendelian randomisation approach can help to make causal inferences. Studies that used common variants in PNPLA3, TM6SF2 and GCKR as instruments to investigate the relationship between NAFLD and coronary artery disease (CAD) have reported contrasting results. Variants in PNPLA3 and TM6SF2 were found to protect against CAD, whereas variants in GCKR were positively associated with CAD. Since all three genes have been associated with non-alcoholic steatohepatitis, the second stage of NAFLD, the question of whether low-grade inflammation is an important mediator of the relationship between NAFLD and CAD arises. In contrast, the differential effects of these genes on plasma lipids (i.e. lipid-lowering for PNPLA3 and TM6SF2, and lipid-raising for GCKR) strongly suggest that plasma lipids account for their differential effects on CAD risk. This concept has recently been confirmed in an extended set of 12 NAFLD susceptibility genes. From these studies it appears that plasma lipids are an important mediator between NAFLD and CVD risk. These findings have important clinical implications, particularly for the design of anti-NAFLD drugs that also affect lipid metabolism.

Roles of oxidative stress, adiponectin, and nuclear hormone receptors in obesity-associated insulin resistance and cardiovascular risk

2014 ◽  
Vol 19 (2) ◽  
Author(s):  
Morihiro Matsuda ◽  
Iichiro Shimomura
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Cardiovascular Disease ◽  
Adipose Tissue ◽  
Cardiovascular Diseases ◽  
Hormone Receptors ◽  
Disease Risk ◽  
Nuclear Hormone Receptors ◽  
Low Grade ◽  
Effective Prevention

AbstractObesity leads to the development of type 2 diabetes mellitus, which is a strong risk factor for cardiovascular disease. A better understanding of the molecular basis of obesity will lead to the establishment of effective prevention strategies for cardiovascular diseases. Adipocytes have been shown to generate a variety of endocrine factors termed adipokines/adipocytokines. Obesity-associated changes to these adipocytokines contribute to the development of cardiovascular diseases. Adiponectin, which is one of the most well-characterized adipocytokines, is produced exclusively by adipocytes and exerts insulin-sensitizing and anti-atherogenic effects. Obese subjects have lower levels of circulating adiponectin, and this is recognized as one of the factors involved in obesity-induced insulin resistance and atherosclerosis. Another pathophysiological feature of obesity may involve the low-grade chronic inflammation in adipose tissue. This inflammatory process increases oxidative stress in adipose tissue, which may affect remote organs, leading to the development of diabetes, hypertension, and atherosclerosis. Nuclear hormone receptors (NRs) regulate the transcription of the target genes in response to binding with their ligands, which include metabolic and nutritional substrates. Among the various NRs, peroxisome proliferator-activated receptor γ promotes the transcription of adiponectin and antioxidative enzymes, whereas mineralocorticoid receptor mediates the effects of aldosterone and glucocorticoid to induce oxidative stress in adipocytes. It is hypothesized that both play crucial roles in the pathophysiology of obesity-associated insulin resistance and cardiovascular diseases. Thus, reduced adiponectin and increased oxidative stress play pathological roles in obesity-associated insulin resistance to increase the cardiovascular disease risk, and various NRs may be involved in this pathogenesis.

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