osteoprotegerin and Diabetic-Angiopathies

Vascular calcification (VC), a disorder that causes blood vessel hardening and dysfunction, is a significant risk factor for type-2 diabetes mellitus (T2DM), which invariably manifests associated cardiovascular complications. Although the clinical effects of VC have been well-documented, the precise cellular events underlying the manifestation and progression of VC are only now coming to light. Current research models indicate that VC likely involves signalling pathways traditionally associated with bone remodelling, such as the OPG/RANKL/TRAIL signalling system. In this respect, receptor activator of NF-κB ligand (RANKL) promotes VC whilst osteoprotegerin (OPG) acts as a RANKL decoy receptor to block this effect, events that contrast with the known functional influence of these proteins during bone metabolism. Moreover, evidence suggests that tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), an alternative decoy ligand for OPG, may exert an anti-calcific influence within the vasculature. In the current review, we conduct a timely examination of this complex VC pathology from both mechanistic and therapeutic perspectives. Our objectives are twofold: (i) to critically assess our current understanding of both osteogenic and vascular calcification pathways, with particular focus on the co-interactive roles of OPG, RANKL, and TRAIL. Extensive in vitro, in vivo, and clinical studies will therefore be reviewed and critical findings highlighted; and (ii) to examine a range of therapeutic approaches of potential relevance to VC pathology. In this regard, a clear focus on VC as it applies to T2DM and cardiovascular disease (and particularly atherosclerosis) will be maintained.

Topics: Animals; Arteries; Atherosclerosis; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Humans; Osteoblasts; Osteoclasts; Osteogenesis; Osteoprotegerin; Plaque, Atherosclerotic; RANK Ligand; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Vascular Calcification

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

Osteoprotegerin (OPG) is a bone-related protein that is also present in the vasculature. Recent data suggest that it may play a special role in arterial disease among patients with diabetes. Diabetic macroangiopathy is characterized by a series of diffuse, non-atherosclerotic alterations that hypothetically increase the vulnerability of the vessel wall to atherogenic processes. One prominent feature of the macroangiopathy is linear media calcifications, which have been found to impose a strong risk of future cardiovascular events in epidemiological studies. The mechanisms behind the development of calcifications are unknown, but may be related to the occurrence of diffuse matrix alterations in the arterial wall in diabetes. Interestingly, we have recently observed that the amounts of OPG are increased in the tunica media in arterial tissue from diabetic patients. OPG has been linked to vascular calcifications in immunohistochemical analysis of atherosclerotic tissue and experimental studies on OPG knockout mice. Thus, it is possible that increased arterial OPG concentrations reflect an osteogenic transformation of the vasculature in patients with diabetes as an aspect of diabetic macroangiopathy. This review will evaluate data about OPG in the vasculature and focus on a possible role of OPG in the arterial wall in diabetes.

Topics: Animals; Arteriosclerosis; Calcinosis; Diabetic Angiopathies; Endothelium, Vascular; Glycoproteins; Humans; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor

Topics: Albuminuria; Atherosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Double-Blind Method; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Osteoprotegerin; Simvastatin

Type 2 Diabetes Mellitus is a chronic metabolic disease that causes endothelial damage and is an important risk factor for atherosclerosis. In the present study vitamin D3 supplementation in rats was used to determine the role of Osteoprotegerin (OPG)/Receptor activator kB ligand (RANKL) signalling in endothelial damage and changes in the expression levels of genes involved in this pathway. We hypothesized that vitamin D3 supplementation affects OPG and RANKL activity in the aorta.. Diabetes was induced in rats via injections of 40 mg/kg of streptozotocin followed by a high fructose (10%) diet. Group 2 (healthy) and 4 (diabetic) received 170 IU/kg of vitamin D3 weekly for 5 weeks, while Group 1 (healthy) and 2 (diabetic) received sterile saline. The aortas of each group were collected to analyse mRNA expression using the real-time PCR method and also to evaluate magnesium and calcium levels using inductively coupled plasma mass spectrometry.. Opg and Il-1b expression levels were significantly associated with both diabetes and vitamin D3 supplementation in the aortas of the study groups (p ≤ 0.05). Opg mRNA expression was also found to correlate with both Icam-1 and Nos3 mRNA expression levels (r = 0.699, p = 0.001 and r = 0.622, p = 0.003, respectively). In addition, when mineral levels in the aortic tissues were compared among all groups, it was found that the interaction of diabetes and vitamin D3 supplementation significantly affected Mg levels and Mg/Ca ratios.. It is concluded that vitamin D3 supplementation has a modulatory effect on OPG/RANKL activity in the vessel wall by ameliorating endothelial damage in diabetes. This effect may contribute to the regulation of cytokine-mediated vascular homeostasis and mineral deposition in the aorta; therefore, further comprehensive studies are proposed to demonstrate this relationship.

Topics: Animals; Aorta; Calcium-Regulating Hormones and Agents; Cholecalciferol; Diabetic Angiopathies; Endothelium, Vascular; Gene Expression Regulation; Osteoprotegerin; RANK Ligand; Rats; Signal Transduction; Treatment Outcome

Osteoprotegerin (OPG) is a tumor necrosis factor receptor super-family member. It specifically acts on bone by increasing bone mineral density and bone volume. Recent studies have evidenced its close relation to the development of atherosclerosis and plaque destabilization. Elevated OPG level has also been associated with the degree of coronary calcification in the general population and it has been considered to be a marker of coronary atherosclerosis.. The aim of this study was to determine the relation between OPG levels and Coronary Artery Calcification score (CACs) in Type 2 diabetic patients in comparison to healthy controls.. Our study included 45 type 2 diabetic patients (mean age 51.7 years; 51.1% male) without evidence of previous CVD and 45 healthy age and sex matched subjects as control. All participants were subjected to full history, full examination and lab investigations. Serum OPG concentration was measured by an enzyme-linked immunosorbent assay (ELISA) and CAC imaging was performed using non contrast Multi detector CT of the heart.. Significant CAC (<10 Agatston units) was seen in 23 patients (51.11 %). OPG was significantly high in diabetic patients in comparison to controls with mean 12.9±5.7 pmol/l in cases, and 8.6±0.5 pmol/l in controls (P value < 0.001). The Coronary Artery Calcification Score (CACS) was positively correlated with age and duration of diabetes. The OPG was positively correlated with age, fasting blood sugar and duration of diabetes. The CACS showed a significantly positive correlation with OPG.. Findings suggested that increasing in serum OPG was consistent with CAC and could be used for the early diagnosis of subclinical atherosclerosis.

Topics: Adult; Asymptomatic Diseases; Atherosclerosis; Biomarkers; Calcinosis; Case-Control Studies; Coronary Artery Disease; Coronary Vessels; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Multidetector Computed Tomography; Osteoprotegerin; Predictive Value of Tests; Severity of Illness Index

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

To assess serum levels of the plaque calcification regulators osteoprotegerin (OPG) and Matrix Gla-proteins (MGP) in individuals with stable angina and acute myocardial infarction submitted to coronary angiography and their relation to coronary artery disease burden.. The study included 40 individuals affected by ST-elevation myocardial infarction (STEMI) and 40 individuals with stable angina who all underwent coronary angiography, with evaluation of the extent of coronary artery disease by Syntax Score calculation and measurement of serum OPG and MGP levels. Osteoporosis was excluded by femoral and vertebral computerized bone mineralometry.. Serum OPG and MGP levels were respectively 3.87 ± 1.07 pmol/l and 6.80 ± 2.43 nmol/l in the stable angina group, 7.57 ± 1.5 pmol/l and 7.18 ± 1.93 nmol/l in the STEMI group (P < 0.01 and P = 0.33, respectively). Pearson correlation coefficient for OPG and Syntax Score, MGP and Syntax score was respectively 0.79 (P < 0.01) and 0.18 (P = 0.22) in the stable angina group, -0.03 (P = 0.43) and 0.10 (P = 0.5) in the STEMI group.Serum OPG and MGP levels were respectively 5.52 ± 1.02 pmol/l and 7.56 ± 1.42 nmol/l in diabetics, 4.3 ± 0.8 pmol/l and 6.52 ± 1.14 nmol/l in nondiabetics (P < 0.05; P < 0.05).. OPG, in a relatively small group of patients with stable angina, correlates proportionally with the extent of coronary artery disease (CAD), as evaluated by the Syntax Score. Higher serum OPG levels can be observed in individuals with STEMI regardless of CAD burden. As for MGP, a potential role as marker of plaque calcification remains unproven.

Topics: Aged; Angina, Stable; Biomarkers; Bone Density; Calcinosis; Calcium-Binding Proteins; Coronary Angiography; Coronary Artery Disease; Diabetic Angiopathies; Extracellular Matrix Proteins; Humans; Male; Matrix Gla Protein; Middle Aged; Myocardial Infarction; Osteoprotegerin

Osteoprotegerin (OPG), which was recently identified as a vascular marker, is increased in patients with diabetes mellitus (DM). This study evaluated the frequency of the OPG gene single nucleotide A163G polymorphism and its association with diabetic microvascular and macrovascular complications.. The A163G polymorphism of the OPG gene was assessed in the peripheral blood of 116 patients with type 2 DM and 107 healthy subjects by polymerase chain reaction and restriction fragment length polymorphism. Microvascular and macrovascular complications were evaluated in diabetic patients.. Statistical analysis showed no significant difference in distribution of the OPG A163G polymorphism in the diabetic and control groups. Similarly, this polymorphism was not associated with microvascular or macrovascular complications.. This OPG polymorphism does not play a role in the development of microvascular and macrovascular complications in patients with DM.

Topics: Adult; Aged; Base Sequence; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Male; Middle Aged; Molecular Sequence Data; Osteoprotegerin; Polymorphism, Genetic

Osteoprotegerin (OPG) is a glycoprotein from tumour necrosis factor receptor superfamily, responsible for osteoclastogenesis inhibition and associated with arterial calcification and stiffness. We describe the association between metabolic syndrome (MS) and OPG in type 2 diabetes mellitus patients.. We consecutively enrolled 1220 patients from our institution's Diabetes Centre from August 2011. Anthropometric data such as fasting blood/urine were obtained, and OPG was measured by enzyme-linked immunosorbent assay (ELISA).. Mean (standard deviation (SD)) of age and diabetes duration was 57.4 (10.9) years and 11.2 (8.9) years, respectively. Prevalence of MS was 64.3% (95% confidence interval (CI): 61.3%-67.2%) and associated with significantly higher OPG (5.44 vs 4.47 pmol/L) and microvascular complications. The presence of microvascular complications was associated with higher OPG: nephropathy (5.54 (2.20) vs 4.65 (1.70) pmol/L, p < 0.0001), neuropathy (6.33 (2.64) vs 5.06 (1.91) pmol/L, p < 0.0001) and retinopathy (6.08 (2.47) vs 5.00 (1.95) pmol/L, p < 0.0001). After adjusting for age, gender, ethnicity, glucose and microvascular complications, OPG remained an independent predictor of MS: (odds ratio (OR) = 1.102 (95% CI: 1.015-1.196), p = 0.021).. Higher OPG levels were associated with risk of MS and microvascular complications. Studies are needed to test whether OPG could be a useful biomarker identifying patients at risk of vascular complications and whether further exploration of this pathway may lead novel therapeutic options.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Chi-Square Distribution; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Logistic Models; Male; Metabolic Syndrome; Microcirculation; Microvessels; Middle Aged; Odds Ratio; Osteoprotegerin; Predictive Value of Tests; Prevalence; Risk Factors; Singapore; Up-Regulation; Young Adult

Osteoprotegerin (OPG) is a secretory glycoprotein that belongs to the tumor necrosis factor receptor family and plays a role in atherosclerosis. OPG has been hypothesized to modulate vascular functions; however, its role in mediating atherosclerosis is controversial. Epidemiological data in patients with cardiovascular disease (CVD) indicate that OPG serum levels are associated with several inflammatory markers, myocardial infarction events, and calcium scores, suggesting that OPG may be causative for CVD.. The present study aimed to evaluate whether the OPG gene (TNFRSF11B) polymorphisms are involved in the development of peripheral arterial occlusive disease (PAOD) and critical limb ischemia (CLI) in patients with type 2 diabetes. This genetic association study included 402 diabetic patients (139 males and 263 females) with peripheral arterial occlusive disease and 567 diabetic subjects without peripheral arterial occlusive disease (208 males and 359 females). The T245G, T950C, and G1181C polymorphisms of the OPG gene were analyzed by polymerase chain reaction and restriction fragment length polymorphism.. We found that the T245G, T950C, and G1181C gene polymorphisms of the OPG gene were significantly (27.9 vs. 12.2 %, P < 0.01; 33.6 vs. 10.4 %, P < 0.01 and 24.4 vs. 12.7 %, P < 0.01, respectively) and independently (adjusted OR 4.97 (3.12-6.91), OR 7.02 (4.96-11.67), and OR 2.85 (1.95-4.02), respectively) associated with PAOD. We also found that these three polymorphisms act synergistically in patients with PAOD and are associated with different levels of risk for PAOD and CLI, depending on the number of high-risk genotypes carried concomitantly by a given individual.. The TNFRSF11B gene polymorphisms under study are associated with PAOD, and synergistic effects between these genotypes might be potential markers for the presence and severity of atherosclerotic disorders.

Topics: Aged; Arterial Occlusive Diseases; Atherosclerosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Extremities; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Ischemia; Male; Osteoprotegerin; Polymorphism, Single Nucleotide; Risk Factors

To identify differences in postexercise phosphocreatine (PCr) recovery, an index of mitochondrial function, in diabetic patients with and without lower extremity complications.. We enrolled healthy control subjects and three groups of patients with type 2 diabetes mellitus: without complications, with peripheral neuropathy, and with both peripheral neuropathy and peripheral arterial disease. We used magnetic resonance spectroscopic measurements to perform continuous measurements of phosphorous metabolites (PCr and inorganic phosphate [Pi]) during a 3-minute graded exercise at the level of the posterior calf muscles (gastrocnemius and soleus muscles). Micro- and macrovascular reactivity measurements also were performed.. The resting Pi/PCr ratio and PCr at baseline and the maximum reached during exercise were similar in all groups. The postexercise time required for recovery of Pi/PCr ratio and PCr levels to resting levels, an assessment of mitochondrial oxidative phosphorylation, was significantly higher in diabetic patients with neuropathy and those with both neuropathy and peripheral arterial disease (P < .01 for both measurements). These two groups also had higher levels of tumor necrosis factor-α (P < .01) and granulocyte colony-stimulating factor (P < .05). Multiple regression analysis showed that only granulocyte colony-stimulating factor, osteoprotegerin, and tumor necrosis factor-α were significant contributing factors in the variation of the Pi/PCr ratio recovery time. No associations were observed between micro- and macrovascular reactivity measurements and Pi/PCr ratio or PCr recovery time.. Mitochondrial oxidative phosphorylation is impaired only in type 2 diabetes mellitus patients with neuropathy whether or not peripheral arterial disease is present and is associated with the increased proinflammatory state observed in these groups.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Neuropathies; Exercise; Female; Granulocyte Colony-Stimulating Factor; Humans; Inflammation Mediators; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria; Muscle Contraction; Muscle, Skeletal; Osteoprotegerin; Oxidative Phosphorylation; Peripheral Arterial Disease; Phosphocreatine; Time Factors; Tumor Necrosis Factor-alpha

Diabetic patients often exhibit severe, asymptomatic coronary artery disease (CAD). The relationship between osteoprotegerin (OPG), inflammatory markers and silent myocardial ischemia remains to be elucidated.. We recruited 45 type 2 diabetic patients and 33 healthy controls and assessed them for silent myocardial ischemia (SMI) by myocardial perfusion imaging. Patient blood was tested for OPG, IL-6 and leptin concentrations.. OPG, leptin and IL-6 levels were found significantly elevated in diabetic patients (p < 0.001, p < 0.01, p < 0.05). Based on our classification of presence/absence of SMI in our diabetic group, we found that there was a significant association between SMI and the biomarkers IL-6 (p < 0.001), leptin (p < 0.001) and OPG (p < 0.05). In multivariate regression analyses, OPG was found to be significantly related to diabetes mellitus and to SMI. Age, sex and smoking increased the association between OPG and SMI.. High OPG, leptin and IL-6 levels are associated with the presence and severity of SMI in type 2 diabetic patients.

Topics: Adult; Biomarkers; Case-Control Studies; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Exercise Test; Female; Humans; Interleukin-6; Leptin; Male; Middle Aged; Multivariate Analysis; Myocardial Ischemia; Myocardial Perfusion Imaging; Osteoprotegerin; Regression Analysis

We aimed to investigate the relationship between serum osteoprotegerin (OPG) level and glycemic control, lipids, renal function, microalbuminuria, insulin resistance and markers of atherosclerosis including C-reactive protein (CRP), fibrinogen and erythrocyte sedimentation rate (ESR) in patients with type 2 diabetes mellitus (DM). A total of 166 patients (99 women and 67 men) with type 2 DM were recruited in the study. Serum OPG level was higher in poorly controlled diabetic patients (HbA(1c) ≥ 7%) than in well-controlled diabetic patients (HbA(1c) < 7%) [4.0 (3.6-5.0) and 3.5 (2.9-4.4) pmol/L, p = 0.02]. There was no difference between the patients with and without microalbuminuria with respect to OPG levels (p > 0.05). LogOPG was correlated with age (r = 0.47, p = 0.0001). After adjustment for age, sex and BMI, logOPG correlated positively with fasting blood glucose (FBG) (r = 0.28, p = 0.001), prandial blood glucose (PBG) (r = 0.22, p = 0.009), glycated hemoglobin (HbA(1c)) (r = 0.26, p = 0.002), logHOMA-IR (r = 0.30, p = 0.006), fibrinogen (r = 0.17, p = 0.04), mean albumin excretion rate (MAER) (r = 0.20, p = 0.01) and negatively with creatinine clearance (r = - 0.20, p = 0.01). Regression analysis revealed that logOPG was independently associated with age (p = 0.0001), HbA(1c) (p = 0.01) and MAER (p = 0.02) (r(2) = 0.25). In conclusion; we found that serum OPG levels are increased in poorly controlled type 2 DM and associated with age, glycemic control and microalbuminuria.

Topics: Atherosclerosis; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Kidney Function Tests; Lipids; Male; Middle Aged; Osteoprotegerin; Postprandial Period; Regression Analysis

Since elevated plasma levels of osteoprotegerin (OPG) represent a risk factor for death and heart failure in patients affected by diabetes mellitus and coronary artery disease, this study aimed to elucidate potential roles of OPG in the pathogenesis of atherosclerosis.. Recombinant human full-length OPG, used at concentrations comparable to the elevated levels found in the serum of diabetic patients, significantly increased the proliferation rate of rodent vascular smooth muscle cells (VSMC). To mimic the moderate chronic elevation of OPG observed in diabetic patients, low doses (1 microg/mouse) of full-length human OPG were injected intraperitoneally every 3 weeks in diabetic apolipoprotein E (apoE)-null mice. The group of animals treated for 12 weeks with recombinant OPG showed a small increase in the total aortic plaque area at necropsy in comparison to vehicle-treated animals. Importantly, while no differences in the amount of interstitial collagen or the degree of macrophage infiltration were observed between OPG-treated and vehicle-treated apoE-null diabetic animals, a significant increase in the number of alpha-actin-positive smooth muscle cells was observed in the plaques of OPG-treated mice.. Our data suggest that OPG promotes VSMC proliferation and might be directly involved in pathogenetic aspects of atherosclerosis.

Topics: Angiopoietin-2; Animals; Apolipoproteins E; Atherosclerosis; Cell Proliferation; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Disease Models, Animal; Humans; Injections, Intraperitoneal; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteoprotegerin; Rats; Recombinant Proteins; RNA, Messenger

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), receptor activator for nuclear factor kappa beta ligand (RANKL) and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) are newly discovered members of the tumour necrosis factor-alpha receptor superfamily. While their role in bone metabolism is well described, their function within the vasculature is poorly understood. OPG inhibits vascular calcification in vitro and high serum levels have been demonstrated in type 2 diabetes, but serum RANKL and TRAIL and their potential correlation with well-established biomarkers of subclinical vascular inflammation such as high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) have not been described.. Sixty-two patients with well-controlled type 2 diabetes and an age, gender and body mass index-matched group of 58 healthy individuals were recruited. Serum OPG, RANKL and TRAIL were measured using commercial enzyme-linked immunosorbent assays, as were hsCRP and IL-6.. Serum OPG, IL-6 and hsCRP levels, but not RANKL or TRAIL, were higher in patients with type 2 diabetes mellitus than in healthy controls, after adjustment for age and gender. After exclusion of diabetes patients with a history of micro- or macrovascular disease, OPG remained significantly higher in those with diabetes, but IL-6 and hsCRP levels were no longer elevated. There was a positive correlation between OPG and IL-6 in the group as a whole, but no correlation was found between RANKL or TRAIL and either hsCRP or IL-6.. OPG, but not RANKL or TRAIL, is significantly increased in type 2 diabetes. Higher OPG (but not IL-6 or hsCRP) in those without vascular disease suggests these biomarkers reflect separate pathophysiological processes in the vasculature.

Topics: Biomarkers; C-Reactive Protein; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Osteoprotegerin; RANK Ligand; TNF-Related Apoptosis-Inducing Ligand

Osteoprotegerin (OPG) is a recently identified inhibitor of bone resorption. Recent studies indicate that OPG is also associated with endothelial dysfunction in Type 2 diabetes. The aim was to investigate the relationship between plasma OPG levels and urinary albumin excretion (UAE) in Type 2 diabetic patients.. This study included 154 newly diagnosed Type 2 diabetic patients and 46 healthy subjects. Plasma OPG and 24-h UAE were measured. High-resolution ultrasound was used to measure flow-mediated (endothelium-dependent arterial) dilation (FMD).. Compared with the normoalbuminuric subgroup, OPG levels in the microalbuminuric subgroup were significantly higher, and OPG levels in macroalbuminuria subgroup were significantly higher than those in the normoalbuminuria and albuminuria subgroups. Multiple regression analysis showed that only FMD (r = -0.26), C-reactive protein (r = 0.23), fasting blood glucose (r = 0.25), 2-h blood glucose (r = 0.21), HbA(1c) (r = 0.28), UAE (r = 0.27) and retinopathy (r = 0.27) were significant factors associated with OPG. Pearson's correlation analyses showed a positive correlation between OPG and logUAE (r = 0.440) and negative correlations between OPG and FMD (r = -0.284), and between FMD and logUAE (r = -0.602).. Plasma OPG levels are significantly associated with UAE in Type 2 diabetic patients.

Topics: Adult; Aged; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Epidemiologic Methods; Female; Humans; Male; Middle Aged; Osteoprotegerin; Ultrasonography

Vascular calcification is frequently accompanied by intima-media thickening, but the associations among these atherosclerotic features and bone-related peptides in diabetic patients are unclear. We enrolled 168 type 2 diabetic patients and 40 non-diabetic subjects consecutively admitted to our hospital. Mean intima-media thickness (mean-IMT) in common carotid arteries was measured by B-mode ultrasonography. Agatston coronary artery calcium score (CACS) was obtained using multidetector-row computed tomography (MDCT). Plasma bone-related peptides osteopontin and osteoprotegerin levels were measured. Diabetic patients had higher mean-IMT (p=0.0002) and log(CACS+1) (p<0.0001) and similar bone-related peptides compared to non-diabetic subjects. In diabetic patients classified into tertiles according to their CACS levels, those with the highest scores showed the highest mean-IMT (p=0.0004) and bone-related peptides (p<0.05) among the groups. log(CACS+1) and mean-IMT were associated (p<0.0001) and were positively correlated with osteopontin (p<0.01) and osteoprotegerin (p<0.01) in diabetic patients. Multivariate analyses revealed that the significant independent determinants of log(CACS+1) were age, duration of diabetes and osteopontin (p<0.0001) and those of mean-IMT were age, hypertension, osteopontin and osteoprotegerin (p<0.0001), respectively. We have demonstrated that vascular calcification in type 2 diabetic patients is frequently accompanied by intima-media thickening, and osteopontin may act as a vascular calcification inhibitor by increasing intima-media thickness.

Topics: Adult; Age of Onset; Aged; Atherosclerosis; Calcinosis; Coronary Artery Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Multivariate Analysis; Osteopontin; Osteoprotegerin; Tomography, X-Ray Computed

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

Arterial medial calcifications occur often in diabetic individuals as part of the diabetic macroangiopathy. The pathogenesis is unknown, but the presence of calcifications predicts risk of cardiovascular events. We examined the effects of insulin on calcifying smooth muscle cells in vitro and measured the expression of the bone-related molecule osteoprotegerin (OPG). Human vascular smooth muscle cells (VSMCs) were grown from aorta from kidney donors. Induction of calcification was performed with beta-glycerophosphate. The influence of insulin (200 microU/ml or 1,000 microU/ml) on calcification was judged by measuring calcium content in the cell layer and by von Kossa staining. OPG was measured in the medium by ELISA. Histochemistry was used for determination of alkaline phosphatase (ALP). Bone sialoprotein (BSP) and OPG mRNA expressions were done by RT-PCR. beta-Glycerophosphate was able to induce calcification in human smooth muscle cells from a series of donors after variable time in culture. Decreased OPG amounts were observed from the cells during the accelerated calcification phase. High dose of insulin (1,000 microU/ml) accelerated the calcification, whereas lower concentrations (200 microU/ml) did not. Calcified cells expressed ALP and BSP activity in high levels. In conclusion, high concentration of insulin enhances in vitro-induced calcification in VSMCs. Altered OPG levels during the calcification raise the possibility that OPG may have a potent function in regulating the calcification process or it may represent a consequence of mineralization. Effects of insulin and modulations by OPG on the calcification process in arterial cells may play a role in the development of calcifications as part of the diabetic macroangiopathy.

Topics: Alkaline Phosphatase; Aorta; Aortic Diseases; Calcinosis; Calcium; Cells, Cultured; Diabetic Angiopathies; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Glycerophosphates; Humans; Insulin; Integrin-Binding Sialoprotein; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteoprotegerin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sialoglycoproteins; Time Factors

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

We sought to evaluate osteoprotegerin, an inhibitor of osteoclastogenesis involved in atherosclerosis, and other novel risk factors as predictive markers of silent myocardial ischemia (SMI).. A total of 465 consecutive diabetic patients with more than one additional risk factor were evaluated for SMI using stress myocardial perfusion imaging (MPI). We studied the association of SMI (positive stress electrocardiogram and/or abnormal MPI) with osteoprotegerin, other novel risk factors (lipoprotein[a], homocysteine, adiponectin, C-reactive protein, and fibrinogen), and conventional risk factors (total, LDL, and HDL cholesterol and triglycerides).. A total of 92 patients were diagnosed with SMI. Of the six novel markers, osteoprotegerin was the only one associated with SMI; the relative risk (RR) of SMI in patients with osteoprotegerin values above the 75th percentile was 3.19 (95% CI 1.99-5.18; P < 0.001) in comparison with those with osteoprotegerin below the 75th percentile. In univariate analyses, the other plasma markers significantly associated with SMI were higher triglycerides (P = 0.04) and lower HDL cholesterol (P = 0.02). The association of osteoprotegerin with SMI remained significant after correcting for other variables associated with SMI at P < 0.15 in univariate analysis (RR 3.95 [95% CI 2.21-7.06]; P < 0.0001). The association of osteoprotegerin with SMI was observed in male (P < 0.0001) and female (P = 0.03) patients, in type 1 (P = 0.002) and type 2 (P = 0.0004) diabetic patients, in patients with (P = 0.0004) or without (P = 0.03) nephropathy, and in patients without (P < 0.0001) but not with (P = 0.2) peripheral arterial disease.. Osteoprotegerin measurement, together with other conventional factors, can help to better define the diabetic population with an increased likelihood for SMI.

Topics: Aged; Biomarkers; Body Mass Index; Cross-Sectional Studies; Diabetic Angiopathies; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Myocardial Ischemia; Osteoprotegerin; Predictive Value of Tests; Risk; Risk Factors

No mouse model is currently available where the induction of type 2 diabetes on an atherosclerotic background could be achieved without significant concomitant changes in plasma lipid levels. We crossbred 2 genetically modified mouse strains to achieve a model expressing both atherosclerosis and characteristics of type 2 diabetes. For atherosclerotic background we used low-density lipoprotein receptor-deficient mice synthetizing only apolipoprotein B100 (LDLR(-/-) ApoB(100/100)). Diabetic background was obtained from transgenic mice overexpressing insulin-like growth factor-II (IGF-II) in pancreatic beta cells. Thorough phenotypic characterization was performed in 6- and 15-month-old mice on both normal and high-fat Western diet. Results indicated that IGF-II transgenic LDLR(-/-)ApoB(100/100) mice demonstrated insulin resistance, hyperglycemia, and mild hyperinsulinemia compared with hypercholesterolemic LDLR(-/-)ApoB(100/100) controls. In addition, old IGF-II/LDLR(-/-)ApoB(100/100) mice displayed significantly increased lesion calcification, which was more related to insulin resistance than glucose levels, and significantly higher baseline expression in aorta of several genes related to calcification and inflammation. Lipid levels of IGF-II/LDLR(-/-)ApoB(100/100) mice did not differ from LDLR(-/-)ApoB(100/100) controls at any time. In conclusion, type 2 diabetic factors induce increased calcification and lesion progression without any lipid changes in a new mouse model of diabetic macroangiopathy.

Topics: Animals; Apolipoproteins B; Atherosclerosis; Blood Glucose; Calcinosis; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Hypercholesterolemia; Hyperglycemia; Insulin Resistance; Insulin-Like Growth Factor II; Lipids; Mice; Mice, Inbred C57BL; Mice, Transgenic; Osteoprotegerin; Receptors, LDL

Topics: Apoptosis Regulatory Proteins; Carrier Proteins; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelium, Vascular; Female; Glycoproteins; Humans; Male; Membrane Glycoproteins; Middle Aged; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

Osteoprotegerin (OPG) is an inhibitor of osteoclastogenesis, which has been recently involved in atherosclerosis. The relationship between coronary atherosclerosis and OPG has never been studied in asymptomatic type 2 diabetic patients.. This is a nested case-control study; 162 asymptomatic type 2 diabetic patients were evaluated for silent myocardial ischemia using stress myocardial perfusion imaging; of 50 patients with positive results, 37 underwent coronary angiography, 20 of whom showed significant coronary artery disease (CAD group). Of 112 patients without silent myocardial ischemia, 20 subjects (NO-CAD group) were selected and matched by age and sex to patients with CAD. OPG, C-reactive protein, adiponectin, lipoprotein(a), albuminuria, and classical risk factors were measured.. The percentages of subjects with OPG levels above median and with nephropathy were higher in the CAD group than in the NO-CAD group (70 vs. 25%, P = 0.004 and 50 vs. 5%, P = 0.001, respectively). LDL cholesterol levels were higher and HDL cholesterol levels lower in the CAD compared with the NO-CAD group (P = 0.033 and P = 0.005, respectively). No other variables were associated with CAD. Logistic regression analysis showed that OPG values above median (odds ratio 8.31 [95% CI 1.18-58.68], P = 0.034) and nephropathy (21.98 [1.24-388.36], P = 0.035) were significant independent predictors of asymptomatic CAD in type 2 diabetic patients.. Our investigation reports the first evidence of an independent association of OPG with asymptomatic CAD in type 2 diabetic patients. The results of this nested case- control study with 20 cases need to be confirmed in a larger population.

Topics: Adrenergic beta-Agonists; Aged; Biomarkers; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipyridamole; Electrocardiography; Exercise Test; Female; Glycated Hemoglobin; Glycoproteins; Humans; Lipids; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Platelet Aggregation Inhibitors; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors

Osteoprotegerin (OPG) is a newly identified inhibitor of bone resorption. Recent studies indicate that OPG also acts as an important regulatory molecule in the vasculature. Plasma levels of OPG seem to be elevated in subjects with diabetes as well as in non-diabetic subjects with cardiovascular disease. The aim of the present study was to examine the association between plasma OPG levels and microvascular complications and glycemic control in patients with type 2 diabetes.. Four groups of 20 subjects in each, individually matched for age and gender, were included in the study: (i) subjects with normal glucose tolerance (NGT); (ii) subjects with impaired glucose tolerance (IGT); (iii) type 2 diabetic patients without retinopathy; and (iv) type 2 diabetic patients with diabetic maculopathy (DMa). Plasma concentration of OPG was measured in duplicate by a sandwich ELISA method. Furthermore, fundus photography, flourescein angiography, and measurements of urinary albumin excretion rate (RIA) were performed.. Plasma OPG was significantly higher in diabetic (iii+iv) than in NGT (i) subjects (3.04+/-0.15 vs 2.54+/-0.16 ng/ml, P<0.05). Plasma OPG was significantly higher in the DMa (iv) group than in the NGT (i) group (3.25+/-0.23 vs 2.54+/-0.16 ng/ml, P=0.01). Moreover, plasma OPG was significantly higher (3.61+/-0.36 ng/ml) in the group of diabetic subjects with both microalbuminuria and DMa (n=7) than in the NGT (i) (2.54+/-0.16 ng/ml, P<0.01), IGT (ii) (2.82+/-0.21 ng/ml, P<0.05), and no retinopathy (iii) groups (2.83+/-0.20 ng/ml, P<0.05).. We found increased levels of OPG in plasma from diabetic patients with microvascular complications. This finding indicates that OPG may be involved in the development of vascular dysfunction in diabetes [corrected].

Topics: Albuminuria; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycoproteins; Humans; Male; Microcirculation; Middle Aged; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor