Osteosarcopenia increases the risk of mortality: a systematic review and meta-analysis of prospective observational studies.

BACKGROUND & AIMS: Osteosarcopenia is a recently recognized geriatric syndrome. The association between osteosarcopenia and mortality risk is still largely underexplored. In this systematic review with meta-analysis of prospective cohort studies, we aimed to explore whether osteosarcopenia could be associated with a higher mortality risk. METHODS: Several databases were searched from the inception to 16th February 2024 for prospective cohort studies dealing with osteosarcopenia and mortality. We calculated the mortality risk in osteosarcopenia vs. controls using the most adjusted estimate available and summarized the data as risk ratios (RRs) with their 95% confidence intervals (CIs). A random-effect model was considered for all analyses. RESULTS: Among 231 studies initially considered, nine articles were included after exclusions for a total of 14,429 participants (mean age: 70 years; 64.5% females). The weighted prevalence of osteosarcopenia was 12.72%. Over a mean follow-up of 6.6 years and after adjusting for a mean of four covariates, osteosarcopenia was associated with approximately 53% increased risk of mortality (RR: 1.53; 95% CI: 1.28-1.78). After accounting for publication bias, the re-calculated RR was 1.48 (95%CI: 1.23-1.72). The quality of the studies was generally good, as determined by the Newcastle Ottawa Scale. CONCLUSIONS: Osteosarcopenia was significantly linked with an increased risk of mortality in older people, indicating the need to consider the presence of osteoporosis in patients with sarcopenia, and vice versa, since the combination of these two conditions typical of older people may lead to further complications, such as mortality.

The single point insulin sensitivity estimator (SPISE) is associated with bone health in Arab adults.

BACKGROUND: The Single Point Insulin Sensitivity Estimator (SPISE) index is a surrogate marker for insulin sensitivity. Given the emerging role of bone as an active endocrine organ, its associations with non-invasive measures of extra-skeletal functions such as insulin sensitivity warrant investigation. AIMS: This study aimed to explore the relationship between the SPISE index and Bone Mineral Density (BMD) in an adult population. METHODS: Data from a total of 1270 Arab adults (84% females, mean age 56.7 ± 8.1 years) from the Osteoporosis Registry Database of the Chair for Biomarkers of Chronic Diseases in King Saud University, Riyadh, Saudi Arabia was used in this study. T-scores and SPISE were calculated. Regression models were used to determine associations between SPISE and bone health indices. RESULTS: The low BMD group (N = 853; T-score <-1.0) had significantly higher SPISE values than those with normal BMD (N = 417; T-score - 1.0 and above) (4.6 ± 1.3 vs. 4.3 ± 1.2, p < 0.001). Multivariate linear regression, adjusted for covariates, confirmed a significant inverse association between SPISE and BMD for all participants (ß=-0.22, p < 0.001), as well as both groups [normal BMD (ß = -0.10, p = 0.02) and low BMD groups (ß = -0.15, p < 0.001)]. SPISE, family history of T2DM, and history of fractures collectively account for 17% of the variances perceived in T-score for all participants (p < 0.001). CONCLUSIONS: A significant inverse association between the SPISE index and BMD was observed in adults, suggesting a link between BMD and extra-skeletal health. Underlying mechanisms need to be investigated prospectively using BMD as secondary outcomes in lifestyle modification programs.

Circulating Interleukins-33 and -37 and Their Associations with Metabolic Syndrome in Arab Adults.

Interleukins (ILs) are a group of cytokines known to have immunomodulatory effects; they include ILs-33 and -37 whose emerging roles in the pathogenesis of metabolic syndrome (MetS) remain under investigated. In this study, we compared circulating IL-33 and IL-37 in Arab adults with and without MetS to determine its associations with MetS components. A total of 417 Saudi participants (151 males, 266 females; mean age ± SD 41.3 ± 9.0 years; mean body mass index ± SD 30.7 ± 6.3 kg/m2) were enrolled and screened for MetS using the ATP III criteria. Anthropometrics and fasting blood samples were taken for the assessment of fasting glucose and lipids. Circulating levels of IL-33 and IL-37 were measured using commercially available assays. The results showed higher levels of serum IL-33 and IL-37 in participants with MetS than those without (IL-33, 3.34 3.42 (2.3-3.9) vs. (1-3.9), p = 0.057; IL-37, 5.1 (2.2-8.3) vs. 2.9 (2.1-6.1), p = 0.01). Additionally, having elevated levels of IL-33 was a risk factor for hypertension, low HDL-c, and hypertriglyceridemia. A stratification of the participants according to sex showed that males had higher IL-33 levels than females [3.7 (3.0-4.1) vs. 3.15 (1.4-3.8), p < 0.001], while females had higher levels of IL-37 than males [3.01 (2.2-7.0) vs. 2.9 (2.1-5.6), p = 0.06]. In conclusion, the presence of MetS substantially alters the expression of ILs-33 and -37. IL-33 in particular can be potentially used as a therapeutic target to prevent MetS progression. Longitudinal and interventional studies are warranted to confirm present findings.

Measures of attributes of locomotor capacity in older people: a systematic literature review following the COSMIN methodology.

BACKGROUND: Locomotor capacity (LC) is an important domain of intrinsic capacity and key determinant of functional ability and well-being in older age. The United Nations Decade of Healthy Ageing (2021-2030) calls for strengthening data and research on healthy ageing, including the measurement of older persons' LC. To advance the measurement and monitoring of LC, there is pressing need to identify valid and reliable measures. OBJECTIVE: To identify all the available tools that were validated for measurement of LC or of its specific attributes in older people and to assess the methodological quality of the studies and measurement properties of the tools. DESIGN: Systematic review. SETTING: Anywhere (Community-dwelling; long-term care facility; etc.). SUBJECTS: Older people. METHODS: We used highly sensitive search strategies to search the following databases: Medline, Embase, Scopus, CINAHL and PsycINFO. The study was conducted following the COnsensus-based Standards for the selection of health Measurement Instruments (COSMIN) methodology for systematic review of outcome measurement instruments. RESULTS: A total of 125 studies were included, which assessed tools for balance (n = 84), muscle power (n = 12), muscle strength (n = 32, including four studies about tools for balance and muscle power) and endurance (n = 1). No studies on tools for muscle function, joint function, or locomotor capacity overall, were retrieved. We identified 69 clinician-report or objective assessment tools for balance, 30 for muscle strength, 12 for muscle power and 1 endurance assessment tool. The GRADE assessment of quality of evidence showed that only a few tools have high quality evidence for both sufficient validity and reliability: The Balance Evaluation Systems Test (BESTest), the Mini-Balance Evaluation Systems Test (Mini-BESTest), the Berg Balance Scale (BBS) and the Timed Up and Go (TUG) test. CONCLUSIONS: A few tools with high quality evidence for sufficient validity and reliability are currently available for balance assessment in older people that may be recommended for use in clinical and research settings. Further validation studies are required for muscle strength, muscle power and endurance assessment tools.

Efficacy of osteoporosis pharmacological treatments in men: a systematic review and meta-analysis.

INTRODUCTION: The objective of this systematic review and meta-analysis is to systematically identify and review the efficacy of pharmacological treatments in men with osteoporosis. METHODS: Medline (via Ovid) and Cochrane CENTRAL were searched up to May 2023 for any randomized controlled trial (RCT) evaluating the efficacy of osteoporotic treatment on the evolution of Bone Mineral Density (BMD) and incidence of fractures of men suffering from primary osteoporosis. If at least two studies used the same pharmacological treatment and evaluated the same outcome, a random effect model meta-analysis was applied to reported pooled mean difference (MD) and 95% confidence interval (CI). RESULTS: From the 1,061 studies identified through bibliographic search, 21 RCTs fitted the inclusion criteria. Bisphosphonates (k = 10, n = 2992 men with osteoporosis) improved all three BMD sites compared to placebo; lumbar spine: MD + 4.75% (95% CI 3.45, 6.05); total hip: MD + 2.72% (95% CI 2.06; 3.37); femoral neck: MD + 2.26% (95% CI 1.67; 2.85). Denososumab (k = 2, n = 242), Teriparatide (k = 2, n = 309) and Abaloparatide (k = 2, n = 248) also produced significant improvement of all sites BMD compared to placebo. Romosozumab was only identified in one study and was therefore not meta-analysed. In this study, Romosozumab increased significantly BMD compared to placebo. Incident fractures were reported in 16 RCTs but only four reported fractures as the primary outcome. Treatments were associated with a lower incidence of fractures. CONCLUSIONS: Medications used in the management of osteoporosis in women appear to provide similar benefits in men with osteoporosis. Therefore, the algorithm for the management of osteoporosis in men could be similar to the one previously recommended for the management of osteoporosis in women.

Knee osteoarthritis and adverse health outcomes: an umbrella review of meta-analyses of observational studies.

BACKGROUND: Knee osteoarthritis (OA) is a common condition, associated with a high rate of disability and poor quality of life. Despite the importance of such evidence in public health, no umbrella review (i.e., a review of other systematic reviews and meta-analyses) has systematically assessed evidence on association between knee OA and adverse health outcomes. AIMS: To map and grade all health outcomes associated with knee OA using an umbrella review approach. METHODS: The search was made across several databases up to 22 April 2022. We used an umbrella review of systematic reviews with meta-analyses of observational studies assessing the effect sizes, based on random effect summary, 95% prediction intervals, heterogeneity, small study effects, and excess significance bias. The evidence was then graded from convincing (class I) to weak (class IV). RESULTS: Among 3,847 studies initially considered, five meta-analyses were included for a total of five different outcomes. Three adverse outcomes were significantly associated with knee OA (i.e., cardiovascular mortality, falls, and subclinical atherosclerosis). The presence of knee OA was associated with a significantly higher risk of cardiovascular mortality (odds ratio, OR = 1.17; 95%CI, confidence intervals: 1.02-1.34), falls (RR = 1.34; 95%CI: 1.10-1.64), and conditions associated with subclinical atherosclerosis (OR = 1.43; 95%CI: 1.003-2.05). The certainty of each of this evidence was weak. CONCLUSIONS: Our umbrella review suggests that knee OA can be considered as putative risk factor for some medical conditions, including cardiovascular diseases and falls, however, it is important to note that the evidence is affected by potential biases.

Acute Glycemic Control in Prediabetes Individuals Favorably Alters Serum NLRP3 Inflammasome and Related Interleukins.

Hyperglycemia associated with prediabetes (PD) alters NLRP3 inflammasome activity and related interleukins, yet no study has evaluated the expression of the NLRP3 inflammasome complex and related interleukins in individuals with a PD condition that did or did not develop type 2 diabetes mellitus (T2DM). This study investigated the effect of 6 months of lifestyle modification on the expression of the NLRP3 inflammasome and related interleukins (1α, 1ß, 18, 33 and 37) in the sera of individuals with a PD condition that did or did not develop T2DM. This interventional study included 67 Saudi adults (mean age = 41.9 ± 8.0 years, mean BMI = 33.2 ± 5.5 kg/m2). Overnight-fasting serum samples were collected at baseline and at the 6-month follow-up. Serum levels of NLRP3, capsase-1 and related ILs were analyzed at both visits using commercially available immunoassay kits. Results showed that IL-1α increased in the PD group that developed T2DM (p = 0.046), IL-33 decreased in the PD group that reverted to normal (p < 0.001) and NLRP3 decreased in the PD group that remained PD (p = 0.01). Results also showed a positive over-time correlation between NLRP3 and both IL-1α and IL-33 (p < 0.001 and p = 0.028, respectively). In conclusion, glycemic control favorably altered NLRP3 inflammasome complex activity, and lifestyle modification in PD individuals is crucial in reversing harmful metabolic and inflammatory phenotypes.

Primary hyperparathyroidism in Saudi Arabia revisited: a multi-centre observational study.

PURPOSE: Primary hyperparathyroidism (PHPT) is a common cause of hypercalcemia and remains understudied within the Arabian population. The present study, the largest of its kind within the Gulf Cooperation Council (GCC) countries, aims to determine the demographics and clinical presentation of PHPT in Saudi Arabia. METHODS: In this multi-center retrospective study involving three tertiary hospitals in different geographic locations of Saudi Arabia namely, Riyadh, Al Ahsa and Jeddah, a total of 205 out of 243 confirmed PHPT cases aged 16 to 93 years old were included (N = 96 from Riyadh; N = 59 from Al Ahsa and N = 50 from Jeddah). Demographics, clinical manifestations and surgical outcomes were recorded as well as laboratory and radiologic investigations including serum parathyroid hormone (PTH), 25(OH)D, adjusted calcium, estimated glomerular filtration rate (eGFR) and nuclear scan outcome. RESULTS: PHPT cases appeared to increase over time when compared to other local studies published so far, with 12.8 cases per 100,000 hospital population. Females outnumber males (3:1) with 86% seen as out-patients. The average age was 59.8 ± 15.5 years. Abnormal PTH scan was seen in 171 patients (83.4%). Kidney stones was the most common renal manifestation (32 cases, 15.6%) and osteoporosis was the most common skeletal manifestation (67 cases, 32.7%). Al Ahsa had the highest prevalence of multiple comorbidities at 54% and the highest prevalence of obesity as a single comorbidity (17%) compared to other regions (p < 0.05). Jeddah recorded the highest prevalence of osteoporosis with bone and joint pains (30%) (p < 0.05). CONCLUSION: Comparison of present data with previous local studies suggest an increasing trend in PHPT cases in Saudi Arabia. Regional variations in the clinical presentation of PHPT were observed and warrant further investigation.

Vitamin D status of Arab Gulf residents screened for SARS-CoV-2 and its association with COVID-19 infection: a multi-centre case-control study.

OBJECTIVES: Vitamin D status in patients with COVID-19 is an on-going controversial issue. This study aims to determine differences in the serum 25(OH)D concentrations of Arab Gulf adult residents screened for SARS-CoV-2 and its association with risk of COVID-19 infection together with other comorbidities. METHODS: In this multi-center, case-control study, a total of 220 male and female adults presenting with none to mild symptoms were screened for COVID-19 (n = 138 RT-PCR-confirmed SARS-CoV-2 positive and 82 negative controls). Medical history was noted. Anthropometrics were measured and non-fasting blood samples were collected for the assessment of glucose, lipids, inflammatory markers and serum 25(OH)D concentrations. RESULTS: Serum 25(OH)D levels were significantly lower in the SARS-CoV-2 positive group compared to the negative group after adjustment for age and BMI (52.8 nmol/l ± 11.0 versus 64.5 nmol/l ± 11.1; p = 0.009). Being elderly (> 60 years) [Odds ratio 6 (95% Confidence Interval, CI 2-18; p = 0.001) as well as having type 2 diabetes (T2D) [OR 6 (95% CI 3-14); p < 0.001)] and low HDL cholesterol (HDL-c) [OR 6 (95% CI 3-14); p < 0.001)] were significant risk factors for COVID-19 infection independent of age, sex and obesity. CONCLUSIONS: Among Arab Gulf residents screened for SARS-CoV-2, serum 25(OH) D levels were observed to be lower in those who tested positive than negative individuals, but it was the presence of old age, diabetes mellitus and low-HDL-c that were significantly associated with risk of COVID-19 infection. Large population-based randomized controlled trials should be conducted to assess the protective effects of vitamin D supplementation against COVID-19.

Severe vitamin D deficiency is not related to SARS-CoV-2 infection but may increase mortality risk in hospitalized adults: a retrospective case-control study in an Arab Gulf country.

PURPOSE: As the world continues to cautiously navigate its way through the coronavirus disease 2019 (COVID-19) pandemic, several breakthroughs in therapies and vaccines are currently being developed and scrutinized. Consequently, alternative therapies for severe acute respiratory coronavirus 2 (SARS-CoV-2) prevention, such as vitamin D supplementation, while hypothetically promising, require substantial evidence from countries affected by COVID-19. The present retrospective case-control study aims to identify differences in vitamin D status and clinical characteristics of hospitalized patients screened for SARS-CoV-2, and determine associations of vitamin D levels with increased COVID-19 risk and mortality. METHODS: A total of 222 [SARS-CoV-2 (+) N = 150 (97 males; 53 females); SARS-CoV-2 (-) N = 72 (38 males, 34 females)] out of 550 hospitalized adult patients screened for SARS-CoV-2 and admitted at King Saud University Medical City-King Khalid University Hospital (KSUMC-KKUH) in Riyadh, Saudi Arabia from May-July 2020 were included. Clinical, radiologic and serologic data, including 25(OH)D levels were analyzed. RESULTS: Vitamin D deficiency (25(OH)D < 50 nmol/l) was present in 75% of all patients. Serum 25(OH)D levels were significantly lower among SARS-CoV-2 (+) than SARS-CoV-2 (-) patients after adjusting for age, sex and body mass index (BMI) (35.8 ± 1.5 nmol/l vs. 42.5 ± 3.0 nmol/l; p = 0.037). Multivariate regression analysis revealed that significant predictors for SARS-CoV-2 include age > 60 years and pre-existing conditions (p < 0.05). Statistically significant predictors for mortality adjusted for covariates include male sex [Odds ratio, OR 3.3 (95% confidence interval, CI 1.2-9.2); p = 0.02], chronic kidney disease [OR 3.5 (95% CI 1.4-8.7); p = 0.008] and severe 25(OH)D deficiency (< 12.5 nmol/l), but at borderline significance [OR 4.9 (95% CI (0.9-25.8); p = 0.06]. CONCLUSION: In hospital settings, 25(OH)D deficiency is not associated with SARS-CoV-2 infection, but may increase risk for mortality in severely deficient cases. Clinical trials are warranted to determine whether vitamin D status correction provides protective effects against worse COVID-19 outcomes.

Diabetes and Covid-19 among hospitalized patients in Saudi Arabia: a single-centre retrospective study.

BACKGROUND: Information on the clinical characteristics and outcomes of hospitalized Covid-19 patients with or without diabetes mellitus (DM) is limited in the Arab region. This study aims to fill this gap. METHODS: In this single-center retrospective study, medical records of hospitalized adults with confirmed Covid-19 [RT-PCR positive for SARS-CoV2] at King Saud University Medical City (KSUMC)-King Khaled University Hospital (KKUH), Riyadh, Saudi Arabia from May to July 2020 were analyzed. Clinical, radiological and serological information, as well as outcomes were recorded and analyzed. RESULTS: A total of 439 patients were included (median age 55 years; 68.3% men). The most prevalent comorbidities were vitamin D deficiency (74.7%), DM (68.3%), hypertension (42.6%) and obesity (42.2%). During hospitalization, 77 out of the 439 patients (17.5%) died. DM patients have a significantly higher death rate (20.5% versus 12.3%; p = 0.04) and lower survival time (p = 0.016) than non-DM. Multivariate cox proportional hazards regression model revealed that age [Hazards ratio, HR 3.0 (95% confidence interval, CI 1.7-5.3); p < 0.001], congestive heart failure [adjusted HR 3.5 (CI 1.4-8.3); p = 0.006], smoking [adjusted HR 5.8 (CI 2.0-17.2); p < 0.001], ß-blocker use [adjusted HR 1.7 (CI 1.0-2.9); p = 0.04], bilateral lung infiltrates [adjusted HR 1.9 (CI 1.1-3.3); p = 0.02], creatinine > 90 µmol/l [adjusted HR 2.1 (CI 1.3-3.5); p = 0.004] and 25(OH)D < 12.5 nmol/l [adjusted HR 7.0 (CI 1.7-28.2); p = 0.007] were significant predictors of mortality among hospitalized Covid-19 patients. Random blood glucose ≥ 11.1 mmol/l was significantly associated with intensive care admission [adjusted HR 1.5 (CI 1.0-2.2); p = 0.04], as well as smoking, ß-blocker use, neutrophil > 7.5, creatinine > 90 µmol/l and alanine aminotransferase > 65U/l. CONCLUSION: The prevalence of DM is high among hospitalized Covid-19 patients in Riyadh, Saudi Arabia. While DM patients have a higher mortality rate than their non-DM counterparts, other factors such as old age, congestive heart failure, smoking, ß-blocker use, presence of bilateral lung infiltrates, elevated creatinine and severe vitamin D deficiency, appear to be more significant predictors of fatal outcome. Patients with acute metabolic dysfunctions, including hyperglycemia on admission are more likely to receive intensive care.

Circulating spexin levels are influenced by the presence or absence of gestational diabetes.

The study aimed to determine whether circulating spexin (SPX) is modified during the course of pregnancy and whether it is affected by the presence of glucose intolerance, i.e., Gestational Diabetes Mellitus (GDM). This prospective study included 102 pregnant women (63 non-GDM and 39 GDM; mean age 29.4 ±â€¯5.1 years; mean BMI 28.0 ±â€¯6.1 kg/m2). Anthropometrics, glycemic and lipid profiles, as well measurements of circulating adipocytokines and SPX were measured at baseline and after 3 and 6 months. In GDM patients, SPX levels increased significantly after 6-months, in parallel with a borderline significant increase in glucose (p = 0.07). In non-GDM patients, however, median SPX level decreased from baseline to 6-months (p < 0.01), and this change was not associated with changes in glucose levels. Change in glucose from baseline to 6-months was positively associated with change in SPX in GDM patients only (R = 0.37; p < 0.05). SPX levels are positively influenced by glucose intolerance in pregnant women with GDM, while they decrease in control women without GDM.

Coexistence of Pre-sarcopenia and Metabolic Syndrome in Arab Men.

OBJECTIVE: The present single-center observational study determined the prevalence and coexistence of sarcopenia, pre-sarcopenia, and metabolic syndrome (MetS) among apparently healthy Arab men and whether having both conditions present a unique cardiometabolic profile that is distinct than having the conditions separately. METHODS: A total of 471 out of 530 Arab men aged 20-77 years old were included after screening for the presence of pre-sarcopenia (ALM/ht2 < 7.26 kg/m2), sarcopenia (presence of both low muscle mass and low function), and MetS. MetS screening was done using the definition by the NCEP-ATP III. Based on the screening results, the participants were classified as control (normal) group (N = 328), MetS only (N = 73), pre-sarcopenia only (N = 64), and MetS + pre-sarcopenia (N = 6). RESULTS: Pre-sarcopenia without MetS was observed in 64 participants (13.6%), while MetS without pre-sarcopenia was observed in 73 participants (15.5%). MetS + pre-sarcopenia was observed only in 6 participants (1.3%). None of the participants had sarcopenia. Age- and BMI-adjusted comparisons showed that those with MetS + pre-sarcopenia had the highest diastolic blood pressure and triglyceride levels as compared to all groups (p values < 0.001). MetS + pre-sarcopenia group also had the highest levels of glucose and the lowest lean arms-legs/BMI ratio than control and pre-sarcopenia groups (p values < 0.001 and 0.005, respectively). CONCLUSION: The prevalence of pre-sarcopenia + MetS is low among young adult Arab men, but shows a unique cardiometabolic profile that is worse than those having only one of the conditions. Further investigations should be done among Arab women and the elderly.

Susceptibility to type 2 diabetes may be modulated by haplotypes in G6PC2, a target of positive selection.

BACKGROUND: The endoplasmic reticulum enzyme glucose-6-phosphatase catalyzes the common terminal reaction in the gluconeogenic/glycogenolytic pathways and plays a central role in glucose homeostasis. In most mammals, different G6PC subunits are encoded by three paralogous genes (G6PC, G6PC2, and G6PC3). Mutations in G6PC and G6PC3 are responsible for human mendelian diseases, whereas variants in G6PC2 are associated with fasting glucose (FG) levels. RESULTS: We analyzed the evolutionary history of G6Pase genes. Results indicated that the three paralogs originated during early vertebrate evolution and that negative selection was the major force shaping diversity at these genes in mammals. Nonetheless, site-wise estimation of evolutionary rates at corresponding sites revealed weak correlations, suggesting that mammalian G6Pases have evolved different structural features over time. We also detected pervasive positive selection at mammalian G6PC2. Most selected residues localize in the C-terminal protein region, where several human variants associated with FG levels also map. This region was re-sequenced in ~560 subjects from Saudi Arabia, 185 of whom suffering from type 2 diabetes (T2D). The frequency of rare missense and nonsense variants was not significantly different in T2D and controls. Association analysis with two common missense variants (V219L and S342C) revealed a weak but significant association for both SNPs when analyses were conditioned on rs560887, previously identified in a GWAS for FG. Two haplotypes were significantly associated with T2D with an opposite effect direction. CONCLUSIONS: We detected pervasive positive selection at mammalian G6PC2 genes and we suggest that distinct haplotypes at the G6PC2 locus modulate susceptibility to T2D.

Effects of a multi-strain probiotic supplement for 12 weeks in circulating endotoxin levels and cardiometabolic profiles of medication naïve T2DM patients: a randomized clinical trial.

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.

Sex-specific vitamin D effects on blood coagulation among overweight adults.

BACKGROUND: Overweight adults are at increased risk for cardiovascular disease and vitamin D deficiency, whereas an important feature to vitamin D physiology is its sex dependence. The aim of this study was to examine whether vitamin D status improvement exerts a sexually dimorphic effect on serum proteins associated with cardiovascular risk among overweight adults. MATERIALS AND METHODS: Unprocessed serum from age- and BMI-matched men (n = 26) and premenopausal women (n = 24) with vitamin D deficiency and after they achieved sufficiency through a 12-month nutritional intervention was analysed using our previously published depletion-free quantitative proteomics method. Key findings were verified with ELISA. Differentially expressed proteins were subjected to in silico bioinformatics assessment using principal component analysis, hierarchical clustering and Metacore™ pathway analysis. All mass spectrometry proteomic data are available via ProteomeXchange (identifier: PXD003663). RESULTS: A total of 282 proteins were differentially expressed after the intervention between men and women (P-value ≤ 0·05), in which the blood coagulation pathway was significantly enriched. In agreement with the proteomics findings, ELISA measurements showed vitamin K-dependent protein C, von Willebrand factor, fibrinogen gamma chain and multimerin-1 proteins, of relevance to blood coagulation, to be differentially affected (P-value ≤ 0·05) between sexes after vitamin D status correction. CONCLUSIONS: This study identified novel protein-level molecular indicators on the sexually dimorphic effect of vitamin D status correction associated with blood coagulation among overweight adults. These sex-mediated vitamin D effects should be factored in the design and interpretation of vitamin D observational and interventional studies testing cardiometabolic outcomes.

Sensitivity of various adiposity indices in identifying cardiometabolic diseases in Arab adults.

BACKGROUND: Obesity is a recognized risk factor for various cardiometabolic diseases and several indices are used clinically to assess overall cardiometabolic risk. This study aims to determine the sensitivity of six anthropometric indices [Body mass index (BMI), waist, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), body adiposity index (BAI) and visceral adiposity index (VAI)] in determining diabetes mellitus type 2, coronary heart disease, dyslipidemia, hypertension and metabolic syndrome (MetS) in Saudi adults recruited from two independent cohorts (2008-2009 and 2013-2014). METHODS: A total of 6,821 Saudi adults [2008-2009, N = 3,971 (1,698 males and 2,273 females); 2013-2014, N = 2,850 (926 males and 1,924 females)] aged 18-70 years old were included in this descriptive, cross-sectional study. Anthropometrics were obtained and fasting blood samples analyzed for glucose and lipids. BMI, WHR, WHtR, BAI and VAI were computed mathematically. RESULTS: VAI was the most sensitive index in determining DMT2 (AUC 0.72; p < 0.001) in the 2008-2009 cohort and MetS (AUC = 0.84; p < 0.001) in the 2013-2014 cohort. WHR was most discriminating for CHD in both cohorts (AUC 0.70 and 0.84 for 2008-2009 and 2013-2014, p values <0.001, respectively). WHtR was most sensitive but rather modest in determining hypertension (AUC 0.66; p < 0.001), while waist circumference was most sensitive for dyslipidemia (AUC 0.72; p < 0.001) in the 2008-2009 cohort and MetS (AUC 0.85; p < 0.001) in the 2013-2014 cohort. BAI was the least sensitive adiposity index. CONCLUSION: Sensitivity of adiposity indices regarding cardiometabolic diseases highlight the importance of body fat distribution in determining overall cardiometabolic risk, with indices involving abdominal obesity being more clinically significant than BMI and BAI. The sensitivity of these adiposity indices should be noted in assessing a particular cardiometabolic disease.

Habitual physical activity is associated with circulating irisin in healthy controls but not in subjects with diabetes mellitus type 2.

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/m(2) ] and 83 DMT2 subjects [age: 54.3 ± 10.3 year; BMI: 29.4 ± 4.7 kg/m(2) ] 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.

A nonsense polymorphism (R392X) in TLR5 protects from obesity but predisposes to diabetes.

The TLR5 gene encodes an innate immunity receptor. Mice lacking Tlr5 (T5KO) develop insulin resistance and increased adiposity. Owing to the segregation of a dominant nonsense polymorphism (R392X, rs5744168), a portion of humans lack TLR5 function. We investigated whether the nonsense polymorphism influences obesity and susceptibility to type 2 diabetes (T2D). R392X was genotyped in two cohorts from Saudi Arabia, a region where obesity and type 2 diabetes (T2D) are highly prevalent. The nonsense allele was found to protect from obesity (p(combined) = 0.0062; odds ratio, 0.51) and to associate with lower body mass index (BMI) (p(combined) = 0.0061); this allele also correlated with a reduced production of proinflammatory cytokines. A significant interaction was noted between rs5744168 and sex in affecting BMI (p(interaction) = 0.006), and stratification by gender revealed that the association is driven by females (p(combined) = 0.0016 and 0.0006 for obesity and BMI, respectively). The nonsense polymorphism also associated with BMI in nonobese women. After correction for BMI, the 392X allele was found to represent a risk factor for T2D with a sex-specific effect (p(interaction) = 0.023) mediated by females (p = 0.021; odds ratio, 2.60). Fasting plasma glucose levels in nondiabetic individuals were also higher in women carrying the nonsense allele (p = 0.012). Thus, in contrast to T5KO mice, loss of human TLR5 function protects from weight gain, but in analogy to the animal model, the nonsense allele predisposes to T2D. These effects are apparently sex-specific. Data in this study reinforce the hypothesis that metabolic diseases, including T2D, are associated with immune dysregulation.

Whole serum 3D LC-nESI-FTMS quantitative proteomics reveals sexual dimorphism in the milieu intérieur of overweight and obese adults.

Linking gender-specific differences to the molecular etiology of obesity has been largely based on genomic and transcriptomic evidence lacking endophenotypic insight and is not applicable to the extracellular fluid compartments, or the milieu intérieur, of the human body. To address this need, this study profiled the whole serum proteomes of age-matched nondiabetic overweight and obese females (n = 28) and males (n = 31) using a multiplex design with pooled biological and technical replicates. To bypass basic limitations of immunodepletion-based strategies, subproteome enrichment by size-exclusion chromatography (SuPrE-SEC) followed by iTRAQ 2D-LC-nESI-FTMS analysis was used. The study resulted in the reproducible analysis of 2472 proteins (peptide FDR < 5%, q < 0.05). A total of 248 proteins exhibited significant modulation between men and women (p < 0.05) that mapped to pathways associated with ß-estradiol, lipid and prostanoid metabolism, vitamin D function, immunity/inflammation, and the complement and coagulation cascades. This novel endophenotypic signature of gender-specific differences in whole serum confirmed and expanded the results of previous physiologic and pharmacologic studies exploring sexual dimorphism at the genomic and transcriptomic level in tissues and cells. Conclusively, the multifactorial and pleiotropic nature of human obesity exhibits sexual dimorphism in the circulating proteome of importance to clinical study design.