Parent-offspring transmission of adipocytokine levels and their associations with metabolic traits

Adipose tissue secreted cytokines (adipocytokines) have significant effects on the physiology and pathology of human metabolism relevant to diabetes and cardiovascular disease. We determined the relationship of the pattern of these circulating hormones with obesity-related phenotypes and whether such pattern is transmitted from parent to offspring. A combined total of 403 individuals from 156 consenting Saudi families divided into initial (119 families with 123 adults and 131 children) and replication (37 families with 58 adults and 91 children) cohorts were randomly selected from the RIYADH Cohort study. Anthropometrics were evaluated and metabolic measures such as fasting serum glucose, lipid profiles, insulin, leptin, adiponectin, resistin, tumor necrosis factor alpha (TNFa), activated plasminogen activator inhibitor 1 (aPAI1), high sensitivity C-reactive protein (hsCRP) and angiotensin II were also assessed. Parent-offspring regressions revealed that with the exception of hsCRP, all hormones measured showed evidence for significant inheritance. Principal component (PC) analysis of standardized hormone levels demonstrated surprising heritability of the three most common axes of variation. PC1, which explained 21% of the variation, was most strongly loaded on levels of leptin, TNFa, insulin, and aPAI1, and inversely with adiponectin. It was significantly associated with body mass index (BMI) and phenotypically stronger in children, and showed a heritability of ,50%, after adjustment for age, gender and generational effects. We conclude that adipocytokines are highly heritable and their pattern of co-variation significantly influences BMI as early as the pre-teen years. Investigation at the genomic scale is required to determine the variants affecting the regulation of the hormones studied

Effects of probiotics in patients with diabetes mellitus type 2 : study protocol for a randomized, double-blind, placebo-controlled trial

Background: Low grade chronic inflammation is observed in patients with type 2 diabetes mellitus (T2DM). Endotoxin derived from gut bacteria may act as a potent inflammatory stimulant. Probiotics, which are believed to contain health promoting live microorganisms, may influence circulating endotoxin levels. Ingestion of live probiotic cultures may alter gut microbiota in a beneficial manner to reduce inflammation; no information is available whether or not they do so in patients with T2DM. Therefore, the aim of this study is to characterize the beneficial effects of probiotics on circulating endotoxin levels and other biomarkers related to systemic low-grade inflammation in patients with T2DM. Methods: One hundred and twenty consenting adult Saudi T2DM patients (naïve or newly diagnosed and without co-morbidities) will be enrolled in this clinical trial and randomized to receive daily placebo or probiotics (Ecologic®Barrier) for 26 weeks in a double-blind manner. Inflammatory and metabolic markers will be measured and fecal samples analyzed. Measurements/samples will be obtained at baseline and after 4, 8, 12/13 and 26 weeks of treatment. Discussion: It is expected that the probiotic product will induce beneficial changes in gut microbiota, reduce the systemic inflammatory state through altering systemic endotoxin levels and, as such, reduce the systemic inflammatory response observed in T2DM subjects. Trial registration: ClinicalTrials.gov Identifier: NCT0176551

Changes in endotoxin levels in T2DM subjects on anti-diabetic therapies

Introduction Chronic low-grade inflammation is a significant factor in the development of obesity associated diabetes. This is supported by recent studies suggesting endotoxin, derived from gut flora, may be key to the development of inflammation by stimulating the secretion of an adverse cytokine profile from adipose tissue. Aims The study investigated the relationship between endotoxin and various metabolic parameters of diabetic patients to determine if anti-diabetic therapies exerted a significant effect on endotoxin levels and adipocytokine profiles. Methods Fasting blood samples were collected from consenting Saudi Arabian patients (BMI: 30.2 ± (SD)5.6 kg/m2, n = 413), consisting of non-diabetics (ND: n = 67) and T2DM subjects (n = 346). The diabetics were divided into 5 subgroups based on their 1 year treatment regimes: diet-controlled (n = 36), metformin (n = 141), rosiglitazone (RSG: n = 22), a combined fixed dose of metformin/rosiglitazone (met/RSG n = 100) and insulin (n = 47). Lipid profiles, fasting plasma glucose, insulin, adiponectin, resistin, TNF-α, leptin, C-reactive protein (CRP) and endotoxin concentrations were determined. Results Regression analyses revealed significant correlations between endotoxin levels and triglycerides (R2 = 0.42; p < 0.0001); total cholesterol (R2 = 0.10; p < 0.001), glucose (R2 = 0.076; p < 0.001) and insulin (R2 = 0.032; p < 0.001) in T2DM subjects. Endotoxin showed a strong inverse correlation with HDL-cholesterol (R2 = 0.055; p < 0.001). Further, endotoxin levels were elevated in all of the treated diabetic subgroups compared with ND, with the RSG treated diabetics showing significantly lower endotoxin levels than all of the other treatment groups (ND: 4.2 ± 1.7 EU/ml, RSG: 5.6 ± 2.2 EU/ml). Both the met/RSG and RSG treated groups had significantly higher adiponectin levels than all the other groups, with the RSG group expressing the highest levels overall. Conclusion We conclude that sub-clinical inflammation in T2DM may, in part, be mediated by circulating endotoxin. Furthermore, that whilst the endotoxin and adipocytokine profiles of diabetic patients treated with different therapies were comparable, the RSG group demonstrated significant differences in both adiponectin and endotoxin levels. We confirm an association between endotoxin and serum insulin and triglycerides and an inverse relationship with HDL. Lower endotoxin and higher adiponectin in the groups treated with RSG may be related and indicate another mechanism for the effect of RSG on insulin sensitivity

Vitamin D supplementation as an adjuvant therapy for patients with T2DM : an 18-month prospective interventional study

Background Vitamin D deficiency has been associated with impaired human insulin action, suggesting a role in the pathogenesis of diabetes mellitus type 2 (T2DM). In this prospective interventional study we investigated the effects of vitamin D3 supplementation on the metabolic profiles of Saudi T2DM subjects pre- and post-vitamin D supplementation over an 18-month period. Methods T2DM Saudi subjects (men, N = 34: Age: 56.6 ± 8.7 yr, BMI, 29.1 ± 3.3 kg/m2; women, N = 58: Age: 51.2 ± 10.6 yr, BMI 34.3 ± 4.9 kg/m2;) were recruited and given 2000 IU vitamin D3 daily for 18 months. Anthropometrics and fasting blood were collected (0, 6, 12, 18 months) to monitor serum 25-hydroxyvitamin D using specific ELISA, and to determine metabolic profiles by standard methods. Results In all subjects there was a significant increase in mean 25-hydroxyvitamin D levels from baseline (32.2 ± 1.5 nmol/L) to 18 months (54.7 ± 1.5 nmol/L; p < 0.001), as well as serum calcium (baseline = 2.3 ± 0.23 mmol/L vs. 18 months = 2.6 ± 0.1 mmol/L; p = 0.003). A significant decrease in LDL- (baseline = 4.4 ± 0.8 mmol/L vs. 18 months = 3.6 ± 0.8 mmol/L, p < 0.001] and total cholesterol (baseline = 5.4 ± 0.2 mmol/L vs. 18 months = 4.9 ± 0.3 mmol/L, p < 0.001) were noted, as well as a significant improvement in HOMA-β function ( p = 0.002). Majority of the improvements elicited were more prominent in women than men. Conclusion In the Saudi T2DM population receiving oral Vitamin D3 supplementation (2000 IU/day), circulating 25-hydroxyvitamin D levels remained below normal 18 months after the onset of treatment. Yet, this “suboptimal” supplementation significantly improved lipid profile with a favorable change in HDL/LDL ratio, and HOMA-β function, which were more pronounced in T2DM females

Association of vitamin B12 with pro-inflammatory cytokines and biochemical markers related to cardiometabolic risk in Saudi subjects

Background: This study aimed to examine the relationship between changes in systemic vitamin B12 concentrations with pro-inflammatory cytokines, anthropometric factors and biochemical markers of cardiometabolic risk in a Saudi population. Methods: A total of 364 subjects (224 children, age: 12.99 ± 2.73 (mean ± SD) years; BMI: 20.07 ± 4.92 kg/m2 and 140 adults, age: 41.87 ± 8.82 years; BMI: 31.65 ± 5.77 kg/m2) were studied. Fasting blood, anthropometric and biochemical data were collected. Serum cytokines were quantified using multiplex assay kits and B12 concentrations were measured using immunoassay analyzer. Results: Vitamin B12 was negatively associated with TNF-α (r = −0.14, p < 0.05), insulin (r = −0.230, p < 0.01) and HOMA-IR (r = −0.252, p < 0.01) in all subjects. In children, vitamin B12 was negatively associated with serum resistin (r = −0.160, p < 0.01), insulin (r = −0.248, p < 0.01), HOMA-IR (r = −0.261, p < 0.01). In adults, vitamin B12 was negatively associated with TNF-α (r = −0.242, p < 0.01) while positively associated with resistin (r = 0.248, p < 0.01). Serum resistin was the most significant predictor for circulating vitamin B12 in all subjects (r2 = −0.17, p < 0.05) and in children (r2 = −0.167, p < 0.01) while HDL-cholesterol was the predictor of B12 in adults (r2 = −0.78, p < 0.05). Conclusions: Serum vitamin B12 concentrations were associated with pro-inflammatory cytokines and biochemical markers of cardiometabolic risks in adults. Maintaining adequate vitamin B12 concentrations may lower inflammation-induced cardiometabolic risk in the Saudi adult population

Lower Limb Muscle Strength and Muscle Mass Are Associated With Incident Symptomatic Knee Osteoarthritis: A Longitudinal Cohort Study

Recent literature suggests that sarcopenia, often represented by low lower limbs muscle mass and strength, can be considered a potential risk factor for knee osteoarthritis (OA), but the available literature is still limited. We therefore aimed to investigate whether sarcopenia is associated with a higher risk of radiographic (ROA) and symptomatic knee OA (SxOA) in a large cohort of North American people in the context of the OA initiative. Sarcopenia at baseline was diagnosed in case of low skeletal muscle mass (i.e., lower skeletal mass index) and poor performance in the chair stands test. The outcomes of interest for this study included ROA (radiographical osteoarthritis) if a knee developed a Kellgren and Lawrence (KL) grade ≥2 at follow-up, and SxOA (symptomatic osteoarthritis) defined as new onset of a combination of painful knee OA. Altogether, 2,492 older participants (mean age: 68.4 years, 61.4% females) were included. At baseline, sarcopenia was present in 6.1% of the population. No significant difference in ROA prevalence was observed between those with and without sarcopenia (p=0.76), whilst people with sarcopenia reported a significant higher prevalence of SxOA (p&lt;0.0001). Using a logistic regression analysis, adjusting for potential confounders at baseline and the diagnosis of sarcopenia during follow-up, sarcopenia was associated with a higher incidence of knee SxOA (odds ratio, OR=2.29; 95%CI [confidence interval]: 1.42-3.71; p=0.001), but not knee ROA (OR=1.48; 95%CI: 0.53-4.10; p=0.45). In conclusion, sarcopenia could be associated with a higher risk of negative knee OA outcomes, in particular symptomatic forms

Favorable Changes in Fasting Glucose in a 6-month Self-Monitored Lifestyle Modification Programme Inversely Affects Spexin Levels in Females with Prediabetes

Spexin (SPX) is a novel peptide thought to have a role in various metabolic regulations. Given its presumed body-weight regulatory functions, we aimed to determine whether lifestyle intervention programs on weight loss and fasting glucose (FG) improvement among people with impaired glucose regulation also alter levels of circulating SPX. A total of 160 Saudi adult males and females with prediabetes were randomly selected from a larger cohort (N = 294) who underwent a 6-month lifestyle modification program to improve their glycemic status. Participants were split into two groups based on differences in glucose levels post-intervention, with the first 50% (improved group) having the most significant reduction in FG. SPX was measured at baseline and after 6 months. Changes in SPX was significant only in the improved group [baseline: median (Q1\u2013Q3) of 164 pg/ml (136\u2013227) vs follow-up: 176 pg/ml (146\u2013285); p &lt; 0.01]. When stratified by sex, the significant increase was observed only in females [159 pg/ml (127\u2013252) vs 182.5 (152,369.1); p &lt; 0.01]. Furthermore, SPX levels showed a significant inverse association with FG (\u3b2 = 120.22, p = 0.003) even after adjustment with age and BMI, again only in females. Circulating SPX levels increase over time in people with prediabetes, particularly women who responded favorably in a 6-month lifestyle intervention program. Whether an unknown mechanism regulating the sexual disparity seen in SPX levels post-intervention exists should be further investigated using a larger sample size

Inflammatory and adipokine status from early to midpregnancy in arab women and its associations with gestational diabetes mellitus

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 (). Adiponectin and resistin significantly decreased from the first to second trimester in women without GDM ( 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 (). Multivariate logistic regression analysis revealed that TNF-α was significantly correlated with GDM (). However, significance was lost after adjustments for maternal and lifestyle risk factors (OR 23.58 (0.50 to 1119.98), ). 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

Vitamin D deficiency prevalence and predictors in early pregnancy among Arab women

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

Polycystic Ovary Syndrome and Insulin Physiology: An Observational Quantitative Serum Proteomics Study in adolescent, Normal-Weight Females

Background: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with insulin resistance, even in the absence of overweight/obesity. The aim of the present study is to examine the global serum proteomic profile of adolescent, normal‐weight females with PCOS in order to gain novel insight in the association of this endocrine disorder with insulin physiology and to identify novel circulating markers that can guide intervention protocols. Methods: Non‐depleted serum from normal‐weight (BMI: 18–23 kg m^(−2)), adolescent females (13–21 years old) with PCOS (n = 20) is compared to BMI‐ and age‐matched healthy controls (n = 20) using our 3D quantitative proteomics methodology. Serum samples from study participants are randomly pooled to form four biological replicates of females with PCOS and four of healthy controls (n = 5 per sample pool). Results: One‐hundred and twenty‐six proteins are differentially expressed in females with PCOS compared to controls. Gene ontology analysis shows significant enrichment for terms related to inflammatory immune response, metabolism and insulin‐like growth factor receptor signaling pathway. Circulating levels of IGF‐1 and ‐2 and IGFBP‐2, ‐3, and ‐4 are found to be lower in females with PCOS compared to healthy controls. Conclusions: The present serum proteomics study provides insight into the pro‐inflammatory status and insulin dysregulation in young females with PCOS and identifies potential serological markers that can guide early intervention protocols