For the past years, the prevalence of obesity is growing in the general population of children, as well as among diabetic patients, resulting in increased risk of cardiovascular complications. Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases in children and young adults, leading to decreased life quality and lifespan, with obesity being recognized recently as a major contributing factor to these health problems. The objective of this study was to analyze and compare the selected novel markers for metabolic complications of obesity and vascular risk factors between obese non-diabetic and obese T1DM children and young adults.

One hundred four subjects, aged between 10 and 24 years (31 with T1DM and excessive body weight, 41 with obesity without diabetes, and 32 with T1DM and normal weight), and 32 matched lean controls were included in the study. Clinical characteristics, blood pressure measurements, daily requirement for insulin, HbA1c%, plasma lipids, fetuin-A, E-selectin, and osteoprotegerin levels were compared with respect to body mass index (BMI), body mass index standard deviation score (BMI-SDS), and carotid intima-media thickness (cIMT) of common carotid arteries.

Patients with T1DM and excessive body weight compared to non-diabetic obese subjects had similar values of systolic blood pressure (125.6 ± 8.2 vs. 127.3 ± 12.9 mmHg, p = 0.515), diastolic blood pressure (78.19 ± 7.03 vs. 78.02 ± 8.01 mmHg, p = 0.918), cholesterol (175.26 ± 34.1 vs. 163.51 ± 26.08 mg/dl, p = 0.102), LDL (108.03 ± 32.55 vs. 112.22 ± 26.36 mg/dl, p = 0.548), and triglyceride levels (118.19 ± 71.20 vs. 117 ± 55.80 mg/dl, p = 0.937); all values were found to be higher compared to non-obese T1DM and healthy controls. HbA1c level and insulin resistance indices were significantly worse in T1DM obese vs. T1DM non-obese patients. Fetuin-A levels were higher among obese non-diabetic patients (p = 0.01), and E-selectin and osteoprotegerin levels were similar in both groups with obesity, but higher than in the reference group. There were no statistical differences in cIMT with T1DM with normal weight, excessive weight, and non-diabetic obese children; however, the cIMT value was higher compared to the reference group.

Novel markers of metabolic complications of obesity are similar between obese T1DM and non-diabetic subjects. Obesity in patients with T1DM results in worse metabolic control, insulin resistance, and increased risk for vascular complications.

Circulating calcification inhibitors: fetuin A (FA) and osteoprotegerin (OPG) together with soluble ligand of receptor activator of nuclear factor kappa-B (sRANKL) have been linked to vascular calcifications and arterial damage. This study aimed to evaluate relationships between FA, OPG, sRANKL, and arterial damage in children with primary hypertension (PH).

In this cross-sectional single-center study, calcification inhibitors (FA, OPG, sRANKL) levels were measured in blood samples of 60 children with PH (median age 15.8, IQR: [14.5-16.8] years) and 20 age-matched healthy volunteers. In each participant, peripheral and central blood pressure evaluation (BP) and ambulatory BP monitoring (ABPM) were performed. Arterial damage was measured using common carotid artery intima media thickness (cIMT), pulse wave velocity (PWV), augmentation index (AIx75HR), and local arterial stiffness (ECHO-tracking-ET) analysis.

Children with PH had significantly higher peripheral and central BP, BP in ABPM, thicker cIMT, higher PWV, and AIx75HR. FA was significantly lower in patients with PH compared to healthy peers without differences in OPG, sRANKL, and OPG/sRANKL and OPG/FA ratios. In children with PH, FA level correlated negatively with cIMT Z-score and ET AIx; sRANKL level correlated negatively with ABPM systolic blood pressure (SBP), SBP load, diastolic BP load, and AIx75HR; OPG/sRANKL ratio correlated positively with SBP load, while OPG/FA ratio correlated positively with ET AIx. In multivariate analysis, FA was a significant determinant of cIMT (mm) and cIMT Z-score.

This study reveals that in children with primary hypertension, arterial damage is related to lower fetuin A concentrations.

Objectives: Type 1 diabetes mellitus (T1D) has been disclosed to be associated with an elevated risk of cardiovascular disease (CVD), as well as increased risks of losing bone mass and progression of osteoporosis (OP). Osteoprotegerin (OPG), as a decoy receptor, has been demonstrated to play a critical role in bone metabolism homeostasis and vascular atherosclerotic diseases. This meta-analysis aimed to investigate the associations between OPG levels and T1D. Methods: Related literatures were searched and identified from the database of the Cochrane Library database, PubMed and EMbase inception to August 3, 2019 in English. The pooled standard mean difference (SMD) with its 95% confidence interval (CI) was calculated in using random-effect model analysis. Chi-square Q statistic and I² test were performed to evaluate and quantified the presence of heterogeneity. Results: Twelve studies with 1288 subjects (794 T1D patients and 494 healthy controls) were finally included. The incorporated results indicated that T1D patients have higher plasma/serum OPG levels than in healthy individuals (SMD = 0.64, 95% CI: 0.06, 1.22). Subgroup analyses suggested that Caucasian and glycosylated hemoglobin A1c (HbA1c) <8.5% groups showed higher OPG levels, however, there was no significant differences of OPG levels regarding subgroups of BMI ≥ or <25, children-adolescents or adults and HbA1c ≥8.5%. Conclusions: The current evidence suggested that circulating OPG levels are significantly higher in T1D than in healthy controls, and the increase of OPG levels are influenced by factors of race and HbA1c.

Type 1 diabetes (T1D) has been associated with a higher fracture risk due to alterations in bone structure and metabolism. On the other hand, the important role of the RANKL/OPG/RANK signaling axis in bone physiology is well established. The aim of this study was to evaluate the levels of receptor activator of nuclear factor kappa-B ligand (RANKL), receptor activator of nuclear factor kappa-B (RANK) and plasma osteoprotegerin (OPG) levels, in T1D youngsters and to investigate factors that could influence the OPG/RANK/RANKL signaling axis such as 25-hydroxy vitamin D [25(OH) D], parathormone (PTH) and age.

Serum RANKL, RANK, 25(OH) D, PTH levels and plasma OPG levels, were measured in 71 youngsters with T1D and 50 healthy controls matched for age and gender.

Plasma OPG levels were significantly lower (p = 0.025) in T1D patients compared to controls. Serum RANKL levels were significantly higher (p = 0.037), while no differences were observed in serum RANK levels (p = 0.946) between the two groups. Serum 25(OH) D levels found significantly decreased (p < 0.001) while serum PTH levels were significantly elevated (p < 0.001) in T1D patients than in controls.

Our results demonstrated that OPG and RANKL may be promising biomarkers for T1D patients. However, their circulating levels were associated with several factors including PTH, 25(OH) D and therefore, may represent an integrative biomarker for a variety of endocrine signaling disturbances observed in T1D.

Patients with type I diabetes mellitus (T1DM) have increased incidence of atherosclerosis and cardiovascular disease. Although these complications are unusual in children with T1DM, prevention, and early intervention could decrease morbidity and mortality. Osteoprotegerin (OPG), asymmetric dimethylarginine (ADMA), and Fetuin-A have been associated with increased cardiovascular risk (CVR). Increased OPG and ADMA, and decreased or increased Fetuin-A serum levels have been associated with increased CVR.

Because patients with T1DM have higher CVR we investigated OPG, ADMA, and Fetuin-A, in children with T1DM.

We determined the serum levels of OPG, receptor activator of nuclear factor-κB ligand (RANKL), ADMA, and Fetuin-A by enzyme-linked immunosorbent assay (ELISA) in 56 children with T1DM aged 12.1 ± 3.4 yr and in 46 normal control children, (C) aged 11.3 ± 3.0 yr.

Serum OPG levels were significantly increased in patients with T1DM (3.352 ± 0.73 pmol/L) compared with C (2.75 ± 0.67 pmol/L, p < 0.0001) but RANKL did not change. ADMA was significantly decreased in T1DM compared with C (0.68 ± 0.13 µmol/L versus 0.82 ± 0.18 µmol/L, p < 0.0001). Fetuin-A was similar in T1DM (0.551 ± 0.13 g/L) and C (0.540 ± 0.11 g/L) subjects. OPG was positively associated with glycosylated hemoglobin A1c (p < 0.001) and negatively associated with BMI (p < 0.01). ADMA and Fetuin-A were not associated with A1c and ADMA was only negatively associated with age (p < 0.05).

OPG is increased, ADMA is decreased, but RANKL and Fetuin-A are unchanged in T1DM children. Whereas increased OPG has been firmly related to increased CVR, more studies, especially longitudinal studies, are needed to delineate the role and clinical significance of decreased ADMA and if Fetuin-A has any role in T1DM.

To investigate the differences in bone turnover between diabetic patients and controls.

A systematic review and meta-analysis.

A literature search was conducted using the databases Medline at PubMed and EMBASE. The free text search terms 'diabetes mellitus' and 'bone turnover', 'sclerostin', 'RANKL', 'osteoprotegerin', 'tartrate-resistant acid' and 'TRAP' were used. Studies were eligible if they investigated bone turnover markers in patients with diabetes compared with controls. Data were extracted by two reviewers.

A total of 2881 papers were identified of which 66 studies were included. Serum levels of the bone resorption marker C-terminal cross-linked telopeptide (-0.10 ng/mL (-0.12, -0.08)) and the bone formation markers osteocalcin (-2.51 ng/mL (-3.01, -2.01)) and procollagen type 1 amino terminal propeptide (-10.80 ng/mL (-12.83, -8.77)) were all lower in patients with diabetes compared with controls. Furthermore, s-tartrate-resistant acid phosphatase was decreased in patients with type 2 diabetes (-0.31 U/L (-0.56, -0.05)) compared with controls. S-sclerostin was significantly higher in patients with type 2 diabetes (14.92 pmol/L (3.12, 26.72)) and patients with type 1 diabetes (3.24 pmol/L (1.52, 4.96)) compared with controls. Also, s-osteoprotegerin was increased among patients with diabetes compared with controls (2.67 pmol/L (0.21, 5.14)).

Markers of both bone formation and bone resorption are decreased in patients with diabetes. This suggests that diabetes mellitus is a state of low bone turnover, which in turn may lead to more fragile bone. Altered levels of sclerostin and osteoprotegerin may be responsible for this.

Osteoprotegerin has been shown to be increased in cardiovascular disorders and type 2 diabetes mellitus. Prediabetes represents a high risk condition for diabetes and diabetic complications. Therefore, we aimed to find the relationship between prediabetes and osteoprotegerin with nuclear factor-B ligand, carotid intima media thickness, and metabolic markers. A total of 54 participants with prediabetes including impaired fasting glucose (n = 21), impaired glucose tolerance (n = 8), impaired fasting glucose and impaired glucose tolerance (n = 25), and 60 healthy individuals as a control were admitted to the study. Metabolic and anthropometric parameters, insulin resistance variables, osteoprotegerin, and nuclear factor-B ligand markers, carotid intima media thickness were examined at baseline for all participants. To evaluate the effect of therapy we determined the same parameters after the end of the study. Measurements of waist circumference, body mass index, body fat percentage and levels of fasting blood glucose, fasting insulin, homeostatic model assessment of insulin resistance, triglyceride levels and hsCRP and carotid intima media thickness were significantly higher in patients with prediabetes (p < 0.05). We also found higher osteoprotegerin and lower nuclear factor-B ligand levels in patients than in controls however, the value was non-significant (p > 0.05). Patients with prediabetes were under lifestyle interventions with (group 1, n = 33) or without metformin (group 2, n = 21) therapy. Baseline anthropometric and metabolic characteristics were not found statistically different in group 1 and group 2. Mean follow up period of the patients were 7.9 ± 2.2 month (min-max: 6-12 months). After the follow up period we evaluated the same parameters and found significant differences between waist circumference, body mass index, body fat percentage, fasting insulin, homeostatic model assessment of insulin resistance, and osteoprotegerin levels (p < 0.05). However, carotid intima media thickness, and nuclear factor-B ligand levels significantly different only in the group treated with metformin (p < 0.05). We also compared the variables after the treatment period with the control group and found significantly lower levels in terms of fasting insulin, homeostatic model assessment of insulin resistance, waist circumference, body mass index, body fat percentage, carotid intima media thickness, osteoprotegerin, and nuclear factor-B ligand values (p < 0.05). Correlation analysis revealed a negative relationship between nuclear factor-B ligand and body mass index, and body fat percentage in group 1 (p = 0.05, r = -0.646, p = 0.01, r = -0.585). Therapy of prediabetes was associated with a significant decrease in osteoprotegerin and certain metabolic variables together with an increase in nuclear factor-B ligand levels particularly in patients with under metformin therapy.

The aim of this study is to investigate the circulating OPG levels in postmenopausal women with diabetes and prediabetes and explore the relationships between serum OPG and insulin resistance. A total of 271 unrelated Chinese postmenopausal women were recruited in this study. The subjects were divided into type 2 diabetes mellitus (T2DM) group (n = 93), impaired glucose regulation (IGR) (n = 90), and normal glucose regulation group (NGR) (n = 88), according to different glucose regulation categories. Serum OPG levels were measured by enzyme-linked immunosorbent assay. The serum OPG concentration in NGR group, 151.00 ± 45.72 pg/mL, was significantly lower than that in IGR group (169.28 ± 64.91 pg/mL) (p = 0.031) and T2DM group (183.20 ± 56.53 pg/mL) (p < 0.01), respectively. In multiple linear regression analysis, HOMA-IR, age, 2hPG, AST, ALP, and eGFR were found to be independent predictors of OPG. Increased serum OPG levels (OR = 1.009, p = 0.006) may be a risk factor for insulin resistance. The present study suggests that OPG might be implicated in the pathogenesis of diabetes and is a potential biomarker of insulin resistance in subjects with diabetes and prediabetes.

Simultaneous lower bone mineral density, metabolic bone markers, parathyroid hormone (PTH), magnesium, insulin-like growth factor 1 (IGF1), and higher levels of total soluble receptor activator of nuclear factor-kappa B ligand (s-RANKL), osteoprotegerin (OPG), and alkaline phosphatase (ALP) are indicative of lower osteoblast and increased osteoclast signaling in children and adolescents with type 1 diabetes mellitus, predisposing to adult osteopenia and osteoporosis.

Type 1 diabetes mellitus (T1DM) is a risk factor for reduced bone mass, disrupting several bone metabolic pathways. We aimed at identifying association patterns between bone metabolic markers, particularly OPG, s-RANKL, and bone mineral density (BMD) in T1DM children and adolescents, in order to study possible underlying pathophysiologic mechanisms of bone loss.

We evaluated 40 children and adolescents with T1DM (mean ± SD age 13.04 ± 3.53 years, T1DM duration 5.15 ± 3.33 years) and 40 healthy age- and gender-matched controls (aged12.99 ± 3.3 years). OPG, s-RANKL, osteocalcin, C-telopeptide cross-links (CTX), IGF1, electrolytes, PTH, and total 25(OH)D were measured, and total body along with lumbar spine BMD were evaluated with dual energy X-ray absorptiometry (DXA). Multivariate regression and factor analysis were performed after classic inference.

Patients had significantly lower BMD, with lower bone turnover markers, PTH, magnesium, and IGF1 than controls, indicating lower osteoblast signaling. Higher levels of total s-RANKL, OPG, and total ALP were observed in patients, with log(s-RANKL) and OPG correlation found only in controls, possibly indicating increased osteoclast signaling in patients. Coupling of bone resorption and formation was observed in both groups. Multivariate regression confirmed simultaneous lower bone turnover, IGF1, magnesium, and higher total s-RANKL, OPG, and ALP in patients, while factor analysis indicated possible activation of RANK/RANKL/OPG system in patients and its association with magnesium and IGF1. Patients with longer disease duration or worse metabolic control had lower BMD.

T1DM children and adolescents have impaired bone metabolism which seems to be multifactorial. Reduced osteoblast and increased osteoclast signaling, resulting from multiple simultaneous disturbances, could lead to reduced peak bone accrual in early adulthood, predisposing to adult osteopenia and osteoporosis.

To derive a more precise estimation of carotid intima-media thickness (CIMT) levels in patients with type 1 diabetes mellitus (T1DM) by meta-analysis.

PubMed and Embase databases were searched to identify all available studies comparing CIMT levels between T1DM group and control group. Meta-analysis was performed to compare the difference of overall mean CIMT levels between the two groups. Publication bias was evaluated by funnel plot, Begg' test and Egger' test. Meta-regression analysis was conducted to investigate the influential factors on CIMT difference. The meta-analysis was conducted by STATA 12.0 software.

A total of 1840 articles were obtained after searching databases; 47 studies were finally included in the meta-analysis. Significant heterogeneity was observed among these studies (Q = 768.75, P < 0.001, I(2) = 94.0%). Compared with the control group, the T1DM group had significantly higher CIMT levels (standardized mean difference: 1.01, 95% CI: 0.75-1.28; P < 0.001). A likely source of heterogeneity was Newcastle-Ottawa Scale (NOS) scores and sample size ratio of patents and controls. The funnel plot did not show a skewed or asymmetrical shape, and the result of Begg' test and Egger' test was P = 0.178 and P = 0.145 respectively. Accordingly, it could be assumed that publication bias was not present.

T1DM patients have significantly increased CIMT levels compared to control subjects.

The effect of C. borivilianum root on blood glucose, glycated hemoglobin (HbAIc), insulin and lipid profile levels in diabetes mellitus are not fully understood. This study therefore investigated the effect of C. borivilianum root on the above parameters and oxidative stress of the pancreas in diabetes.

C. borivilianum root aqueous extract (250 and 500 mg/kg/day) was administered to streptozotocin (STZ)-induced male diabetic rats for 28 days. Body weight, blood glucose, HbA1c, insulin, lipid profile levels and glucose homeostasis indices were determined. Histopathological changes and oxidative stress parameters i.e. lipid peroxidation (LPO) and antioxidant enzymes activity levels of the pancreas were investigated.

C. borivilianum root extract treatment to diabetic rats maintained near normal body weight, blood glucose, HbA1c, lipid profile and insulin levels with higher HOMA-β cell functioning index, number of Islets/pancreas, number of β-cells/Islets however with lower HOMA-insulin resistance (IR) index as compared to non-treated diabetic rats. Negative correlations between serum insulin and blood glucose, HbA1c, triglyceride (TG) and total cholesterol (TC) levels were observed. C. borivilianum root extract administration prevented the increase in lipid peroxidation and the decrease in activity levels of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) with mild histopathological changes in the pancreas of diabetic rats.

C. borivilianum root maintains near normal levels of these metabolites and prevented oxidative stress-induced damage to the pancreas in diabetes.