Bone metabolism markers are associated with neck circumference in adult Arab women.

The study aimed to determine whether neck circumference is associated with bone metabolism markers among adult Arab women and found modest but significant associations with bone resorption markers, suggesting that neck circumference, a surrogate measure of upper subcutaneous fat, influences bone turnover expression among adult females. INTRODUCTION: Body fat distribution is associated with decreased bone resorption and neck circumference (NC), a surrogate measure for upper body fat, has never been tested as a marker that can reflect bone turnover. This is the first study aimed to analyze the associations between NC and several bone biomarkers among adult Saudi women. METHODS: This cross-sectional study included a total of 265 middle-aged Saudi women [86 non-obese (mean age 52.7 ± 8.1; mean BMI 26.9 ± 2.3) and 179 obese (mean age 50.6 ± 7.5; mean BMI 35.7 ± 4.5)] recruited from primary care centers in Riyadh, Saudi Arabia. Anthropometrics included BMI, NC, waist and hip circumferences, total body fat percentage (%), and blood pressure. Biochemical parameters included glucose and lipid profile which were measured routinely. Serum levels of 25(OH) D, parathyroid hormone, RANKl, sclerostin, C-terminal telopeptide of collagen I (CTX-I), Dkk1, IL1ß, osteoprotegerin, osteopontin, and osteocalcin were measured using commercially available assays. RESULTS: In all groups, NC was inversely associated with PTH (R = - 0.22; p < 0.05) and positively associated with osteoprotegerin (R = 0.20; p < 0.05) even after adjustments for age and BMI. Using all anthropometric indices as independent variables showed that only NC explained the variance perceived in CTX-I (p = 0.049). In the non-obese, waist-hip ratio (WHR) was significantly associated with sclerostin (R = 0.40; p < 0.05) and body fat was significantly associated with osteopontin (R = 0.42; p < 0.05). CONCLUSION: NC is modestly but significantly associated with bone biomarkers, particularly the bone resorption markers, among adult Arab women. The present findings highlight the importance of NC as measure of upper body subcutaneous fat in influencing bone biomarker expression in adult females.

Effect of acute downhill running on bone markers in responders and non-responders.

This study showed that procollagen type 1 amino-terminal pro-peptide and N-MID osteocalcin significantly increased after exercise independent of the form of muscle contraction. Thus, these preliminary results will be useful for future studies that will consider bone turnover characteristics of responders and non-responders to acute and chronic aerobic exercise. INTRODUCTION: The aim of the current study was to compare the effects of acute flat running (FR) and downhill running (DHR) on bone turnover markers in men. METHODS: Fourteen healthy young active men performed three exercise tests in a counterbalanced order, including rest condition, FR, and DHR, at 60% maximal aerobic capacity on a treadmill with 0 and - 12% inclines. Blood samples were taken in the pre-exercise, immediately post-exercise, and 24-h post-exercise periods, and bone markers included total procollagen type 1 amino-terminal pro-peptide (total PINP) and N-MID osteocalcin. RESULTS: Total P1NP significantly increased after exercise independent of the form of muscle contraction (p > 0.05). N-MID osteocalcin increased after DHR by 17% compared to after pre-exercise, but the difference did not reach significance (p = 0.07; partial eta square, 0.21). Biomarker responses to exercise were dependent on the exercise form and independent of hormone type in half of the participants who were classified as responders. Physiological parameters and changes in muscle voluntary contraction did not explain the differences between responders and non-responders. CONCLUSION: The effect of acute DHR on bone turnover is determined by biomarker type and participant characteristics. Future studies should discriminate between the characteristics of responders and those of non-responders.

Identification and management of patients at increased risk of osteoporotic fracture: outcomes of an ESCEO expert consensus meeting.

Osteoporosis represents a significant and increasing healthcare burden in Europe, but most patients at increased risk of fracture do not receive medication, resulting in a large treatment gap. Identification of patients who are at particularly high risk will help clinicians target appropriate treatment more precisely and cost-effectively, and should be the focus of future research. INTRODUCTION: The purpose of the study was to review data on the identification and treatment of patients with osteoporosis at increased risk of fracture. METHODS: A working group convened by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis met to review current data on the epidemiology and burden of osteoporosis and the patterns of medical management throughout Europe. RESULTS: In Europe in 2010, the cost of managing osteoporosis was estimated at €37 billion and notably the costs of treatment and long-term care of patients with fractures were considerably higher than the costs for pharmacological prevention. Despite the availability of effective treatments, the uptake of osteoporosis therapy is low and declining, in particular for secondary fracture prevention where the risk of a subsequent fracture following a first fracture is high. Consequently, there is a significant treatment gap between those who would benefit from treatment and those who receive it, which urgently needs to be addressed so that the burden of disease can be reduced. CONCLUSIONS: Implementation of global fracture prevention strategies is a critical need. Future research should focus on identifying specific risk factors for imminent fractures, periods of high fracture risk, patients who are at increased risk of fracture and therapies that are most suited to such high-risk patients and optimal implementation strategies in primary, secondary and tertiary care.

Serum 25-hydroxyvitamin D status among Saudi children with and without a history of fracture.

BACKGROUND: The significance of vitamin D deficiency in the incidence of bone fractures in children has been under investigated. Here, we aimed to associate serum 25-hydroxyvitamin D levels and fractures in Saudi children. MATERIALS AND METHODS: This cross-sectional study was conducted in 1022 Saudi children without fracture history [476 boys (age 14.56 ± 1.81, BMI 22.38 ± 5.81) and 546 girls (age 13.57 ± 1.67, BMI 22.24 ± 4.94)] and 234 Saudi children with a history of fracture [148 boys (age 14.25 ± 1.39, BMI 22.66 ± 6.08) and 86 girls (age 13.76 ± 1.35, BMI 21.33 ± 1.35)]. Anthropometric and fasting serum biochemical data were collected. Serum 25-hydroxyvitamin D level was assessed using electrochemiluminescence. RESULTS: Mean circulating 25-hydroxyvitamin (25OH) D level in subjects with a history of fracture was significantly lower in both boys (p < 0.01) and girls (p < 0.01) than those without, however both groups had low mean 25(OH)D levels. Furthermore, age was positively associated with 25-hydroxyvitamin D in boys (p < 0.05) and negatively in girls (p < 0.05) with a history of fracture. CONCLUSION: In conclusion, vitamin D levels were significantly lower in children with a history of bone fractures in both boys and girls than those without such a history; even in the absence of fracture history, vitamin D status correction is warranted in the general Saudi pediatric population.

Comparisons in childhood obesity and cardiometabolic risk factors among urban Saudi Arab adolescents in 2008 and 2013.

BACKGROUND: We aimed to compare the prevalence of childhood obesity and other cardiometabolic risk factors from two independent cohorts (2008 and 2013) in Riyadh, Saudi Arabia. METHODS: A total of 4549 adolescents aged 12-18 years [2454 boys, 2095 girls], taken from two independent cohorts, 5 years apart (2008 and 2013), were included. Anthropometrics were measured, and fasting blood samples were taken to ascertain glucose and lipid profile. RESULTS: The overall prevalence of obesity was significantly higher in 2013 [15.3 (95% confidence interval 13.7-16.9)] than 2008 [12.6 (11.3-13.9)] (P = 0.012). Stratified by sex, the prevalence of obesity among boys was significantly higher in 2013 than 2008 [2008 = 12.0 (10.3-13.7) versus 2013 = 17.4 (15.1-19.7); P < 0.001]. The age groups 13 and 15 years had a significantly higher mean triglycerides in 2013 than 2008 (P-values 0.003 and <0.001, respectively) and lower mean HDL-cholesterol also in the 13 years old age group (P < 0.001). CONCLUSIONS: The prevalence of childhood obesity in Saudi Arabia has increased in particular age groups (13-15 years) during a 5-year span. Special attention is warranted in these vulnerable age groups, particularly in boys, as cardiometabolic risk factors appear to worsen.

Upregulation of inflammasome activity and increased gut permeability are associated with obesity in children and adolescents.

BACKGROUND: Immune activation contributes to the persistent state of inflammation associated with metabolic dysfunction in obesity. The specific immune receptors that sense metabolic stress signals and trigger inflammation are nevertheless largely unknown, and little is known on inflammatory and immune gene regulation in obesity. METHODS: The study includes a cross-sectional and a longitudinal arm. Forty children and adolescents were enrolled: 22 obese subjects and 18 age-matched normal weight controls. Obese subjects participated in an 18-month therapeutic protocol, based on intensive lifestyle modification (dietary regimen, physical activity and behavioral interventions). Expression of genes involved in the inflammasome pathway, plasma concentration of the inflammasome-associated pro-inflammatory cytokines (interleukin (IL)-1ß and IL-18) and indexes of microbial translocation (lipopolysaccharide (LPS), soluble CD14 (sCD14) and intestinal fatty acid-binding protein) were analyzed at baseline in obese subjects compared with controls, and after 18 months in obese subjects. RESULTS: Cross-sectional analyses showed that the LPS-induced expression of genes involved in inflammasome (NLRP3, caspase 5 and NAIP), Nod-like receptors (NLRX1 and NOD1), downstream signaling (P2RX7, RAGE, RIPk2, TIRAP and BIRC2) and effector molecules (IFN-γ, IL-12ß, IL-1ß, CCL2, CCL5, IL-6 and TNFα) was significantly increased in obese subjects at baseline as compared with normal weight controls. The baseline plasma concentration of inflammasome-related cytokines (IL-1ß and IL-18) and of microbial translocation markers (LPS and sCD14) was augmented in obese subjects as compared with controls as well. Longitudinal analyses indicated that intensive lifestyle modification resulted in a normalization of parameters in subjects with a significant reduction of BMI after 18 months. CONCLUSIONS: In children and adolescents, obesity is characterized by the activation of the inflammasome and by an alteration of gut permeability. Successful lifestyle modification is effective in reducing inflammation, suggesting that inhibition of the inflammasome may be a potential therapeutic strategy in obesity.

Hypovitaminosis D associations with adverse metabolic parameters are accentuated in patients with Type 2 diabetes mellitus: a body mass index-independent role of adiponectin?

BACKGROUND: Hypovitaminosis D has been associated with an increased prevalence of Type 2 diabetes mellitus (DMT2) and metabolic syndrome manifestations. The purpose of this study was to examine the association between 25-hydroxy-vitamin D (25-OH-VitD) levels and indices of insulin resistance (IR), including adipocytokines, in a Saudi population with or without DMT2. SUBJECTS AND METHODS: A total of 266 subjects (153 DMT2 and 113 healthy controls) aged 26-80 yr were randomly selected from the existing Biomarkers Screening in Riyadh Program (RIYADH Cohort). Subjects were assessed clinically, anthropometry was performed, morning blood chemistries, including fasting glucose (FG), triglycerides, total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol were obtained. Homeostasis model assessment of IR (HOMA-IR) was calculated, and serum 25-OH-VitD, leptin, adiponectin, resistin, insulin, high sensitivity CRP (hsCRP), and tumor necrosis factor α concentrations were measured using specific assays. RESULTS: In DMT2 subjects, negative correlations between 25-OH-vitD and body mass index (BMI), FG, insulin, HOMA-IR, cholesterol, LDL-C, and hsCRP were observed, while a positive correlation between 25-OH-VitD and adiponectin was detected. The later remained significant after controlling for BMI. Interestingly, only weak and nonsignificant associations between 25-OH-VitD and metabolic parameters were observed in the control group, whereas, when the entire population was examined, negative correlations were evident primarily between 25-OH-VitD and FG, HOMA-IR, total cholesterol, LDL-C. These associations remained significant after controlling for BMI. CONCLUSIONS: These results suggest that hypovitaminosis D associations with metabolic disturbances are accentuated in DMT2. The BMIindependent positive correlation between 25-OH-VitD and adiponectin suggests a potential role for this adipocytokine as a link between 25-OH-VitD and IR in patients with DMT2.

Normal circulating PTH in Saudi healthy individuals with hypovitaminosis D.

Recent studies in the Middle East have shown an increased incidence of vitamin D deficiency across this region of year-round sunlight. There is scarcity of information, however, as to the levels of 1,25-dihydroxyvitamin D [1,25(OH)2D], the active form of vitamin D, and its associations with cardiometabolic parameters in an Arab cohort and this study aims to fill this gap. In a cross-sectional study, 33 male and 43 female (22 children and 54 adults, total 76) Saudis with previously established low levels of serum 25-hydroxyvitamin D [25(OH)D] (<50 ng/ml or 20 nmol/l) were recruited. Anthropometrics were obtained and fasting blood samples were taken for a routine measurement of glucose, lipid profile, calcium, and albumin, while serum 25(OH)D, 1,25-(OH)2D, and intact PTH were quantified using specific ELISAs. Serum calcium, intact PTH, and 1,25(OH)2D were all within the normal range in both children and adults in both genders. In all subjects, serum 1,25(OH)2D was not associated with intact PTH, while circulating 1,25(OH)D inversely correlated with systolic blood pressure (p=0.01) and waist circumference (p=0.04). Thus, vitamin D deficient Saudi children and adults with normal levels of 1,25-(OH)2D also had normal circulating calcium and PTH. This study suggests that local cutoffs should be set that will be of clinical significance in the identification of those at true risk for harder end-points, such as secondary hyperparathyroidism and bone-related diseases.

Urinary iodine is associated with insulin resistance in subjects with diabetes mellitus type 2.

BACKGROUND: Diabetes Mellitus (DM) is a major health problem worldwide and its prevalence in Saudi Arabia has reached 31.6%. Patients with diabetes mellitus are at an increased risk of thyroid disease. The purpose of this study was to examine the urinary excretion of iodine in type 2 DM (T2DM) patients, and to assess the clinical implication of iodine status on T2DM. METHODS: A total of 266 adult Saudis aged 18-55 years (109 T2DM patients and 157 healthy controls) were randomly selected from the Riyadh Cohort Study. Subjects were assessed for anthropometry, morning blood chemistries including fasting glucose, and lipid profile; serum concentrations of leptin, adiponectin, resistin, insulin, aPAI, hsCRP, Ang II, TNF-α, TSH, T3, T4, urine creatinine, urine iodine were measured using specific assays. RESULTS: The concentration of urine iodine was significantly lower in T2DM than in healthy control subjects (84.6±2.3 vs. 119.4±3.4, p<0.001), which remained significant after creatinine correction and controlling for age (p=0.01). Furthermore, urinary iodine is negatively correlated with waist, hips, SAD, glucose, insulin, HOMA-IR triglyceride, resistin, angiotensin II (Ang II), and CRP, while it was positively associated with TSH. CONCLUSIONS: The decreased levels of iodine concentration in T2DM patients and its likely deleterious effects on metabolic functions calls for a systematic approach to thyroid disease screening in diabetic patients. Routine annual urinary iodine determination is recommended and should target T2DM patients at risk of thyroid dysfunction.

The PD-1/PD-L1 pathway in human pathology.

T-cell activation is dependent on signals delivered through the antigen-specific T-cell receptor and accessory receptors on T-cells. Integration of signals through this family of costimulatory and inhibitory receptors and their ligands regulates the balance between T-cell activation, tolerance, and immunopathology. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals and exert a vital and diverse range of immunoregulatory roles in T-cell activation, tolerance, and immune-mediated tissue damage. In this review, we revisit current understanding of the immunoregulatory functions of PD-1 and its ligands and their involvement in immune-mediated diseases.

Blood thiamine and its phosphate esters as measured by high-performance liquid chromatography: levels and associations in diabetes mellitus patients with varying degrees of microalbuminuria.

BACKGROUND: Thiamine deficiency has been linked to microvascular complications in patients with diabetes mellitus (DM). In this study, we aim to assess blood and urine thiamine status by high performance liquid chromatography (HPLC) in patients with DM Type 1 and Type 2 (DMT1, DMT2) and to identify associations with markers of incipient nephropathy and kidney dysfunction. SUBJECTS AND METHODS: A total of 205 subjects (43 DMT1 and 162 DMT2) with and without microalbuminuria and 26 non-diabetic controls were included. Fasting blood samples were collected and anthropometric parameters were measured. Fasting blood, lipid and renal profile were determined routinely. Blood thiamine concentration, its phosphate esters and urine thiamine were quantified using HPLC. RESULTS: Blood thiamine concentrations (ng 1-1) were decreased by 75.7% and 49.6% in patients with DMT1 and DMT2, respectively [controls (54.8+/-11.4); DMT1 (41.5+/-17.9); DMT2 (27.2+/-12.7), p<0.001]. Among those with normo-albuminuria, urinary excretion of thiamine was significantly increased to 390.1 microg/ml and 1212.4 microg/ml in DMT1 and DMT2 respectively, as compared to controls (326.4 microg/ml). DMT1 and DMT2 patients with micro- albuminuria on the other hand had 2.5- and 3.4-fold increase in urinary excretion of thiamine compared to controls. CONCLUSION: Low levels of blood thiamine are present in patients with DMT1 and DMT2, and are associated with increased thiamine clearance.

Gender-specific associations between insulin resistance, hypertension, and markers of inflammation among adult Saudis with and without diabetes mellitus type 2.

PURPOSE: In view of the important roles of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and the acute phase reactant C-reactive protein (CRP) in glucose metabolism and pathogenesis of diabetes mellitus type 2 (DMT2), we assessed gender-specific differences and relative associations of these inflammatory biomarkers to insulin resistance (IR) and risk markers for DMT2. MATERIALS AND METHODS: Serum levels of TNF-α, IL-6 and CRP were determined in 119 clinically diagnosed DMT2 cases, 114 non-DMT2 subjects with IR, and 97 age-matched controls. Fasting blood samples were collected and serum glucose levels, lipid profile, and inflammatory markers were analyzed. RESULTS: In women, a significant association between elevated levels of IL-6 and risk of developing IR [Odds ratio (OR), 4.389, 95 % Confidence Interval (CI) 1.6-11.52, p = 0.004] was found. Significant associations were also found between elevated levels of CRP and risk of hypertension only in female subjects [OR (95% CI) 2.153 (1.04-4.53), p = 0.046]. While, in male subjects, a significant association between elevated levels of TNF-α and risk of developing IR [OR (95% CI) 2.32 (1.09-4.93), p = 0.029] was found. CONCLUSION: The present study showed apparent gender differences in the association of IL-6, CRP, and TNF-a with risks of IR and hypertension, and this could be attributed to sexual dimorphism in fat distribution.

Bioequivalence of Jusline following subcutaneous administration in healthy subjects.

OBJECTIVE: The aim of the current work is to evaluate the pharmacokinetic and pharmacodynamic profile of a new human insulin preparation (jusline) following subcutaneous administration in healthy subjects, and to compare this profile with Humulin insulin. METHODS: 20 healthy male subjects received a single dose of 0.2 U/kg of test (Jusline) or reference insulin (Humulin) during an euglycemic clamp keeping blood sugar constant (90 +/- 5 mg/dl) by changing the glucose infusion rate. Pharmacokinetic and pharmacodynamic measurements were taken from blood measurements of glucose, insulin, and C-peptide levels for tested insulin formulations. RESULTS: The mean values of the individual AUC ratios were well within the 90% confidence interval (100.5% for Regular, 101.9% for NPH, and 100.0% for Premixed Regular/NPH (30/70)). Similarly, Cmax and tmax were within the bioequivalence limit (80 - 125%). The maximum GIR were 10.20 mg/kg/min and 9.72 mg/kg/min for Jusline Regular and Humulin Regular, respectively. The maximum GIR were 7.09 mg/kg/min and 7.91 mg/kg/min for Jusline NPH and Humulin NPH, respectively. The maximum GIR and tGIRmax were 6.39 mg/kg/min and 6.63 mg/kg/ min for Jusline Premixed Regular/NPH (30/70) and Humulin Premixed Regular/NPH (30/70), respectively. Both insulin products produced similar suppression of endogenous C-peptide level (-29.76% to -50.22%). CONCLUSION: The present study demonstrated that after subcutaneous administration, there are no significant differences between Jusline and Humulin to promote peripheral glucose uptake.

Fasting serum adiponectin concentration is reduced in Indo-Asian subjects and is related to HDL cholesterol.

AIMS: Adiponectin is a 30-kDa protein secreted by adipose tissue. The aim of the present study was to compare serum adiponectin in male Indo-Asian and Caucasian subjects and examine its association with fat topography and metabolic parameters. METHODS: Diabetic and non-diabetic male subjects (n = 48) were studied. A single observer carried out blood pressure and anthropometric measurements. Serum glucose, insulin, lipid profile and adiponectin (measured by RIA) were measured on a fasting sample. RESULTS: There was no statistically significant difference in serum adiponectin between diabetic and BMI-matched non-diabetic subjects. However, serum adiponectin was lower in Indo-Asians compared with BMI-matched Caucasians, [median adiponectin (interquartile range) 3.3 (2.1-3.9) vs. 4.9 (3.5-6.6) microg/ml respectively (p = 0.016)]. Univariate analysis showed serum adiponectin to be positively associated with HDL in diabetic (p = 0.039) and non-diabetic subjects (p = 0.0098). Waist circumference (p = 0.02), saggital diameter (p = 0.04) were negatively correlated with serum adiponectin in diabetic subjects. Multiple regression analysis including waist, HDL, fasting insulin, age, diabetes and ethnicity in all subjects showed HDL to be the best predictor of serum adiponectin. CONCLUSIONS: Serum adiponectin is associated with HDL cholesterol and central obesity. Caucasians have higher serum adiponectin levels compared with Indo-Asians. Further studies are needed to explore basis for the association of adiponectin with HDL cholesterol and the reason for lower levels in Indo-Asians.