osteoprotegerin and Diabetes-Mellitus--Type-1

Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs), the bone-reabsorbing cells, and osteoblasts (OBs), and the bone-forming cells. This equilibrium is regulated by numerous cytokines, but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/β-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis, respectively. The pro-osteoblastogenic activity of the Wnt/β-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1). RANKL, sclerostin and DKKs-1 are often up-regulated in bone diseases, and they are the target of new monoclonal antibodies.. The authors performed a systematic literature search in PubMed and EMBASE to June 2018, reviewed and selected articles, based on pre-determined selection criteria.. We re-evaluated the role of RANKL, osteoprotegerin, sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases, such as type 1 diabetes mellitus (T1DM), alkaptonuria (AKU), hemophilia A, osteogenesis imperfecta (OI), 21-hydroxylase deficiency (21OH-D) and Prader-Willi syndrome (PWS). To do so, we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways have been investigated, and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed.. The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases. Furthermore, for some of them, bone damage began in childhood but only manifested with age. The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children, although further studies need to be carried out.

Topics: Adrenal Hyperplasia, Congenital; Alkaptonuria; Biomarkers; Bone Remodeling; Bone Resorption; Child; Diabetes Mellitus, Type 1; Hemophilia A; Humans; Intercellular Signaling Peptides and Proteins; Osteogenesis Imperfecta; Osteoprotegerin; Prader-Willi Syndrome; RANK Ligand; Up-Regulation; Wnt Signaling Pathway

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.

Topics: Adaptor Proteins, Signal Transducing; Biomarkers; Bone Morphogenetic Proteins; Bone Remodeling; Case-Control Studies; Collagen Type II; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Genetic Markers; Humans; Osteocalcin; Osteoprotegerin; Peptide Fragments; Procollagen; Tartrate-Resistant Acid Phosphatase

Over the last years our knowledge on the mechanisms involved in the pathogenesis of cardiovascular disease has been enriched by the discovery of new molecules emerging as novel risk factors. Osteoprotegerin (OPG) is a soluble glycoprotein, member of the tumor necrosis factor (TNF)-related superfamily, involved in bone resorption. It was first described as a key regulator of bone homeostasis and vascular calcification in mice. Clinical studies have suggested that serum OPG is associated with vascular calcification in humans. The role of OPG in the development of macroangiopathy in diabetes is not yet clear. It is possible that the increased OPG levels in diabetes reflect a compensatory response to arterial injury and that it is not involved in the pathogenesis of atherosclerosis. Whether harmful or not, determination of serum OPG levels has been suggested as a prognostic biomarker of cardiovascular disease. In addition, increased OPG levels have been reported in diabetic patients with microvascular complications. The potential of OPG administration for therapeutic reasons is challenging for future investigators. This review summarizes the current knowledge on the association between OPG and macrovascular as well microvascular complications of diabetes.

Topics: Animals; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Vascular Diseases

Among the most serious consequences of diabetes mellitus is the development of diabetic angiopathy, of which the clinical features are cardiovascular disease, retinopathy, nephropathy and neuropathy. Diabetic kidney problems affect up to one third of all patients with diabetes mellitus and are a major cause of end-stage renal failure. Although a huge number of pharmaceutical interventions are available today, diabetic angiopathy remains a leading cause of mortality and morbidity in diabetes mellitus, therefore, an urgent need exists to develop new therapeutic strategies. Recent data support the hypothesis that dysregulation of the complement system and of members of the tumor necrosis factor (TNF) superfamily may be involved in the development of diabetic vascular complications. The mannose-binding lectin pathway-an overall regulatory component of the complement system-is a particularly promising biomarker as it is directly involved in the development of diabetic angiopathy. In addition, two components of the TNF superfamily, namely TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) and osteoprotegerin, may be involved in the pathogenesis of diabetic angiopathy. Several ways of specifically manipulating the complement and TNF superfamily systems already exist, but whether or not these drugs provide new targets for intervention for late diabetic complications is still to be revealed.

Topics: Complement Activation; Complement Pathway, Mannose-Binding Lectin; Complement System Proteins; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Osteoprotegerin; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factors

Alveolar bone resorption results from the inflammatory response to periodontal pathogens. Systemic diseases that affect the host response, such as type 1 diabetes mellitus (DM1), can potentiate the severity of periodontal disease (PD) and accelerate bone resorption. However, the biological mechanisms by which DM1 modulates PD are not fully understood. The aim of this study was to determine the influence of DM1 on alveolar bone resorption and to evaluate the role of receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) in osteoclastogenesis in rats. PD was induced by means of ligature in nondiabetic and in streptozotocyn-induced DM1 rats. Morphological and morphometric analyses, stereology and osteoclast counting were performed. RANKL and OPG mRNA levels, protein content, and location were determined. PD caused alveolar bone resorption, increased the number of osteoclasts in the alveolar bone crest and also promoted changes in RANKL/OPG mRNA expression. DM1 alone showed alveolar bone destruction and an increased number of osteoclasts at the periapical and furcal regions. DM1 exacerbated these characteristics, with a greater impact on bone structure, resulting in a low OPG content and a higher RANKL/OPG ratio, which correlated with prominent osteoclastogenesis. This work demonstrates that the effects of PD and DM1 enhance bone destruction, confirms the importance of the RANKL signaling pathway in bone destruction in DM1 in animal models and suggests the existence of alternative mechanisms potentiating bone degradation in PD.

Topics: Alveolar Bone Loss; Animals; Bone Resorption; Diabetes Mellitus, Type 1; Humans; Immunohistochemistry; Male; Osteoclasts; Osteoprotegerin; Periodontal Diseases; Rats; Rats, Wistar

To investigate the relationship between the plasma osteoprotegerin (OPG) level and endothelium-dependent arterial dilation in type 1 diabetic patients.. Sandwich ELISA method was used to detect the plasma OPG levels of 22 newly diagnosed type 1 diabetic patients before and 6 months after treatment and of 28 healthy subjects. All patients were then given insulin therapy for 6 months. High resolution ultrasound was used to measure the brachial artery diameter at rest, after reactive hyperemia and after sublingual administration of glyceryltrinitrate (GTN).. The plasma OPG level of the patients before treatment was 3.09 ng/L +/- 0.70 ng/L, significantly higher than that of the healthy controls (2.07 ng/L +/- 0.75 ng/L, P < 0.001). After 6 months treatment, the OPG level of the patients decreased to 2.58 ng/L +/- 0.59 ng/L, significantly lower than that before treatment (P < 0.001). The flow-mediated endothelium-dependent arterial dilation in the patients before treatment was 3.35% +/- 0.67%, significantly lower than that of the healthy controls (5.17% +/- 0.83%, P < 0.001), and was increased to 4.27% +/- 0.63% after 6 months treatment, significantly higher than that before (P < 0.001). Multivariate analysis showed that OPG level was significantly associated with endothelium-dependent arterial dilation, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and ultra-sensitive C-reactive protein (CRP) at baseline (all P < 0.01). The absolute change in OPG level was significantly correlation with the changes in endothelium-dependent arterial dilation, FBG, HbA1c, and CRP in the diabetic patients during the course of treatment (all P < 0.01).. Plasma OPG level is elevated in newly diagnosed diabetic patients, and the plasma OPG level is significantly associated with endothelial function.

Topics: Adolescent; Adult; Blood Glucose; Brachial Artery; Child; Diabetes Mellitus, Type 1; Endothelium, Vascular; Female; Humans; Hypoglycemic Agents; Insulin; Lipids; Male; Osteoprotegerin; Time Factors; Treatment Outcome; Vasodilation

Treatment for type 1 diabetes (T1D) requires stimulation of functional β cell regeneration and survival under stress. Previously, we showed that inhibition of the RANKL/RANK [receptor activator of nuclear factor kappa Β (NF-κB) ligand] pathway, by osteoprotegerin and the anti-osteoporotic drug denosumab, induces rodent and human β cell proliferation. We demonstrate that the RANK pathway mediates cytokine-induced rodent and human β cell death through RANK-TRAF6 interaction and induction of NF-κB activation. Osteoprotegerin and denosumab protected β cells against this cytotoxicity. In human immune cells, osteoprotegerin and denosumab reduce proinflammatory cytokines in activated T-cells by inhibiting RANKL-induced activation of monocytes. In vivo, osteoprotegerin reversed recent-onset T1D in nonobese diabetic/Ltj mice, reduced insulitis, improved glucose homeostasis, and increased plasma insulin, β cell proliferation, and mass in these mice. Serum from T1D subjects induced human β cell death and dysfunction, but not α cell death. Osteoprotegerin and denosumab reduced T1D serum-induced β cell cytotoxicity and dysfunction. Inhibiting RANKL/RANK could have therapeutic potential.

Topics: Animals; Cell Death; Cytokines; Denosumab; Diabetes Mellitus, Type 1; Humans; Mice; NF-kappa B; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Rodentia

Diabetic osteoporosis (DOP) belongs to secondary osteoporosis caused by diabetes; it has the characteristics of high morbidity and high disability. In the present study, we constructed a type 1 diabetic rat model and administered chondroitin sulfate (200 mg/kg) for 10 weeks to observe the preventive effect of chondroitin sulfate on the bone loss of diabetic rats. The results showed that chondroitin sulfate can reduce blood glucose and relieve symptoms of diabetic rats; in addition, it can significantly increase the bone mineral density, improve bone microstructure, and reduce bone marrow adipocyte number in diabetic rats; after 10 weeks of chondroitin sulfate administration, the SOD activity level was upregulated, as well as CAT levels, indicating that chondroitin sulfate can alleviate oxidative stress in diabetic rats. Chondroitin sulfate was also found to reduce the level of serum inflammatory cytokines (TNF-α, IL-1, IL-6, and MCP-1) and alleviate the inflammation in diabetic rats; bone metabolism marker detection results showed that chondroitin sulfate can reduce bone turnover in diabetic rats (decreased RANKL, CTX-1, ALP, and TRACP 5b levels were observed after 10 weeks of chondroitin sulfate administration). At the same time, the bone OPG and RUNX 2 expression levels were higher after chondroitin sulfate treatment, the bone RANKL expression was lowered, and the OPG/RANKL ratio was upregulated. All of the above indicated that chondroitin sulfate could prevent STZ-induced DOP and repair bone microstructure; the main mechanism was through anti-oxidation, anti-inflammatory, and regulating bone metabolism. Chondroitin sulfate could be used to develop anti-DOP functional foods and diet interventions for diabetes.

Topics: Animals; Blood Glucose; Bone and Bones; Bone Density; Bone Marrow; Bone Remodeling; Chondroitin Sulfates; Cytokines; Diabetes Mellitus, Type 1; Drug Evaluation, Preclinical; Lipogenesis; Male; Osteoporosis; Osteoprotegerin; Oxidative Stress; RANK Ligand; Rats; X-Ray Microtomography

To compare advanced glycation end-products (AGE, RAGE) and 3-nitrotyrosine (3-HT) in patients with DM 1 after successful simultaneous pancreas-kidney transplantation (SPK) and kidney transplantation alone (KTA). To assess relationship between levels of AGE, RAGE, 3-HT and renal transplant (RT) function, carbohydrate and mineral metabolism.. The study included 58 patients who received kidney transplantation in end-stage renal disease (ESRD). 36 patients received SPK. There were performed routine laboratory, examination of AGE, RAGE, 3-NT, parathyroid hormone (PTH), 25(OH)vitamin D, calcium, phosphorus, FGF23, osteoprotegerin (OPG), and fetuin-A levels.. All patients after SPK reached normoglycemia (HbA1c 5.7 [5.3; 6.1] %; C-peptide 3.24 [2.29; 4.40] ng/ml) with the achievement of significant difference vs patients after KTA. Arterial hypertension (AH) was more frequent in recipients of SPK before transplantation than after (p=0.008). AH also persisted in greater number of cases in patients after KTA than after SPK. Patients after SPK had higher AGE (р=0.0003) and lower RAGE (р=0.000003) levels. OPG in patients after SPK was significantly higher (р=0.04). The correlation analysis revealed significant positive correlation between 3-HT and OPG (p0.05; r=0.30), RAGE and eGFR (r=-0.52), HbA1c (r=0.48), duration of AH (r=0.34), AGE with HbA1c (r=0.51).. The results of the "metabolic memory" markers analysis may indicate their contribution to the persistence of the metabolic consequences of CKD and DM 1 after achievement of normoglycemia and renal function restoration and their possible participation in development of recurrent nephropathy, vascular calcification, and bone disorders.. Цель. Сравнить состояние конечных продуктов гликирования (AGE, RAGE) и 3-нитротирозина (3-НТ) у пациентов с сахарным диабетом 1-го типа после успешной сочетанной трансплантации почки и поджелудочной железы (СТПиПЖ), изолированной трансплантации почки (ИТП). Оценить взаимосвязь уровней AGE, RAGE, 3-НТ с функцией ренального трансплантата, состоянием углеводного и минерального обмена. Материалы и методы. В исследование включили 58 пациентов после трансплантации почки по поводу терминальной стадии хронической болезни почек (36 реципиентов после СТПиПЖ). Всем больным проводились клинико-лабораторное обследование, определение уровней AGE, RAGE, 3-НТ, паратгормона, 25(ОН)витамина D, FGF23, остеопротегерина (ОПГ) и фетуина А. Результаты. У пациентов после СТПиПЖ наблюдалась нормогликемия (гликированный гемоглобин HbA1c 5,7 [5,3; 6,1] %; С-пептид 3,24 [2,29; 4,40] нг/мл) с достижением значимой разницы при сравнении с больными после ИТП. Артериальная гипертензия (АГ) значимо чаще наблюдалась у реципиентов СТПиПЖ до трансплантации, чем после (р=0,008), у больных после ИТП АГ также сохранялась чаще, чем у пациентов после СТПиПЖ. Соответственно, больные после СТПиПЖ гораздо реже нуждались в антигипертензивной терапии (р=0,001). Уровень AGE был значимо выше (р=0,0003), RAGE значимо ниже (р=0,000003) у пациентов после СТПиПЖ, ОПГ значимо больше у реципиентов СТПиПЖ (р=0,04). Обнаружена положительная корреляция 3-НТ с ОПГ (p0,05; r=0,30), RAGE с расчетной скоростью клубочковой фильтрации (r=-0,52), HbA1c (r=0,48), длительностью АГ (r=0,34), AGE с HbA1c (r=0,51). Заключение. Результаты анализа маркеров метаболической памяти могут отражать их вклад в персистенцию метаболических последствий хронической болезни почек и сахарного диабета 1-го типа после достижения нормогликемии и восстановления почечной функции после СТПиПЖ, участие в развитии возвратной нефропатии, сосудистой кальцификации и костных нарушений.

Topics: alpha-2-HS-Glycoprotein; C-Peptide; Calcium; Diabetes Mellitus, Type 1; Glycated Hemoglobin; Glycation End Products, Advanced; Graft Survival; Humans; Kidney Transplantation; Minerals; Osteoprotegerin; Oxidative Stress; Pancreas; Pancreas Transplantation; Parathyroid Hormone; Phosphorus; Vitamin D

Type 1 diabetes (T1D) may be associated with numerous complications including bone metabolism disorders. The aim of the study was to evaluate the bone metabolism markers twice in children with a newly diagnosed T1D and after an average of seven months of its duration in relation to parameters of the clinical course of diabetes.. In 100 T1D patients and 52 control subjects, the following bone turnover markers were evaluated: osteocalcin - OC, osteoprotegerin - OPG, sRANKL, and deoxypyridoline in urine - DPD and DXA examination was also performed.. Lower OC concentration at T1D onset in comparison to controls (p < 0.001) and its increase during follow-up (p < 0.001) was ob-served. The OPG concentration was elevated at T1D onset as compared to the control group (p = 0.024) and decreased thereafter (p < 0.001). The s-RANKL level increased during follow-up (p < 0.001) and was lower than in controls (p < 0.001). Urine DPD con-centration also increased during follow-up in the T1D patient group (p < 0.001) and was higher in comparison to the control group (p = 0.021). BMD-TBLH was higher in the control group as compared to patients both at T1D onset (p = 0.025) and in follow-up ob-servation (p = 0.034). Moreover, OPG correlated positively with glycated haemoglobin (HbA1c) (p = 0.004) and negatively with fasting C-peptide level (p = 0.046) and BMI Z-score (p = 0.003), whereas s-RANKL correlated positively with both fasting (p < 0.001) and stimulated C-peptide levels (p < 0.001).. Bone metabolism disorders observed at T1D onset in children and modified after reaching the metabolic control of the disease seem to be most strongly associated with preserved insulin secretion.. Cukrzyca typu 1 (type 1 diabetes – T1D) może być związana z licznymi powikłaniami, w tym zaburzeniami metabolizmu kostnego.. była dwukrotna ocena markerów metabolizmu kostnego u dzieci z nowo rozpoznaną T1D i po 7 miesiącach jej trwania w odniesieniu do parametrów przebiegu klinicznego cukrzycy.. U 100 chorych na T1D i 52 osób z grupy kontrolnej oceniano następujące markery obrotu kostnego: osteokalcynę – OC, osteoprotege-rynę – OPG, sRANKL i deoksypirydolinę w moczu – DPD, oraz wykonano badanie DXA.. Stwierdzono mniejsze stężenie OC w momencie wystąpienia T1D w porównaniu z grupą kontrolną (p < 0,001) oraz jego zwiększenie w trakcie obserwacji (p < 0,001). Stężenie OPG było większe u pacjentów w momencie wystąpienia T1D w porównaniu z grupą kon-trolną (p = 0,024), a następnie ulegało zmniejszeniu (p < 0,001). Stężenie s-RANKL zwiększało się u pacjentów z T1D w czasie obser-wacji (p < 0,001) i było mniejsze niż w grupie kontrolnej (p < 0,001). Stężenie DPD w moczu również się zwiększało podczas obser-wacji w grupie pacjentów z T1D (p < 0,001) i było większe w porównaniu z grupą kontrolną (p = 0,021). BMD-TBLH był wyższy w grupie kontrolnej w porównaniu z pacjentami, zarówno w momencie wystąpienia T1D (p = 0,025), jak i w dalszej obserwacji (p = 0,034). Ponadto OPG korelowało dodatnio z HbA1c (p = 0,004) i ujemnie ze stężeniem peptydu C na czczo (p = 0,046) i BMI Z-score (p = 0,003), natomiast s-RANKL korelowało dodatnio ze stężeniem peptydu C zarówno na czczo (p < 0,001), jak i po stymulacji (p < 0,001).. Zaburzenia metabolizmu kostnego obserwowane w momencie wystąpienia T1D u dzieci i ulegające modyfikacji po osiągnięciu kontroli metabolicznej choroby wydają się najsilniej związane z przetrwałą insulinosekrecją.

Topics: Adolescent; Bone Density; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Humans; Insulin Secretion; Male; Osteocalcin; Osteoprotegerin; RANK Ligand

We aimed to analyse the association between plasma circulating microRNAs (miRNAs) and the immunometabolic profile in children with type 1 diabetes and to identify a composite signature of miRNAs/immunometabolic factors able to predict type 1 diabetes progression.. Plasma samples were obtained from children at diagnosis of type 1 diabetes (n = 88) and at 12 (n = 32) and 24 (n = 30) months after disease onset and from healthy control children with similar sex and age distribution (n = 47). We quantified 60 robustly expressed plasma circulating miRNAs by quantitative RT-PCR and nine plasma immunometabolic factors with a recognised role at the interface of metabolic and immune alterations in type 1 diabetes. Based on fasting C-peptide loss over time, children with type 1 diabetes were stratified into the following groups: those who had lost >90% of C-peptide compared with diagnosis level; those who had lost <10% of C-peptide; those showing an intermediate C-peptide loss. To evaluate the modulation of plasma circulating miRNAs during the course of type 1 diabetes, logistic regression models were implemented and the correlation between miRNAs and immunometabolic factors was also assessed. Results were then validated in an independent cohort of children with recent-onset type 1 diabetes (n = 18). The prognostic value of the identified plasma signature was tested by a neural network-based model.. Plasma circulating miR-23~27~24 clusters (miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27a-3p and miR-27b-3p) were upmodulated upon type 1 diabetes progression, showed positive correlation with osteoprotegerin (OPG) and were negatively correlated with soluble CD40 ligand, resistin, myeloperoxidase and soluble TNF receptor in children with type 1 diabetes but not in healthy children. The combination of plasma circulating miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27b-3p and OPG, quantified at disease onset, showed a significant capability to predict the decline in insulin secretion 12 months after disease diagnosis in two independent cohorts of children with type 1 diabetes.. We have pinpointed a novel miR-23a-3p/miR-23b-3p/miR-24-3p/miR-27b-3p/OPG plasma signature that may be developed into a novel blood-based method to better stratify patients with type 1 diabetes and predict C-peptide loss.

Topics: C-Peptide; Diabetes Complications; Diabetes Mellitus, Type 1; Humans; MicroRNAs; Osteoprotegerin

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.

Topics: Adolescent; Biomarkers; Case-Control Studies; Child; Child, Preschool; Diabetes Mellitus, Type 1; Disease Progression; Female; Humans; Male; Osteoprotegerin; Parathyroid Hormone; Prognosis; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Reference Values; Vitamin D

Background Although carotid intima media thickness (CIMT) is an established marker of endothelial dysfunction, limited data exist on relative laboratory biomarkers in youngsters with type 1 diabetes mellitus (T1DM). Our aim was to study CIMT and the biomarkers of the osteoprotegerin (OPG)/RANKL system in young T1DM patients and controls, and also in subgroups of patients with increased risk for endothelial dysfunction, such as those with overweight/obesity, poor metabolic control or the presence of microalbuminuria. Methods CIMT and OPG/RANKL of 56 T1DM children and adolescents were compared to 28 healthy controls. Results Anthropometric, laboratory, CIMT and OPG/RANKL measurements were similar between patients and controls. Overweight/obese patients had greater CIMT than the normal weight ones (0.50 vs. 0.44 mm, p=0.001). Microalbuminuric patients had greater CIMT (0.49 vs. 0.44 mm, p=0.035) than the normoalbuminuric ones, with no difference in terms of OPG/RANKL. In the microalbuminuric group, OPG (r=-0.90, p=0.036) and RANKL (r=-0.92, p=0.024) were significantly negatively associated with CIMT. Following linear regression analysis, in the total patients group, microalbuminuria was the only factor significantly associated with CIMT (beta±SE: 0.050±0.021, p=0.035), body mass index (BMI)-z-scores were negatively associated with OPG (beta±SE: -0.25±0.12, p=0.05), while in the microalbuminuric group, CIMT was negatively associated with OPG (beta±SE: -0.070±0.019, p=0.036). During the forward stepwise procedure, microalbuminuria and age were the only variables negatively associated with RANKL (b=-0.334, p=0.034, b=-35.95, p=0.013, respectively). Conclusions In T1DM pediatric patients, overweight/obesity and microalbuminuria were associated with greater CIMT and with impaired OPG/RANKL levels, as biochemical indices of calcification of the atherosclerotic plaque.

Topics: Adolescent; Biomarkers; Blood Glucose; Body Mass Index; Carotid Intima-Media Thickness; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Endothelium, Vascular; Female; Humans; Male; Osteoprotegerin; Overweight; RANK Ligand; Ultrasonography

Type 1 diabetes mellitus (T1DM) and estrogen deficiency are associated with several alterations in bone turnover. Zinc (Zn) is required for growth, development, and overall health. Zinc has been used in complementary therapy against bone loss in several diseases. We hypothesized that Zn supplementation represents a potential therapy against severe bone loss induced by the combined effect of estrogen deficiency and T1DM. We evaluated the protective effect of Zn against bone alterations in a chronic model of these disorders. Female Wistar rats were ramdomized into 3 groups (5 rats each): control, OVX/T1DM (ovariectomized rats with streptozotocin-induced T1DM), and OVX/T1DM+Zn (OVX/T1DM plus daily Zn supplementation). Serum biochemical, bone histomorphometric, and molecular analyses were performed. Histomorphometric parameters were similar between the control and OVX/T1DM+Zn groups, suggesting that Zn prevents bone architecture alterations. In contrast, the OVX/T1DM group showed significantly lower trabecular width and bone area as well as greater trabecular separation than the control. The OVX/T1DM and OVX/T1DM+Zn groups had significantly higher serum alkaline phosphatase activity than the control. The supplemented group had higher levels of serum-ionized calcium and phosphorus than the nonsupplemented group. The RANKL/OPG ratio was similar between the control and OVX/T1DM+Zn groups, whereas it was higher in the OVX/T1DM group. In conclusion, Zn supplementation prevents bone alteration in chronic OVX/T1DM rats, as demonstrated by the reduced RANKL/OPG ratio and preservation of bone architecture. The findings may represent a novel therapeutic approach to preventing OVX/T1DM-induced bone alterations.

Topics: Alkaline Phosphatase; Animals; Blood Glucose; Bone and Bones; Bone Density; Calcium; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dietary Supplements; Female; Osteoprotegerin; Ovariectomy; Phosphorus; RANK Ligand; Rats; Rats, Wistar; Zinc

Osteoprotegerin (OPG) is an arterial calcification marker which has been associated with vascular damage. Elevated OPG concentrations associated with low-grade inflammatory processes are found in diabetic subjects.. The aim of the study was to assess concentrations of OPG in relation to the presence of diabetic complications in patients with diabetes type 1 (DM 1) participating in the Poznań Prospective Study (PoProStu).. The study included 74 patients with DM1 (48 men) with a median age of 39 years (interquartile range [IQR]: 34-43) and a median 15-year history (IQR: 14-16) of diabetes, who were participants in the PoProStu. Serum OPG concentration was measured using the ELISA method, and serum concentration of C-reactive protein was measured with a high sensitivity test (hsCRP). The visceral adipose index (VAI) was used to determine indirect markers of insulin resistance (IR). The prevalence of microangiopathic diabetes complications was assessed.. Retinopathy was diagnosed in 28 patients (38%), diabetic kidney disease (DKD) in 28 (38%) patients, and neuropathy in 17 (23%) patients. The median OPG level was 43.8 (28.0-74.0) pg/mL. Patients with retinopathy had higher levels of OPG than those without retinopathy: 47.5 (35.0-88.0) vs 35.4 (24.7-69.4) pg/mL (p = 0.04). Positive correlations were observed between OPG concentration and hsCRP (Rs = 0.53; p < 0.001), HbA1c level (Rs = 0.36; p = 0.002), VAI (Rs = 0.23; p = 0.04) and waist circumference (Rs = 0.24; p = 0.04).. Higher concentrations of osteoprotegerin in DM1 patients are related to the presence of retinopathy. The study results indicate that OPG might play a role in the pathogenesis of vascular complications in association with hyperglycemia and low-grade inflammatory processes.

Topics: Adult; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Retinopathy; Female; Glycated Hemoglobin; Humans; Logistic Models; Male; Osteoprotegerin; Prospective Studies

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.

Topics: Adolescent; alpha-2-HS-Glycoprotein; Arginine; Biomarkers; Cardiovascular Diseases; Child; Cohort Studies; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Cardiomyopathies; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Greece; Humans; Male; Osteoprotegerin; RANK Ligand; Reproducibility of Results

Elevated osteoprotegerin (OPG) levels have been reported in patients with diabetes complications. We investigated whether plasma OPG levels can be used as a marker of cardiovascular risk in children and adolescents with type 1 diabetes (T1D).. Plasma blood samples were obtained from 243 subjects (143 children and adolescents with T1D and 100 healthy controls). OPG concentrations were measured by enzyme-linked immunosorbent assay (ELISA) method. All data were analyzed by using PASW statistics 18.. A significant higher plasma OPG level was found in children with T1D compared to controls (p < 0.001). A significant increase of OPG levels has been related to the glucose level ≥ 7 mmol/L (2.44 [0.01-6.22] vs. 2.16 [0.13-6.22] pmol/L, p = 0.019), microalbuminuria ≥ 30 mg/24 h (3.71 [0.160-6.03] vs. 2.26 [0.01-6.22] pmol/L, p < 0.001), and cystatin-C ≥ 0.789 mg/L (2.64 [0.37-6.22] vs. 2.11 [0.01-5.82] pmol/L, p < 0.001). We noted a significant higher frequency of children with increased cystatin-C levels in the group with elevated plasma level of OPG compared with those with normal levels (49 vs. 18%, respectively) with an odds ratio (OR) = 4.42 [1.41-13.84] (p = 0.006). We showed a significant increase of OPG levels when the number of cardiovascular risk factors exceeds 3 (p = 0.001).. OPG may be a potential biomarker of cardiovascular risk in T1D. Implementation of OPG determination in the clinical laboratory setting would be useful in order to better stratify patients and to assess the most adequate treatment.

Topics: Adolescent; Biomarkers; Blood Glucose; Cardiovascular Diseases; Case-Control Studies; Child; Child, Preschool; Comorbidity; Cystatin C; Diabetes Mellitus, Type 1; Enzyme-Linked Immunosorbent Assay; Female; Glycated Hemoglobin; Humans; Male; Osteoprotegerin; Reproducibility of Results; Risk Factors; Tunisia; Up-Regulation

Type 1 diabetes is associated with osteopenia and increased fragility fractures, attributed to reduced bone formation. However, the molecular mechanisms mediating these effects remain unknown. Insulin promotes osteoblast formation and inhibits the activity of the FoxO transcription factors. FoxOs, on the other hand, inhibit osteoprogenitor proliferation and bone formation. Here, we investigated whether FoxOs play a role in the low bone mass associated with type 1 diabetes, using mice lacking FoxO1, 3, and 4 in osteoprogenitor cells (FoxO1,3,4

Topics: Animals; Bone Resorption; Cancellous Bone; Cell Lineage; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; Femur; Forkhead Transcription Factors; Gene Deletion; Glucose; Integrases; Male; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Osteoblasts; Osteoprotegerin; Stem Cells; X-Ray Microtomography

Type 1 diabetes mellitus (T1DM) is associated with several skeletal alterations, particularly in conditions of poor glycaemic control. Insulin therapy is the major conservative treatment for T1DM; however, the effects of this hormone on bone markers of T1DM rats are limited, and the regulatory mechanisms remain elusive. Therefore, the evaluation of molecular and non-molecular parameters in a chronic animal model of T1DM-induced bone loss, treated with and without insulin, may help in elucidating the insulin mechanisms. Male Wistar rats were assigned into three groups: control, T1DM (T1DM rats induced with streptozotocin [STZ] at 40 mg/kg intravenously) and T1DM plus insulin therapy (T1DMI). After 8 weeks, we evaluated the serum biochemical, tibia histomorphometric and biomechanical parameters, as well as the gene expression of the receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG) and osteocalcin (OC) of femur mRNA. Compared with T1DM, the T1DMI group showed less bone loss, which was revealed by the increased trabecular width (TbWi, p < 0.001) and trabecular bone area (BAr, p < 0.01), reduced trabecular separation (TbSp, p < 0.01) and increased Young's modulus (p < 0.05). Moreover, molecular analyses indicated that the expression of OPG and OC was up-regulated (p < 0.001 and p < 0.05, respectively). In summary, the up-regulation of OPG and OC in the T1DMI group supports an anabolic effect of insulin, which was demonstrated by the maintenance of bone architecture and flexibility. These results suggest that insulin therapy may prevent T1DM-induced bone loss via the effects on the bone formation.

Topics: Anabolic Agents; Animals; Bone Density; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Femur; Insulin; Male; Osteocalcin; Osteoprotegerin; RANK Ligand; Rats; Rats, Wistar; RNA, Messenger; Tibia; Up-Regulation

Diabetes mellitus is associated with an increased fracture risk, however the fracture risk is 7 fold increased in patients with type 1 diabetes (T1D) and 1.4 fold increased in patients with type 2 diabetes (T2D) with decreased and increased bone mineral density, respectively. Oral ingestion of glucose causes an acute decrease in bone turnover markers, and thus glucose levels may affect bone turnover in diabetes.. The aim was to examine disparities in bone turnover markers between patients with T1D and T2D and evaluate the effect of glucose on bone turnover.. A cross-sectional study was conducted. Patients diagnosed with T1D (n=98) or T2D (n=96) were included from the outpatient clinics at two University Hospitals. All individuals had normal renal function. Glucose and bone turnover markers were measured in non-fasting blood samples.. P-procollagen type 1 amino terminal propeptide (P1NP), p-osteocalcin (OC), and s-Receptor Activator of Nuclear factor Kappa beta Ligand (RANKL) were lower in patients with T2D compared to T1D, and s-osteoprotegerin (OPG) was higher in T2D. P-C-terminal cross-linked telopeptide of type-I collagen (CTX), p-fibroblast growth factor-23 (FGF-23), p-sclerostin, and p-undercarboxylated osteocalcin (ucOC) were similar in between the two groups of patients. Increasing non-fasting glucose levels were inversely related to p-CTX, p-P1NP, p-OC, and p-ucOC and directly related to s-OPG in simple linear and multiple linear regressions adjusted for factors influencing bone turnover markers including HbA1c.. Bone turnover markers were lower in patients with T2D compared to T1D. Acute blood glucose alterations may change bone turnover mediated by OPG and have detrimental effects on bone health in diabetes.. ClinicalTrials.govNCT01870557.

Topics: Aged; Biomarkers; Blood Glucose; Bone and Bones; Bone Remodeling; Collagen Type I; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fasting; Female; Fibroblast Growth Factor-23; Glycated Hemoglobin; Humans; Linear Models; Male; Middle Aged; Osteocalcin; Osteoprotegerin; Peptide Fragments; Peptides; Procollagen

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.

Topics: Absorptiometry, Photon; Adolescent; Biomarkers; Bone Density; Bone Diseases, Metabolic; Bone Remodeling; Case-Control Studies; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Lumbar Vertebrae; Male; Osteoclasts; Osteoporosis; Osteoprotegerin; RANK Ligand; Signal Transduction

It is known that type 1 diabetes (T1D) reduces bone mass and increases the risk for fragility fractures, an effect that has been largely ascribed to decreased bone formation. However, the potential role of decreased angiogenesis as a factor in osteogenesis reduction has not been extensively studied. Furthermore, there is controversy surrounding the effect of T1D on bone resorption. This study characterized bone microstructure, bone strength, and bone turnover of streptozotocin (STZ)-induced diabetic mice (T1D mice) and explored the role of angiogenesis in the pathogenesis of T1D-induced osteoporosis. Results demonstrate that T1D deteriorated trabecular microarchitecture and led to reduced bone strength. Furthermore, T1D mice showed reduced osteoblast number/bone surface (N.Ob/BS), mineral apposition rate, mineral surface/BS, and bone formation rate/BS, suggesting attenuated bone formation. Decreased angiogenesis was shown by a reduced number of blood vessels in the femur and decreased expression of platelet endothelial cell adhesion molecule (CD31), nerve growth factor, hypoxia-inducible factor-1α, and vascular endothelial growth factor was observed. On the other hand, reduced bone resorption, an effect that could lead to impaired osteogenesis, was demonstrated by lower osteoclast number/BS and decreased tartrate-resistant acid phosphatase and cathepsin K mRNA levels. Reduced number of osteoblasts and decreased expression of receptor activator for nuclear factor-κB ligand could be responsible for compromised bone resorption in T1D mice. In conclusion, T1D mice display reduced bone formation and bone resorption, suggesting decreased bone turnover. Furthermore, this study points to impairments in angiogenesis as a pivotal cause of decreased bone formation.

Topics: Angiogenesis Inducing Agents; Animals; Blood Vessels; Bone Density; Bone Remodeling; Bone Resorption; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Female; Femur; Immunohistochemistry; Mice, Inbred C57BL; Neovascularization, Physiologic; Osteogenesis; Osteoporosis; Osteoprotegerin; RANK Ligand; Real-Time Polymerase Chain Reaction; Reproducibility of Results; Streptozocin

Several studies have established an association between diabetes and alterations in bone metabolism; however, the underlying mechanism is not well established. Although zinc is recognized as a potential preventive agent against diabetes-induced bone loss, there is no evidence demonstrating its effect in chronic diabetic conditions. This study evaluated the effects of zinc supplementation in a chronic (90 days) type 1 diabetes-induced bone-loss model. Male Wistar rats were distributed in three groups: control, type 1 diabetes mellitus (T1DM), and T1DM plus zinc supplementation (T1DMS). Serum biochemical analysis; tibia histomorphometric, biomechanical, and collagen-content analyses; and femur mRNA expression were evaluated. Relative to T1DM, the zinc-supplemented group showed increased histomorphometric parameters such as TbWi and BAr and decreased TbSp, increased biomechanical parameters (maximum load, stiffness, ultimate strain, and Young's modulus), and increased type I collagen content. Interestingly, similar values for these parameters were observed between the T1DMS and control groups. These results demonstrate the protective effect of zinc on the maintenance of bone strength and flexibility. In addition, downregulation of OPG, COL1A, and MMP-9 genes was observed in T1DMS, and the anabolic effects of zinc were evidenced by increased OC expression and serum ALP activity, both related to osteoblastogenesis, demonstrating a positive effect on bone formation. In contrast, T1DM showed excessive bone loss, observed through reduced histomorphometric and biomechanical parameters, characterizing diabetes-associated bone loss. The bone loss was also observed through upregulation of OPG, COL1A, and MMP-9 genes. In conclusion, zinc showed a positive effect on the maintenance of bone architecture and biomechanical parameters. Indeed, OC upregulation and control of expression of OPG, COL1A, and MMP-9 mRNAs, even in chronic hyperglycemia, support an anabolic and protective effect of zinc under chronic diabetic conditions. Furthermore, these results indicate that zinc supplementation could act as a complementary therapy in chronic T1DM.

Topics: Animals; Biomechanical Phenomena; Bone Density; Bone Resorption; Collagen Type I; Collagen Type I, alpha 1 Chain; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dietary Supplements; Elastic Modulus; Femur; Gene Expression Regulation; Humans; Male; Matrix Metalloproteinase 9; Osteocalcin; Osteoprotegerin; Rats; Rats, Wistar; RNA, Messenger; Streptozocin; Tibia; Zinc

Diabetes mellitus comprises a heterogeneous group of disorders with the main feature of hyperglycemia. Chronic hyperglycemia increases the severity of periodontal disease via an exacerbated inflammatory response, activated by advanced glycation end products and their receptor, RAGE. Therefore, anti-inflammatory agents represent potential inhibitors of this pathological interaction. In particular, green tea has been shown to possess anti-inflammatory properties mediated by its polyphenol content.. This study investigated the mechanisms by which green tea attenuates the spontaneous onset of diabetes-induced periodontitis.. Diabetes was induced in rats via a single intraperitoneal injection of streptozotocin (STZ). Diabetic and control animals were divided into water-treated and green tea-treated subgroups and were analyzed at 15, 30, 60 and 90 days after diabetes induction. Immunohistochemistry was performed to quantitatively evaluate tumor necrosis factor-α (TNF-α), receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin (OPG), interleukin-10 (IL-10) and runt-related transcription factor 2 (RUNX-2) expression in serial sections of each hemimaxilla. Morphometric measurements of the distance from the cementum-enamel junction (CEJ) of the superior distal root of the first molar to the alveolar bone crest (ABC) were performed to assess bone loss.. Diabetes resulted in significant bone loss and alterations in the number of cells that stained positive for inflammatory mediators. In the diabetic rats treated with green tea, we observed a decreased number of cells expressing RANKL and TNF-α compared with that observed in the diabetic rats treated with water. Additionally, green tea increased the numbers of cells that stained positive for OPG, RUNX-2 and IL-10 in the diabetic rats.. Green tea intake reduces expression of the pro-inflammatory cytokine TNF-α and the osteoclastogenic mediator RANKL to normal levels while increasing expression of the anti-inflammatory cytokine IL-10, the osteogenesis-related factor RUNX-2 and the anti-osteoclastogenic factor OPG. Therefore, green tea represents a potential therapeutic agent for the treatment of diabetes-related periodontal disease.

Topics: Animals; Core Binding Factor Alpha 1 Subunit; Cytokines; Diabetes Mellitus, Type 1; Gene Expression Regulation; Male; Osteoprotegerin; Periodontium; Rats; Rats, Wistar; Tea

The aim of this study was to investigate the availability of osteoprotegerin (OPG) as a marker of atherosclerosis and compare serum OPG levels with ankle-brachial index (ABI) in diabetic patients.. A total of 31 type 1 and 31 type 2 diabetic patients without macrovascular complications and 20 healthy volunteers were included. Serum OPG levels and ABI were measured.. The duration of diabetes was significantly higher in type 1 diabetics than in type 2, although there was no significant difference between mean HbA1c levels. There was a weak and inverse correlation between OPG and atherosclerosis in type 1 diabetics only (P = 0.046, r = -0.360). There was a weak, positive correlation between ABI and HbA1c in all participant groups (P = 0.047, r = 0.220), and a weak-medium correlation in type 2 diabetics (P = 0.021, r = 0.414). After the adjustment of OPG levels to atherosclerosis risk factors, only the age factor was found to be effective on OPG.. The inverse correlation of serum OPG with atherosclerosis in type 1 diabetics suggests that atherosclerosis may be related to increased duration of diabetes. Since the study participants did not show macrovascular complications, future prospective studies on the development of diabetic complications and correlation with OPG might give further information about the availability of OPG as a marker of atherosclerosis.

Topics: Adult; Age Factors; Ankle Brachial Index; Atherosclerosis; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Osteoprotegerin

To investigate early alterations on bone mineral density (BMD) and RANK, RANKL and OPG mRNA expression in peripheral blood leukocytes (PBL) in children and adolescents with type 1 diabetes (T1D) and the relationship with glycemic control and bone biomarkers.. This cross-sectional study included 75 children and adolescents with T1D and 100 individuals without diabetes (normoglycemic-NG) aged 6-20 years old. T1D individuals were considered to have good (T1DG) or poor (T1DP) glycemic control according to the values of HbA1c. Phosphorus, magnesium, total and ionized calcium, osteocalcin, alkaline phosphatase and tartaric-resistant acid phosphatase (TRAP) values were determined in blood samples. BMD was measured by DEXA. RANK, RANKL and OPG mRNA expression was measured in PBL by real-time PCR.. Osteocalcin values were decreased in diabetic groups in comparison to NG group (p<0.05), and a negative correlation with both serum glucose (r=-0.265, p<0.01) and Hb1Ac (r=-0.252, p<0.01) in T1D group was found. BMD was lower in diabetic groups in comparison with NG group (p<0.05) and a negative correlation was observed between BMD and both serum glucose (r=-0.357, p<0.01) and HbA1c (r=-0.351, p<0.01) in T1D group. OPG mRNA expression was significantly increased in T1D and T1DP groups in comparison with NG group (p<0.05). In conclusion, children and adolescents with early onset T1D presented low bone mineral density associated to unsatisfactory glycemic control, increased OPG mRNA expression and low osteocalcin concentration.

Topics: Adolescent; Adult; Alkaline Phosphatase; Biomarkers; Bone Density; Calcium; Case-Control Studies; Child; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Female; Humans; Hyperglycemia; Hypoglycemia; Leukocytes, Mononuclear; Male; Osteocalcin; Osteoprotegerin; Phosphorus; RANK Ligand; Real-Time Polymerase Chain Reaction; Receptor Activator of Nuclear Factor-kappa B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Young Adult

To investigate the relationship between bone-derived osteocalcin (OC), osteoprotegerin (OPG), Receptor Activator of Nuclear Factor NF-ĸB ligand (RANKL), and fat tissue-derived leptin and adiponectin with a clinical outcome of type 1 diabetes mellitus (T1DM) in children and adolescents.. 78 patients (43 girls and 35 boys), aged 11.5±4.3 years with T1DM and 11 age- and BMI-matched controls were included into the study. Patients were divided into 3 groups according to HbA1c level, I - below 7% [53 mmol/mol], II - 7-9% [53-75 mmol/mol] and III - above 9% [75 mmol/mol]. Blood samples for biochemical measurements were drawn at 8.00 AM, when the patients were in a fasting state. HbA1c was measured by the standardized IFCC method. OC, OPG, RANKL, leptin and adiponectin were measured by ELISA. ANOVA, and multiple regression analysis were used for statistical analysis.. Significant differences in leptin and osteocalcin levels between groups with different HbA1c values were observed (p=0.03, p=0.04). Multiple regression analysis adjusted for age showed that serum OC and leptin negatively correlated with HbA1c levels (r=-0.22, p=0.004 and r=-0.27, p=0.0001, respectively). In contrast, serum OPG correlated positively with HbA1c (r=0.26, p=0.02) as well as with adiponectin (r=0.26, p=0.02) and RANKL (r=0.27, p=0.02) levels. The correlation of OC with HbA1c was the strongest in group I - patients with good metabolic control of DM (r=-0.43, p=0.03). In that group, in multiple regression analysis adjusted for age and BMI leptin correlated positively with daily dose of insulin (r=0.52, r=0.009). In group II and III in multiple regression analysis adjusted for age and BMI OC correlated negatively with leptin (r=-0.37, p=0.01).. Our data suggest significant relationships between bone, fat tissue and glucose metabolism in pediatric patients with T1DM. The results can confirm that poor metabolic control is associated with reduced bone formation. On the other hand fat and bone tissue can influence glucose metabolism, potentiality in insulin-dependent manner. From these data leptin or OC may be potentially used as additional therapeutic agents for T1DM.

Topics: Adiponectin; Adolescent; Biomarkers; Child; Diabetes Mellitus, Type 1; Female; Humans; Insulin; Leptin; Male; Osteocalcin; Osteoprotegerin; RANK Ligand

Besides their role in bone metabolism, receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) are also known to be associated with inflammation. We explored associations between the extent/severity of periodontitis and circulating levels of sRANKL and OPG and their ratio using a cross-sectional study design.. The extent of periodontal inflammation and tissue destruction and the serum levels of sRANKL (pg/ml) and OPG (pg/ml) were determined in 80 subjects with type 1 diabetes mellitus (T1DM). Plaque-, age-, gender-, smoking-, HbA1c- and body mass index-adjusted associations between periodontal parameters and serum sRANKL, OPG and their ratio were studied using multiple linear regression analysis.. Adjusted regression analyses of all the subjects indicated a significant positive association between AL ≥ 4 mm and severity of periodontitis and the level of serum OPG. A major drop in the strength and statistical significance of the above association was observed when the analyses included only non-smokers. Serum sRANKL level and sRANKL/OPG ratio were not associated with periodontitis.. Our observations suggest that serum OPG may be an indicator of periodontal tissue destruction in T1DM.

Topics: Adolescent; Adult; Age Factors; Aged; Alveolar Bone Loss; Body Mass Index; Cross-Sectional Studies; Dental Plaque Index; Diabetes Mellitus, Type 1; Female; Gingival Hemorrhage; Glycated Hemoglobin; Humans; Longitudinal Studies; Male; Middle Aged; Osteoprotegerin; Periodontal Attachment Loss; Periodontal Pocket; Periodontitis; RANK Ligand; Retrospective Studies; Sex Factors; Smoking; Young Adult

Osteoprotegerin (OPG) is involved in the process of vascular calcification. We investigated whether OPG is associated with the development and progression of diabetes complications in adults with type 1 diabetes (T1D).. Serum OPG was measured in 1,939 adults with T1D participating in the Finnish Diabetic Nephropathy (FinnDiane) Study. Patients with end-stage renal disease (dialysis or transplantation) at baseline were excluded from analysis. Data on cardiovascular (CV) events and mortality during follow-up were verified from hospital discharge registries (ICD codes) and the Finnish National Death Registry, respectively. The follow-up time was 10.4 ± 2.0 (mean ± SD) years.. Only patients with macroalbuminuria and/or renal impairment had elevated OPG concentrations, when compared with participants without overt kidney disease. Patients with retinopathy or CV disease also had higher OPG concentrations, but this was attributable to their higher frequency of chronic kidney disease. OPG predicted an incident CV event (hazard ratio 1.21 [95% CI 1.01-1.45]; P = 0.035) and peripheral vascular disease/amputation events (1.46 [1.13-1.88]; P = 0.004) during follow-up.. We showed that serum OPG is an independent predictor of CV complications. OPG may be directly involved in extraosseous calcification, resulting in stiffening of the arteries and subsequent vascular insufficiency in patients with T1D.

Topics: Adult; Albuminuria; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Female; Finland; Humans; Male; Osteoprotegerin

The aim of the present study was to determine the plasma osteoprotegerin (OPG) levels in Type 1 diabetic patients with albuminuria.. A total of 80 Type 1 diabetic subjects and 30 control subjects were enrolled. Diabetic subjects were divided into normoalbuminuric group, microalbuminuric group and macroalbuminuric group according to urinary albumin excretion rate (UAER) and serum creatinine measurements. Plasma osteoprotegerin level was measured by enzyme-linked immunoassay.. The serum OPG levels were significantly elevated in patients with microalbuminuria (3.62 ± 0.70 ng/l) and macroalbuminuria (4.45 ± 0.76 ng/l) as compared with patients with normoalbuminuria (2.77 ± 0.78 ng/l) and control subjects (2.29 ± 0.37 ng/l). And the plasma osteoprotegerin level in macroalbuminuric group was also higher than that in microalbuminuria group. The plasma osteoprotegerin level had a positive correlation with the fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), glycohemoglobin A1c (HbA1C), highly sensitive C-reactive protein (hsCRP)and UAER. Multivariate regression analysis revealed that the plasma osteoprotegerin level was an independent factor associated with albuminuria in Type 1 diabetes.. The plasma values of osteoprotegerin were elevated in Type 1 diabetic patients with nephropathy and gradually increased with the severity, so there is a association between plasma osteoprotegerin levels and the presence and severity of diabetic nephropathy. This finding supports the growing concept that osteoprotegerin may act as an important regulatory molecule in the angiopathy, and particularly, that it may be involved in the development of nephropathy in Type 1 diabetes.

Topics: Adult; Albuminuria; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Humans; Male; Osteoprotegerin

Recently, an association between two polymorphisms (1181G>C and 245T>G) of the osteoprotegerin (OPG) gene and diabetic Charcot neuroarthropathy was suggested on the basis of studies of a limited number of samples derived from subjects from one geographical region (Italy). The aim of this study was to assess the presence of various osteoprotegerin gene polymorphisms in patients with diabetes and Charcot neuroarthropathy compared with subjects with diabetic neuropathy but no Charcot foot and healthy controls from another geographical region (Poland).. DNA was isolated from 54 patients with Charcot neuroarthropathy, 35 subjects with diabetic neuropathy but no Charcot foot, and 95 healthy controls to evaluate OPG gene polymorphisms and their possible contribution to the development of Charcot neuroarthropathy.. Statistically significant differences between the group of subjects with neuropathy but no Charcot neuroarthropathy and the control group were found for 1217C>T, 950T>C and 245T>G polymorphisms, between the group of patients with Charcot neuroarthropathy and the control group for 1181G>C and 950T>C polymorphisms, and between the group of subjects with neuropathy but no Charcot neuroarthropathy and the group of patients with Charcot neuroarthropathy for 1217C>T and 245T>G polymorphisms.. We suggest that genetic factors, particularly OPG gene polymorphisms, may play a role in the development of diabetic Charcot neuroarthropathy.

Topics: Adult; Arthropathy, Neurogenic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Osteoprotegerin; Poland; Polymorphism, Single Nucleotide

The aim of this study is to establish whether abnormal mineral metabolism is present in patients with type 1 DM with normal renal function and in the absence of microalbuminuria. Serum levels of 1,25-dihydroxyvitamin D, osteoprotegerin (OPG) and receptor activator for nuclear factor kappa β ligand (RANKL) and other determinants of bone metabolism were measured in 35 patients with type 1 DM and in 25 age-, sex- and ethnicity-matched healthy controls. Serum OPG (1.98 vs. 2.98 pmol/l: P = 0.001), 1,25-dihydroxyvitamin D (41.1 vs. 48.2 pmol/l: P = 0.035) and magnesium (0.84 vs. 0.89 mmol/l P = 0.029) levels were significantly lower in patients with type 1 DM compared to normal controls. RANKL levels were similar in both groups. The groups did not differ with respect to calcium, phosphate, PTH, 25-hydroxyvitamin D, tubular reabsorption of phosphate and cross-linked N-telopeptides of type 1-collagen levels. Abnormalities of mineral metabolism including low serum OPG and 1,25-dihydroxyvitamin D levels occur in patients with type 1 DM with normal renal function and in the absence of microalbuminuria. These abnormalities may promote altered bone metabolism and vascular pathology.

Topics: Adult; Bone and Bones; Bone Density; Case-Control Studies; Diabetes Complications; Diabetes Mellitus, Type 1; Down-Regulation; Female; Humans; Male; Middle Aged; Minerals; Osteoprotegerin; RANK Ligand; Vitamin D

Markers of micro- and macrovascular disease are needed in type 1 diabetes in order to identify patients at risk of severe complications. Osteoprotegerin (OPG) is expressed in vascular myocytes, and increasing levels have been reported in type 1 diabetes. Consequently, we investigated OPG as a non-invasive marker of micro- and macrovascular complications in long-term type 1 diabetic patients.. This was a cross-sectional study of 200 type 1 diabetic patients with long diabetes duration from a population-based cohort from Fyn County, Denmark. Patients were examined in 2007-2008, and OPG was measured and correlated to diabetes-associated complications: retinopathy, nephropathy, neuropathy and macrovascular disease.. Median age and duration of diabetes was 58.7 years (range 37.7-84.4 years) and 43 years (range 34-70 years), respectively. Median level of OPG was 1257 pg/ml (range 379-5706 pg/ml). In univariate analyses, OPG was related to age, duration of diabetes, female gender, nephropathy and inversely to diastolic blood pressure. In an age- and sex-adjusted model, higher levels of OPG were associated with a higher risk of nephropathy (OR 2.54, 95% confidence interval 1.09-5.90 for third vs. first tertile). Statistical significance was, however, lost in a multivariate model, and proliferative diabetic retinopathy, neuropathy and macrovascular disease was not associated with OPG in either model.. Some associations of OPG and nephropathy were found in a long-term type 1 diabetic cohort. Prospective studies are needed in order to determine whether OPG can be used to predict nephropathy.

Topics: Adult; Aged; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Female; Humans; Male; Microvessels; Middle Aged; Multivariate Analysis; Osteoprotegerin; Time Factors

Osteoprotegerin (OPG) has been linked to different diabetes complications, including cardiovascular disease, and new findings have indicated a specific role in diabetic peripheral neuropathy, but the exact mechanism is unknown. To investigate a possible association between OPG and diabetic peripheral sensory neuropathy, we therefore analysed plasma OPG in Type 1 and Type 2 diabetic patients with and without peripheral neuropathy.. Two hundred Type 1 diabetes mellitus (T1DM) patients and 305 Type 2 diabetes mellitus (T2DM) patients participated in the study. Plasma OPG was measured with a sandwich immunoassay. Peripheral neuropathy was assessed by the Semmes-Weinstein monofilament test.. In T2DM, plasma OPG concentrations were significantly higher in the peripheral neuropathy group (P < 0.001). Furthermore, there was a significant relationship between the presence of neuropathy in T2DM and plasma OPG levels on logistic regression (P = 0.006). However, when investigated in a full multiple regression model including other long-term diabetes complications, the association became insignificant (P = 0.092). In T1DM, the difference in plasma OPG between groups did not reach significance (P = 0.066). However, plasma OPG significantly correlated to peripheral neuropathy in this group also (P = 0.022), although this correlation was not significant in a multiple linear regression model (P = 0.051).. Plasma OPG levels are related to peripheral neuropathy in both Type 1 and Type 2 diabetes, although with the strongest relationship in T2DM. Before understanding the significance of this, the pathological mechanism involved and, speculatively, a possible use of plasma OPG as a peripheral sensory neuropathy marker, a larger prospective study is needed.

Topics: Aged; Biomarkers; Cohort Studies; Denmark; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Logistic Models; Male; Middle Aged; Osteoprotegerin

To determine plasma concentrations of bone metabolism markers in type 1 diabetes mellitus patients and non-diabetic and to evaluate the influence of periodontitis on biomarkers of bone formation in these patient groups.. Plasma concentrations of receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), C-terminal telopeptide of type 1 collagen and osteocalcin were measured in type 1 diabetes mellitus patients (n=63) and non-diabetics (n=38) who were also subdivided on the basis of their periodontal status.. Diabetics had significantly lower osteocalcin concentrations, lower RANKL to OPG ratios and higher OPG concentrations (as shown by other researchers) than non-diabetics. The ratio of RANKL to OPG was altered by the periodontal status. Osteocalcin had a negative correlation and OPG a positive correlation with the percentage of glycated haemoglobin in the blood.. Because, osteocalcin, a biomarker of bone formation, is lower in patients with periodontitis and in patients with type 1 diabetes mellitus with and without periodontitis than in non-diabetics without periodontitis, this might indicate that diabetics are less able to replace bone lost during active bursts of periodontitis and explain the greater severity of disease seen in studies of patients with diabetes.

Topics: Adult; Biomarkers; Bone Resorption; Collagen Type I; Diabetes Mellitus, Type 1; Female; Gingival Hemorrhage; Gingival Recession; Glycated Hemoglobin; Humans; Male; Middle Aged; Osteocalcin; Osteogenesis; Osteoprotegerin; Peptide Fragments; Peptides; Periodontal Attachment Loss; Periodontal Pocket; Periodontitis; Procollagen; RANK Ligand; Young Adult

The bone-related peptide osteoprotegerin is produced by vascular cells and is involved in the process of vascular calcification. The aim of this study was to investigate the predictive value of plasma levels of osteoprotegerin in relation to mortality, cardiovascular events and deterioration in kidney function in patients with type 1 diabetes.. This prospective observational follow-up study included 397 type 1 diabetic patients with overt diabetic nephropathy (243 men; age [mean+/-SD] 42.1 +/- 10.6 years, duration of diabetes 28.3 +/- 9.9 years, GFR 67 +/- 28 ml min(-1) 1.73 m(2)) and a group of 176 patients with longstanding type 1 diabetes and persistent normoalbuminuria (105 men; age 42.6 +/- 9.7 years, duration of diabetes 27.6 +/- 8.3 years).. The median (range) follow-up period was 11.3 (0.0-12.9) years. Among patients with diabetic nephropathy, individuals with high osteoprotegerin levels (fourth quartile) had significantly higher all-cause mortality than patients with low levels (first quartile) (covariate-adjusted hazard ratio [HR] 3.00 [1.24-7.27]). High osteoprotegerin levels also predicted cardiovascular mortality (covariate-adjusted HR 4.88 [1.57-15.14]). Furthermore, patients with high osteoprotegerin levels had significantly higher risk of progression to end-stage renal disease than patients with low levels (covariate-adjusted HR 4.32 [1.45-12.87]). In addition, patients with high levels of plasma osteoprotegerin had an elevated rate of decline in GFR.. High levels of osteoprotegerin predict all-cause and cardiovascular mortality in patients with diabetic nephropathy. Furthermore, high levels of osteoprotegerin predict deterioration of kidney function towards end-stage renal disease.

Topics: Adult; Biomarkers; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Female; Glycated Hemoglobin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Predictive Value of Tests; Survival Analysis

Osteoprotegerin (OPG) regulates osteoclast and immune functions and appears to represent a protective factor for vascular system. However, the role of OPG in endothelial dysfunction of type 1 diabetic patients has not been evaluated. The purpose of this study was to investigate the relationship between plasma OPG levels and endothelium-dependent arterial dilation in type 1 diabetic patients.. This study subjects included 22 newly diagnosed type 1 diabetic patients and 28 healthy subjects. All patients were then given insulin therapy for 6 months. Plasma OPG concentration was measured in duplicate by a sandwich ELISA method, and high-resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperemia and after sublingual glyceryltrinitrate (GTN).. Plasma OPG level in patients before treatment was 3.09+/-0.70 ng/L, which was significantly higher than that in control (2.07+/-0.75 ng/L) (p<0.001). After 6 months treatment, OPG levels decreased markedly (2.58+/-0.59 ng/L) (p<0.001). The flow-mediated endothelium-dependent arterial dilation in patients before treatment was 3.35+/-0.67%, which was significantly lower than that in control (5.17+/-0.83%) (p<0.001), and improved markedly after 6 months treatment (4.27+/-0.63%) (p<0.001). In multivariate analysis, OPG was significantly associated with endothelium-dependent arterial dilation, fasting blood glucose (FBG), hemoglobin A1c (HbA1c), and ultra sensitive C-reactive protein (CRP) at baseline (p<0.01). The absolute changes in OPG showed significant correlation with the changes in endothelium-dependent arterial dilation, FBG, HbA1c, and CRP in diabetic patients during the course of treatment (p<0.01).. This study shows that plasma OPG levels are elevated in newly diagnosed type 1 diabetic patients, and that plasma OPG levels are significantly associated with endothelial function.

Topics: Adolescent; Adult; Brachial Artery; Child; Diabetes Mellitus, Type 1; Dilatation, Pathologic; Endothelium; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypoglycemic Agents; Insulin; Male; Osteoprotegerin; Ultrasonography

The TNF-alpha super-family of cytokines comprises structurally related proteins that play pivotal roles in regulating cell death, immune response and inflammation. A new member of the family namely Tumor necrosis factor alpha-Related Apoptosis-Inducing Ligand (TRAIL) is involved not only in apoptosis and immune regulation, but also it has a provocative role in vascular biology as reported recently. In this report we provide evidence that this new function of TRAIL may have a significance in the pathogenesis of diabetes and in particular in the vascular alterations that occur late during the natural history of the illness. Noteworthy, depending on the type of diabetes and on the disease stage, TRAIL can have a dual role, either as immune modulator as well as a regulatory molecule of the vascular wall fitness.

Topics: Animals; Apoptosis; Atherosclerosis; Autoimmune Diseases; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Early Growth Response Protein 1; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation; Humans; Islets of Langerhans; Mice; Mice, Inbred NOD; Mice, Knockout; Models, Biological; Models, Immunological; NF-kappa B; Osteoprotegerin; Rats; Receptors, TNF-Related Apoptosis-Inducing Ligand; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha; Tunica Media; Umbilical Veins

The bone-related peptide osteoprotegerin (OPG) has recently been found in increased amounts in the vasculature in diabetes. It is produced by vascular smooth muscle and endothelial cells, and may be implicated in the development of vascular calcifications. OPG is present in the circulation, where increased amounts have been observed in patients with diabetes. In this study, we examined whether plasma OPG is associated with the glycaemic and vascular status of patients with type 1 diabetes.. Two gender-, age- and duration-comparable groups of type 1 diabetic patients either with (n = 199) or without (n = 192) signs of diabetic nephropathy were studied. Plasma OPG was determined by an ELISA.. The plasma OPG concentration was significantly higher in patients with nephropathy than those without (3.11 (2.49-3.99) vs 2.57 (2.19-3.21) (median (interquartiles), ng/ml), P < 0.001). Plasma OPG correlated with haemoglobin A1c (HbA1c), systolic blood pressure and age in both groups and, in addition, with kidney function in the nephropathic group. These correlations remained significant in multivariate models. In addition, we found that plasma OPG concentrations were increased among patients with cardiovascular diseases (CVD), both in the normoalbuminuric and the nephropathic groups. The differences between nephropathic and normoalbuminuric, as well as subgroups with and without CVD, could largely be ascribed to changes in HbA1c, age, systolic blood pressure and creatinine.. OPG is associated with glycaemic control and CVD in patients with type 1 diabetes, compatible with the hypothesis that OPG is associated with the development of diabetic vascular complications.

Topics: Adult; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glycated Hemoglobin; Glycoproteins; Humans; Male; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

To assess the prevalence and severity of bone disease in type 1 diabetic patients and to determine serum markers of bone remodeling as well as their relationship with bone mineral density (BMD).. BMD [by dual energy x-ray absorptiometry (DXA)] and serum markers of bone remodeling [osteocalcin, c-terminal telopeptide of type I collagen (CTX)], leptin and osteoprotegerin (OPG) were measured in 42 adult males with type 1 diabetes. Twenty-four non-diabetic subjects served as controls.. In 40% of the patients, osteopenia at the lumbar spine (L1-L4) and/or at the left hip was found, and 7% met criteria for osteoporosis. L1-L4 BMD z-score was correlated with age (r=0.365, P=0.018) and a similar trend was observed at left hip. L1-L4 BMD z-score was negatively correlated with CTX and osteocalcin (r=-0.343, P=0.028; r=-0.376, P=0.024, respectively). A significant correlation was evidenced between BMD z-score at both lumbar spine and left hip and leptin values (r=0.343, P=0.03; r=0.395, P=0.012, respectively) but after adjustment for weight this correlation was no longer significant. Osteocalcin, CTX and leptin concentrations were comparable between patients and controls, while OPG concentrations tend to be higher in diabetic subjects (P=0.08). CTX was negatively correlated with age (r=-0.390, P=0.012) and positively correlated with osteocalcin (r=0.696, P<0.001). OPG was positively correlated with age (r=0.507, P=0.001).. Our results suggest that in diabetic subjects osteopenia is a relatively frequent complication but bone loss is attenuated with age progression. Whether this is also mediated by OPG and/or leptin remains to be confirmed.

Topics: Adult; Aged; Biomarkers; Bone Density; Bone Remodeling; Collagen; Diabetes Mellitus, Type 1; Humans; Leptin; Male; Middle Aged; Osteocalcin; Osteoprotegerin; Reference Values

Extracellular matrix modifications and linear medial calcifications are elements of diabetic macroangiopathy. We hypothesised that the bone-related protein osteoprotegerin (OPG) may occur in altered amounts in the arterial wall in diabetes, putatively associated with altered synthesis from vascular cells.. The amount of OPG in the thoracic aorta, obtained at autopsy from 21 diabetic and 42 sex- and age-matched controls, was measured in tissue extracts by an ELISA. The production of OPG was estimated in conditioned media by an ELISA, and OPG mRNA was estimated by RT-PCR in vascular cells grown in vitro.. The content of OPG was increased in tunica media samples from diabetic individuals. No differences between diabetic and non-diabetic subjects were observed in tunica intima. Human vascular smooth muscle cells (HVSMCs) produced approximately 30 times more OPG than human umbilical vein endothelial cells. The OPG production into the medium decreased dose- and time-dependently after insulin treatment (maximal effect approximately 60% of control) in HVSMCs, whereas TNF-alpha supplement gave rise to increased OPG synthesis in a time- and dose-dependent manner (maximal effect approximately 200% of control). Similar effects on OPG mRNA expression were observed. Addition of growth hormone (10 ng/ml) or extra glucose (25 mmol/l) to the growth medium had no effect.. Increased OPG concentrations in the arterial wall in diabetes may be part of generalised matrix alterations, putatively related to the development of vascular calcifications. Altered arterial OPG content may be a consequence of the effects of hormones and cytokines, like insulin and TNF-alpha.

Topics: Aorta, Thoracic; Autopsy; Cells, Cultured; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Endothelium, Vascular; Glycoproteins; Humans; Insulin; Muscle, Smooth, Vascular; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reference Values; RNA, Messenger; Tumor Necrosis Factor-alpha; Umbilical Veins

Diabetic patients experience a higher risk for severe periodontitis; however, the underlying mechanism remains unclear. We investigated the contribution of antibacterial T-cell-mediated immunity to enhanced alveolar bone loss during periodontal infection in nonobese diabetic (NOD) mice by oral inoculation with Actinobacillus actinomycetemcomitans, a G(-) anaerobe responsible for juvenile and severe periodontitis. The results show that 1) inoculation with A. actinomycetemcomitans in pre-diabetic NOD mice does not alter the onset, incidence, and severity of diabetes; 2) after A. actinomycetemcomitans inoculation, diabetic NOD mice (blood glucose >200 mg/dl and with severe insulitis) exhibit significantly higher alveolar bone loss compared with pre-diabetic and nondiabetic NOD mice; and 3) A. actinomycetemcomitans-reactive CD4+ T-cells in diabetic mice exhibit significantly higher proliferation and receptor activator of nuclear factor kappaB ligand (RANKL) expression. When diabetic mice are treated with the RANKL antagonist osteoprotegerin (OPG), there is a significant reversal of alveolar bone loss, as well as reduced RANKL expression in A. actinomycetemcomitans-reactive CD4+ T-cells. This study clearly describes the impact of autoimmunity to anaerobic infection in an experimental periodontitis model of type 1 diabetes. Thus, microorganism-reactive CD4+ T-cells and the RANKL-OPG axis provide the molecular basis of the advanced periodontal breakdown in diabetes and, therefore, OPG may hold therapeutic potential for treating bone loss in diabetic subjects at high risk.

Topics: Actinobacillus Infections; Aggregatibacter actinomycetemcomitans; Alveolar Bone Loss; Animals; Bacteria, Anaerobic; Carrier Proteins; CD4-Positive T-Lymphocytes; Diabetes Mellitus, Type 1; Glycoproteins; Humans; Membrane Glycoproteins; Mice; Mice, Inbred NOD; Osteoprotegerin; Prediabetic State; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Children and adolescents with type 1 (insulin-dependent) diabetes mellitus (T1DM) show several impairment of bone metabolism and structure, resulting in a higher risk of decreased bone mass and its related complications later in life. Alterations of the nuclear factor-kappaB ligand (RANKL)/osteoprotegerin (OPG) system have been implicated in several metabolic bone diseases characterized by increased osteoclast differentiation and activation and enhanced bone resorption.. We aimed to assess OPG levels and to investigate the possible relation between OPG levels, bone status and glycemic control in a group of prepubertal children with T1DM without microvascular complications.. Twenty-six prepubertal T1DM children (median age 9.9 years, range 4.1-13.1 years) were studied. In all patients, serum OPG, hemoglobin (Hb)A1c, parathyroid hormone (PTH) and 25-dihy-droxyvitamin D (25-D) levels were evaluated. Bone quality was determined by measuring the attenuation of ultrasound waves by bone (broadband ultrasound attenuation (BUA)) at the calcaneal site. The data were compared with those of a group of 45 age-, sex-and body-size-matched healthy children.. Children with T1DM showed a reduced Z-score BUA in comparison with the control group (Student's t-test, P < 0.0001). Plasma OPG levels were significantly higher in diabetic children than in controls (Student's t-test, P < 0.0001). In T1DM children, Z-score BUA values displayed a significant correlation with OPG (Student's t-test, r = -0.62; P = 0.001), and HbA1c (r = -0.59; P = 0.007). OPG levels were significantly correlated with HbA1c (r = 0.56; P = 0.008). In a multiple regression analysis including age, duration of diabetes, physical activity, calcium intake, mean HbA1c and Z-score BUA, only HbA1c significantly predicted serum OPG levels (beta 0.67; P = 0.003).. Prepubertal children with T1DM have a significant increase of OPG levels. OPG serum concentrations are correlated to calcaneal BUA and HbA1c values. OPG could be a new marker of reduced bone mass in children with T1DM.

Topics: Adolescent; Bone and Bones; Bone Density; Child; Child, Preschool; Diabetes Mellitus, Type 1; Female; Glycated Hemoglobin; Glycoproteins; Humans; Male; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Ultrasonography

We have previously shown that the selection of haplotype tag single nucleotide polymorphisms (htSNPs) and their statistical analysis in a multi-locus transmission/disequilibrium test (TDT) results in a more cost-effective genotyping strategy in disease association studies of genes by minimising redundancy due to linkage disequilibrium between SNPs. Further savings can be achieved by the use of a two-stage genotyping strategy. This approach is illustrated here in conjunction with the multi-locus TDT in determining whether common alleles of the immune regulatory genes RANK and its ligand TRANCE (RANKL) are associated with type 1 diabetes (T1D). A saving of approximately 75% of potential genotyping reactions could be made with minimal loss of power. There was little evidence from our analysis for association between the TRANCE and RANK genes and T1D in the populations tested.

Topics: Carrier Proteins; Diabetes Mellitus, Type 1; Genotype; Glycoproteins; Linkage Disequilibrium; Membrane Glycoproteins; Osteoprotegerin; Polymorphism, Single Nucleotide; RANK Ligand; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Inflammation can activate self-reactive CD8(+) T cells and induce autoimmunity. Here we show in a CD8(+) T cell-mediated model of type 1 diabetes that CD4(+)CD25(+) Treg cells prevent beta cell destruction following localized inflammation in the islets of Langerhans. These Treg cells accumulate preferentially in the pancreatic lymph nodes and islets but not other lymph nodes or spleen. PLN-derived Treg cells are extremely potent; only 2 x 10(3) cells are needed to prevent diabetes development, and their capacity to regulate is dependent on TNF-related activation induced cytokine-receptor activator of NFkappaB signals. Indeed, blockade of this pathway results in decreased frequency of CD4(+)CD25(+) Treg cells in the PLN, resulting in intra-islet differentiation of CD8(+) T cells into CTLs and rapid progression to diabetes.

Topics: Animals; Biomarkers; Carrier Proteins; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Differentiation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Disease Models, Animal; Female; Glycoproteins; Islets of Langerhans; Ligands; Lymph Nodes; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Osteoprotegerin; Pancreas; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Interleukin-2; Receptors, Tumor Necrosis Factor; Signal Transduction; T-Lymphocytes, Cytotoxic