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Objective. To examine differences in maternal serum levels of adipokines (adiponectin, leptin, and resistin) and inflammatory markers (tumor necrosis factor-alpha (TNF-α) and interlukin-6 (IL-6)) from early to midpregnancy among Arab women with or without gestational diabetes mellitus (GDM), along with their links to GDM risk. Methods. This is a multicenter prospective study involving 232 Saudi women attending obstetric care. Both circulating adipokine and markers of inflammation were observed at the first (eight to 12 weeks) and second trimesters (24 to 28 weeks). GDM was screened at 24 to 28 weeks using the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria. Results. Age and body mass index- (BMI-) matched circulating TNF-α was significantly higher in women with GDM in comparison to non-GDM women ( p = 0.01 ). Adiponectin and resistin significantly decreased from the first to second trimester in women without GDM ( p = 0.002 and 0.026, respectively). Leptin presented a significant rise from the first to second trimester in both groups, with a higher increase in women with GDM ( p = 0.013 ). Multivariate logistic regression analysis revealed that TNF-α was significantly correlated with GDM ( p = 0.03 ). However, significance was lost after adjustments for maternal and lifestyle risk factors (OR 23.58 (0.50 to 1119.98), p = 0.11 ). Conclusion. Inflammatory and adipocytokine profiles are altered in Arab women with GDM, TNF-α in particular. Further studies are needed to establish whether maternal inflammatory and adipocytokine profile influence fetal levels in the same manner.

The present study aimed to determine the serum organochlorine pesticides (OCPs) levels and risk of exposure among Saudi adults. Most OCPs are considered as endocrine-disrupting chemicals, and exposure can induce adverse health effects in both humans and wildlife. Serum OCP levels have not been documented in the Saudi population. Serum OCP concentrations were quantified using gas chromatography mass spectrometry (GC-MS/MS) in 302 serum samples collected from adult Saudis. All studied OCPs were detected in all participants. High concentrations of DDT and its metabolites (DDE and DDD) were detected in both males and females, with concentrations being significantly higher in males. High concentrations of 2,4-DDE, 4,4-DDE, and gamma-HCH were detected (18.31, 16.12, and 15.15 ng g−1 lipid and 5.9, 7.1, and 8.6 ng g−1 lipid for males and females, respectively). Alpha-HCH, Beta-HCH, 2,4-DDT, and 4,4-DDT were detected at concentrations lower than 2 ng g−1. Levels of OCPs varied according to age and body mass index (BMI). Serum concentrations of OCPs significantly differed between Saudi males and females and were influenced by age and BMI. This study is the first to document serum OCP concentrations in Saudi adults from Riyadh, KSA. Monitoring programs are suggested for evaluating serum OCP concentrations in the general population to track toxicity levels and serve as an indicator of possible adverse health effects. Keywords: Organochlorine pesticides, GC-MS/MS, Public health, Saudi Arabia

Summary Objective The aim of this trial was to characterize the beneficial effects of probiotics on decreasing endotoxin levels and other cardiometabolic parameters in Arab patients with type 2 diabetes mellitus (T2DM). Methods Saudi adults with naive T2DM (n = 30; 12 males and 18 females) were randomly allocated to receive twice daily placebo or 2.5 × 109 cfu/g of Ecologic®Barrier (multi-strain probiotics; n = 31; 14 males and 17 females) in a double-blind manner over a 6 month period, respectively. Anthropometrics were measured and fasting blood samples were collected to analyze endotoxin, glycemic parameters [glucose, insulin, c-peptide and homeostasis model assessment for insulin resistance (HOMA-IR)], lipids [triglycerides, total cholesterol, low and high-density lipoprotein (LDL and HDL, respectively) cholesterol and total/HDL-cholesterol ratio], inflammatory markers [tumor-necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP)] and adipocytokines [leptin, adiponectin and resistin] at baseline and after 3 and 6 months of intervention. Results Multi-strain probiotics supplementation for 6 months caused a significant decrease in circulating levels of endotoxin by almost 70% over 6 months, as well as glucose (38%), insulin (38%), HOMA-IR (64%), triglycerides (48%), total cholesterol (19%), total/HDL-cholesterol ratio (19%), TNF-α (67%), IL-6 (77%), CRP (53%), resistin (53%), and a significant increase in adiponectin (72%) as compared with baseline. Only HOMA-IR had a clinically significant reduction (−3.4, 64.2%) in the probiotics group as compared to placebo group at all time points. No other clinically significant changes were observed between the probiotic or placebo group at 3 and 6 months in other markers. Conclusion Multi-strain probiotic supplementation over 6 months as a monotherapy significantly decreased HOMA-IR in T2DM patients, with the probiotic treatment group highlighting reduced inflammation and improved cardiometabolic profile. As such, multi-strain probiotics is a promising adjuvant anti-diabetes therapy. Trial registration ClinicalTrials.gov Identifier: NCT01765517 .

There are limited studies on the association of endotoxin, a potent mediator of gut-derived inflammation and telomere length (TL). We investigated (1) the influence of adiposity on endotoxin and TL amongst Saudi adults according to type 2 diabetes mellitus (T2DM) status and (2) the influence vitamin D may have on TL attrition. Anthropometric data and fasting blood samples were taken from 775 Saudi adults visiting different primary care centers in Riyadh [387 T2DM and 388 non-T2DM]. TL, derived from peripheral blood mononuclear cells, was analyzed by Quantitative real-time polymerase chain reaction and circulating endotoxin levels by Limulus Amebocyte Lysate assay. Subjects were stratified based on obesity and T2DM status. A significant lower TL was observed in the non-obese T2DM group as compared with their non-obese, non-T2DM counterparts (p = 0.002). Significant inverse associations between TL, endotoxin and endotoxin activity were observed in the cohort with obesity. Regression analysis showed that endotoxin was a significant predictor for TL in all subjects and even after stratification according to subgroups; with variances perceived in circulating TL stronger among non-T2DM obese (10%; p = 0.003) than non-T2DM non-obese (12%; p = 0.007). Also, in the non-T2DM group, TL and HDL-cholesterol predicted 29% of the variances perceived in 25(OH)D (p 0.001). Taken together these findings show that circulating endotoxin and 25(OH)D are associated with premature biological ageing influenced by adiposity and metabolic state; suggesting future intervention studies to manipulate gut microbiome and or vitamin D levels may offer ways to mitigate premature TL attrition.

Type 2 diabetes is characterized by failure to control glucose homeostasis, with numerous diabetic complications attributable to the resulting exposure of cells and tissues to chronic elevated concentrations of glucose and fatty acids. This, in part, results from formation of advanced glycation and advanced lipidation end-products that are able to modify protein, lipid, or DNA structure, and disrupt normal cellular function. Herein we used mass spectrometry to identify proteins modified by two such adduction events in serum of individuals with obesity, type 2 diabetes, and gestational diabetes, along with similar analyses of human and mouse skeletal muscle cells and mouse pancreatic islets exposed to glucolipotoxic stress. We also report that carnosine, a histidine containing dipeptide, prevented 65-90% of 4-hydroxynonenal and 3-nitrotyrosine adduction events, and that this in turn preserved mitochondrial function and protected stimulus-secretion coupling in cells exposed to metabolic stress. Carnosine therefore offers significant therapeutic potential against metabolic diseases.

Studies have explored how vitamin B12 status affects sleep among elders and children, but this remains to be investigated among young adults. We used the Pittsburgh Sleep Quality Index (PSQI) to assess the association between serum vitamin B12 and sleep among female college students in Saudi Arabia. In this cross-sectional study, we enrolled 355 participants (age (years), 20.7 ± 1.5, body mass index, 23.6 kg/m2 ± 5.2) at King Saud University, Riyadh, Saudi Arabia. Fasting blood samples were analyzed regarding the serum vitamin B12 and blood lipids. Anthropometric, socio-demographic, clinical history, stress, physical activity, and dietary data were collected. We assessed the sleep statuses of the participants using the PSQI. Around 72% of the participants were “poor” sleepers (PSQI &gt, 5). Subgroup analysis within the tertiles showed that participants with higher vitamin B12 in the second and third tertiles reported better scores for sleep quality (B ± SE = −12.7 ± 5.6, p = 0.03, B ± SE = −32.7 ± 16.4, p = 0.05, respectively) and also reported a lower use of sleep medication (B ± SE = −21.2 ± 9.9, p = 0.03, in the second tertile only), after adjusting for the waist–hip ratio and stress. However, sleep was not found to be directly associated with either serum vitamin B12 or dietary vitamin B12. In conclusion, the serum vitamin B12 results show that the participants with higher vitamin B12 in the second and third tertiles reported better scores on the sleep quality scale and a lower use of sleep medication. However, no such associations were observed with the overall PSQI. More studies with larger sample sizes are needed to establish a direct relationship between sleep and vitamin B12.

Central adiposity is one of the significant determinants of obesity-related hypertension risk, which may arise due to the abdominal fat depot's pathogenic inflammatory nature. Pro-inflammatory cytokines and adipokines up-regulation through nuclear factor-kappa B (NF-κB) activation in adipose tissue has been considered an essential function in the pathogenesis of obesity-related hypertension. This study aimed to ascertain the NF-κB inhibitor (SN50) effect on TNF-α and angiotensinogen (AGT) secretion and expression in mediating the anti-inflammatory effect through its impact on NF-κB activity in humans adipose tissue. Primary human adipocytes were isolated from 20 subjects among 10 overweight and 10 obese with and without hypertension and treated with 10ng/ml LPS in the presence and absence of NF-κB inhibitor, SN50 (50μg/ml). TNF-α secretion and NF-κB p65 activity were detected in supernatants extracted from cultured cells treated and untreated with LPS (10ng/ml) and SN50 (50μg/ml) using enzyme-linked immunosorbent assay (ELISA). The western blot technique detected the protein of NF-κB p65 and AGT. Gene expression of TNF-α and AGT was detected in cells and performed using quantitative real-time polymerase chain reaction (RT-PCR). Treatment of AbdSc adipocytes with LPS (10ng/ml) caused a significant increase in NF-κB p65 among overweight and obese subjects with and without hypertension (P= 0.001) at 24 hours incubation. In contrast, SN50-NF-κB inhibitor causes a reduction of NF-κB p65 in overweight (P=

Central adiposity is one of the significant determinants of obesity-related hypertension risk, which may arise because of the pathogenic inflammatory nature of the abdominal fat depot. Pro-inflammatory cytokine and adipokine upregulation through nuclear factor-kappa B (NF-κB) activation in adipose tissue has been considered to have an important function in the pathogenesis of obesity-related hypertension. This study aimed to ascertain the effect of an NF-κB inhibitor (SN50) on TNF-α and angiotensinogen (AGT) secretion and expression in mediating the anti-inflammatory effect through its effects on NF-κB activity in human adipose tissue. Primary human adipocytes were isolated from 20 subjects among 10 overweight subjects and 10 obese subjects with and without hypertension and treated with 10 ng/mL of lipopolysaccharides (LPS) in the presence and absence of NF-κB inhibitor SN50 (50 μg/mL). TNF-α secretion and NF-κB p65 activity were detected in supernatants extracted from cultured cells treated and untreated with LPS (10 ng/mL) and SN50 (50 μg/mL) using commercially available assays. The NF-κB p65 protein and AGT were detected by the western blot technique. Gene expression of TNF-α and AGT were detected in cells and performed using quantitative real-time polymerase chain reaction (RT-PCR). Treatment of abdominal subcutaneous (AbdSc) adipocytes with LPS (10 ng/mL) caused a significant increase in NF-κB p65 in overweight subjects and obese subjects with and without hypertension (p = 0.001) at 24 h of incubation, whereas, SN50-NF-κB inhibitor caused a reduction in NF-κB p65 in overweight subjects (p < 0.001) and obese subjects with and without hypertension (p = 0.001) at 24 h of incubation. Treatment of AbdSc adipocytes with 10 ng/mL LPS caused a significant increase in TNF-α secretion in overweight subjects and obese subjects at all time points (p < 0.001), whereas SN50 led to a decrease in TNF-α secretion at 3 and 12 h of incubation. Treatment of AbdSc adipocytes with LPS (10 ng/mL) caused a twofold increase in TNF-α and AGT gene expression compared with untreated cells, whereas, in the presence of SN50, it reduced mRNA AGT levels in both groups. Taken together, these adipokines with NF-κB activation may represent important biomarkers to evaluate hypertension risk and may provide insight into the pathogenesis of obesity-related hypertension.

Dietary intake influences gut microbiota activity. Nevertheless, there is a lack of evidence available that illustrates the acute effects of high glucose meal on metabolic endotoxemia. The present study assessed the acute impact of high glucose meal on endotoxemia and other clinical parameters in Saudi females with varying degrees of glycemia.\ud \ud The subjects were 64 consenting pre-menopausal women, grouped into 3: control [n = 14 lean, non-T2DM, BMI = 22.2 ± 2.2 kg/m2]; overweight [n = 16, non-T2DM, BMI = 28.5 ± 1.5 kg/m2] and T2DM [n = 34, BMI = 35.2 ± 7.7 kg/m2]. After an overnight fast, all subjects were given a standardized high-glucose (75 g) meal. Anthropometrics were taken and blood samples were withdrawn at baseline and postprandial (0, 2 and 4-hours), serum glucose, endotoxin and lipid profile were quantified.\ud \ud At baseline, total cholesterol, LDL-cholesterol, triglycerides and serum glucose levels were significantly higher (P values

Context Dysfunctional endoplasmic reticulum (ER) and mitochondria are known to contribute to the pathology of metabolic disease. This damage may occur, in part, as a consequence of ER-mitochondria cross-talk in conditions of nutrient excess such as obesity. To date, insight into this dynamic relationship has not been characterized in adipose tissue. Therefore, this study investigated whether ER stress contributes to the development of mitochondrial inefficiency in human adipocytes from lean and obese participants. Methods Human differentiated adipocytes from Chub-S7 cell line and primary abdominal subcutaneous adipocytes from lean and obese participants were treated with tunicamycin to induce ER stress. Key parameters of mitochondrial function were assessed, including mitochondrial respiration, membrane potential (MMP), and dynamics. Results ER stress led to increased respiratory capacity in a model adipocyte system (Chub-S7 adipocytes) in a concentration and time dependent manner (24 h: 23%↑; 48 h: 68%↑, P < 0.001; 72 h: 136%↑, P < 0.001). This corresponded with mitochondrial inefficiency and diminished MMP, highlighting the formation of dysfunctional mitochondria. Morphological analysis revealed reorganization of mitochondrial network, specifically mitochondrial fragmentation. Furthermore, p-DRP1, a key protein in fission, significantly increased (P < 0.001). Additionally, adipocytes from obese subjects displayed lower basal respiration (49%↓, P < 0.01) and were unresponsive to tunicamycin in contrast to their lean counterparts, demonstrating inefficient mitochondrial oxidative capacity. Conclusion These human data suggest that adipocyte mitochondrial inefficiency is driven by ER stress and exacerbated in obesity. Nutrient excess–induced ER stress leads to mitochondrial dysfunction that may therefore shift lipid deposition ectopically and thus have further implications on the development of related metabolic disorders.

Background: Nutrient excess during obesity can contribute to type 2 diabetes mellitus (T2DM) risk via endoplasmic reticulum (ER) stress within adipose tissue. Investigating ’Superfoods’ such as broccoli that contain nutrients which may be able to combat this disruption is therefore important to potentially reduce the risk of developing T2DM in obesity. Methods: Differentiated human adipocytes (Chub-S7, n=6) were treated with a broccoli extract (BE; hybrid Brassica oleracea var. italic; 10ng/ml) alone or in combination with tunicamycin (Tun; 750ng/ml), an inducer of ER stress. ER stress genes (ATF4, ATF6 and CHOP) were measured at three time points (24hr, 48hr, 72hr, n=3) using qPCR. ER stress proteins (BiP, P-eIF2α and eIF2α) were measured at 18 time points (0hr - 72hr) using Western Blot. Results: Tun increased ER stress gene expression 4.5-fold (p Conclusion: These studies suggest that BE is able to alleviate ER stress in human adipocytes, possibly via mevalonate pathway activation, thus reducing the risk of subjects developing insulin resistance and T2DM. As such, there is the potential to develop a BE dietary supplement to reduce ER stress and reduce the impact of obesity on T2DM. Disclosure A. Murphy: None. G. Barker: None. G. Tripathi: None. P.G. McTernan: None. Funding Engineering and Physical Sciences Research Council

Vitamin B12 (B12) is an essential micronutrient required for optimal hematopoietic, neurologic and other several metabolic reactions. Animal and clinical studies show that B12-deficiency is associated with maternal obesity, insulin resistance, and metabolic syndrome. Given the key metabolic role of adipose tissue, we investigated whether B12 deficiency may affect triglyceride synthesis and lipid metabolism leading to adipose tissue inflammation. The AbdSc pre-adipocyte cell line (Chub-S7) and human AbdSc primary pre-adipocytes were differentiated under different B12 concentrations (25pM,100pM,1nM,500nM). Human Om, Sc-AT and blood samples were collected from 106 pregnant women at delivery. SerumB12 and relevant metabolic risk factors were measured. Gene expression was performed by q-RTPCR, de novo triglyceride synthesis was quantified by radioactive tracing, ß-oxidation and palmitate-induced oxygen consumption rate was determined using seahorse-XF analyser. Adipocytes cultured in low-B12 conditions showed significantly increased expression (P

ObjectiveCardiovascular disease is the leading cause of death in kidney transplant recipients (KTRs), yet incompletely accountable by traditional risk factors. Inflammation is an unconventional cardiovascular risk factor, with gut-derived endotoxemia potentially driving inflammation and endothelial disease. Comparable data are lacking in kidney transplantation. This study investigated the associations of endotoxemia with inflammation, endothelial activation, and 5-year cardiovascular events in KTRs. Determinants of endotoxemia were also explored.Design and MethodsThis is a single-center cross-sectional study with prospective follow-up from a prevalent cohort of 128 KTRs.Main Outcome MeasuresDemographic, nutritional and clinical predictors of inflammation (high-sensitivity C-reactive protein [hsCRP]), endothelial activation (sE-selectin), and endotoxemia (endotoxin) were assessed. Follow-up data on 5-year cardiovascular event rates were collected.ResultsEndotoxemia (P = .03), reduced 25-hydroxyvitamin D (P = .04), high fructose intake (P P P = .002) were independently associated with elevated hsCRP. In turn, endotoxemia (P = .007) and increasing hsCRP (P = .02) were both independently associated with raised sE-selectin. Furthermore, endotoxemia predicted increased cardiovascular event rate (P = .02), independent of hsCRP and a global measure of cardiovascular risk estimated by a validated algorithm of 7-year risk for major adverse cardiac events in kidney transplantation. Determinants of endotoxemia included reduced 25-hydroxyvitamin D (P P P = .01), and abdominal obesity (P = .01).ConclusionsEndotoxemia in KTRs contributes to inflammation, endothelial activation, and increased cardiovascular events. This study highlights the clinical relevance of endotoxemia in KTRs, suggesting future interventional targets.

Background: Field cancerisation proposes that there are pre-malignant genetic mutations in the macroscopically normal mucosal tissue around colorectal cancer. This study aims to evaluate fibroblast growth factor 7 (FGF7) tissue expression in the mucosal field around colorectal cancer.\ud \ud Methods: Gene and protein expression of FGF7, its receptor, FGFR2 and its downstream targets; FRS2α, Erk 1/2 and Akt was measured from mucosal samples in 34 control subjects and 17 cancer patients. Serial samples from tumour, adjacent to tumour and at the resection margin were utilised.\ud \ud Results: FGF7 gene expression was significantly higher in tumour (2.3-fold), adjacent mucosa (3.2-fold) and resection margin (2.8-fold) of cancer patients compared with control subjects (P

Vitamin B12 insufficiency is a global health issue among women of childbearing age, yet few studies have investigated its prevalence and risk factors among healthy Middle Eastern populations. This cross-sectional study included 346 Saudi women aged 19&ndash, 30 years and enrolled at King Saud University, Riyadh, Saudi Arabia. A series of questionnaires were administered to record the study participants&rsquo, sociodemographic status, medical history, dietary intake, and physical activity. Participants&rsquo, anthropometric data were also recorded and their fasting blood samples were analyzed. The rate of vitamin B12 insufficiency (&le, 220 pmol/L) was approximately 6% among the study participants. After adjusting for confounding factors, it was observed that the risk factors for vitamin B12 insufficiency included daily sitting time &ge, 7 h, low income (&lt, 10,000 Saudi riyal) and increasing age. The recommended dietary allowance of vitamin B12 (&gt, 2.4 mcg/day) has been shown to confer reasonable protection against vitamin B12 insufficiency. These study findings highlight that a combination of increased physical activity and dietary vitamin B12 intake above the current recommended dietary allowance may help improve the serum vitamin B12 levels of young women of childbearing age, especially those with a low socioeconomic status. Timely detection and protection against vitamin B12 insufficiency in this subpopulation are important to prevent maternal and fetal health risks.

Background: Vitamin D deficiency is associated with obesity and type 2 diabetes mellitus (T2DM), although the use of circulating Vitamin D levels as a predictor of weight loss induced T2DM remission is unclear. Therefore, the aim of this study was to analyze whether pre-bariatric surgery vitamin D levels may predict T2DM outcomes 12 months post-SG. Method: A cohort of 220 obese participants (74.5% female) with T2DM (Age: 50±9.5yr, BMI: 51.4±7Kg/m2; n=103) and without T2DM (Age: 46±9yr, BMI: 53.5±6.5Kg/m2; n=117) undergoing SG participated in an ethics approved study in a single bariatric centre in the UK. Patient anthropometric and biochemical data including vitamin D were collected at baseline and 12 months post-SG; no vitamin D supplementation at baseline was given. Results: Baseline vitamin D levels inversely correlated with baseline BMI (P Conclusion: Baseline Vitamin D levels appear to be an independent indicator for successful T2DM remission and weight loss, 12 months following SG. The use of baseline Vitamin D levels may help us predict those more likely to do well and prioritize post-surgery support to achieve success for all participant groups. Disclosure A. Aladel: None. M.K. Piya: None. S. Azharian: None. M. Christian: None. V. Menon: None. P.G. McTernan: None.

Background: Delivery of nutrient excess in obesity causes endoplasmic reticulum (ER) stress within adipose tissue; this activates the unfolded protein response (UPR) and contributes to type 2 diabetes mellitus (T2DM) risk. This study aimed to utilise freeze-dried broccoli extract (BE) as a nutrient to mitigate such cellular damage in human adipocytes, and create a mathematical model to understand pathway dynamics. Methods: Differentiated human adipocytes (Chub-S7; n=6) were treated with BE (10ng/ml) alone or combined with tunicamycin (Tun; 750ng/ml), an inducer of ER stress. UPR proteins (BiP, PERK, P-PERK, eIF2α, P-eIF2α) were measured (18 time points; 0hr-72hr) using Western Blot and transcriptomics. Mass action kinetics was used to create ordinary differential equations (ODEs) to model the UPR for predictive analysis. Results: Tun increased UPR proteins 9.5 fold (P Conclusion: BE acts to alleviate ER stress in human adipocytes by reducing the UPR through the mevalonate pathway. Furthermore, modelling pathway dynamics using experimental data may provide insight into predicting nutrient capabilities to reduce inflammation. Disclosure A. Murphy: None. S. Azharian: None. G. Tripathi: None. G. Barker: None. M.J. Chappell: None. P.G. McTernan: None.

Background: Fibroblast growth factor 19 (FGF-19) and FGF-21 regulate glucose tolerance and insulin sensitivity, which in type 2 diabetes mellitus (T2DM) conditions becomes dysregulated. Whilst weight loss can restore this functionality, bariatric surgery can have a specific impact due to mechanical changes on gut/liver physiology. We aimed to analyse the effects of different bariatric surgeries: sleeve gastrectomy (SG), laparoscopic adjusted gastric banding (LAGB) and biliopancreatic diversion (BPD) on changes in FGF-19 and FGF-21 levels. Methods: Obese and T2DM women (n=41 BMI>35 Kg/m2) undergoing SG (n=14), LABG (n=13), and BPD (n=14) participated in an ethics approved study. Anthropometry, biochemical data, and adipose tissue (AT) biopsies were collected before and 6 months after surgery. FGF-19, FGF-21 levels and AT inflammation (TLR2, MYD88, TRAF6, IKK and NFkb) was assessed. Results: Post surgery SG led to 63% reduction in FGF-21 whilst LABG and BPD led to 41% and 4% decrease respectively. There was a significant differences in FGF-21 levels between SG and BPD (p=0.021). Moreover, FGF-21 change in SG positivly correlated with changes in glucose (p=0.019), insulin (p=0.047), HOMA-IR (p=0.022) and triglyceride (p=0.027); absent in BPD and LABG. FGF-21 levels in SG appeared as a significant predictor of HOMA-IR change post surgery (p Inflamatory markers post surgery were significantly reduced in all surgeries (TLR2: p Conclusion: SG appears to have a beneficial influence on FGF-21 and FGF-19 levels irrespective of reduced AT inflammation. Our FGF findings therfore suggests that SG provides better glucose homeostatis outcomes than LAGB and BPD. Disclosure S. Azharian: None. A. Murphy: None. P.G. McTernan: None. M.K. Piya: None. G. Tripathi: None.

Background:Antiretroviral therapy in HIV-positive patients leads to insulin resistance which is central to the pathogenesis of various metabolic abnormalities and cardiovascular disease seen in this patient group. We have investigated the dose–response relationship of telmisartan, an antihypertensive, on adipocytes in vitro in order to determine whether it may have metabolic beneficial effects.Methods:Using in vitro chronic toxicity models (3T3-F442A murine and primary human adipocytes), we evaluated the effects of different concentrations of telmisartan on adipocyte differentiation and adipogenic gene expression using lipid accumulation assays and real-time polymerase chain reaction, respectively. Adipokine secretion and expression of insulin signalling mediators were evaluated using enzyme-linked immunosorbent assays.Results:Telmisartan partially reversed the deleterious effects of antiretrovirals on adipocyte lipid accumulation, expression of adipogenic regulators (peroxisome proliferator receptor-gamma and lipin 1), adipokine secretion and expression of the insulin signalling mediator pAktSer473. The metabolic effects of telmisartan followed a non-monotonic response with the maximal effect observed at 5 µM in the primary human adipocyte model.Conclusion:Telmisartan has beneficial metabolic effects in adipocytes in vitro, but its potential to reduce antiretroviral-induced cardiometabolic disease in HIV-infected individuals needs to be evaluated in a well-designed adequately powered clinical trial.

Data regarding the prevalence and predictors of vitamin D deficiency during early pregnancy are limited. This study aims to fill this gap. A total of 578 Saudi women in their 1st trimester of pregnancy were recruited between January 2014 and December 2015 from three tertiary care antenatal clinics in Riyadh, Saudi Arabia. Information collected includes socio-economic, anthropometric, and biochemical data, including serum vitamin D (25(OH)D) levels, intake of calcium and vitamin D, physical activity, and sun exposure indices. Pregnant women with 25(OH)D levels 3.5), low HDL-cholesterol, and living in West Riyadh were significant independent predictors for vitamin D deficiency, with odds ratios (ORs) (95% confidence interval) of 25.4 (5.5–117.3), 17.8 (2.3–138.5), 4.0 (1.7–9.5), 3.3 (1.4–7.9), 2.8 (1.2–6.4), and 2.0 (1.1–3.5), respectively. Factors like increased physical activity, sun exposure at noon, sunrise or sunset, high educational status, and residence in North Riyadh were protective against vitamin D deficiency with ORs 0.2 (0.1–0.5); 0.2 (0.1–0.6); 0.3 (0.1–0.9); and 0.4 (0.2–0.8), respectively. All ORs were adjusted for age, BMI, sun exposure, parity, summer season, vitamin D intake, multivitamin intake, physical activity, education, employment, living in the north, and coverage with clothing. In conclusion, the prevalence of vitamin D deficiency among Saudi women during early pregnancy was high (81%). Timely detection and appropriate supplementation with adequate amounts of vitamin D should reduce the risks of vitamin D deficiency and its complications during pregnancy.

Aims/hypothesis Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a circulatory macrophage-derived factor that increases with obesity and leads to a higher risk of cardiovascular disease (CVD). Despite this, its role in adipose tissue and the adipocyte is unknown. Therefore, the aims of this study were to clarify the expression of Lp-PLA2 in relation to different adipose tissue depots and type 2 diabetes, and ascertain whether markers of obesity and type 2 diabetes correlate with circulating Lp-PLA2. A final aim was to evaluate the effect of cholesterol on cellular Lp-PLA2 in an in vitro adipocyte model. Methods Analysis of anthropometric and biochemical variables from a cohort of lean (age 44.4 ± 6.2 years; BMI 22.15 ± 1.8 kg/m2, n = 23), overweight (age 45.4 ± 12.3 years; BMI 26.99 ± 1.5 kg/m2, n = 24), obese (age 49.0 ± 9.1 years; BMI 33.74 ± 3.3 kg/m2, n = 32) and type 2 diabetic women (age 53.0 ± 6.13 years; BMI 35.08 ± 8.6 kg/m2, n = 35), as part of an ethically approved study. Gene and protein expression of PLA2 and its isoforms were assessed in adipose tissue samples, with serum analysis undertaken to assess circulating Lp-PLA2 and its association with cardiometabolic risk markers. A human adipocyte cell model, Chub-S7, was used to address the intracellular change in Lp-PLA2 in adipocytes. Results Lp-PLA2 and calcium-independent PLA2 (iPLA2) isoforms were altered by adiposity, as shown by microarray analysis (p

International audience; The metabolic health benefits of fermented milks have already been investigated using clinical biomarkers but the development of transcriptomic analytics in blood offers an alternative approach that may help to sensitively characterise such effects. We aimed to assess the effects of probiotic yoghurt intake, compared to non-fermented, acidified milk intake, on clinical biomarkers and gene expression in peripheral blood. To this end, a randomised, crossover study was conducted in fourteen healthy, young men to test the two dairy products. For a subset of seven subjects, RNA sequencing was used to measure gene expression in blood collected during postprandial tests and after two weeks daily intake. We found that the postprandial response in insulin was different for probiotic yoghurt as compared to that of acidified milk. Moreover changes in several clinical biomarkers were associated with changes in the expression of genes representing six metabolic genesets. Assessment of the postprandial effects of each dairy product on gene expression by geneset enrichment analysis revealed significant, similar modulation of inflammatory and glycolytic genes after both probiotic yoghurt and acidified milk intake, although distinct kinetic characteristics of the modulation differentiated the dairy products. The aryl hydrocarbon receptor was a major contributor to the down-regulation of the inflammatory genesets and was also positively associated with changes in circulating insulin at 2h after yoghurt intake (p = 0.05). Daily intake of the dairy products showed little effect on the fasting blood transcriptome. Probiotic yoghurt and acidified milk appear to affect similar gene pathways during the postprandial phase but differences in the timing and the extent of this modulation may lead to different physiological consequences. The functional relevance of these differences in gene expression is supported by their associations with circulating biomarkers.

Background The present randomized clinical trial characterized the beneficial effects of a multi-strain probiotics supplementation on improving circulating endotoxin levels (primary endpoint) and other cardiometabolic biomarkers (secondary endpoint) in patients with T2DM. Methods A total of 78 adult Saudi T2DM patients (naïve and without co-morbidities) participated in this clinical trial and were randomized to receive twice daily placebo or probiotics [(2.5 × 109 cfu/g) containing the following bacterial strains: Bifidobacterium bifidum W23, Bifidobacterium lactis W52, Lactobacillus acidophilus W37, Lactobacillus brevis W63, Lactobacillus casei W56, Lactobacillus salivarius W24, Lactococcus lactis W19 and Lactococcus lactis W58 (Ecologic®Barrier)] in a double-blind manner for 12 weeks. Anthropometrics and cardiometabolic profiles were obtained at baseline and after 12/13 weeks of treatment. Results After 12/13 weeks of intervention and using intention-to-treat analysis, no difference was noted in endotoxin levels between groups [Placebo − 9.5% vs. Probiotics − 52.2%; (CI − 0.05 to 0.36; p = 0.15)]. Compared with the placebo group however, participants in the probiotics groups had a significant but modest improvement in WHR [Placebo 0.0% vs. Probiotics 1.11%; (CI − 0.12 to − 0.01; p = 0.02)] as well as a clinically significant improvement in HOMA-IR [Placebo − 12.2% vs. Probiotics − 60.4%; (CI − 0.34 to − 0.01; p = 0.04)]. Conclusion Using a multi-strain probiotic supplement daily for 12/13 weeks significantly improved HOMA-IR and modestly reduced abdominal adiposity among medication naïve T2DM patients. Trial Registration: ClinicalTrials.gov Identifier: NCT01765517, Registered January 10, 2013

Background Irisin, a novel myokine, has been shown to increase following vigorous exercise, with studies suggesting that it mediates some of the beneficial effects of exercise. Irisin might play a role in ‘browning’ of white adipocytes, thus increasing energy expenditure. The role of irisin in exercise and energy expenditure in subjects with diabetes mellitus type 2 (DMT2) remains largely unknown. We aimed to investigate the association between circulating irisin and habitual physical activity in subjects with and without DMT2. Material and methods In this cross-sectional study, 164 Saudi adults: 81 non-DMT2 controls [age: (mean ± SD) 51·6 ± 10·9; BMI: 29·6 ± 4·3 kg/m2] and 83 DMT2 subjects [age: 54·3 ± 10·3 year; BMI: 29·4 ± 4·7 kg/m2] were studied. Anthropometric and fasting serum biochemical data were collected. Circulating irisin was measured using an enzyme-linked immunosorbent assay (ELISA). Frequency intensity time (FIT) index was used to assess the level of habitual physical activity. Results We observed significantly higher levels of irisin in DMT2 subjects than in controls (P < 0·001). FIT index was positively associated (r = 0·20, P = 0·03) with circulating irisin in controls only. Additionally, irisin levels were significantly higher in tertile 3 (0·75 ± 0·07 μg/mL) than tertile 1 (0·49 ± 0·06 μg/mL) of the FIT index in healthy controls, whilst no such relation with physical activity was observed in DMT2 subjects. Conclusion This cross-sectional study has shown a weak association of irisin with physical activity levels in healthy controls but not in DMT2 subjects, suggesting the possibility of discordant regulation in the condition of DMT2.

Objective Meal duration may influence cardiometabolic health. The aim of this study was to explore postprandial effects of meal duration on human metabolism and appetite. Design Postprandial comparisons following a standard meal eaten slowly over 40 min (‘D40’) and the same meal eaten quickly over 10 min (‘D10’) on a different day. Each participant therefore acted as their own control, thereby limiting confounding factors. Patients Obese premenopausal Caucasian women (n = 10) with confirmed normoglycaemia were recruited from an obesity clinic at UHCW, Coventry UK. Subjects underwent whole-body calorimetry (8-h) on two separate days. Measurements Following standard lunch (D40 vs D10), 4-h postprandial analysis included thermic effect of food (TEF) and bloods taken at predefined times (including baseline fasting). Analytes included lipid profile, adiponectin, insulin, glucose, ghrelin, leptin, endotoxin, gut and pancreatic hormones. Appetite was measured using visual-analogue scales and ad libitum food intake at subsequent meal. Paired sample t-tests [including area under the curve (AUC)] were used to compare D40 and D10 trials. Results Postprandial TEF (over 240-min) was significantly greater for D40 than D10 [mean (SEM): 80·9 kcal (3·8) vs 29·9 kcal (3·4); 10·6% vs 3·9%, respectively, P = 0·006; AUC 71·7 kcal.h vs 22·4 kcal.h, respectively, P = 0·02]. Postprandial plasma NEFA was significantly lower, and adiponectin levels were significantly higher for D40 than D10 [AUC (SEM): NEFA 627 μmol.h/l (56) vs 769 μmol.h/l (60), respectively, P = 0·02; adiponectin 33·4 μg.h/ml (3·9) vs 27·3 μg.h/ml (3·8), respectively, P = 0·04]. Other postprandial analytes and appetite measures were equivalent. Conclusions In obese women, eating slowly associates with enhanced TEF, elevated serum adiponectin and suppressed NEFA.

Probiotic yogurt and milk supplemented with probiotics have been investigated for their role in ‘low-grade’ inflammation but evidence for their efficacy is inconclusive. This study explores the impact of probiotic yogurt on metabolic and inflammatory biomarkers, with a parallel study of gut microbiota dynamics. The randomised cross-over study was conducted in fourteen healthy, young men to test probiotic yogurt compared with milk acidified with 2 % d-(+)-glucono-δ-lactone during a 2-week intervention (400 g/d). Fasting assessments, a high-fat meal test (HFM) and microbiota analyses were used to assess the intervention effects. Baseline assessments for the HFM were carried out after a run-in during which normal milk was provided. No significant differences in the inflammatory response to the HFM were observed after probiotic yogurt compared with acidified milk intake; however, both products were associated with significant reductions in the inflammatory response to the HFM compared with the baseline tests (assessed by IL6, TNFα and chemokine ligand 5) (PBilophila wadsworthia after acidified milk (log 2-fold-change (FC)=–1·5, Padj=0·05) and probiotic yogurt intake (FC=–1·3, Padj=0·03), increased abundance of Bifidobacterium species after acidified milk intake (FC=1·4, Padj=0·04) and detection of Lactobacillus delbrueckii spp. bulgaricus (FC=7·0, PadjStreptococcus salivarius spp. thermophilus (FC=6·0, Padj

A dose-response strategy may not only allow investigation of the impact of foods and nutrients on human health but may also reveal differences in the response of individuals to food ingestion based on their metabolic health status. In a randomized crossover study, we challenged 19 normal-weight (BMI: 20-25 kg/m(2)) and 18 obese (BMI: >30 kg/m(2)) men with 500, 1000, and 1500 kcal of a high-fat (HF) meal (60.5% energy from fat). Blood was taken at baseline and up to 6 h postprandially and analyzed for a range of metabolic, inflammatory, and hormonal variables, including plasma glucose, lipids, and C-reactive protein and serum insulin, glucagon-like peptide-1, interleukin-6 (IL-6), and endotoxin. Insulin was the only variable that could differentiate the postprandial response of normal-weight and obese participants at each of the 3 caloric doses. A significant response of the inflammatory marker IL-6 was only observed in the obese group after ingestion of the HF meal containing 1500 kcal [net incremental AUC (iAUC) = 22.9 +/- 6.8 pg/mL x 6 h, P = 0.002]. Furthermore, the net iAUC for triglycerides significantly increased from the 1000 to the 1500 kcal meal in the obese group (5.0 +/- 0.5 mmol/L X 6 h vs. 6.0 +/- 0.5 mmol/L X 6 h; P=0.015) but not in the normal-weight group (4.3 +/- 0.5 mmol/L X 6 h vs. 4.8 +/- 0.5 mmol/L x 6 h; P=0.31). We propose that caloric dose-response studies may contribute to a better understanding of the metabolic impact of food on the human organism. This study was registered at clinicaltrials.gov as NCT01446068.

Peripheral action of irisin improves glucose homeostasis and increases energy expenditure, with no data on a central role of irisin in metabolism. These studies sought to examine 1) presence of irisin in human cerebrospinal fluid (CSF) and banked human hypothalamic tissue, 2) serum irisin in maternal subjects across varying adiposities with or without gestational diabetes (GDM), and 3) their respective neonate offspring. CSF, serum, and neonatal cord serum were collected from 91 pregnant women with and without GDM attending for an elective cesarean section [body mass index (BMI): 37.7 ± 7.6 kg/m2; age: 32 ± 8.3 yr]. Irisin was assessed by ELISA and correlated with biochemical and anthropometric data. Irisin expression was examined in human hypothalamus by immunohistochemical staining. Serum irisin in pregnant women was significantly lower in nonobese compared with obese and GDM subjects, after adjusting for BMI, lipids, and glucose. Irisin was present in neonatal cord serum (237 ± 8 ng/ml) and maternal CSF (32 ± 1.5 ng/ml). CSF irisin correlated positively with serum irisin levels from nonobese and obese pregnant women ( P < 0.01), with CSF irisin significantly raised in GDM subjects ( P < 0.05). Irisin was present in human hypothalamic sections in the paraventricular neurons, colocalized with neuropeptide Y. Irisin was detectable in CSF and in paraventricular neurons. Maternal serum irisin was lower in nonobese pregnant women after adjusting for BMI and a number of metabolic parameters. These studies indicate that irisin may have a central role in metabolism in addition to the known peripheral role. Further studies investigating the central action of irisin in human metabolic disease are required.

Background: The prevalence and consequences of hypervolemia in kidney transplant recipients (KTRs) have not been investigated. Specifically, its impact on blood pressure (BP) and relationship with N-terminal fragment of prohormone B-type natriuretic peptide (NT-proBNP) are unknown. The objectives of this study were to establish the prevalence of hypervolemia among clinically stable KTRs, investigate the predictors of posttransplant hypervolemia, assess its impact on blood pressure, and determine its relationship with NT-proBNP.Methods: This single-center cross-sectional study enrolled 123 clinically stable KTRs. Extracellular volume status was determined by multifrequency bioimpedance analysis. Mild and severe hypervolemia were defined as percentage volume expansion of greater than 7% and greater than 15%, respectively. Systolic BP (SBP) and diastolic BP (DBP) were measured, with mean arterial pressure (MAP) calculated. Serum NT-proBNP was quantified using a noncompetitive immunoluminometric assay. Potential demographic, nutritional, and clinical predictors of extracellular volume status, BP, and NT-proBNP levels were assessed.Results: Hypervolemia was present in 30% of KTRs, with 5% classified as severe hypervolemia. Significant predictors of volume expansion were increased sodium intake, advancing age, and reduced fat mass (PConclusions: Hypervolemia is unexpectedly common among clinically stable KTRs. It is closely associated with elevated BP. The relationship with increased sodium intake signals potential therapeutic focus. Further study is warranted to prospectively investigate objective measures of extracellular volume status among KTRs.

OBJECTIVE: Central obesity and sub-clinical inflammation increase metabolic risk, this study examined the intracellular inflammatory pathways in adipose tissue (AT) that contribute to this risk. DESIGN AND METHODS: This study therefore addressed the influence of NFκB and JNK activation in human abdominal subcutaneous (AbdSc) and omental (Om) AT, the effect of adiposity, T2DM status and the role of TNFα in vitro, using molecular biology techniques. RESULTS: Our data showed NFκB activity is increased in Om AT versus AbdSc AT (P