Markers Of Metabolic Dysfunction Research Articles

Investigation Of Blood Lactate As A Marker Of Metabolic Dysfunction During Pregnancy

Investigation Of Blood Lactate As A Marker Of Metabolic Dysfunction During Pregnancy

Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus

BackgroundThe GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus.MethodPlasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase‐associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13).ResultsAt baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group.ConclusionWeight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.

Ethnic differences in complement system biomarkers and their association with metabolic health in men of Black African and White European ethnicity.

Inflammation plays a fundamental role in the development of several metabolic diseases, including obesity and type 2 diabetes (T2D); the complement system has been implicated in their development. People of Black African (BA) ethnicity are disproportionately affected by T2D and other metabolic diseases but the impact of ethnicity on the complement system has not been explored. We investigated ethnic differences in complement biomarkers and activation status between men of BA and White European (WE) ethnicity and explored their association with parameters of metabolic health. We measured a panel of 15 complement components, regulators, and activation products in fasting plasma from 89 BA and 96 WE men. Ethnic differences were statistically validated. Association of complement biomarkers with metabolic health indices (BMI, waist circumference, insulin resistance, and HbA1c) were assessed in the groups. Plasma levels of the key complement components C3 and C4, the regulators clusterin and properdin and the activation marker iC3b were significantly higher in BA compared to WE men after age adjustment, while FD levels were significantly lower. C3 and C4 levels positively correlated with some or all markers of metabolic dysfunction in both ethnic groups while FD was inversely associated with HbA1c in both groups, and clusterin and properdin were inversely associated with some markers of metabolic dysfunction only in the WE group. Our findings of increased levels of complement components and activation products in BA compared to WE men suggest differences in complement regulation that may impact susceptibility to poor metabolic health.

FAT/CD36 Participation in Human Skeletal Muscle Lipid Metabolism: A Systematic Review

Fatty acid translocase/cluster of differentiation 36 (FAT/CD36) is a multifunctional membrane protein activated by a high-fat diet, physical exercise, fatty acids (FAs), leptin, and insulin. The principal function of FAT/CD36 is to facilitate the transport of long-chain fatty acids through cell membranes such as myocytes, adipocytes, heart, and liver. Under high-energy expenditure, the different isoforms of FAT/CD36 in the plasma membrane and mitochondria bind to the mobilization and oxidation of FAs. Furthermore, FAT/CD36 is released in its soluble form and becomes a marker of metabolic dysfunction. Studies with healthy animals and humans show that physical exercise and a high-lipid diet increase FAT/CD36 expression and caloric expenditure. However, several aspects such as obesity, diabetes, Single Nucleotide polymorphisms (SNPs), and oxidative stress affect the normal FAs metabolism and function of FAT/CD36, inducing metabolic disease. Through a comprehensive systematic review of primary studies, this work aimed to document molecular mechanisms related to FAT/CD36 in FAs oxidation and trafficking in skeletal muscle under basal conditions, physical exercise, and diet in healthy individuals.

Hippocampal acidity and volume are differentially associated with spatial navigation in older adults

The hippocampus is negatively affected by aging and is critical for spatial navigation. While there is evidence that wayfinding navigation tasks are especially sensitive to preclinical hippocampal deterioration, these studies have primarily used volumetric hippocampal imaging without considering microstructural properties or anatomical variation within the hippocampus. T1ρ is an MRI measure sensitive to regional pH, with longer relaxation rates reflecting acidosis as a marker of metabolic dysfunction and neuropathological burden. For the first time, we investigate how measures of wayfinding including landmark location learning and delayed memory in cognitively normal older adults (N = 84) relate to both hippocampal volume and T1ρ in the anterior and posterior hippocampus. Regression analyses revealed hippocampal volume was bilaterally related to learning, while right lateralized T1ρ was related to delayed landmark location memory and bilateral T1ρ was related to the delayed use of a cognitive map. Overall, results suggest hippocampal volume and T1ρ relaxation rate tap into distinct mechanisms involved in preclinical cognitive decline as assessed by wayfinding navigation, and laterality influenced these relationships more than the anterior-posterior longitudinal axis of the hippocampus.

Decrease of dipeptidyl peptidase 4 activity is associated with weight loss after bariatric surgery

PurposeDipeptidyl peptidase 4 (DPP4) is expressed and secreted by adipocytes. DPP4 induces insulin resistance independently of its effect on glucagon-like peptide 1, thus it is conceivable that DPP4 directly contributes to metabolic dysfunction in patients with morbid obesity. The aim of this study was to investigate the impact of weight loss induced by bariatric surgery on DPP4 activity, and whether these changes are associated with improvements in markers of metabolic dysfunction and fatty liver disease.Materials and MethodsWe included 68 non-diabetic patients who underwent bariatric surgery. Serum DPP4 activity was measured using a fluorogenic substrate before and after surgery.ResultsResults: After a median follow-up period of 12 (IQR 11-17) months, median serum DPP4 activity decreased from 230 (IQR: 194-273) to 193 (164-252) pmol/min (p=0.012). The decrease in DPP4 activity was significantly correlated with decreases in BMI, improved cholesterol levels, reduced hepatic injury markers as well as improved post-prandial insulin sensitivity. After multivariable adjustment, ΔDPP4 activity remained significantly associated with Δcholesterol (beta=0.341, p=0.025), ΔLDL cholesterol (beta=0.350, p=0.019), Δgamma-glutamyltransferase (beta=0.323, p=0.040) and ΔMatsuda index (beta=-0.386, p=0.045).ConclusionWe demonstrated that weight loss induced by bariatric surgery results in decreased circulating DPP4 activity beyond the initial phase of weight loss. The associations between decreased DPP4 activity and improved cholesterol levels as well as hepatic injury markers point towards pleiotropic effects of DPP4 beyond glucose metabolism which warrant further investigation.

Increased Growth Differentiation Factor 15 in Patients with Hypoleptinemia-Associated Lipodystrophy.

Objective. Similar to obesity, lipodystrophy (LD) causes adipose tissue dysfunction and severe metabolic complications. Growth differentiation factor 15 (GDF15) belongs to the transforming growth factor β superfamily and is dysregulated in metabolic disease including obesity and diabetes mellitus. Circulating levels in LD and the impact of leptin treatment have not been investigated so far. Material and Methods. GDF15 serum levels were quantified in 60 LD patients without human immunodeficiency virus infection and 60 controls matched for age, gender, and body mass index. The impact of metreleptin treatment on circulating GDF15 was assessed in a subgroup of patients. GDF15 mRNA expression was determined in metabolic tissues of leptin-deficient lipodystrophic aP2-nSREBP1c-Tg mice, obese ob/ob mice, and control C57Bl6 mice. Results. Median GDF15 serum concentrations were significantly higher in LD patients (819 ng/L) as compared to the control group (415 ng/L) (p < 0.001). In multiple linear regression analysis, an independent and positive association remained between GDF15 on one hand and age, patient group, hemoglobin A1c, triglycerides, and C-reactive protein on the other hand. Moreover, there was an independent negative association between GFD15 and estimated glomerular filtration rate. Circulating GDF15 was not significantly affected by metreleptin treatment in LD patients. Gdf15 was upregulated in leptin-deficient lipodystrophic mice as compared to controls. Moreover, Gdf15 mRNA expression was downregulated by leptin treatment in lipodystrophic and obese animals. Conclusions. Serum concentrations of GDF15 are elevated in LD patients and independently associated with markers of metabolic dysfunction. Gdf15 expression is higher in lipodystrophic mice and downregulated by leptin treatment.

Psoriatic skin inflammation induces a pre-diabetic phenotype via the endocrine actions of skin secretome

ObjectivePsoriasis is a chronic inflammatory skin disease that is thought to affect ∼2% of the global population. Psoriasis has been associated with ∼30% increased risk of developing type 2 diabetes (T2D), with numerous studies reporting that psoriasis is an independent risk-factor for T2D, separate from underlying obesity. Separately, studies of skin-specific transgenic mice have reported altered whole-body glucose homeostasis in these models. These studies imply a direct role for skin inflammation and dysfunction in mediating the onset of T2D in psoriasis patients, potentially via the endocrine effects of the skin secretome on key metabolic tissues. We used a combination of in vivo and ex vivo mouse models and ex vivo human imiquimod (IMQ) models to investigate the effects of psoriasis-mediated changes in the skin secretome on whole-body metabolic function. MethodsTo induce psoriatic skin inflammation, mice were topically administered 75 mg of 5% IMQ cream (or Vaseline control) to a shaved dorsal region for 4 consecutive days. On day 5, mice were fasted for glucose and insulin tolerance testing, or sacrificed in the fed state with blood and tissues collected for analysis. To determine effects of the skin secretome, mouse skin was collected at day 5 from IMQ mice and cultured for 24 h. Conditioned media (CM) was collected and used 1:1 with fresh media to treat mouse explant subcutaneous adipose tissue (sAT) and isolated pancreatic islets. For human CM experiments, human skin was exposed to 5% IMQ cream for 20 min, ex vivo, to induce a psoriatic phenotype, then cultured for 24 h. CM was collected, combined 1:1 with fresh media and used to treat human sAT ex vivo. Markers of tissue inflammation and metabolic function were determined by qPCR. Beta cell function in isolated islets was measured by dynamic insulin secretion. Beta-cell proliferation was determined by measurement of Ki67 immunofluorescence histochemistry and BrDU uptake, whilst islet apoptosis was assessed by caspase 3/7 activity. All data is expressed as mean ± SEM. ResultsTopical treatment with IMQ induced a psoriatic-like phenotype in mouse skin, evidenced by thickening, erythema and inflammation of the skin. Topical IMQ treatment induced inflammation and signs of metabolic dysfunction in sub-cutaneous and epidydimal adipose tissue, liver, skeletal muscle and gut tissue. However, consistent with islet compensation and a pre-diabetic phenotype, IMQ mice displayed improved glucose tolerance, increased insulin and c-peptide response to glucose, and increased beta cell proliferation. Treatment of sAT with psoriatic mouse or human skin-CM replicated the in vivo phenotype, leading to increased inflammation and metabolic dysfunction in mouse and human sAT. Treatment of pancreatic islets with psoriatic mouse skin-CM induced increases in beta-proliferation and apoptosis, thus partially replicating the in vivo phenotype. ConclusionsPsoriasis-like skin inflammation induces a pre-diabetic phenotype, characterised by tissue inflammation and markers of metabolic dysfunction, together with islet compensation in mice. The in vivo phenotype is partially replicated by exposure of sAT and pancreatic islets to psoriatic-skin conditioned media. These results support the hypothesis that psoriatic skin inflammation, potentially via the endocrine actions of the skin secretome, may constitute a novel pathophysiological pathway mediating the development of T2D.

The Association Between Serum Ferritin Concentration and Visceral Adiposity Estimated by Whole-Body DXA Scan in Women With Polycystic Ovary Syndrome.

Objective: Women with polycystic ovary syndrome (PCOS) are characterized by insulin resistance and higher prevalence of obesity. Serum ferritin is increased in obesity and is associated with insulin resistance. The aim of the present study was to evaluate the relationships between serum ferritin concentration with insulin resistance and body composition estimated by dual-energy X-ray absorptiometry (DXA) in PCOS women in comparison to the control group.Patients and Methods: One hundred four women were enrolled to the study−65 women with PCOS and 39 women matched for age and BMI as a control group. Serum ferritin concentration and oral glucose tolerance test (OGTT) were performed. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. DXA was performed to estimate fat, fat-free mass, and visceral adipose tissue (VAT).Results: Women with PCOS have higher serum concentration of ferritin (p = 0.002), insulin at baseline (p = 0.03), at 60 min of OGTT (p = 0.01), at 120 min of OGTT (p = 0.004), HOMA-IR (p = 0.03), and VAT (p = 0.0001) in comparison to the control group. We observed a relationship of serum ferritin with insulin concentration at baseline (r = 0.25, p = 0.04) and at 120 min of OGTT (r = 0.31, p = 0.01) and with HOMA-IR (r = 0.30, p = 0.01) in the PCOS group. We noticed an association between serum ferritin concentration and VAT (r = 0.42, p = 0.001), trunk fat mass (r = 0.25, p = 0.04), and android fat mass (r = 0.25, p = 0.04) in the PCOS group. Multiple regression analysis revealed that ferritin (p = 0.02, β = 0.17), insulin at baseline (p = 0.001, β = 0.30), glucose at the 120 min of OGTT (p = 0.007, β = 0.26), and triglycerides (p = 0.001, β = 0.33) were independent predictors of VAT amount in PCOS women.Conclusions: Elevated serum ferritin concentration is connected with insulin resistance as well as with DXA-estimated VAT, android, and trunk fat mass in PCOS women, and could be a marker of metabolic dysfunction.

Systematic Review of the Effects of Ultraviolet Radiation on Markers of Metabolic Dysfunction.

Emerging findings suggest that exposure to ultraviolet wavelengths of sunlight modulates metabolic function. Here we review the metabolic effects of exposure to ultraviolet radiation (UVR), focusing on the effects of phototherapies (that administer UVR), and advice to increase sun exposure in individuals enrolled in clinical trials and intervention studies. We identified 25 studies in which the effects of UVR on metabolic outcomes were examined, including: narrowband ultraviolet B phototherapy (nbUVB, n = 12); psoralen ultraviolet A phototherapy (n = 4); other types of UVR phototherapy (n = 5); and sun exposure advice (n = 5). Most studies recruited a small number of participants (≤100), who were middle-aged individuals undergoing treatment for psoriasis flare, with phototherapy or sun exposure advice administered for ≤12 weeks. Data obtained at baseline were usually compared with an endpoint following treatment with UVR, for a limited number of outcomes. There were few studies in which markers of glucose metabolism were assessed, with some beneficial effects of sun exposure (but not phototherapy) reported. LDL-cholesterol levels were lower in individuals receiving sun exposure advice, while treatment with nbUVB reduced blood concentrations of inflammatory markers (C-reactive protein and interleukin-6). Future studies should focus on determining whether the effects of these interventions change with time, and if they are dependent on the source of UVR (i.e. phototherapy or sun exposure) and wavelength(s) of light administered. Furthermore, studies need to measure a variety of (clinical) markers of glucose metabolism, adiposity and inflammation, control for factors such as skin type and sex, and stratify participants for metabolic disease diagnosis.

Alterations in plasma non-esterified fatty acid (NEFA) kinetics and relationship with insulin resistance in polycystic ovary syndrome.

Are non-esterified fatty acid (NEFA) kinetics altered in women with polycystic ovary syndrome (PCOS)? Women with PCOS, particularly obese subjects, have dysregulated plasma NEFA kinetics in response to changes in plasma insulin and glucose levels, which are associated with insulin resistance (IR) independently of the fasting plasma NEFA levels. Elevated plasma NEFA levels are associated with IR in many disorders, although the homeostasis of NEFA kinetics and its relationship to IR in women with PCOS is unknown. We prospectively compared insulin sensitivity and NEFA kinetics in 29 PCOS and 29 healthy controls women matched for BMI. This study was conducted in a tertiary institution. Plasma NEFA, glucose and insulin levels were assessed during a modified frequently sampled intravenous glucose tolerance test (mFSIVGTT). Minimal models were used to assess insulin sensitivity (Si) and NEFA kinetics (i.e. model-derived initial plasma NEFA level [NEFA0], phi constant [Φ], reflecting glucose-mediated inhibition of lipolysis and measures of maximum rate of lipolysis [SFFA] and NEFA uptake from plasma [KFFA]). The study provides new evidence that women with PCOS have defective NEFA kinetics characterized by: (i) lower basal plasma NEFA levels, measured directly and modeled (NEFA0), and (ii) a greater glucose-mediated inhibition of lipolysis in the remote or interstitial space (reflected by a lower affinity constant [Φ]). There were no differences, however, in the maximal rates of adipose tissue lipolysis (SFFA) and the rate at which NEFA leaves the plasma pool (KFFA). The differences observed in NEFA kinetics were exacerbated, and almost exclusively observed, in the obese PCOS subjects. Our study did not study NEFA subtypes. It was also cross-sectional and based on women affected by PCOS as defined by the 1990 National Institutes of Health (NIH) criteria (i.e. Phenotypes A and B) and identified in the clinical setting. Consequently, extrapolation of the present data to other phenotypes of PCOS should be made with caution. Furthermore, our data is exploratory and therefore requires validation with a larger sample size. Dysfunction in NEFA kinetics may be a marker of metabolic dysfunction in nondiabetic obese women with PCOS and may be more important than simply assessing circulating NEFA levels at a single point in time for understanding the mechanism(s) underlying the IR of PCOS. This work was supported by NIH grants R01-DK073632 and R01-HD29364 to R.A.; a Career Development Award from MD Medical Group, Moscow, RF, to D.L. and Augusta University funds to Y.-H.C. RA serves as consultant to Ansh Labs, Medtronics, Spruce Biosciences and Latitude Capital. U.E., Z.A., D.L., R.M., Y.-H.C., R.C.B. and Y.D.I.C. have no competing interests to declare. Not applicable.

Soluble ST2 is a biomarker for cardiovascular mortality related to abnormal glucose metabolism in high-risk subjects.

Inflammation plays a role in the development and progression of type 2 diabetes macroangiopathy. Interleukin 33 (IL-33) drives production of Th2-associated cytokines. The soluble form of suppression of tumorigenicity 2 (sST2) acting as a decoy receptor blocks IL-33 and tones down Th2 inflammatory response. We investigated the role of sST2 as a predictor of CV and all-cause mortality in a cohort of patients affected by established atherosclerotic disease. 399 patients with atherosclerotic disease from the Tor Vergata Atherosclerosis Registry performed follow-up every year by phone interview. The primary endpoint was cardiovascular death and the secondary endpoint was death for any other disease. sST2 plasma levels were significantly increased from normal glucose-tolerant patients to patients with history of type 2 diabetes (p < 0.00001). Levels of sST2 were significantly correlated with fasting plasma glucose (R = 0.16, p = 0.002), HbA1c (R = 0.17, p = 0.002), and HOMA (R = 0.16, p = 0.004). Dividing patients in tertiles of sST2 levels, those belonging to the highest tertile showed an increased rate of all-cause and cardiovascular mortality, (all-cause mortality p = 0.045 and CVD mortality p = 0.02). A multivariate Cox analysis revealed that sST2 increased the risk in cardiovascular mortality per SD by hazard ratio 1.050 (95% CI 1.006-1.097, p = 0.025) after adjustment for age and hs-CRP while it did not significantly change the risk for all-cause mortality. High circulating level of sST2 is associated to increased CVD mortality and markers of metabolic dysfunction in subjects with atherosclerotic disease.

Prenatal pesticide exposure associated with glycated haemoglobin and markers of metabolic dysfunction in adolescents

BackgroundPesticide exposure has been associated with increased risk of diabetes mellitus in adults, but potential effects of prenatal exposure on glucose regulation have not been investigated.The aim of this study was to investigate if maternal occupational pesticide exposure in pregnancy was associated with glycated haemoglobin A1c (HbA1c) in adolescents and whether an association was modified by sex and paraoxonase-1 (PON1) Q192R polymorphism. MethodsA prospective cohort study of children whose mothers were either occupationally exposed or unexposed to pesticides in early pregnancy. At age 10-to-16 years, the children (n = 168) underwent clinical examinations including pubertal stage assessment (accepted by 141 children) and blood sampling. PON1 Q192R genotype was available for 139 children and 103 mothers.The main outcome measure was HbA1c but other relevant biomarkers were also included. ResultsPrenatal pesticide exposure was associated with a 5.0% (95% confidence interval: 1.8; 8.2) higher HbA1c compared to unexposed children after adjustment for confounders. After stratification, the association remained significant for girls (6.2% (1.6; 11.1)) and if the child or the mother had the PON1 192R-allele (6.1% (1.6; 10.8) and 7.1% (2.0; 12.6), respectively). Besides, an exposure-related increase was seen for the leptin-to-adiponectin ratio, for plasminogen activator inhibitor type-1 in girls, and for interleukin-6 in children whose mothers had the R-allele. ConclusionPrenatal pesticide exposure was associated with higher HbA1c and changes in related biomarkers in adolescents. Our results suggest an adverse effect on glucose homeostasis and support previous findings from this cohort of an exposure-associated metabolic risk profile with higher susceptibility related to female sex and the PON1 192R-allele.

Mitochondrial SLC25 proteins interact with NLRP3 to regulate inflammasome function

Abstract The NLRP3 protein is a key initiator of inflammation in humans. NLRP3 becomes activated by a multitude of danger signals, including pathogens, markers of metabolic dysfunction, and internalized particulates. Upon activation, NLRP3 nucleates formation of a multiprotein complex called the inflammasome, in which caspase-1 activity mediates processing of the pro-inflammatory cytokines IL-1β and IL-18 and induces pyroptosis, a pro-inflammatory form of cell death that serves to release the mature cytokines along with other inflammatory mediators, thus initiating the inflammatory response. While multiple regulators of the NLRP3 inflammasome have been described, specific ligand(s) of NLRP3 and its mechanism of activation remain largely unknown. We performed a proteomics screen using co-immunoprecipitation (IP) and mass spectrometry to identify cellular proteins that bind NLRP3. Using this screen, we identified multiple NLRP3 interactors, including a family of solute carrier (SLC) proteins that localize to the inner mitochondrial membrane. Co-IP experiments verified that four of these proteins, namely SLC25A1, a citrate transporter, SLC25A6, an ADP/ATP translocase, SLC25A11, a 2-oxoglutarate/malate carrier, and SLC25A13, a calcium-dependent glutamate transporter, specifically interact with NLRP3. Because of its linkage with known metabolic disease, we further assessed the role of SCL25A13 in inflammasome function. When ectopically expressed, SLC25A13 enhanced IL-1β release from cells, while CRISPR/Cas9 knockout of SLC25A13 from THP-1 macrophages partially abrogated NLRP3-dependent pyroptosis. Our studies reveal a novel role for mitochondrial SLC25 proteins in regulation of the NLRP3 inflammasome.

Serum IGFBP-2 levels are associated with reduced insulin sensitivity in obese children.

Insulin-like growth factor binding protein 2 (IGFBP-2) may represent a critical link between body composition and insulin sensitivity. We investigated the relationship between circulating IGFBP-2 levels, body composition, insulin sensitivity, energy intake and physical activity in children with obesity. Children were recruited via the Weight Management Service at the Royal Children's Hospital, Melbourne, as part of the Childhood Overweight BioRepository of Australia (COBRA). Comprehensive anthropometric, biochemical and environmental data were collected and compared to serum IGFBP-2 levels (measured by enzyme-linked immunosorbent assay). Multiple regression modelling was used to assess the influence of circulating IGFBP-2 levels on anthropometric and biochemical measures. One hundred and ninety-four children were included in this study (46% male). Circulating IGFBP-2 negatively correlated with age, anthropometric measures, blood pressure and insulin concentration. Positive associations were observed between insulin sensitivity index-homeostasis model assessment (ISI-HOMA) and serum IGFBP-2. In multiple regression modelling, IGFBP-2 significantly contributes to variance in systolic blood pressure (-19%, P < 0.05), circulating triglycerides (-16%, P < 0.05) and ISI-HOMA (18%, P < 0.05). No associations were observed between dietary energy intake or physical activity and IGFBP-2 levels. Circulating IGFBP-2 levels in children with obesity correlate inversely with body mass and markers of metabolic dysfunction, and positively with insulin sensitivity. These findings suggest that reduced levels of IGFBP-2 may play an important role in the pathogenesis of obesity complications in early life.

Insulin Resistance and Hypertension in Obese Youth With Sleep-Disordered Breathing Treated With Positive Airway Pressure: A Prospective Multicenter Study.

There is evidence that cardiometabolic disease associated with obesity and sleep-disordered breathing (SDB) in adults is present in youth. SDB is often treated with positive airway pressure (PAP) in youth with obesity. Our aims were to determine: (1) the prevalence of cardiometabolic disease and (2) whether PAP improves markers of cardiometabolic disease, in youth with obesity and newly diagnosed moderate-severe SDB. A prospective multicenter cohort study was conducted in youth (8 to 16 years old) with obesity, prescribed PAP therapy for newly diagnosed moderate-severe SDB. Assessments occurred at baseline and at 6 and 12 months. Outcomes included markers of insulin resistance (change in homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months = primary outcome), hypertension (24-hour ambulatory/blood pressure) and inflammation (high-sensitivity C-reactive protein: hs-CRP). Twenty-seven participants were enrolled. Of those with baseline testing available, 10/25 (40%) had HOMA-IR above the 97th percentile, 10/23 (44%) were hypertensive, 16/23 (70%) had loss of nocturnal blood pressure dip and hs-CRP was elevated in 16/27 (64%). There were no significant changes over time in markers of metabolic dysfunction or blood pressure, nor between PAP-adherent and non-adherent subgroups. In youth with obesity and SDB, metabolic dysfunction and hypertension were highly prevalent. There were no statistically significant improvements in cardiometabolic markers 1 year after the prescription of PAP therapy, although clinically relevant improvements were seen in insulin resistance and systolic blood pressure load, important predictors of future risk of cardiovascular disease. Larger, longer-term studies are needed to determine whether PAP improves cardiometabolic outcomes in obese youth. A commentary on this article appears in this issue on page 1025.

Abstract P295: High Dietary Fat Intake Attenuates Pressure Overload-induced Cardiac Remodelling in a Spontaneous Hypertensive Rat Model

Heart failure with preserved ejection fraction (HFpEF) is emerging as a metabolic disease. HFpEF initiation and progression is associated with the pro-inflammatory state found in conditions such as hypertension, obesity and diabetes. Although the role of dietary fat in the genesis of metabolic disorders and tissue inflammation has been characterised, dietary fat induced cardiac pathology and inflammation in the context of pressure-overload is less well defined. In this study, we reveal the cardioprotective effects of saturated fat intake on cardiac phenotype and cardiac inflammation in an established rat model of hypertension. Ten week old male normotensive Wistar (WKY), control rats (n=10), and matched SHR (n=20), were split into low-10%kcal and high-45%kcal fat chow. After 16 wks of diet intake, bodyweight profiles were similar among all groups (p=NS). Unconscious tail-cuff plethysmography confirmed elevated arterial pressure (&gt;140mmHg) in both SHR dietary groups, (SBP in 45%kcal; 154.4 ± 21.7 mmHg, p&lt;0.05 and 10%kcal; 151.4 ± 31.5 mmHg, p&lt;NS). Endpoint echocardiography revealed increased LVMi (normalised: tibia length) in 10%kcal, which was ameliorated in 45%kcal (respectively; 24.7 ± 2.2 mg/mm vs. WKY, p&lt;0.05 and 22.5 ± 1.3 mg/mm, vs. WKY, p=NS). Furthermore, anterior wall thickness in both systole and diastole was greater in 10%kcal fed animals (p&lt;0.01 vs. WKY). Left ventricular remodelling was exaggerated in 10%kcal vs. 45%kcal, with significant increases in cardiomyocyte cross-sectional area and collagen deposition (vs. WKY control). In SHR groups, cardiac CD68 + macrophage infiltration was increased (10%kcal; 122.5 cells/mm 2 , &amp; 45%kcal; 151.1 cells/mm 2 , p&lt;0.05 vs. WKY). Alterations in markers of metabolic dysfunction was evident with increased total cholesterol (10%kcal, 21.7 ± 0.52 mg/dL, p&lt;0.01 vs. WKY and 45%kcal; 22.01 ± 0.83 mg/dL, p&lt;0.001 vs. WKY), and glycated hemoglobin (HbA1c) in high-fat fed rats vs. 10%kcal control (p&lt;0.05). In summary, dietary fat intake may prevent heart failure development, despite cardiac inflammation and dysfunctional metabolism. Collectively, our data show long-term saturated fat intake attenuates pathological cardiac fibrosis and hypertrophy in a rat model of chronic pressure-overload.

Osteopontin is BMI-independently Related to Early Endothelial Dysfunction in Children.

Osteopontin (OPN) has been proposed to predict adverse cardiac events in patients with adult type 2 diabetes. We investigated potential associations of circulating OPN and OPN expression in adipose tissue (AT) with obesity and early metabolic and cardiovascular dysfunction in children. Furthermore, we assessed the functional relevance of OPN on primary human endothelial cells. Serum OPN was determined in healthy lean (n = 65) and obese (n = 100) children by ELISA. Expression levels were assessed in sc AT samples from healthy lean (n = 33) and overweight and obese (n = 31) children by qRT-PCR. Direct effects of recombinant (rh) OPN on adhesion molecule and ENOS expression were assessed in human coronary arterial endothelial cells. OPN serum concentrations decreased with pubertal development in lean children. The degree of obesity was negatively associated with OPN serum levels. Multiple regression analysis revealed that body mass index (BMI) standard deviation score (SDS), next to pubertal status, was the strongest independent predictor for OPN serum concentrations. Metabolically, the homeostasis model assessment index and circulating plasma insulin were negatively correlated with OPN serum levels secondary to obesity. In contrast, independent from BMI, OPN was positively related to VCAM-1 levels, intima media thickening, and negatively associated with endothelial function. Functionally, full-length rhOPN did not affect adhesion molecule and ENOS mRNA expression in primary human coronary arterial endothelial cells. In addition, OPN expression levels in AT positively correlated with BMI SDS, AT inflammation, and markers of metabolic dysfunction but were not related to OPN serum levels. Our findings suggest that OPN levels are BMI-independently related to markers of early endothelial dysfunction in children.

Abstract 1154: Serum and urine markers of metabolic dysfunction in colorectal cancer: A pilot study

Abstract Objective: Intra-tumor hypoxia portends a poor prognosis and may result in resistance to chemotherapy and radiotherapy, but systemic markers of hypoxia have not been investigated. In this study, by-products of anaerobic metabolism were measured in the serum and urine of patients with metastatic colorectal cancer (CRC) and compared to patients with local disease. Material and methods: In this prospective pilot study, 42 patients with biopsy-proven colorectal adenocarcinoma (21 with metastatic and 21 with local disease) were recruited at St. Joseph's Hospital and the Juravinski Hospital and Cancer Centre in Hamilton, ON, Canada. Exclusion criteria included resection of the primary tumor, metastectomy, insulin-dependent diabetes, chemotherapy or radiation therapy within 2 weeks, infection requiring antibiotics, hospitalization within 2 weeks and creatinine clearance &amp;lt;30 mL/min. 24 hour urine citrate, plasma lactate, serum ketones, venous blood gas (VBG), serum bicarbonate and indirect markers of small molecules, both charged (anion gap) and un-charged (osmolar gap) were investigated. Results of patients with metastatic CRC were compared to i) results of the local CRC cohort, and ii) reference values using t-tests. Results: The average age of study participants was 67±13 years. All patients had active cancer at the time of their study investigations; those with metastatic were on a drug holiday for a time period that ranged from 2 weeks to 12 months. None of the included patients were diagnosed with de-novo metastatic disease. The average pCO2 (50±3 mmHg) and calculated serum osmolality (299±3 mmol/kg) border the upper limit of normal among patients with metastatic CRC. Further, the average pCO2 (50±3 vs. 45±4 mmHg, p = 0.05), calculated serum osmolality (299±3 vs. 292±3 mmol/kg, p = 0.01), and serum bicarbonate (28±1 vs. 26±1 mmol/L, p = 0.03) were statistically higher among patients with metastatic CRC as compared to those with local disease. Serum ketones were negative in all patients. Measured serum osmolality, osmolar gap, lactate, anion gap, pH and 24 hour urine citrate did not vary significantly between the two groups. Conclusions: In our pilot study, pCO2 and serum bicarbonate levels were statistically higher among patients with metastatic colorectal cancer (n = 21) as compared to those with local disease (n = 21). We hypothesize that higher levels of pCO2 are observed in patients with metastatic colorectal cancer due to a higher burden of disease and a greater extent of glycolysis. Higher bicarbonate levels, which were concurrently observed, are likely a result of physiological compensation for elevated pCO2 in order to maintain a normal pH. Serum pCO2 and bicarbonate may have the potential to serve as novel biomarkers in colorectal cancer and other tumors that are known to be hypoxic. Future studies to assess their correlation with intra-tumor hypoxia or clinical prognosis are warranted. Citation Format: Katarzyna Joanna Jerzak, Marissa Laureano, Peter A. Kavsak, Sukhbinder Dhesy-Thind, Kevin Zbuk. Serum and urine markers of metabolic dysfunction in colorectal cancer: A pilot study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1154. doi:10.1158/1538-7445.AM2015-1154

Sedentary time is not independently related to postural stability or leg strength in women 50-67 years old.

Most research on sedentary behaviour has focused on cardiometabolic outcomes and markers of metabolic dysfunction, while neuromuscular outcomes have received less attention. The objective of the present study was to determine whether sedentary time is negatively associated with laboratory-based measures of lower body muscular strength and postural stability in middle-aged women. Forty-nine women (56.6 ± 4.1 years) participated in the study. Participants wore an ActiGraph GT3X accelerometer for 7 days to quantify sedentary time and physical activity. Following a familiarization session, assessments of lower body muscular strength and postural stability were performed. Peak torque of knee extensors and flexors was assessed using an isokinetic dynamometer. Postural stability was assessed using computerized dynamic posturography and a composite equilibrium score (CES) was calculated. Participants spent 9.4 ± 1.3 h per day (65% of wear time) sedentary and 28.2 ± 17.3 min per day (3.3% of wear time) in moderate to vigorous physical activity (MVPA). Postural stability and relative peak torque of the knee flexors were significantly associated with time spent sedentary (r = -0.35, p = 0.01 and r = -0.31, p = 0.03, respectively). Multiple linear regression analyses showed that after adjusting for MVPA, sedentary time was not significantly related to either CES or peak torque of the knee extensors or flexors. In contrast to our hypothesis, postural stability and leg strength were not independently related to sedentary time. While sedentary behaviour may be an important risk factor for cardiometabolic disease, the present results suggest MVPA may be more important to neuromuscular outcomes.