osteoprotegerin and Diabetes-Mellitus

Charcot Foot (CF), part of a broader condition known as Charcot Neuro-Osteoarthropathy (CNO), is characterized by neuropathic arthropathy with a progressive alteration of the foot. CNO is one of the most devastating complications in patients with diabetes mellitus and peripheral neuropathy but can also be caused by neurological or infectious diseases. The pathogenesis is multifactorial; many studies have demonstrated the central role of inflammation and the Receptor Activator of NF-κB ligand (RANKL)-Receptor Activator of NF-κB (RANK)-Osteoprotegerin (OPG) pathway in the acute phase of the disease, resulting in the serum overexpression of RANKL. This overexpression and activation of this signal lead to increased osteoclast activity and osteolysis, which is a prelude to bone destruction. The aim of this narrative review is to analyze this signaling pathway in bone remodeling, and in CF in particular, to highlight its clinical aspects and possible therapeutic implications of targeting drugs at different levels of the pathway. Drugs that act at different levels in this pathway are anti-RANKL monoclonal antibodies (Denosumab), bisphosphonates (BP), and calcitonin. The literature review showed encouraging data on treatment with Denosumab, although in a few studies and in small sample sizes. In contrast, BPs have been re-evaluated in recent years in relation to the high possibility of side effects, while calcitonin has shown little efficacy on CNO.

Topics: Bone Density Conservation Agents; Calcitonin; Denosumab; Diabetes Mellitus; Diabetic Foot; Humans; NF-kappa B; Osteolysis; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

The aim of this review is to gain a better understanding of osteoporotic fractures and the different mechanisms that are driven in the scenarios of bone disuse due to spinal cord injury and osteometabolic disorders due to diabetes.. Despite major advances in understanding the pathogenesis, prevention, and treatment of osteoporosis, the high incidence of impaired fracture healing remains an important complication of bone loss, leading to marked impairment of the health of an individual and economic burden to the medical system. This review underlines several pathways leading to bone loss and increased risk for fractures. Specifically, we addressed the different mechanisms leading to bone loss after a spinal cord injury and diabetes. Finally, it also encompasses the changes responsible for impaired bone repair in these scenarios, which may be of great interest for future studies on therapeutic approaches to treat osteoporosis and osteoporotic fractures.

Topics: Bone Remodeling; Bone Resorption; Bony Callus; Diabetes Complications; Diabetes Mellitus; Fracture Healing; Humans; Osteoporosis; Osteoporotic Fractures; Osteoprotegerin; RANK Ligand; Spinal Cord Injuries; Wnt Signaling Pathway

Background Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease ( CVD ) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear. Methods and Results Three independent reviewers systematically searched PubMed, EMBASE , and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow-up of 4.2 years, 4066 CVD events were recorded. In a random-effects meta-analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12-1.50; P<0.001; I

Topics: Acute Coronary Syndrome; Angina Pectoris; Biomarkers; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus; Heart Diseases; Humans; Kidney Diseases; Myocardial Infarction; Myocardial Revascularization; Osteoprotegerin; Risk; Stroke

β-Cell dysfunction in type 1 and type 2 diabetes is accompanied by a progressive loss of β-cells, and an understanding of the cellular mechanism(s) that regulate β-cell mass will enable approaches to enhance hormone secretion. It is becoming increasingly recognized that enhancement of human β-cell proliferation is one potential approach to restore β-cell mass to prevent and/or cure type 1 and type 2 diabetes. While several reports describe the factor(s) that enhance β-cell replication in animal models or cell lines, promoting effective human β-cell proliferation continues to be a challenge in the field. In this review, we discuss recent studies reporting successful human β-cell proliferation including WS6, an IkB kinase and EBP1 inhibitor; harmine and 5-IT, both DYRK1A inhibitors; GNF7156 and GNF4877, GSK-3β and DYRK1A inhibitors; osteoprotegrin and Denosmab, receptor activator of NF-kB (RANK) inhibitors; and SerpinB1, a protease inhibitor. These studies provide important examples of proteins and pathways that may prove useful for designing therapeutic strategies to counter the different forms of human diabetes.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Proliferation; Denosumab; Diabetes Mellitus; Dyrk Kinases; Glycogen Synthase Kinase 3 beta; Harmine; Humans; I-kappa B Kinase; Insulin-Secreting Cells; Monoamine Oxidase Inhibitors; Osteoprotegerin; Phenylurea Compounds; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Receptor Activator of Nuclear Factor-kappa B; RNA-Binding Proteins; Serine Proteinase Inhibitors; Serpins; Tryptamines

The link between vascular calcification (VC) and increased mortality is now well established. Over time, as clinical importance of this phenomenon has begun to be fully considered, scientists have highlighted more and more physiopathological mechanisms and signaling pathways that underlie VC. Several conditions such as diabetes, dyslipidemia and renal diseases are undoubtedly identified as predisposing factors. But even if the process is better understood, many questions still remain unanswered. This review briefly develops the various theories that attempt to explain mineralization genesis. Nonetheless, the main purpose of the article is to provide a profile of the various existing biomarkers of VC. Indeed, in the past years, a lot of inhibitors and promoters, which form a dense and interconnected network, were identified. Given importance to assess and control mineralization process, a focusing on accumulated knowledge of each marker seemed to be necessary. Therefore, we tried to define their respective role in the physiopathology and how they can contribute to calcification risk assessment. Among these, Klotho/fibroblast growth factor-23, fetuin-A, Matrix Gla protein, Bone morphogenetic protein-2, osteoprotegerin, osteopontin, osteonectin, osteocalcin, pyrophosphate and sclerostin are specifically discussed.

Topics: alpha-2-HS-Glycoprotein; Biomarkers; Bone Morphogenetic Protein 2; Calcium-Binding Proteins; Diabetes Complications; Diabetes Mellitus; Dyslipidemias; Extracellular Matrix Proteins; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Gene Expression Regulation; Humans; Matrix Gla Protein; Osteoprotegerin; Renal Insufficiency, Chronic; Risk Assessment; Signal Transduction; Vascular Calcification

Kidney transplantation is the treatment of choice for chronic kidney disease (CKD), but in kidney transplant recipients (KTRs) cardiovascular events are the first cause of death with a functioning graft, ranging from 36 to 55%. The impact of vascular calcification (VC) on morbidity and mortality of KTRs is not appreciated enough nowadays.. This review summarizes 13 important studies on VC in KTRs, comparing the results with CKD and dialysis populations. We focused on VC evaluation and use of coronary artery calcification (CAC) and aorta calcification (AoC) scores. We also evaluated the influence of traditional and non-traditional progression risk factors.. VC strongly predicts cardiovascular events and all-cause mortality in KTRs. VC assessment is important in KTRs and based essentially on multislice computed tomography or electron beam computed tomography recognition of lesions. Quantitative measurement of CAC and AoC scores is essential for a correct definition of the calcium burden before and after kidney transplant. Progression of CAC slows down but does not halt after kidney transplant. A variable association of both traditional and non-traditional risk factors is shown. There is a strong association between baseline CAC score and CAC progression. A significant improvement in secondary hyperparathyroidism after transplantation favorably affects the progression of CAC. Low 25(OH)D3 levels are an independent determinant of CAC progression. Diabetes is a risk factor for the presence of CAC in KTRs, but has not been independently associated with CAC progression. The data published on the use of immunosuppressive drugs as progression factors are few and inconclusive.

Topics: alpha-2-HS-Glycoprotein; Aorta; Calcifediol; Calcium-Binding Proteins; Cardiovascular Diseases; Coronary Vessels; Diabetes Mellitus; Disease Progression; Extracellular Matrix Proteins; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Matrix Gla Protein; Osteoprotegerin; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Vascular Calcification

Osteoprotegerin (OPG) is a 401 amino acid N-glycosylated protein, which is highly expressed in a large number of tissues. OPG mainly binds to two ligands, i.e. RANKL (receptor activator of nuclear factor κB ligand) and TRAIL (tumor necrosis factor- related apoptosis-inducing ligand). Upon binding to the former ligand, OPG inhibits the activation of osteoclasts and promotes apoptosis of osteoclasts, whereas the binding of OPG with TRAIL prevents apoptosis of tumor cells. There is now emerging evidence that OPG participates in the pathogenesis of atherosclerosis and cardiovascular diseases by amplifying the adverse effects of inflammation and several traditional risk factors such as hyperlipidemia, endothelial dysfunction, diabetes mellitus, and hypertension. Some epidemiological studies also showed a positive association between OPG levels and cardiovascular morbidity and mortality. The aim of this article is to provide an overview of the main biochemical, physiological, and pathological aspects of OPG biology in cardiovascular disease.

Topics: Aging; Aortic Diseases; Atherosclerosis; Blood Flow Velocity; Blood Pressure; Cardiovascular Diseases; Diabetes Mellitus; Endothelium, Vascular; Gene Expression; Humans; Inflammation; Lipids; Obesity; Osteoprotegerin; Polymorphism, Genetic; Prognosis; Vascular Calcification

The receptor activator of NF-κB ligand-osteoprotegerin (RANKL-OPG) bi-molecular system is the "bottle-neck" regulator of osteoclastogenesis and bone resorption, both in physiological and pathological conditions. This review aims to elaborate the current knowledge on RANKL and OPG in periodontal disease, and to evaluate their diagnostic and prognostic potential as biomarkers of the disease.. To pursue this aim, electronic and manual searches were performed for identifying clinical and in vivo studies on RANKL and OPG in gingival tissue, gingival crevicular fluid, saliva and blood. Smoking and diabetes mellitus were also considered for their potential effects.. Papers fulfilling the inclusion criteria demonstrate that RANKL is up-regulated, whereas OPG is down-regulated in periodontitis, compared to periodontal health, resulting in an increased RANKL/OPG ratio. This ratio is further up-regulated in smokers and diabetics, and is not affected by conventional periodontal treatment.. The increased RANKL/OPG ratio may serve as a biomarker that denotes the occurrence of periodontitis, but may not necessarily predict on-going disease activity. Its steadily elevated levels post treatment may indicate that the molecular mechanisms of bone resorption are still active, holding an imminent risk for relapse of the disease. Additional adjunct treatment modalities that would "switch-off" the RANKL/OPG ratio may therefore be required.

Topics: Alveolar Bone Loss; Animals; Biomarkers; Dental Plaque; Diabetes Mellitus; Gingiva; Gingival Crevicular Fluid; Humans; Lymphocytes; Osteoblasts; Osteoporosis; Osteoprotegerin; Periodontal Ligament; Periodontitis; RANK Ligand; Saliva; Smoking

 Previous studies have reported conflicting results on the relation between serum osteoprotegerin (OPG) concentration and carotid intima media thickness (CIMT)..  The present study was conducted to investigate the relations between OPG, risk factors for cardiovascular diseases (CVD) and carotid intima media thickness (CIMT) in a large cross-sectional study including 6516 subjects aged 25-85years who participated in a population-based health survey..  CIMT increased significantly across tertiles of OPG after adjustment for traditional cardiovascular risk factors such as age, gender, smoking, total cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index (BMI), systolic blood pressure, CVD and diabetes mellitus (P<0.0001). There was a significant interaction between age and OPG (P=0.026). The risk of being in the uppermost quartile of CIMT was reduced (OR 0.52, 95% CI 0.30-0.88) with each standard deviation (SD) higher level of OPG in subjects <45years (n=444), whereas subjects ≥55years of age (n=4884) had an increased risk of being in the uppermost quartile of CIMT (OR 1.19, 95% CI 1.10-1.29) after adjustment for traditional CVD risk factors.. Age has a differential impact on the association between OPG and CIMT in a general population. The present findings may suggest that increased serum OPG does not promote early atherosclerosis in younger subjects.

Topics: Adult; Aged; Aged, 80 and over; Atherosclerosis; Blood Pressure; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Male; Middle Aged; Norway; Osteoprotegerin; Risk Factors; Tunica Intima; Tunica Media

Topics: Anorexia Nervosa; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Female; Glycoproteins; Humans; Kidney Diseases; Male; Multiple Myeloma; Osteitis Deformans; Osteoprotegerin; Prostatic Neoplasms; Reagent Kits, Diagnostic; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reference Values; Specimen Handling; Urinary Bladder Neoplasms

Vascular calcification, long thought to result from passive degeneration, involves a complex, regulated process of biomineralization resembling osteogenesis. Evidence indicates that proteins controlling bone mineralization are also involved in the regulation of vascular calcification. Artery wall cells grown in culture are induced to become osteogenic by inflammatory and atherogenic stimuli. Furthermore, osteoclast-like cells are found in calcified atherosclerotic plaques, and active resorption of ectopic vascular calcification has been demonstrated. In general, soft tissue calcification arises in areas of chronic inflammation, possibly functioning as a barrier limiting the spread of the inflammatory stimulus. Atherosclerotic calcification may be one example of this process, in which oxidized lipids are the inflammatory stimulus. Calcification is widely used as a clinical indicator of atherosclerosis. It progresses nonlinearly with time, following a sigmoid-shaped curve. The relationship between calcification and clinical events likely relates to mechanical instability introduced by calcified plaque at its interface with softer, noncalcified plaque. In general, as calcification proceeds, interface surface area increases initially, but eventually decreases as plaques coalesce. This phenomenon may account for reports of less calcification in unstable plaque. Vascular calcification is exacerbated in certain clinical entities, including diabetes, menopause, and osteoporosis. Mechanisms linking them must be considered in clinical decisions. For example, treatments for osteoporosis may have unanticipated effects on vascular calcification; the converse also applies. Further understanding of processes governing vascular calcification may yield new therapeutic options for vascular disease.

Topics: Animals; Arteriosclerosis; Calcinosis; Calcium-Binding Proteins; Diabetes Mellitus; Endpoint Determination; Extracellular Matrix Proteins; Glycoproteins; Humans; Matrix Gla Protein; Menopause; Mice; Mice, Knockout; Minerals; Osteogenesis; Osteopontin; Osteoporosis; Osteoprotegerin; Phosphates; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sialoglycoproteins

Patients with end-stage renal disease have greatly elevated risks of atherosclerotic disease. Vascular calcification in advanced atherosclerosis is a common feature in ESRD patients. Risk factors of atherosclerosis in ESRD patients are coronary risk factors such as hypertension, diabetes and hyperlipidemia and hyperphosphatemia. Bone associated proteins including osteopontin, matrix Gla protein and osteoprotegerin may be involved in the progression of atherosclerosis.

Topics: Arteriosclerosis; Calcium-Binding Proteins; Diabetes Complications; Diabetes Mellitus; Extracellular Matrix Proteins; Glycoproteins; Humans; Hyperlipidemias; Hypertension; Kidney Failure, Chronic; Matrix Gla Protein; Osteopontin; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Sialoglycoproteins

The biomarker Osteoprotegerin (OPG) is associated with coronary artery disease (CAD). The main purpose of this study was to evaluate the diagnostic value of OPG in healthy subjects and in patients with suspected angina pectoris (AP).. A total of 1805 persons were enrolled: 1152 healthy subjects and 493 patients with suspected AP. For comparison 160 patients with acute myocardial infarction (MI) were included. To uncover subclinical coronary atherosclerosis, a non-contrast cardiac-CT scan was performed in healthy subjects; while in patients with suspected AP a contrast coronary angiography was used to detect significant stenosis. OPG concentrations were analyzed and compared between groups. ROC-analyses were performed to estimate OPG cut-off values.. OPG concentrations increased according to disease severity with the highest levels found in patients with acute MI. No significant difference (p = 0.97) in OPG concentrations was observed between subgroups of healthy subjects according to severity of coronary calcifications. A significant difference (p < 0.0001) in OPG concentrations was found between subgroups of patients with suspected stable AP according to severity of CAD. ROC-analysis showed an AUC of 0.62 (95% CI: 0.57-0.67). The optimal cut-off value of OPG (<2.29 ng/mL) had a sensitivity of 56.2% (95% CI: 49.2-63.0%) and a specificity of 62.9% (95% CI: 57.3-68.2%).. OPG cannot be used to differentiate between healthy subjects with low versus high levels of coronary calcifications. In patients with suspected AP a single OPG measurement is of limited use in the diagnosis of CAD.

Topics: Angina Pectoris; Area Under Curve; Biomarkers; Calcinosis; Calcium; Comorbidity; Coronary Angiography; Coronary Artery Disease; Coronary Disease; Diabetes Mellitus; Female; Humans; Hyperlipidemias; Hypertension; Male; Middle Aged; Myocardial Infarction; Osteoprotegerin; ROC Curve; Sampling Studies; Severity of Illness Index; Smoking; Tomography, X-Ray Computed

Previous studies showed that subclinical abnormal left atrial (LA) function could be diagnosed with LA speckle tracking evaluation long before chamber enlargement. Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor superfamily and was recently found to be an indicator for adverse cardiovascular outcomes and a risk factor for new onset atrial fibrillation. The authors hypothesized that OPG values could predict LA mechanical dysfunction and LA remodeling assessed by two-dimensional speckle tracking echocardiography (2D-STE) in patients with hypertension (HT) and diabetes mellitus (DM).. A single center study was conducted including consecutive patients presenting to the authors' outpatient clinic. Enrolled patients needed to have been treated for HT and DM for at least 1 year.. The study included 80 patients (mean age, 57.5 ± 8.3 years). Patients in the impaired LA strain group were older (p = 0.035), had lower low density lipoprotein (LDL) cholesterol (mg/dl) (p = 0.021), and higher OPG (pmol/l) (p = 0.004) values than patients in the normal LA strain group. Univariate logistic regression analysis demonstrated that age (p = 0.039), LDL cholesterol (mg/dl) (p = 0.025), and OPG (pmol/l) (p = 0.008) values were associated with impaired LA strain. Backward multivariate logistic regression analysis showed that LDL cholesterol (mg/dl) (OR: 0.982, CI 95% 0.964-0.999, p = 0.049) and OPG (pmol/l) (OR: 1.438, CI 95% 1.043-1.983, p = 0.027) were independently associated with impaired LA strain.. In hypertensive and diabetic patients, higher OPG values were associated with impaired LA function assessed by 2D-STE. In this high-risk patient group, serum OPG can be used as a risk predictor for LA mechanical dysfunction.. ZIELSETZUNG: Frühere Studien belegen, dass eine subklinisch gestörte linksatriale (LA) Funktion mithilfe der linksatrialen Speckle-tracking-Analyse lange vor einer Kammervergrößerung diagnostiziert werden kann. Osteoprotegerin (OPG) gehört zur Familie der Tumor-Nekrose-Faktor(TNF)-Rezeptor-Superfamilie und wurde vor Kurzem als Indikator eines ungünstigen kardiovaskulären Verlaufs und als Risikofaktor für neu auftretendes Vorhofflimmern identifiziert. Es wird postuliert, dass die OPG-Werte bei Patienten mit Hypertonie (HT) und Diabetes mellitus (DM) ein Prädiktor für mechanische LA-Dysfunktion und LA-Remodeling in der zweidimensionalen Speckle-tracking-Echokardiographie (2D-STE) sind.. In eine Single-Center-Studie wurden konsekutiv Patienten eingeschlossen, die sich in der Klinik der Autoren ambulant vorstellten. Voraussetzung für den Einschluss war eine mindestens 1‑jährige Behandlung wegen HT und DM.. Insgesamt 80 Patienten wurden in die Studie eingeschlossen (Durchschnittsalter 57,5 ± 8,3 Jahre). Die Patienten in der Gruppe mit gestörtem LA-Strain waren älter (p = 0,035), hatten einen niedrigeren Low-density-Lipoprotein(LDL)-Cholesterin-Spiegel (mg/dl; p = 0,021) und höhere OPG-Spiegel (pmol/l; p = 0,004) als Patienten in der Gruppe mit normalem LA-Strain. Eine univariate logistische Regressionsanalyse ergab, dass das Alter (p = 0,039), LDL-Cholesterin (mg/dl; p = 0,025) und OPG (pmol/l; p = 0,008) mit einem gestörten LA-Strain assoziiert waren. In einer rückwärts gerichteten multivariaten logistischen Regressionsanalyse waren LDL-Cholesterin (mg/dl; OR 0,982, 95%-Konfidenzintervall [KI] 0,964–0,999, p = 0,049) und OPG (pmol/l; OR 1,438, 95%-KI 1,043–1,983, p = 0,027) unabhängig mit einem gestörten LA-Strain assoziiert.. Bei Patienten mit Hypertonie und Diabetes waren höhere OPG-Werte mit einer gestörten LA-Funktion in der 2D-STE assoziiert. In dieser Hochrisikogruppe kann der Serum-OPG-Spiegel als Risikoprädiktor der mechanischen LA-Dysfunktion genutzt werden.

Topics: Aged; Atrial Function, Left; Atrial Remodeling; Diabetes Mellitus; Heart Atria; Humans; Hypertension; Middle Aged; Osteoprotegerin

Elevated circulating levels of osteoprotegerin (OPG) are known to add to the prediction of cardiovascular mortality. Our objective was to clarify the long-term risk associated with serum OPG and the possible influence of diabetes and statins on OPG levels in patients with stable coronary artery disease (CAD).. We assessed the placebo-treated group (n = 1998) from the CLARICOR trial (NCT00121550), a cohort with stable CAD. At entry, 15% of the participants had diabetes and 41% received statins. Serum OPG levels were measured in blood drawn at randomization. Participants were followed through public registers for 10 years.. OPG levels correlated positively with diabetes status, age, CRP and female sex, but negatively with the use of statins. CAD participants with diabetes had significantly elevated serum OPG levels compared to participants without diabetes, p < 0.0001. The participants without diabetes treated with statins presented with significantly lower serum OPG levels than the corresponding non-statin-users (p < 0.0001). However, statin use showed no association with OPG levels in the participants with diabetes. High OPG levels at entry showed long-term associations with all-cause mortality and cardiovascular events (hazard ratio associated with factor 10 OPG increase 15.9 (95% CI 11.0-22.9) and 6.38 (4.60-8.90), p = 0.0001, even after adjustment for standard predictors (3.16 (1.90-5.25) and 2.29 (1.53-3.44), p < 0.0001).. Circulating OPG holds long-term independent predictive ability for all-cause mortality and cardiovascular events in CAD participants. OPG levels were associated with diabetes, age, and female sex and statin treatment was associated with lower OPG levels in the absence of diabetes.

Topics: Biomarkers; Coronary Artery Disease; Diabetes Mellitus; Female; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Osteoprotegerin; Risk Factors

Osteoprotegerin (OPG) plays protective roles against the development of vascular calcification (VC) which greatly contributes to the increased cardiovascular events in patients with chronic kidney disease (CKD). The present study aimed to find the non-traditional, kidney-related cardiovascular risk factors correlated to serum OPG and the effect of serum OPG on the arterial stiffness measured by brachial ankle pulse wave velocity (baPWV) in patients with the pre-dialysis CKD.. We cross-sectionally analyzed the data from the patients in whom baPWV and the serum OPG were measured at the time of enrollment in a prospective pre-dialysis CKD cohort study in Korea.. Along with traditional cardiovascular risk factors such as age, diabetes mellitus, pulse pressure, and baPWV, non-traditional, kidney-related factors such as albuminuria, plasma level of hemoglobin, total CO. Non-traditional, kidney-related cardiovascular risk factors in addition to traditional cardiovascular risk factors were related to serum level of OPG in CKD. Serum OPG level was significantly related to baPWV. Our study suggests that kidney-related factors involved in CKD-specific pathways for VC play a role in the increased secretion of OPG into circulation in patients with CKD.. ClinicalTrials.gov Identifier: NCT01630486.

Topics: Adult; Aged; Blood Pressure; Cardiovascular Diseases; Creatinine; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Linear Models; Male; Middle Aged; Osteoprotegerin; Pulse Wave Analysis; Renal Insufficiency, Chronic; Risk Factors; Vascular Stiffness

Arterial calcification (AC) is frequent in patients with end stage renal disease and is also considered a risk factor for later morbidity and mortality. However, long-term factors associated with the process are not well known. We analyzed the trends over time of biomarkers related with development and progression of AC in incident patients on peritoneal dialysis (PD).. We performed a prospective study with 186 patients on PD followed up for 1 year. We analyzed the progression of AC in the abdominal aorta and pelvic vessels by calcification score (CaSc), using16-cut computerized multidetector tomography at baseline and 1 year. Variables related with PD treatment, inflammation, and mineral metabolism were measured at baseline, 6, and 12 months of follow-up. Changes in biochemical variables were analyzed for their relationship with changes in AC.. Over 1 year, the number of patients with AC increased from 47 to 56%, and CaSc from 355 (interquartile range [IQR] 75-792) to 529 (IQR 185-1632). A total of 43.5% of patients remained free of calcification, 11.7% had new calcifications, and 44.8% had progression of calcification. Older age, diabetes, high systolic blood pressure, body mass index, cholesterol, and osteoprotegerin (OPG), as well as lower levels of albumin, serum creatinine, and osteocalcin, were associated with development of new, and rapid progression of, calcification. In multivariate logistic analysis, OPG remained the most significant (OR 1.27, 95% CI 1.11-1.47, p < 0.001).. OPG was the strongest risk factor associated with new development and rapid progression of AC in incident PD patients.

Topics: Adult; Age Factors; Aorta, Abdominal; Biomarkers; Diabetes Mellitus; Disease Progression; Female; Follow-Up Studies; Humans; Incidence; Kidney Failure, Chronic; Male; Mexico; Middle Aged; Osteoprotegerin; Peritoneal Dialysis; Prospective Studies; Risk Factors; Vascular Calcification; Young Adult

Biomechanical stress and inflammatory biomarkers relate to global contractility dysfunction; however, adding these biomarkers into a risk model constructed on clinical data does not improve its prediction value in chronic heart failure (CHF).. The aim of this study was to evaluate whether biomarkers predict declining of left ventricular global contractility function in diabetic patients with ischemia-induced CHF.. The study retrospectively evolved 54 diabetic patients who had systolic or diastolic ischemia-induced CHF that was defined as left-ventricular ejection fraction (LVEF) ≤45% or 46-55% respectively assessed by quantitative echocardiography and other conventional criteria according to current clinical guidelines. Two-dimensional transthoracic echocardiography and tissue Doppler imaging were performed according to a conventional method. Radial, longitudinal, and circumferential strain and strain rate values were obtained by speckle-tracking Imaging analysis of both LV short axis and long axis views. Serum adiponectin, NT-pro brain natriuretic peptide (BNP), osteoprotegerin, and hs- C-reactive protein (CRP) were determined at baseline by ELISA.. We found lower global longitudinal strain and strain rate in diabetic patients with LVEF <45% than these in diabetic patients that did not have LVEF (Р=0.001 for all cases). Multivariate logistic regression analysis showed that NT-proBNP (r=0.432; P=0.001 and r=0.402; P=0.001, respectively), osteoprotegerin (r=0.422; P=0.001 and r=0.401; P=0.001, respectively), hs-CRP (r=0.408; P=0.001 and r=0.404; P=0.001, respectively) were independently inversely associated with global longitudinal strain and strain rate in CHF patients.. We suggest that osteoprotegerin may be useful in improving the NT-proBNP based model as predictor of decreased global contractility function in diabetic patients with CHF.

Topics: Biomarkers; Diabetes Mellitus; Female; Heart Failure; Humans; Kidney Function Tests; Male; Middle Aged; Natriuretic Peptide, Brain; Osteoprotegerin; Peptide Fragments; Retrospective Studies; Risk Factors; Ventricular Dysfunction, Left

This cross-section study was designed to assess the effect of topical application of melatonin to the gingiva on salivary RANKL, osteoprotegrin (OPG) and melatonin levels as well as plasma melatonin in 30 patients with diabetes and periodontal disease and in a control group of 30 healthy subjects. Salivary RANKL and OPG were measured by enzyme-linked immunosorbent assay and salivary and plasma melatonin by radioimmunoassay using commercial kits. Periodontograms were performed using the Florida Probe(®). Diabetic patients were treated with topical application of melatonin (1% orabase cream formula) once daily for 20 days. Patients with diabetes showed significantly higher mean levels of salivary RANKL than healthy subjects as well as significantly lower values of salivary OPG and salivary and plasma melatonin. After treatment with melatonin, there was a statistically significant decrease of the gingival index, pocket depth and salivary levels of RANKL, and a significant rise in salivary values of OPG. Changes of salivary OPG levels before and after topical melatonin treatment correlated significantly with changes in the gingival index and pocket depth. Treatment with topical melatonin was associated with an improvement in the gingival index and pocket depth, a reduction in salivary concentrations of RANKL and increase in salivary concentrations of OPG, which indicates that melatonin has a favorable effect in slowing osteoclastogenesis, improving the quality of alveolar bone and preventing the progression of periodontal disease.

Topics: Administration, Topical; Adult; Aged; Diabetes Mellitus; Female; Gingiva; Humans; Male; Melatonin; Middle Aged; Osteoprotegerin; Periodontal Diseases; RANK Ligand; Saliva

Abdominal aortic calcification (AC) has been reported to be associated with cardiovascular disease (CVD) in hemodialysis patients but is rarely discussed in peritoneal dialysis (PD) patients. We examined the independent predictors and predictive power for survival of AC in prevalent PD patients.. AC was detected by computed tomography (CT) and represented as the percentage of the total aortic cross-section area affected by AC (%AC). The predictors of %AC ≥ 15 were examined by multiple logistic regression analysis. Cox proportional hazard analysis was used to determine the hazard ratios associated with high %AC. A total of 183 PD patients were recruited to receive CT scans and divided into group 1 (%AC < 15, n = 97), group 2 (%AC ≥ 15, n = 41), and group 3 (diabetic patients, n = 45). Group 1 patients had lower osteoprotegerin (OPG) levels than group 2 patients (798 ± 378 vs. 1308 ± 1350 pg/mL, p < 0.05). The independent predictors for %AC ≥ 15 included the atherogenic index, OPG, and C-reactive protein (CRP). The age-adjusted hazard ratios associated with %AC ≥ 15 were 3.46 (p = 0.043) for mortality and 1.90 (p = 0.007) for hospitalization.. %AC can predict mortality and morbidity in non-diabetic PD patients, and 15% is a good cut-off value for such predictions. There are complex associations among mineral metabolism, inflammation, and dyslipidemia in the pathogenesis of AC.

Topics: Adult; Aged; Aorta, Abdominal; Biomarkers; C-Reactive Protein; Calcinosis; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Mellitus; Dyslipidemias; Female; Follow-Up Studies; Humans; Inflammation; Male; Middle Aged; Osteoprotegerin; Peritoneal Dialysis; Prospective Studies; Taiwan; Tomography, X-Ray Computed

Vascular calcification is common among patients undergoing dialysis and is associated with mortality. Factors such as osteoprotegerin (OPG), osteopontin (OPN), bone morphogenic protein-7 (BMP-7), and fetuin-A are involved in vascular calcification.. OPG, OPN, BMP-7, and fetuin-A were measured in blood samples from 602 incident dialysis patients recruited from United States dialysis centers between 1995 and 1998 as part of the Choices for Healthy Outcomes In Caring for ESRD Study. Their association with all-cause and cardiovascular mortality were assessed using Cox proportional hazards models adjusted for demographic characteristics, comorbidity, serum phosphate, and calcium. An interaction with diabetes was tested because of its known association with vascular calcification. Predictive accuracy of selected biomarkers was explored by C-statistics in nested models with training and validation subcohorts.. Higher OPG and lower fetuin-A levels were associated with higher mortality over up to 13 years of follow-up (median, 3.4 years). The adjusted hazard ratios (HR) for highest versus lowest tertile were 1.49 (95% confidence interval [95% CI], 1.08 to 2.06) for OPG and 0.69 (95% CI, 0.52 to 0.92) for fetuin-A. In stratified models, the highest tertile of OPG was associated with higher mortality among patients without diabetes (HR, 2.42; 95% CI, 1.35 to 4.34), but not patients with diabetes (HR, 1.26; 95% CI, 0.82 to 1.93; P for interaction=0.001). In terms of cardiovascular mortality, higher fetuin-A was associated with lower risk (HR, 0.85 per 0.1 g/L: 95% CI, 0.75 to 0.96). In patients without diabetes, higher OPG was associated with greater risk (HR for highest versus lowest tertile, 2.91; 95% CI, 1.06 to 7.99), but not in patients with diabetes or overall. OPN and BMP-7 were not independently associated with outcomes overall. The addition of OPG and fetuin-A did not significantly improve predictive accuracy of mortality.. OPG and fetuin-A may be risk factors for all-cause and cardiovascular mortality in patients undergoing dialysis, but do not improve risk prediction.

Topics: Adult; Aged; alpha-2-HS-Glycoprotein; Biomarkers; Bone Morphogenetic Protein 7; Chi-Square Distribution; Comorbidity; Diabetes Mellitus; Female; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Osteopontin; Osteoprotegerin; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Renal Dialysis; Risk Assessment; Risk Factors; United States; Vascular Calcification

Recently, the role of osteoprotegerin (OPG) in the pathogenesis of heart failure through different mechanisms has received much attention. Subclinical changes in left ventricular (LV) function can be identified using quantification of myocardial strain, and global longitudinal strain (GLS) is a superior predictor of outcomes than ejection fraction. We hypothesized that increased OPG levels could predict subclinical LV systolic dysfunction in treated diabetic hypertensive patients with preserved LV ejection fraction.. The study was composed of 86 diabetic hypertensive and 30 nondiabetic hypertensive patients. All patients underwent echocardiography and venous blood samples were taken for determination of OPG. The relation between OPG levels and LV GLS was investigated using 2-dimensional speckle tracking echocardiography.. Diabetic hypertensive patients had higher diastolic peak early/early diastolic tissue velocity and lower systolic tissue velocity, GLS, GLS rate systolic, and GLS rate early diastolic than nondiabetic hypertensive patients (P = 0.009, P = 0.049, P < 0.001, P = 0.004, and P < 0.001, respectively). Diabetic hypertensive patients were divided into 2 groups according to median GLS value (> 18.5 and ≤ 18.5). The patients with GLS ≤ 18.5 had higher diastolic blood pressure (mm Hg; P = 0.048), OPG (pmol/L; P < 0.001), and hemoglobin A1c (%; P = 0.042) values than those with GLS > 18.5. In multivariate logistic regression analysis, OPG was found to be an independent predictor of impaired GLS (P = 0.001). Receiver operating characteristic curve analysis revealed that OPG values of > 6.45 (pmol/L) identified the patients with GLS ≤ 18.5.. Plasma OPG values could predict subclinical LV systolic dysfunction in diabetic hypertensive patients.

Topics: Aged; Cross-Sectional Studies; Diabetes Mellitus; Echocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Osteoprotegerin; Prognosis; Retrospective Studies; Stroke Volume; Systole; Ventricular Dysfunction, Left; Ventricular Function, Left

Topics: Diabetes Mellitus; Echocardiography; Female; Humans; Male; Myocardial Infarction; Osteoprotegerin; Percutaneous Coronary Intervention; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left

Diabetes mellitus (DM) may alter bone remodeling, as osteopenia and osteoporosis are among the complications. Moreover, DM increases the risk and severity of chronic inflammatory periodontal disease, in which bone resorption occurs. Broad evidence suggests that chronic inflammation can contribute to the development of DM and its complications. Hyperglycemia is a hallmark of DM that may contribute to sustained inflammation by increasing proinflammatory cytokines, which are known to cause insulin resistance, via toll-like receptor (TLR)-4-mediated mechanisms. However, the mechanisms by which bone-related complications develop in DM are still unknown. Studies done on the effect of high glucose concentrations on osteoblast functions are contradictory because some suggest increases (although others suggest reductions) in the biomineralization process. Therefore, we evaluated the effect of high glucose levels on biomineralization and inflammation markers in a human osteoblastic cell line. Cells were treated with either physiological 5.5 mM or increasing concentrations of glucose up to 24 mM, and we determined the following: i) the quantity and quality of calcium-deposit crystals in culture and ii) the expression of the following: a) proteins associated with the process of biomineralization, b) the receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG), c) cytokines IL1, IL6, IL8, IL10, MCP-1 and TNF alpha, and d) TLR-2, -3, -4 and -9. Our results show that high glucose concentrations (12 mM and particularly 24 mM) alter the biomineralization process in osteoblastic cells and provoke the following: i) a rise in mineralization, ii) an increase in the mRNA expression of RANKL and a decrease of OPG, iii) an increase in the mRNA expression of osteocalcin, bone sialoprotein and the transcription factor Runx2, iv) a diminished quality of the mineral, and v) an increase in the expression of IL1beta, IL6, IL8, MCP-1 and IL10 mRNAs. In addition we found that both high glucose levels and hyperosmotic conditions provoked TLR-2, -3, -4 and -9 overexpression in osteoblastic cells, suggesting that they are susceptible to osmotic stress.

Topics: Alkaline Phosphatase; Bone Remodeling; Calcification, Physiologic; Calcium; Cells, Cultured; Cytokines; Diabetes Mellitus; Glucose; Humans; Osteoblasts; Osteoprotegerin; RANK Ligand; RNA, Messenger; Toll-Like Receptors

Atherosclerosis is the main cause of cardiovascular disease, but the extent of atherosclerosis in individual patients is difficult to estimate. A biomarker of the atherosclerotic burden would be very valuable. The aim of the present study was to evaluate the association of plasma osteoprotegerin (OPG) to clinical and subclinical atherosclerotic disease in a large community-based, cross-sectional population study. In the Copenhagen City Heart Study, OPG concentrations were measured in 5,863 men and women. A total of 494 participants had been hospitalized for ischemic heart disease or ischemic stroke, and compared to controls, this group with clinical atherosclerosis had higher mean OPG (1,773 vs 1,337 ng/L, p <0.001) and high-sensitivity C-reactive protein (2.3 vs 1.6 mg/L, p <0.001). In a multivariate model with age, gender, body mass index, hypertension, diabetes, hypercholesterolemia, smoking status, estimated glomerular filtration rate, high-sensitivity C-reactive protein, and OPG, OPG remained significantly associated with clinical atherosclerosis (p <0.01); high-sensitivity C-reactive protein, in contrast, did not (p = 0.74). In the control group without clinical atherosclerosis, OPG was independently associated with hypertension, diabetes, hypercholesterolemia, smoking, and subclinical peripheral atherosclerosis as measured by ankle brachial index. For each doubling of the plasma OPG concentration, the risk for subclinical peripheral atherosclerosis increased by 50% (p <0.001) after multivariate adjustment. In conclusion, OPG appears to be a promising biomarker of atherosclerosis that is independently associated with traditional risk factors of atherosclerosis, subclinical peripheral atherosclerosis, and clinical atherosclerotic disease such as ischemic heart disease and ischemic stroke.

Topics: Adult; Aged; Aged, 80 and over; Ankle Brachial Index; Atherosclerosis; Biomarkers; C-Reactive Protein; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Hypercholesterolemia; Hypertension; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Risk Factors; Smoking; Young Adult

Recent studies in mice have demonstrated that insulin signaling in osteoblasts stimulates bone formation and reduces osteoprotegerin production; the latter results in an increase in bone resorption, which then leads to the release of undercarboxylated osteocalcin from bone. Undercarboxylated osteocalcin, in turn, enhances insulin sensitivity.. The objective of the study was to test whether physiological changes in insulin levels regulate bone metabolism in humans.. This investigation was an analysis of samples from a prospective study.. The study was conducted at a clinical research unit.. Fourteen subjects underwent a 7-h stepped insulin infusion accompanied by a glucose clamp and somatostatin infusion along with replacement infusions of GH and glucagon, thus isolating possible effects of insulin on bone. Insulin was infused at rates achieving low (∼150 pmol/liter), intermediate (∼350 pmol/liter), or high (∼700 pmol/liter) plasma insulin levels.. Bone turnover markers, undercarboxylated osteocalcin, and osteoprotegerin levels at the end of the low, intermediate, and high dose insulin infusions were measured.. Values for the outcome measures at the end of the intermediate- and high-dose insulin infusions were no different from values at the end of the low-dose insulin infusion. However, measures of insulin sensitivity (glucose infusion and disappearance rates) correlated positively with C-terminal telopeptide of type I collagen levels.. Acute changes in insulin levels, as occur during meals, do not regulate bone turnover, undercarboxylated osteocalcin, or osteoprotegerin levels. However, the correlation of measures of insulin sensitivity with bone resorption suggests the need for further studies in humans on the possible regulation of bone metabolism by insulin.

Topics: Absorptiometry, Photon; Biomarkers; Blood Glucose; Bone and Bones; C-Peptide; Diabetes Mellitus; Endpoint Determination; Female; Glucagon; Glucose Clamp Technique; Human Growth Hormone; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Osteocalcin; Osteoprotegerin; Peptide Fragments; Procollagen; Prospective Studies

The aim of the study was to assess the factors potentially involved in coronary artery calcifications (CAC) in end-stage renal disease patients. 253 hemodialysis (HD) patients (92 females, 161 males), aged 62.5 +/- 13.5, who had been on HD treatment for at least 6 months, were enrolled in a cross-sectional study. Calcium-phosphate product (Ca x P), body mass index (BMI), fetuin-A, osteoprotegerin (OPG), osteopontin, transforming growth factor-beta1 (TGF-beta1), fibroblast growth factor-23 (FGF-23) and matrix Gla protein (MGP) were considered. CAC was assessed using multislice spiral computed tomography and calcium score was quantified by means of the Agatston score. The median calcium score was 364 Agatston (range 0-7,336). CAC was detected in 228/253 patients (90.1%). Multivariate regression analysis, adjusted for age and for dialysis vintage, showed that TGF-beta1, OPG and days with Ca x P >55 mg/dl are independent predictors of CAC, while MGP was shown to be a protective factor. Surprisingly, results showed that BMI was a protective factor too: the interpolation with cubic spline function revealed a significant reduction in calcium score in patients with a high BMI (>28). However, when diabetes was considered in the regression analysis, only OPG emerged as a predictor of a high CAC score. The interpolation with spline function continued to show a significant reduction in CAC score in nondiabetic and in diabetic patients with the highest BMI quartile. The protective effect of a high BMI on CAC might represent another example of inverse biology in dialysis patients but it needs to be further addressed in larger longitudinal studies.

Topics: Adult; Aged; Body Mass Index; Calcinosis; Calcium; Cardiomyopathies; Cross-Sectional Studies; Diabetes Mellitus; Female; Fibroblast Growth Factor-23; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osteoprotegerin; Transforming Growth Factor beta1

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

Despite accumulating evidence showing that TNF-related apoptosis inducing ligand (TRAIL) plays a role in vascular biology and that its decoy receptor osteoprotegerin (OPG) is expressed in the vessel wall, modulation of these TNF and TNF-R family members in the early phases of diabetes mellitus has not been investigated. The expression of TRAIL and of OPG was examined both at the mRNA and protein levels in control and streptozotocin (SZT)-induced diabetic rats at early time points after the induction of diabetes mellitus. No differences in the steady-state mRNA levels of TRAIL were noticed by quantitative RT-PCR among the two groups of animals. On the other hand, diabetic rats showed a rapid and significant increase of the steady-state mRNA levels of OPG in the aortic wall of diabetic animals with respect to vehicle-treated (control) animals. These findings were confirmed at the protein level by analysing the amount of TRAIL and OPG proteins in aortic lysates by either Western blot or immunohistochemistry. Thus, an abnormal elevation of the OPG/TRAIL ratio in the vessel wall characterizes the early onset of diabetes mellitus and might represent a molecular mechanism involved in the vascular dysfunction characterizing diabetes mellitus.

Topics: Animals; Aorta; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Gene Expression Regulation; Male; Osteoprotegerin; Rats; Rats, Wistar; RNA, Messenger; TNF-Related Apoptosis-Inducing Ligand

The bone-related protein osteoprotegerin (OPG) may be involved in the development of vascular calcifications, especially in diabetes, where it has been found in increased amounts in the arterial wall. Experimental studies suggest that members of the TGF-superfamily are involved in the transformation of human vascular smooth muscle cells (HVSMC) to osteoblast-like cells. In this study, we evaluated the effect of BMP-2, BMP-7 and transforming growth factor beta (TGF-beta1) on the secretion and mRNA expression of OPG and its ligands receptor activator of nuclear factor-kappabeta ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL) in HVSMC. All three growth factors decreased OPG protein production significantly; these results were paralleled by reduced OPG mRNA expression. TRAIL mRNA levels were also decreased. RANKL mRNA expression declined when treated with TGF-beta1 but were increased by both BMPs. Members of the TGF-superfamily, i.e. TGF-beta1, BMP-2 and BMP-7 exert effects on OPG and its ligands, indicating that these peptides may be involved in the development of vascular calcifications. The downregulation of OPG by these peptides does, however, not suggest that these factors are directly involved in OPG accumulation in diabetes.

Topics: Actins; Bone Morphogenetic Proteins; Calcinosis; Cells, Cultured; Diabetes Mellitus; Humans; Muscle, Smooth, Vascular; Osteoprotegerin; RANK Ligand; RNA, Messenger; TNF-Related Apoptosis-Inducing Ligand; Transforming Growth Factor beta

We examined the association between serum osteoprotegerin (OPG) levels, systemic inflammation and arterial stiffness in normal and diabetic patients.. The study subjects comprised 49 newly diagnosed diabetic patients and 72 age- and sex-matched normal glucose controls. Anthropometric parameters, blood pressure, fasting blood glucose (FBG), lipid profiles, serum OPG, high-sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and brachial-ankle pulse wave velocity (baPWV) were measured.. Serum OPG levels (6.1 +/- 1.4 vs. 5.4 +/- 1.3 pmol/l, P = 0.011) and baPWV (1562 +/- 354 vs. 1399 +/- 257 cm/s, P = 0.004) were significantly higher in the diabetic group than in the normal glucose group. Serum OPG levels in normal and diabetic patients correlated significantly with systolic blood pressure (r = 0.20, P = 0.035), FBG (r = 0.30, P = 0.002), right baPWV (r = 0.22, P = 0.021), left baPWV (r = 0.26, P = 0.006), homeostasis model assessment insulin resistance (HOMA-IR) (r = 0.19, P = 0.045), IL-6 (r = 0.32, P = 0.001) and hsCRP (r = 0.21, P = 0.027) after adjusting for age and sex. Multiple regression analysis showed that serum OPG level was significantly associated with age, FBG, IL-6, systolic blood pressure, triglyceride and hsCRP (R(2) = 0.299).. In summary, serum OPG and baPWV levels are elevated in diabetic patients and serum OPG levels are significantly associated with inflammation and arterial stiffness.

Topics: Biomarkers; Blood Glucose; Brachial Artery; C-Reactive Protein; Case-Control Studies; Diabetes Mellitus; Female; Glycoproteins; Humans; Hypertension; Inflammation; Insulin Resistance; Interleukin-6; Lipids; Male; Middle Aged; Osteoprotegerin; Pulsatile Flow; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Regression Analysis; Signal Processing, Computer-Assisted; Systole; Triglycerides

Osteoprotegerin (OPG) and its ligand are cytokines that regulate osteoclastogenesis and that may be involved in the regulation of vascular calcification. We examined whether serum OPG levels were associated with stroke, mortality, and cardiovascular risk factors, including diabetes, as well as with bone mineral density and fractures in a sample of 490 participants in a prospective cohort of white women, at least 65 yr of age. We found that OPG levels, assayed blinded from serum obtained at baseline, were about 30% greater in women with diabetes (mean +/- SD, 0.30 +/- 0.17 ng/mL) than in those without diabetes (0.23 +/- 0.10 ng/mL; P = 0.0001). OPG levels were associated with all-cause mortality [age-adjusted odds ratio, 1.4/SD (0.11 ng/mL) increase in serum OPG level; 95% confidence interval, 1.2--1.8] and cardiovascular mortality (odds ratio, 1.4; 95% confidence interval, 1.1--1.8); these effects were not confounded by diabetes. OPG levels were not associated with baseline bone mineral density or with subsequent strokes or fractures. The association of serum OPG levels with diabetes and with cardiovascular mortality raises the possibility that OPG may be a cause of or a marker for vascular calcification.

Topics: Aged; Biomarkers; Blood Pressure; Bone Density; Cardiovascular Diseases; Cause of Death; Cohort Studies; Confidence Intervals; Diabetes Mellitus; Estrogen Replacement Therapy; Female; Fractures, Bone; Glycoproteins; Humans; Mortality; Observer Variation; Odds Ratio; Osteoprotegerin; Prospective Studies; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; San Francisco; Smoking; Stroke; White People