osteoprotegerin and Diabetes-Mellitus--Type-2

Coronary artery calcification (CAC) is one of the critical cardiovascular complications that lead to elevated morbidity and mortality among patients with type 2 diabetes (T2M). The association between osteoprotegerin (OPG) and CAC could potentially provide a reasonable chance for preventive therapy in type 2 diabetic patients and benefit the rate of mortality. Since measurement of CAC score is relatively expensive and requires radiation exposure, the current systematic review aims to provide clinical evidence for evaluating the prognostic role of OPG in determining CAC risk among subjects with T2M. Web of Science, PubMed, Embase, and Scopus, were investigated until July 2022. We assessed human studies investigating the association of OPG with CAC in type 2 diabetic patients. Quality assessment was performed by Newcastle-Ottawa quality assessment scales (NOS). Out of 459 records, 7 studies remained eligible to be included. Observational studies that provided odds ratio (OR) estimates with 95% confidence intervals (CIs) for the association between OPG and the risk of CAC were analyzed by random-effects model. In order to provide a visual summary of our findings, the estimation of pooled OR from cross-sectional studies was reported as 2.86 [95% CI 1.49-5.49], which is consistent with the findings of the cohort study. Results revealed that the association between OPG and CAC was significant among diabetic patients. OPG is hypothesized to be a potential marker in predicting the presence of high coronary calcium score among subjects with T2M that could be recognized as a novel target for further pharmacological investigations.

Topics: Biomarkers; Cohort Studies; Coronary Artery Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Osteoprotegerin; Risk Factors; Vascular Calcification

To summarize evidence on the potential involvement of the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappa B (NF-κΒ) ligand (RANKL)/receptor activator of NF-κΒ (RANK) axis in the pathogenesis of metabolic diseases.. The OPG-RANKL-RANK axis, which has been originally involved in bone remodeling and osteoporosis, is now recognized as a potential contributor in the pathogenesis of obesity and its associated comorbidities, i.e., type 2 diabetes mellitus and nonalcoholic fatty liver disease. Besides bone, OPG and RANKL are also produced in adipose tissue and may be involved in the inflammatory process associated with obesity. Metabolically healthy obesity has been associated with lower circulating OPG concentrations, possibly representing a counteracting mechanism, while elevated serum OPG levels may reflect an increased risk of metabolic dysfunction or cardiovascular disease. OPG and RANKL have been also proposed as potential regulators of glucose metabolism and are potentially involved in the pathogenesis of type 2 diabetes mellitus. In clinical terms, type 2 diabetes mellitus has been consistently associated with increased serum OPG concentrations. With regard to nonalcoholic fatty liver disease, experimental data suggest a potential contribution of OPG and RANKL in hepatic steatosis, inflammation, and fibrosis; however, most clinical studies showed reduction in serum concentrations of OPG and RANKL. The emerging contribution of the OPG-RANKL-RANK axis to the pathogenesis of obesity and its associated comorbidities warrants further investigation by mechanistic studies and may have potential diagnostic and therapeutic implications.

Topics: Diabetes Mellitus, Type 2; Humans; Ligands; NF-kappa B; Non-alcoholic Fatty Liver Disease; Obesity; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Experimental and clinical studies aimed at investigating the mechanism(s) underlying vascular complications of diabetes indicate that a great number of molecules are involved in the pathogenesis of these complications. Most of these molecules are inflammatory mediators or markers generated by immune or adipose tissue. Some of them, i.e. resistin and sortilin, have been shown to be involved in the cross talk between adipocytes and inflammatory cells. This interaction is an attractive area of research, particularly in type 2 diabetes and obesity. Other proteins, such as adiponectin and visfatin, appear to be more promising as possible vascular markers. In addition, some molecules involved in calcium/phosphorus metabolism, such as klotho and FGF23, have an involvement in the pathogenesis of diabetic vasculopathy, which appears to be dependent on the degree of vascular impairment. Inflammatory markers are a promising tool for treatment decisions while measuring plasma levels of adipokines, sortilin, Klotho and FGF23 in adequately sized longitudinal studies is expected to allow a more precise characterization of diabetic vascular disease and the optimal use of personalized treatment strategies.

Topics: Adaptor Proteins, Vesicular Transport; Adipokines; Adipose Tissue; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Exosomes; Fibroblast Growth Factor-23; Glucuronidase; HMGB Proteins; Humans; Immune System; Interleukin-1; Klotho Proteins; Osteoprotegerin; Prevalence; Serum Amyloid P-Component; Signal Transduction; Tumor Necrosis Factor-alpha

To investigate the differences in bone turnover between diabetic patients and controls.. A systematic review and meta-analysis.. A literature search was conducted using the databases Medline at PubMed and EMBASE. The free text search terms 'diabetes mellitus' and 'bone turnover', 'sclerostin', 'RANKL', 'osteoprotegerin', 'tartrate-resistant acid' and 'TRAP' were used. Studies were eligible if they investigated bone turnover markers in patients with diabetes compared with controls. Data were extracted by two reviewers.. A total of 2881 papers were identified of which 66 studies were included. Serum levels of the bone resorption marker C-terminal cross-linked telopeptide (-0.10 ng/mL (-0.12, -0.08)) and the bone formation markers osteocalcin (-2.51 ng/mL (-3.01, -2.01)) and procollagen type 1 amino terminal propeptide (-10.80 ng/mL (-12.83, -8.77)) were all lower in patients with diabetes compared with controls. Furthermore, s-tartrate-resistant acid phosphatase was decreased in patients with type 2 diabetes (-0.31 U/L (-0.56, -0.05)) compared with controls. S-sclerostin was significantly higher in patients with type 2 diabetes (14.92 pmol/L (3.12, 26.72)) and patients with type 1 diabetes (3.24 pmol/L (1.52, 4.96)) compared with controls. Also, s-osteoprotegerin was increased among patients with diabetes compared with controls (2.67 pmol/L (0.21, 5.14)).. Markers of both bone formation and bone resorption are decreased in patients with diabetes. This suggests that diabetes mellitus is a state of low bone turnover, which in turn may lead to more fragile bone. Altered levels of sclerostin and osteoprotegerin may be responsible for this.

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

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

Type 2 diabetes is associated with increased cardiovascular morbidity and mortality and early vascular ageing. This takes the form of atherosclerosis, with progressive vascular calcification being a major complication in the pathogenesis of this disease. Current research and drug targets in diabetes have hitherto focused on atherosclerosis, but vascular calcification is now recognised as an independent predictor of cardiovascular morbidity and mortality. An emerging regulatory pathway for vascular calcification in diabetes involves the receptor activator for nuclear factor κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). Important novel biomarkers of calcification are related to levels of glycation and inflammation in diabetes. Several therapeutic strategies could have advantageous effects on the vasculature in patients with diabetes, including targeting the RANKL and receptor for AGE (RAGE) signalling pathways, since there has been little success-at least in macrovascular outcomes-with conventional glucose-lowering therapy. There is substantial and relevant clinical and basic science evidence to suggest that modulating RANKL-RANK-OPG signalling, RAGE signalling and the associated proinflammatory milieu alters the natural course of cardiovascular complications and outcomes in people with diabetes. However, further research is critically needed to understand the precise mechanisms underpinning these pathways, in order to translate the anti-calcification strategies into patient benefit.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Osteoprotegerin; RANK Ligand; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Signal Transduction; Vascular Calcification

New-onset diabetes might help to yield biomarkers for the early diagnosis of pancreatic cancer (PaC). In this study, we computationally predicted and experimentally validated osteoprotegerin (OPG) being associated with pancreatic cancer related new-onset diabetes. We first performed a meta-analysis on microarray datasets to search for genes specifically highly expressed in PaC, and then filtered for cytokines involved in islet dysfunction. The expression of OPG in PaC and normal pancreas were validated by immunohistochemistry. Serum OPG levels in healthy controls, non-cancerous diabetes and PaC patients with or without diabetes were detected by enzyme-linked immunosorbent assay (ELISA). In silico assay found that OPG up-regulated in PaC tissues in comparison to normal pancreas. Immunohistochemical data further confirmed that OPG was overexpressed in PaC samples. Furthermore, increased expression of OPG in PaC tissues correlated to the occurrence of new-onset diabetes, and adversely affected the patients' overall survival in both univariate and multivariate analysis. In addition, the serum levels of OPG were significantly higher in pancreatic cancer patients with new-onset diabetes than other groups including pancreatic patients without diabetes, new-onset type 2 diabetes and healthy controls. In conclusion, there is a close association between OPG and pancreatic cancer related new-onset diabetes, and OPG might serve as a potential biomarker for the early diagnosis of pancreatic cancer from populations with new-onset diabetes.

Topics: Biomarkers, Tumor; Data Mining; Diabetes Mellitus, Type 2; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Osteoprotegerin; Pancreatic Neoplasms; Protein Array Analysis

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

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

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

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

Type 2 diabetes mellitus (T2DM) related bone fracture. The effects of glucagon-like peptide-1 receptor analogs for the treatment of T2DM on bone are controversial in human studies. This study aimed to compare the effects of GLP-1 receptor analogs exenatide and insulin glargine treatment on bone turnover marker levels and bone mineral density (BMD) in postmenopausal female patients with T2DM. Thirty female patients with T2DM who were naive to insulin and incretin-based treatments, with spontaneous postmenopause, were randomized to exenatide or insulin glargine arms and were followed up for 24 weeks. BMD was evaluated using dual-energy X-ray absorptiometry and bone turnover markers by serum enzyme-linked immunosorbent assay. The body mass index significantly decreased in the exenatide group compared to the glargine group (P < .001). Receptor activator of nuclear factor kappa-B (RANK) and RANK ligand (RANKL) levels were significantly decreased with exenatide treatment (P = .009 and P = .015, respectively). Osteoprotegerin (OPG) level significantly increased with exenatide treatment (P = .02). OPG, RANK, RANKL levels did not change with insulin glargine treatment. No statistically significant difference was found between the pre- and posttreatment BMD, alkaline phosphatase, bone-specific alkaline phosphatase, and type 1 crosslinked N-telopeptide levels in both treatment arms. Despite significant weight loss with exenatide treatment, BMD did not decrease, OPG increased, and the resorption markers of RANK and RANKL decreased, which may reflect early antiresorptive effects of exenatide via the OPG/RANK/RANKL pathway.

Topics: Alkaline Phosphatase; Bone Density; Bone Remodeling; Diabetes Mellitus, Type 2; Exenatide; Female; Humans; Insulin Glargine; Osteoprotegerin; Postmenopause; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

The poor glycemic status seems to be an important factor affecting implant complication rates, including peri-implant bone loss.. This trial evaluated the influence of glycemic control of type 2 diabetes mellitus (T2DM) patients on implant stabilization and on the levels of bone markers in peri-implant fluid during the healing.. Systemically healthy patients (SH,n = 19), better-controlled T2DM (BCDM,n = 16), and poorly controlled T2DM (PCDM,n = 16) indicated for implant therapy were recruited. The implant stability quotient (ISQ) was determined at implant placement, 3, 6, and 12 months. Levels of transforming growth factor- β (TGF-β), fibroblast growth factor (FGF), osteopontin (OPN), osteocalcin (OC), and osteoprotegerin (OPG) in the peri-implant fluid were quantified at 15 days, and 3, 6, and 12 months, using the Luminex assay.. OPG and OPN levels were higher in SH at 12 months than at15 days (p < .05), whereas OC and TGF-β were lower in PCDM at 12 months compared with the 15-day and 3-month follow-ups, respectively (p < .05). Inter-group analyses showed lower OPN levels in PCDM compared with SH at 12 months (p < .05). The ISQ was higher at 12 months when compared with baseline and 3 months in SH (p < .05), whereas no differences were observed during follow-up in diabetics, regardless of glycemic control (p > .05). No difference in ISQ was observed among groups over time (p > .05).. Poor glycemic control negatively modulated the bone factors during healing, although T2DM, regardless of glycemic status, had no effect on implant stabilization.

Topics: Adult; Aged; Biomarkers; Blood Glucose; Bone Regeneration; Dental Implants; Diabetes Mellitus, Type 2; Female; Gingival Crevicular Fluid; Humans; Male; Middle Aged; Osteocalcin; Osteopontin; Osteoprotegerin; Single-Blind Method; Transforming Growth Factor beta

The etiologic role of inflammatory pathways in the development of diabetic complications, especially cardiovascular events, has been established. The anti-inflammatory role of metformin and pioglitazone has been described; however, no study to date has compared the efficacy of these common oral agents in this regard. In this study, the authors aimed to compare the anti-inflammatory properties of pioglitazone and metformin, with respect to their effect on serum concentrations of highly sensitive C-reactive protein (hsCRP), osteoprotegerin (OPG), intercellular adhesion molecule-1 (ICAM-1) and adiponectin.. In an open-label randomized clinical trial, 117 patients with newly diagnosed type 2 diabetes mellitus were visited; 84 fulfilled the inclusion criteria, and were randomly allocated to 2 arms receiving either 1,000 mg/d metformin or 30 mg/d pioglitazone, respectively. Biochemical assessments were made at baseline and the end of the 3 months trial.. Significant reduction in FPG, insulin and HbA1c in women and men of both arms were observed. Log-hsCRP values significantly decreased in both arms. A decreasing, but non-significant trend in log-OPG levels was observed in women of the metformin arm (p=0.063). A greater reduction in log-ICAM levels was identifiable in men receiving pioglitazone compared to the other arm (p=0.008); in addition, the same trend was observed in log-OPG values (p=0.029). Nonetheless, reduction in log-ICAM and log-OPG levels was comparable between the 2 arms. A significant increase in adiponectin was observed in both men and women in the pioglitazone arm (p<0.001), whereas changes were non-significant in the metformin arm.. Remarkably, patients receiving pioglitazone revealed more significant reduction in inflammatory markers.

Topics: Adiponectin; Anti-Inflammatory Agents, Non-Steroidal; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Inflammation Mediators; Intercellular Adhesion Molecule-1; Male; Metformin; Middle Aged; Osteoprotegerin; Pioglitazone; Sex Characteristics; Thiazolidinediones

Statin therapy improves lipid profiles and reduces vascular inflammation, but its effects on central arterial stiffness in type 2 diabetes are unclear. The aim of this study was to determine whether statin therapy reduces central arterial stiffness, in a dose-dependent manner, in male patients with type 2 diabetes. Fifty-one patients ceased statin therapy for 6 weeks, followed by randomisation to either 10 or 80 mg of atorvastatin. At randomization, 3 and 12 months, central arterial stiffness was measured via carotid-femoral pulse wave velocity (PWV), along with serum markers of vascular inflammation including high-sensitivity c-reactive protein (hsCRP) and osteoprotegerin (OPG). PWV decreased from 10.37 ± 1.30 to 9.68 ± 1.19 m/sec (p < 0.01 from baseline) at 3 months and 9.10 ± 1.17 m/sec (p < 0.001 from baseline) at 12 months. hsCRP and OPG decreased significantly at 3 and 12 months. Reductions in PWV did not differ significantly between the groups. Baseline PWV and OPG values correlated strongly (r = 0.48, p < 0.01), as did their response to atorvastatin over 12 months (r = 0.36 delta-OPG and delta-PWV, p < 0.01). Atorvastatin therapy appeared to reduce central arterial stiffness in male type 2 diabetes, with no dose-dependent effect observed. The correlation observed between reductions in PWV and OPG suggests that atorvastatin reduces PWV via direct anti-inflammatory effects on the vasculature.

Topics: Adult; Aged; Aged, 80 and over; Atorvastatin; Biomarkers; C-Reactive Protein; Diabetes Mellitus, Type 2; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Osteoprotegerin; Pulse Wave Analysis; Treatment Outcome; Vascular Stiffness

The aim of this study was to assess the effects of single oral bolus of 300,000 IU Vitamin D3 on serum levels and on bone and metabolic parameters in diabetic patients. This study is a Phase IV, randomized, double-blind, placebo-controlled, monocenter clinical trial. Thirty patients, 60 years or older, with type 2 diabetes mellitus, and diabetic foot complications, were enrolled and monitored for 24 weeks: 14 were treated with Vitamin D3 and 16 with placebo. Parameters including glucose, adiponectin, leptin, osteoprotegerin (OPG), 25-hydroxyvitamin D [25(OH)D], beta-CrossLaps, osteocalcin, bone-specific isoenzyme of alkaline phosphatase, tumor necrosis factor-α and parathyroid hormone were measured at screening and baseline and 12 and 24 weeks after treatment. Analysis of covariance was used to compare treatment groups. Analysis of the data detected a significant increase in 25(OH)D serum levels both at 12 and 24 weeks with respect to baseline values only in the treated patients. Significant variations with respect to baseline values were noted in OPG (P = 0.0085) and in leptin (P = 0.0442) levels: these were lower in the placebo group at week 24 but higher in the treated group. Vitamin D3 supplementation significantly increased serum leptin and OPG levels. Further, large-scale clinical trials are warranted to confirm these results.

Topics: Aged; Aged, 80 and over; Blood Glucose; Cholecalciferol; Diabetes Mellitus, Type 2; Female; Humans; Italy; Leptin; Male; Middle Aged; Osteoprotegerin

The aim of this study was to evaluate the effects of full-mouth scaling and root planing (FMSRP) and partial-mouth scaling and root planing (PMSRP), up to 12 mo after treatment, on clinical parameters, and levels of cytokines and osteoclastogenesis-related factors in type 2 diabetic subjects with chronic periodontitis.. Thirty-four subjects received FMSRP (n = 17) or PMSRP (n = 17) within 24 h or in multiple sessions, respectively. Clinical parameters and local levels of tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin (IL)-17, IL-23, IL-4, receptor activator of NF-β ligand and osteoprotegerin were assessed at baseline, and 3, 6 and 12 mo after therapies.. Clinical parameters improved after both therapies (p < 0.05), and no between-group differences were observed at any time-point (p > 0.05). Overall, there were no considerable differences in the local levels of the biomarkers studied between groups (p > 0.05). The IL-23 concentration and total amount of IFN-γ increased in the FMSRP group and decreased in the PMSRP group from baseline to 3 mo and from baseline to 6 mo, respectively (p < 0.05).. Both PMSRP and FMSRP promoted benefits in clinical parameters and showed a similar modulation of cytokines and osteoclastogenesis-related factors at 12 mo in type 2 diabetic subjects.

Topics: Adult; Aged; Biomarkers; Chronic Periodontitis; Cytokines; Dental Scaling; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Gingival Crevicular Fluid; Humans; Interferon-gamma; Interleukin-17; Interleukin-23; Interleukin-4; Male; Middle Aged; Osteoclasts; Osteoprotegerin; Periodontal Attachment Loss; Periodontal Pocket; Prospective Studies; RANK Ligand; Root Planing; Single-Blind Method; Treatment Outcome; Tumor Necrosis Factor-alpha

Osteoprotegerin (OPG) acts as an important regulatory molecule in atherosclerosis. Recent studies report that thiazolidinediones could affect OPG expression. We investigated the relationship between OPG and inflammatory cytokines and the effects of pioglitazone (a PPARγ (PPARG) agonist) versus metformin on serum OPG levels in type 2 diabetic patients.. Sixty-seven type 2 diabetic patients were included in this study. They were assigned to pioglitazone (15 mg/day, n=34) or metformin (1000 mg/day, n=33) during 24 weeks. Various anthropometric and metabolic parameters, OPG, interleukin 6 (IL6), C-reactive protein (CRP), adiponectin, and homeostasis model assessment of insulin resistance (HOMA-IR), were measured at baseline and at 6 months of treatment.. Serum OPG levels correlated significantly with fasting plasma glucose (FPG), HbAlc, HOMA-IR, IL6, and CRP, and inversely correlated with adiponectin after adjusting for age (P<0.05). Multiple regression analysis showed that FPG, HbAlc, and adioponectin were independently correlated with OPG level. After 6 months of treatment, the reduction in FPG and HbAlc levels was similar between the two groups. Pioglitazone treatment significantly increased body mass index (P<0.05) and waist circumference (P<0.05) and decreased triglycerides (P<0.05) and HOMA-IR (P<0.01). The adiponectin concentration was increased (P<0.05), and OPG and CRP levels were decreased in the pioglitazone group (P<0.05), but were unchanged in the metformin group. The changes in serum OPG in the pioglitazone group showed significant correlation with changes in FPG, HbAlc, and adiponectin.. In type 2 diabetic patients, pioglitazone decreases OPG levels, and this decrease in OPG levels might be associated with the increase in adiponectin.

Topics: Adiponectin; Adult; Aged; Biomarkers; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Male; Metformin; Middle Aged; Osteoprotegerin; Pioglitazone; Thiazolidinediones

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes mellitus (T2DM). We suggested that plasma osteoprotegerin (OPG), a strong, independent predictor of cardiovascular disease, could discriminate between anti-diabetic treatments depending on their benefits regarding cardiovascular disease. The South Danish Diabetes Study, an investigator-driven, randomized, controlled clinical trial lasting 2 years, was used to test this hypothesis in patient groups with different medication strategies (insulin aspart or NPH insulin, added either metformin/placebo or rosiglitazone/placebo). A total of 371 individuals were eligible for the study. Basic variables were analysed along with measurement of plasma OPG and HbA(1c) at the beginning and end of the study. Only rosiglitazone treatment caused a significant decrease in plasma OPG concentrations (p = 0.003), while no significant change was seen in the other treatment groups. The effect of rosiglitazone on plasma OPG remained significant in a univariate analysis adjusted for change in HbA(1c) (p = 0.013). Of note, the change in plasma OPG significantly correlated with HbA(1c) improvement in rosiglitazone-treated patients (R = 0.29, p = 0.0002), while this correlation was poor in those not receiving rosiglitazone (R = 0.06, p =0.48). Treatment with rosiglitazone among patients with T2DM reduces the concentration of plasma OPG. This is not seen with metformin despite similar reductions in HbA(1c) . Alteration in the OPG/RANKL pathway by glitazones may have implications for the understanding of both cardiovascular effects and bone side effects of the drug.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Male; Middle Aged; Osteoprotegerin; Rosiglitazone; Thiazolidinediones; Treatment Outcome

Osteoprotegerin (OPG), a glycoprotein, is a member of the tumor necrotizing factor alpha receptor super-family. By considering the possible role of OPG in cardiovascular disease (CVD), higher incidence of CVD in people with type 2 diabetic nephropathy (T2DN), and anti-atherosclerotic effects of statins, the present study aimed to investigate the effects of lovastatin on serum levels of OPG and soluble receptor activator of nuclear factor-κB ligand (sRANKL) in people with T2DN.. Thirty patients completed the study course, out of 38 adult male patients with T2DN who were initially enrolled. Lovastatin, 20mg/d, was administered for 90 days. Afterwards, lovastatin was withdrawn for the next 30 days. Serum levels of OPG and sRANKL were measured using commercial ELISA kits at baseline, after 90 days of intervention, and after 30 days of withdrawal of lovastatin.. Serum level of OPG was significantly increased (10.76 ± 16.44) and decreased (-7.38 ± 11.98) during 90 days of intervention and 30 days of withdrawal periods, respectively, while, sRANKL level was significantly decreased (-1192.08 ± 578.20) and increased (4418.67 ± 2124.66) during the same periods, respectively.. Lovastatin therapy increased serum OPG level and decreased sRANKL level in people with T2DN. The withdrawal of lovastatin decreased serum OPG level, while sRANKL level was extensively increased.

Topics: Blood Glucose; Demography; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fasting; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Lovastatin; Male; Middle Aged; Osteoprotegerin

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

Topics: Cells, Cultured; Cinacalcet; Diabetes Mellitus, Type 2; Glucose; Humans; Osteoblasts; Osteoprotegerin; Parathyroid Hormone; RANK Ligand

Topics: Apoptosis; Denosumab; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Humans; Insulin-Secreting Cells; Osteoprotegerin; RANK Ligand

To identify and determine the association of SNP (rs2073618) of OPG gene in diabetics with and without retinopathy and in healthy controls.. Descriptive study. Place and Duration of the Study: Department of Biochemistry and Molecular Biology, Army Medical College, Rawalpindi in collaboration with Chemical Pathology Laboratory, Pak Emirates Military Hospital, Rawalpindi and Armed Forces Institute of Ophthalmology, Rawalpindi, from June 2021 to May 2022.. Participants aged 25-70 years were inducted and divided into three equal groups. Group I consisted of diabetics with retinopathy (n = 50), group II was diabetics without retinopathy (n = 50), and group III was healthy individuals (n = 50). DNA was extracted and allele specific PCR technique was adopted using specifically designed primers. Results were analysed using the software Statistical Package for Social Sciences (SPSS) version 22.0 and online bio-informatics tool SNPstats.. CC, CG, and GG genotypes were found to be present in 94%, 4%, and 2% in diabetics without retinopathy, 92%, 4%, and 4% in diabetics with retinopathy, respectively, and 100% presence of CC genotype only in healthy controls. C and G alleles were present in 96% and 4%, respectively, in diabetics without retinopathy, with 100% presence of only C allele in healthy subjects. The genotypic assessment using the models showed no significant association.. SNP rs2073618 of OPG gene was identified in all study groups without any significant distribution or association with the development of diabetic retinopathy. The major genotype C/C was found in the majority of subjects in all groups.. Allele specific PCR, Diabetic retinopathy, Single nucleotide polymorphism, Type 2 Diabetes mellitus.

Topics: Diabetes Mellitus, Type 2; Diabetic Retinopathy; Humans; Osteoprotegerin; Polymorphism, Single Nucleotide

Vascular calcification (VC) is a major predictor of cardiovascular diseases that represent the principal cause of mortality among type-2 diabetic patients. Accumulating data suggest the vital role of some microRNAs on vascular calcification as an epigenetic regulator. Thus, we assessed herein, the role of serum miR-433-3p in vascular calcification in type-2 diabetic patients.. Twenty healthy subjects (control group) and forty diabetic patients (20 without VC and 20 with VC) were involved in the study. miR-433-3p gene expression was measured. Runx2, Dickkopf-1 (DKK1), β-catenin, Receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG) levels in serum were assessed by ELISA technique.. Diabetes patients had significantly lower levels of miR-433-3p expression in comparison to the control group, with the lowest levels being found in diabetic patients with VC. Furthermore, Runx2, β-catenin, and RANKL levels were significantly increased with concomitant lower DKK1 and OPG levels detected in the two diabetic groups especially those with VC.. Collectively, the study documented that down-regulation of miR-433-3p may contribute to the development of VC through activating WNT/β-Catenin and RANKL/RANK/OPG signaling pathways.

Topics: beta Catenin; Core Binding Factor Alpha 1 Subunit; Diabetes Mellitus, Type 2; Humans; MicroRNAs; Osteoprotegerin; Signal Transduction; Vascular Calcification

There are reports of link of osteoprotegerin (OPG) gene polymorphism to type-2 diabetes (T2D) and hypertension (HTN). The objective of the study was to assess the allele frequency of OPG (rs2073618) gene polymorphism and its association with heart rate variability (HRV) and blood pressure variability profile as CVD risks in diabetes mellitus patients with hypertension undergoing treatment. T2D patients on treatment without hypertension (n = 172), with hypertension (n = 177) and 191 healthy volunteers were recruited for the study. Their blood pressure variability including baroreflex sensitivity (BRS), heart rate variability (HRV), OPG, insulin, lipid profile, receptor-activator for NFkB (RANK), receptor-activator for NFkB-Ligand (RANKL), and tumor necrosis factor-α (TNF-α) were estimated. Allele frequency of OPG (rs2073618) gene polymorphism was assessed from the DNA samples. BRS and HRV indices were decreased, and RANKL/OPG and TNF-α were increased in T2D and T2D + HTN groups, respectively compared to healthy control group. The reduction in BRS was contributed by increased inflammation and reduced SDNN of HRV in GG genotype in T2D + HTN. In GG + GC subgroup, it was additionally contributed by rise in RANKL/OPG level (β - 0.219; p 0.008). Presence of mutant GG genotype contributed to the risk of hypertension among T2D patients (OR 3.004) as well as in general population (OR 2.79). It was concluded that CV risks are more in T2D patients with HTN expressing OPG rs2073618 gene polymorphism.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Heart Disease Risk Factors; Humans; Hypertension; Osteoprotegerin; Polymorphism, Single Nucleotide; RANK Ligand; Risk Factors; Tumor Necrosis Factor-alpha

The RANKL-GLYC study aims to explore the impact of the rapid correction of chronic hyperglycemia on the receptor activator of nuclear factor-kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG). RANKL and OPG are considered the main factors in the pathophysiology of Charcot neuroarthropathy, a devastating complication of the joints that remains poorly understood. The study began recruiting patients in September 2021 and ends in June 2022; the final study results are scheduled for January 2023.

Topics: Chronic Disease; Diabetes Mellitus, Type 2; Humans; Hyperglycemia; NF-kappa B; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

High serum levels of osteoprotegerin (OPG) are found in patients with obesity, type 2 diabetes, sepsis, or septic shock and are associated with a high mortality rate in stroke. The primary known function of OPG is to bind to the receptor activator of NF-

Topics: Diabetes Mellitus, Type 2; Humans; Inflammation; Lipopolysaccharides; Macrophages; Obesity; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; TNF Receptor-Associated Factor 6; Toll-Like Receptor 4

Cardiovascular disease (CVD) is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Epidemiological studies suggest serum Osteoprotegrin (OPG)/Tumour-necrosis-factor-related-apoptosis-inducing- ligand (TRAIL) ratio may be a useful marker of cardiovascular risk. This study aimed to compare serum levels of TRAIL, OPG and OPG/TRAIL ratio in people with T2DM, with and without a history of CVD, and controls; and to determine which of these indices, if any, predict cardiovascular risk.. In this single centre observational study of 133 participants, people with T2DM, with and without a history of a cardiovascular event in the last 5 years, were recruited along with a control cohort without T2DM or CVD. Demographic information and anthropometric measurements were recorded. Blood samples were taken and OPG and TRAIL were measured using ELISA.. People with T2DM and CVD had higher OPG/TRAIL ratios compared to controls or those with a new diagnosis of T2DM. After adjustment for potential confounding factors, OPG/TRAIL ratio was significantly associated with the presence of CVD in people with T2DM and an OPG/TRAIL ratio cut-off > 38.6 predicted the presence of CVD in this cohort with a sensitivity of 80% and specificity of 82%.. This study suggests that OPG/TRAIL ratio may have a role as a biomarker of CVD in people with T2DM.

Topics: Biomarkers; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Osteoprotegerin; TNF-Related Apoptosis-Inducing Ligand

Thyroid nodule prevalence is increasing lately, especially in diabetes, but the mechanism of which is not clear. In this study, we investigated if osteoprotegerin (OPG) is involved in the pathogenesis of thyroid nodules in diabetes.. A total of 7568 individuals with detailed information and ultrasound examination results were studied for the prevalence of thyroid nodules. Among them, 1883 were with type 2 diabetes and 5685 were non-diabetic. Then, 1120 individuals were randomly selected for the measurement of OPG. Diabetic rats were made by feeding a high-fat-high-fructose diet for 28 weeks. Rats fed with a normal diet were as controls. Fresh thyroid tissues were obtained and fixed, dehydrated, and embedded in paraffin for hematoxylin-eosin staining and observing pathological changes. qPCR and western blot were used to detect OPG expression in rat thyroid tissues.. We found that HbA1c is an independent risk factor for thyroid nodules (Exp [β] = 1.158, p < 0.001). The prevalence of thyroid nodules in type 2 diabetes was higher than that in non-diabetes (53.9% vs. 46.7%, p < 0.001). Serum OPG levels were significantly elevated in the diabetes group than in the non-diabetes group (3160.17 pg/ml vs. 2819.39 pg/ml, p < 0.01). The expression of OPG increased significantly in the thyroid tissues of diabetic rats.. Osteoprotegerin may be associated with thyroid nodule development in diabetes.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Osteoprotegerin; Rats; Thyroid Nodule

Decreased baroreflex sensitivity (BRS) has been shown to be a marker of cardiovascular (CV) risk. In the present study, the difference in CV risk biomarkers in type 2 diabetes (T2D) patients receiving oral antidiabetic drugs (OAD) with and without hypertension has been assessed.. Ninety-two T2D patients on OAD without hypertension (control group) and eighty-eight diabetic patients with hypertension on OAD and antihypertensive drugs (test group) matched for age, gender, body mass index, serum glucose, glycated haemoglobin, and duration of the disease were recruited for the study. Their blood pressure (BP) variability including BRS, heart rate variability (HRV), insulin, lipid profile, osteoprotegerin (OPG), and tumor necrosis factor-α (TNF-α) were estimated. The association of various factors with BRS was assessed by Spearman correlation and multiple regression analysis.. BRS was decreased (13.90 ± 5.27 vs 6.76 ± 4.58), HRV sympathetic indices [LFnu, LF-HF ratio (1.30 ± 0.49 vs 1.93 ± 0.62)], HOMA-IR, atherogenic index of plasma (AIP), OPG (223.08 ± 103.86 vs 287.60 ± 121.36) and TNF-α were increased, and parasympathetic indices [TP (1012.90 ± 316.18 vs 625.88 ± 229.84), RMSSD, SDNN, NN50, pNN50] were decreased in the test group compared to control group. In control group, parasympathetic indices, AIP, OPG, and TNF-α had a significant correlation and OPG had an independent association (β - 0.344; p 0.004) with BRS. In test group, BP, LF-HF ratio, parasympathetic indices, AIP, OPG, and TNF-α had significant correlation, and TNF-α alone (β - 0.297; p 0.022) had an independent contribution to decreased BRS.. Despite antidiabetic and antihypertensive treatments, T2D patients with hypertension had more cardiometabolic risks in comparison to normotensive T2D patients. Inflammation could be the inciting factor for rise in BP and decrease in BRS (CV risk) in hypertensive T2D patients. Hypertension in diabetes could attenuate the link of OPG to the reduction in BRS. Reduction in BRS could be a physiological marker of CV risk in T2D patients treated with OAD.

Topics: Antihypertensive Agents; Baroreflex; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Humans; Hypertension; Hypoglycemic Agents; Osteoprotegerin; Tumor Necrosis Factor-alpha

Obesity and diabetes prevalence are increasing worldwide. We aimed to detect the possible association of osteoprotegerin (OPG) gene expression with visceral adiposity indices and cardiometabolic risk factors among obese women.. The study enrolled 150 controls and 150 obese cases subdivided into two subgroups non-diabetic (n = 70) and 80 patients with type 2 diabetes mellitus (T2DM). Circulating OPG gene expression levels were figured out by real time PCR (Polymerase Chain Reaction). Serum OPG levels were assessed by Enzyme Linked Immunosorbent Assay. Our results explored that OPG serum levels were lower in the obese women compared to control group (p < 0.001) and obese diabetics had higher serum levels of OPG in comparison to obese non-diabetic patients (p < 0.001). Expression levels of OPG were higher in obese women than controls (p < 0.001). Moreover, the blood expression levels of OPG gene were higher in diabetic obese patients than non-diabetics. We found positive correlations between parameters of metabolic syndrome and obesity indices. After adjustment of the traditional risk factors, stepwise linear regression analysis test revealed that OPG expression levels were independently correlated with glycated hemoglobin, high-density lipoprotein-cholesterol, and waist-to-hip ratio.. OPG mRNA levels were associated with surrogate markers of insulin resistance in Egyptian obese women.

Topics: Adult; Biomarkers; Diabetes Mellitus, Type 2; Egypt; Female; Gene Expression Regulation; Humans; Insulin Resistance; Middle Aged; Obesity; Osteoprotegerin

Osteoprotegerin (OPG), a well-known protein that inhibits osteoclast formation and activity, might also be a potential marker for identifying patients with high cardiovascular risk. This study aimed to compare OPG levels, FMD, and CIMT measurements in subjects with vs. without diabetes and investigate the association of serum osteoprotegerin level with the early atherosclerotic markers, endothelial function, and carotid intima-media thickness (CIMT) in patients with type 2 diabetes mellitus (DM2).. Forty-nine patients with DM2 (F/M: 26/23, 49.3 ± 10.0 years) and 45 healthy volunteers (F/M: 26/19, 48.3 ± 7.5 years) were included in this cross-sectional study. Serum OPG levels were measured by solid-phase enzyme-linked immunosorbent assay (ELISA). Fasting plasma glucose (FPG) and HbA1c levels were measured. CIMT was measured by B-mode ultrasound, and endothelial function was evaluated via flow-mediated dilation (FMD) of the brachial artery with Doppler ultrasonography.. Serum OPG levels were significantly higher in patients with DM2 (617.0 ± 111.0 pg/mL) compared to controls (481.0 ± 96.0 pg/mL, p < 0.001). While CIMT in diabetic patients (0.65 + 0.13 mm) was higher than controls (0.54 ± 0.10 mm, p = 0.009), FMD measurement was lower in DM2 group (4.2% ± 3.1 mm vs. 7.6% ± 4.1 mm, p = 0.01). Univariate analysis showed that OPG was associated with the presence of diabetes (OR: 6.999, p = 0.001, R. Osteoprotegerin and CIMT levels were increased, and FMD measurements were decreased in patients with DM2. No association between CIMT, FMD, and OPG measurements was observed. The presence of DM and hypertension were associated with circulating OPG levels.

Topics: Adult; Biomarkers; Blood Glucose; Brachial Artery; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Osteoprotegerin; Ultrasonography

The musculoskeletal system consisting of bones and muscles have been recognized as endocrine organs secreting hormones that are involved in regulating metabolic and inflammatory pathways. Obesity and type 2 diabetes (T2D) are associated with several musculoskeletal system complications. We hypothesized that an interaction exists between adipomyokines namely, irisin and METRNL, and various molecules involved in bone remodeling in individuals with obesity and T2D. A total of 228 individuals were enrolled in this study, including 124 non-diabetic (ND) and 104 T2D. A Multiplex assay was used to assess the level of various osteogenic molecules namely osteoactivin, Syndecan, osteoprotegerin (OPG) and osteonectin/SPARC. Our data shows elevated levels of Osteoactivin, Syndecan, OPG and SPARC in T2D as compared to ND individuals (p ≤ 0.05). Using Spearman's correlation, a positive correlation was observed between irisin and Osteoactivin as well as OPG (p < 0.05). Similarly, a positive association was observed between METRNL and Osteoactivin (p < 0.05). The strong positive association shown in this study between irisin, METRNL and various molecules with osteogenic properties emphasize a possible interaction between these organs. This report suggests that having a dysregulation in the level of the aforementioned molecules could potentially affect the development of bone and muscle related complications that are associated with obesity and T2D.

Topics: Adipokines; Adult; Bone Remodeling; Diabetes Mellitus, Type 2; Female; Fibronectins; Humans; Male; Membrane Glycoproteins; Middle Aged; Obesity; Osteogenesis; Osteonectin; Osteoprotegerin; Syndecan-4

The aim was to assess the effect of scaling and root planing (SRP) with and without adjunct photodynamic therapy (PDT) on the levels of osteoprotegerin (OPG) receptor activator of NF-kappa B ligand (RANKL) in the unstimulated whole saliva (UWS) of type-2 diabetic and normoglycemic individuals with chronic periodontitis (CP).. Type-2 diabetic and normoglycemic subjects with CP (Groups 1 and 2, respectively) were divided into test- (SRP + PDT) and control (SRP only) groups. Patient demographics were recorded; and periodontal parameters (marginal bone loss [MBL], probing depth [P.D], plaque index [PI], gingival index [GI], and clinical attachment loss [CAL]) were assessed at baseline and at 3-months-follow-up. Rate of flow of unstimulated whole saliva and levels of RANKL and osteoprotegerin were measured at both time intervals. P < 0.05 was considered statistically significant.. Eighty-four persons with CP (42 with and 42 without type-2 DM) were included. At baseline, clinicoradiographic parameters were comparable in all groups. At 3-months of follow-up, there was no significant difference in the clinicoradiographic parameters in all groups. At 3-months of follow-up, there was no significant reduction in whole salivary RANKL and osteoprotegerin levels among individuals in the test and control groups among CP patients with and without CP.. The whole salivary RANKL/OPG ratio remains high in patients with poorly-controlled type-2 DM after SRP with or without adjunct PDT.

Topics: Chronic Periodontitis; Dental Scaling; Diabetes Mellitus, Type 2; Humans; Osteoprotegerin; Photochemotherapy; Photosensitizing Agents; Root Planing

A large British study, with almost 3000 patients, identified diabetes as main risk factor for delayed and nonunion fracture healing, the treatment of which causes large costs for the health system. In the past years, much progress has been made to treat common complications in diabetics. However, there is still a lack of advanced strategies to treat diabetic bone diseases. To develop such therapeutic strategies, mechanisms leading to massive bone alterations in diabetics have to be well understood. We herein describe an in vitro model displaying bone metabolism frequently observed in diabetics. The model is based on osteoblastic SaOS-2 cells, which in direct coculture, stimulate THP-1 cells to form osteoclasts. While in conventional 2D cocultures formation of mineralized matrix is decreased under pre-/diabetic conditions, formation of mineralized matrix is increased in 3D cocultures. Furthermore, we demonstrate a matrix stability of the 3D carrier that is decreased under pre-/diabetic conditions, resembling the in vivo situation in type 2 diabetics. In summary, our results show that a 3D environment is required in this in vitro model to mimic alterations in bone metabolism characteristic for pre-/diabetes. The ability to measure both osteoblast and osteoclast function, and their effect on mineralization and stability of the 3D carrier offers the possibility to use this model also for other purposes, e.g., drug screenings.

Topics: Alkaline Phosphatase; Bone and Bones; Bone Resorption; Calcification, Physiologic; Carbonic Anhydrase II; Cathepsin K; Cell Differentiation; Cell Line, Tumor; Coculture Techniques; Diabetes Mellitus, Type 2; Gene Expression Regulation; Humans; Metabolic Networks and Pathways; Models, Biological; Osteoblasts; Osteoclasts; Osteoprotegerin; RANK Ligand; Tartrate-Resistant Acid Phosphatase; THP-1 Cells; Tissue Scaffolds

Carotid atherosclerosis represents one of the complications of diabetes mellitus. In particular, plaque instability contributes to disease progression and stroke incidence. High mobility group box-1 (HMGB1) is a nuclear protein involved in promotion and progression of atherosclerosis and cardiovascular diseases. The aim of this study was to analyze the relationship between HMGB1 serum levels, main inflammatory cytokines, the presence of internal carotid stenosis and unstable plaque in a diabetic population.. We studied 873 diabetic patients, including 347 patients with internal carotid artery stenosis (ICAS) who underwent carotid endarterectomy and 526 diabetic patients without internal carotid artery stenosis (WICAS). At baseline, HMGB1 and the main inflammatory cytokines serum levels were evaluated. For ICAS patients, the histological features of carotid plaque were also collected to differentiate them in patients with stable or unstable atherosclerotic lesions.. We found that HMGB1 serum levels, osteoprotegerin, high-sensitivity C-reactive protein, tumor necrosis factor-alpha and interleukin-6, were significantly higher in diabetic ICAS patients compared to diabetic WICAS patients. Among ICAS patients, individuals with unstable plaque had higher levels of these cytokines, compared to patients with stable plaque. A multivariable stepwise logistic regression analysis showed that HMGB1 and osteoprotegerin remained independently associated with unstable plaque in ICAS patients.. The present study demonstrated that HMGB1 is an independent risk factor for carotid plaque vulnerability in an Italian population with diabetes mellitus, representing a promising biomarker of carotid plaque instability and a possible molecular target to treat unstable carotid plaques and to prevent stroke.

Topics: Aged; Biomarkers; C-Reactive Protein; Carotid Stenosis; Case-Control Studies; Diabetes Mellitus, Type 2; Female; HMGB1 Protein; Humans; Inflammation Mediators; Interleukin-6; Italy; Male; Osteoprotegerin; Plaque, Atherosclerotic; Prognosis; Risk Assessment; Risk Factors; Rupture, Spontaneous; Tumor Necrosis Factor-alpha

M. pumilum has been claimed to protect the bone against the adverse effect of estrogen deficiency. Additionally, it also exhibits anti-diabetic activity. In view of these, this study aims to identify the mechanisms underlying the bone protective effect of M. pumilum in the presence of both estrogen deficiency and diabetes mellitus (DM).. Ovariectomized, diabetic female rats were given M. pumilum leave aqueous extract (MPLA) (50 and 100 mg/kg/day), estrogen, glibenclamide and estrogen plus glibenclamide for 28 consecutive days. At the end of the treatment, fasting blood glucose (FBG), serum insulin, Ca. MPLA helps to overcome the adverse effect of estrogen deficiency and DM on the bone and thus this herb could potentially be used for the treatment and prevention of osteoporosis in postmenopausal women with diabetes.

Topics: Animals; Bone and Bones; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Estrogens; Female; Inflammation; Osteoprotegerin; Ovariectomy; Oxidative Stress; Plant Extracts; Plant Leaves; Primulaceae; RANK Ligand; Rats; Rats, Sprague-Dawley; Receptor Activator of Nuclear Factor-kappa B; Signal Transduction

The aim of this study is to evaluate the relationship between OPG and the degree of glycaemic control in a population of elderly subjects.. Data presented included 172 elderly subjects, of whom 107 were hospitalized for a hip fracture and 65 were non fractured outpatients. All participants received a multidimensional geriatric evaluation and underwent blood sampling. HbA1c, OPG, CTX and OC were measured and DXA scans were performed. Carotid intima-media thickness (IMT) was measured in all outpatients. Diabetic patients had more comorbidities, higher mean values of lumbar spine and femoral neck BMD and T-score, lower circulating levels of OC and CTX, and higher circulating levels of OPG compared to non-diabetic subjects. OPG was directly correlated with HbA1c. This association was most evident in non-fractured elderly subjects. Moreover, diabetic patients with IMT>1.5 mm had greater mean values of OPG than non-diabetic subjects with high IMT and than elderly subjects with IMT < 1.5 mm, with and without T2DM.. Diabetic patients have reduced circulating levels of OC and CTX, and elevated serum levels of OPG, suggesting a state of low bone turnover. Reduced bone turnover causes an increase of BMD and could lead to a poor bone quality. OPG and HbA1c were directly correlated and OPG mean values were higher in diabetic patients with poor glucose control. Diabetic osteopathy could be considered a late complication of T2DM, directly related with the degree of glucose control and the duration of the disease.

Topics: Age Factors; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; Bone Density; Bone Diseases; Collagen Type I; Diabetes Mellitus, Type 2; Female; Frail Elderly; Glycated Hemoglobin; Health Status; Humans; Male; Osteocalcin; Osteoprotegerin; Peptides; Prevalence; Risk Factors; Rome

Poor glycaemic control elevates the risk for vascular complications. Biomarkers for predicting susceptibility to glycaemic worsening are lacking. This 3-year prospective analysis assessed the utility of several circulating diabetes-related biomarkers for predicting loss of glycaemic control, and their contribution to albuminuria progression in type 2 diabetes mellitus (T2DM).. T2DM subjects with adequately-controlled diabetes (HbA1c < 8%) at initial recruitment were analysed (N = 859). Baseline plasma levels of osteoprotegerin (OPG), C-reactive protein (CRP), adiponectin, intercellular-cell adhesion molecule-1, and vascular-cell adhesion molecule-1 were quantified using immunoassay. Definitions for development of uncontrolled diabetes and albuminuria progression were HbA1c ≥ 8.0% and increase in albuminuria category at follow-up, respectively.. At follow-up, 185 subjects developed uncontrolled diabetes. Higher baseline CRP and OPG levels were observed in the high-risk individuals, and predicted increased risk for developing uncontrolled diabetes. OPG, but not CRP, was associated with albuminuria progression after multivariable adjustment. The relationship was attenuated following adjustment for development of uncontrolled diabetes, which emerged as a significant associate. Mediation analysis revealed that loss of glycaemic control explained 64.5% of the relationship between OPG and albuminuria progression.. OPG outperformed other diabetes-related biomarkers to be a potentially useful biomarker for predicting loss of glycaemic control and its associated albuminuria deterioration.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Biomarkers; Blood Glucose; C-Reactive Protein; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Middle Aged; Osteoprotegerin; Prognosis; Young Adult

The highly selective magnesium transporter non-imprinted in Prader-Willi/Angelman syndrome region protein 2 (NIPA2) has recently been associated with the development and progression of type 2 diabetes osteoporosis, but the mechanisms involved are still poorly understood. Because mitophagy is involved in the pathology of type 2 diabetes osteoporosis, the present study aimed to explore the relationship among NIPA2, mitophagy and osteoblast osteogenic capacity. NIPA2 expression was reduced in C57BKS background db/db mice and in vitro models of type 2 diabetes osteoporosis, and the activation of mitophagy in primary culture osteoblast-derived from db/db mice and in high glucose-treated human fetal osteoblastic cells (hFOB1.19) was observed. Knockdown, overexpression of NIPA2 and pharmacological inhibition of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) showed that NIPA2 increased osteoblast function, which was likely regulated by PTEN induced kinase 1 (PINK1)/E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy via the PGC-1α/forkhead box O3a(FoxO3a)/mitochondrial membrane potential (MMP) pathway. Furthermore, the negative effect of mitophagy on osteoblast function was confirmed by pharmacological regulation of mitophagy and knockdown of Parkin. Taken together, these results suggest that NIPA2 positively regulates the osteogenic capacity of osteoblasts via the mitophagy pathway in type 2 diabetes.

Topics: Alkaline Phosphatase; Animals; Bone and Bones; Cation Transport Proteins; Cells, Cultured; Collagen Type I; Core Binding Factor Alpha 1 Subunit; Diabetes Mellitus, Type 2; Down-Regulation; Forkhead Box Protein O3; Glucose; Humans; Magnesium; Male; Mice, Inbred C57BL; Mitophagy; Osteoblasts; Osteocalcin; Osteogenesis; Osteoporosis; Osteoprotegerin; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; RNA, Messenger; Signal Transduction

The objective of the study was to detect the levels of osteoprotegerin (OPG) and 25-hydroxyvitamin D [25(OH)D], as well as the expression of bone sialoprotein (BSP) mRNA, in the peripheral blood of patients with newly diagnosed type 2 diabetes mellitus (T2DM) under different bone mass conditions, and to explore its role and significance in the development process of T2DM combined with osteoporosis (OP).. A total of 225 patients hospitalised in the Endocrinology Department and General Department from May 2017 to May 2018 were enrolled and categorised into five groups: the pure T2DM group (group A, 45 patients), the bone mass reduction group (group B, 45 patients), the T2DM + bone mass reduction group (group C, 45 patients), the OP group (group D, 45 patients), and the T2DM + OP group (group E, 45 patients); meanwhile, age-matched healthy subjects undergoing physical examination in our hospital were collected as the normal control group (group NC, 45 cases). Logistic regression analysis was used to analyse the influencing factors of bone mass in patients with T2DM.. Compared with group B, the expression levels of glycated haemoglobin (HbA1c), 25(OH)D, N-terminal propeptide of type I procollagen (PINP), fasting plasma glucose (FPG), fasting plasma insulin (FINS), high-density lipoprotein cholesterol (HDL-C), and BSP mRNA were significantly increased while OPG and b-collagen degradation products (b-CTX) were significantly decreased in group A.. The expression of BSP mRNA and the decrease of 25(OH)D and OPG in peripheral blood may participate in the development of diabetes and osteoporosis.

Topics: Adult; Biomarkers; Blood Glucose; Bone Density; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Integrin-Binding Sialoprotein; Male; Middle Aged; Osteoprotegerin; Risk Assessment; Vitamin D

An increased osteoprotegerin (OPG) level has been reported in both type-2 diabetes mellitus (T2DM) and cardiovascular diease (CVD) that are linked to sympathovagal imbalance (SVI). We explored the link of osteoprotegerin with cardiovagal modulation in T2DM.. We assessed fasting serum OPG, high-sensitive C-reactive protein (hsCRP), glucose, insulin and lipid profile in patients having T2DM receiving oral antidiabetic drugs (OAD) (n = 42) compared with age, gender and body composition-matched healthy participants without diabetes (n = 42). Rate pressure product (RPP), spectral indices of heart rate variability (HRV) and body composition were recorded in both the groups. Association of HOMA-IR and OPG with various parameters were assessed.. Osteoprotegerin, HOMA-IR, hsCRP, coronary lipid risk factor were significantly increased, markers of cardiovagal modulation (TP, SDNN, RMSSD) were considerably decreased, ratio of low-frequency to high-frequency (LH-HF ratio), the indicator of SVI, and RPP, the marker of myocardial work stress were significantly higher in patients with diabetes, suggesting an overall elevated CVD risks in them. HOMA-IR was correlated with RMSSD, lipid risk factors and OPG. Rise in OPG was correlated with decreased cardiovagal modulation in patients with diabetes. There was significant contribution of OPG in decreasing TP, suggesting impaired cardiovagal modulation.. T2DM patients receiving OAD had higher cardiometabolic risks compared to age, gender and body composition-matched healthy individuals. Increased level of OPG is linked to decreased cardiovagal modulation in T2DM patients.

Topics: Administration, Oral; Adult; Biomarkers; Cardiometabolic Risk Factors; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Heart; Humans; Hypoglycemic Agents; India; Male; Metformin; Middle Aged; Osteoprotegerin; Risk Assessment; Sulfonylurea Compounds; Treatment Outcome; Up-Regulation; Vagus Nerve

Osteopontin (OPN), osteoprotegerin (OPG) and osteocalcin (OC) are matrix glycoproteins which mediate bone mineralization; moreover, their effects on glucose/insulin homeostasis have recently been demonstrated. Higher circulating OPN and OPG levels have been associated with the presence of insulin resistance, atherosclerosis and coronary heart disease. No data are available on contextual changes of these markers in type 2 diabetes mellitus (T2DM). Therefore, aims of this study were to evaluate serum OPN, OPG and OC levels in T2DM patients and their clinical correlates.. We recruited 83 consecutive T2DM patients referring to our diabetes outpatient clinics at Sapienza, University of Rome, and 71 non-diabetic sex and age-comparable subjects as a control group. Study population underwent metabolic characterization and carotid ultrasound for intima-media thickness measurement. Plasma OPN, OPG and OC were measured by MILLIPLEX Multiplex Assays Luminex.. T2DM patients had significantly higher circulating OPN and OPG levels than controls (14.3 ± 13.6 vs 10.6 ± 13.7 ng/ml p < 0.001, 0.70 ± 0.60 vs 0.54 ± 4.1 ng/ml, p = 0.02) while OC levels were similar in the two cohorts (6.35 ± 5.8 vs 7.80 ± 7.0 ng/ml, p = n.s). OPN and OPG positively correlated with greater systolic blood pressure (SBP) values, HOMA-IR and HOMA-β, and with the presence of dyslipidemia and carotid atherosclerosis. The association between greater OPN and OPG levels and SBP was independent from possible confounders (both p = 0.01).. Circulating OPN and OPG levels are increased in T2DM patients and identify a particularly unfavourable metabolic profile, mostly expressed by higher SBP. Bone peptides may represent novel markers of vascular stress and accelerated atherosclerosis in diabetes, constituting a possible tool for cardiovascular risk stratification in diabetes.

Topics: Adult; Aged; Biomarkers; Cardiovascular Diseases; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Male; Metabolic Syndrome; Metabolome; Middle Aged; Osteocalcin; Osteopontin; Osteoprotegerin; Prognosis; Risk Factors

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

The role of RANKL/RANK/OPG system on bone remodeling is well known, and there is evidence that it is also important to cardiovascular and kidney pathology, although the underlying mechanisms are not elucidated so far. Thus, we investigated in a mice model of diet-induced obesity and diabetes if renal histopathological changes are associated with the expression of RANKL/RANK/OPG system and matrix metalloproteinases (MMPs). Three months old C57BL/6 mice were fed with control (C) AIN93 M diet or high-fat high sucrose (HFHS) diets for 21 weeks (CEUA/UFF #647/15). The two groups presented weight gain, but it was higher in the HFHS group compared to the C group (+35%, P = 0.0001). The HFHS group also had increased epididymal, inguinal and retroperitoneal fat pad weight (+121%, P = 0.0006; +287%, P = 0.0007 and; +286%, P < 0.0001, respectively), and hyperglycemia (+43%, P = 0.02). The kidney of some HFHS fed mice displayed mononuclear inflammatory cell infiltrate (40%), perivascular fibrosis (20%), and focal tubule mineralization (20%). Glomeruli hypertrophy was not detected. Unexpectedly, OPG, RANK, MMP-2, and MMP-9 expression was not altered in HFHS groups (Western blot analysis). In conclusion, the expression of RANKL/RANK/OPG system proteins and MMPs was not influenced by diet-induced obesity and diabetes in the kidney of male C57BL/6 mice, although some adverse histopathological remodeling is noticed in the renal tissue.

Topics: Animals; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Kidney; Male; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Obesity; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Studies addressing the link between gene polymorphism and Charcot neuropathic osteoarthopathy (CN) have been limited to analyse osteoprotegerin gene. Aim is to understand the association of RANKL gene variants on the susceptibility of diabetic neuropathy and CN and to measure the serum levels of sRANKL among Indian population with type 2 diabetes. 77 subjects (48 males: 29 females) were recruited and divided into 3 groups. Group 1 Control: normal glucose tolerance (NGT). Group 2: Type 2 diabetes mellitus and neuropathy (DPN). Group 3: Established type 2 diabetes mellitus, DPN, and CN. Subjects were genotyped for RANKL SNP 693 C/G and 643 C/T using polymerase chain reaction-restriction fragment length polymorphism. sRANKL levels were measured using ELISA (enzyme-linked immunosorbent assay). The serum levels of sRANKL were significantly different between the 3 groups. In RANKL -643 C/T the frequency of "CT" genotype and the minor allele "T" was greater among the DPN and CN group compared with the NGT. Further statistical analysis found a significant difference in genotypic frequencies between DPN and NGT subjects with CT genotype. In RANK L -693 C/G the frequency of homozygote mutant "GG" and the minor allele "G" was greater among the DPN and CN group compared with the NGT. Significant differences in genomic frequencies were observed among "GG" genotype. RANKL -643 C/T was significantly associated with DPN alone while -693 C/G was significantly associated with both DPN and CN. Thus, the study suggests RANKL polymorphism might be considered as an independent risk factor for the development of CN.

Topics: Arthropathy, Neurogenic; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Gene Frequency; Humans; India; Male; Middle Aged; Osteoprotegerin; Polymorphism, Single Nucleotide; Receptor Activator of Nuclear Factor-kappa B

Osteoprotegerin plays a role in the development of several bone diseases. In addition, osteoprotegerin may contribute to the development of vascular disease. Little is known about the association between serum osteoprotegerin levels and the presence or severity of peripheral arterial disease (PAD). The aim of this study was to examine the association between serum osteoprotegerin levels and both the presence as well as the severity of lower extremity arterial disease in patients with type 2 diabetes (T2DM).. The study included 165 consecutive patients with T2DM (57 % males, mean age 65.0 ± 0.7 years). PAD was diagnosed by measurement of the toe-brachial index (TBI). Serum osteoprotegerin was measured using ELISA.. The mean osteoprotegerin level was significantly higher in patients with PAD in comparison to patients without PAD (18.2 ± 1.0 vs. 13.1 ± 2.0 pmol/L, p = 0.014). Significant univariate correlations between TBI and osteoprotegerin level (r = -0.308; p < 0.001), age, body mass index, and HDL cholesterol were observed. In the multivariate linear regression analysis, serum osteoprotegerin (β = -0.005; p = 0.020), higher age, and male gender were significant predictors of TBI. When 25(OH) vitamin D was introduced into the mentioned model, OPG was no longer a significant predictor of TBI and was replaced in the model with vitamin D (β = 0.009, p = 0.001). This finding suggests a role of OPG as a mediator of the effects of 25(OH) vitamin D.. Serum osteoprotegerin level is significantly associated with both the presence and severity of PAD in patients with T2D. Osteoprotegerin might be a biomarker for the presence of atherosclerotic disease in patients with T2DM.

Topics: Aged; Ankle Brachial Index; Biomarkers; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Humans; Linear Models; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Peripheral Arterial Disease; Predictive Value of Tests; Risk Factors; Severity of Illness Index; Up-Regulation

Dedifferentiation could explain reduced functional pancreatic β-cell mass in type 2 diabetes (T2D).. Here we model human β-cell dedifferentiation using growth factor stimulation in the human β-cell line, EndoC-βH1, and human pancreatic islets.. Fibroblast growth factor 2 (FGF2) treatment reduced expression of β-cell markers, (INS, MAFB, SLC2A2, SLC30A8, and GCK) and activated ectopic expression of MYC, HES1, SOX9, and NEUROG3. FGF2-induced dedifferentiation was time- and dose-dependent and reversible upon wash-out. Furthermore, FGF2 treatment induced expression of TNFRSF11B, a decoy receptor for RANKL and protected β-cells against RANKL signaling. Finally, analyses of transcriptomic data revealed increased FGF2 expression in ductal, endothelial, and stellate cells in pancreas from T2D patients, whereas FGFR1, SOX,9 and HES1 expression increased in islets from T2D patients.. We thus developed an FGF2-induced model of human β-cell dedifferentiation, identified new markers of dedifferentiation, and found evidence for increased pancreatic FGF2, FGFR1, and β-cell dedifferentiation in T2D.

Topics: Cell Dedifferentiation; Cells, Cultured; Diabetes Mellitus, Type 2; Fibroblast Growth Factor 2; Humans; Insulin-Secreting Cells; Osteoprotegerin; RANK Ligand; Receptor, Fibroblast Growth Factor, Type 1; SOX9 Transcription Factor; Transcription Factor HES-1

The serum level of osteoprotegerin (encoded by OPG or TNFRSF11B) was previously shown to be increased in patients with ischemic stroke. A single nucleotide polymorphism rs3134069 in the TNFRSF11B gene was previously associated with ischemic stroke in a population of diabetic patients in Italy. It remains to be determined whether rs3134069 is associated with ischemic stroke in the general population or populations without diabetes.. We genotyped rs3134069 and performed a case-control association study to test whether rs3134069 is associated with ischemic stroke in 2 independent Chinese Han populations, including a China-Central population with 1629 cases and 1504 controls and a China-Northern population with 1206 cases and 720 controls.. This study demonstrates that rs3134069 in TNFRSF11B increases risk of ischemic stroke by decreasing TNFRSF11B expression.

Topics: Adult; Aged; Asian People; Brain Ischemia; Case-Control Studies; Chi-Square Distribution; China; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Odds Ratio; Osteoprotegerin; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Risk Assessment; Risk Factors; Stroke

Tissue cross-talk is emerging as a determinant way to coordinate the different organs implicated in glucose homeostasis. Among the inter-organ communication factors, muscle-secreted myokines can modulate the function and survival of pancreatic beta-cells. Using primary human myotubes from soleus, vastus lateralis and triceps brachii muscles, we report here that the impact of myokines on beta-cells depends on fiber types and their metabolic status. We show that Type I and type II primary myotubes present specific mRNA and myokine signatures as well as a different sensitivity to TNF-alpha induced insulin resistance. Finally, we show that angiogenin and osteoprotegerin are triceps specific myokines with beta-cell protective actions against proinflammatory cytokines. These results suggest that type I and type II muscles could impact insulin secretion and beta-cell mass differentially in type 2 diabetes through specific myokines secretion.

Topics: Cytokines; Diabetes Mellitus, Type 2; Homeostasis; Humans; Inflammation; Insulin Resistance; Insulin-Secreting Cells; Muscle Cells; Muscle Fibers, Skeletal; Muscle, Skeletal; Osteoprotegerin; Primary Cell Culture; Ribonuclease, Pancreatic; Tumor Necrosis Factor-alpha

In bone marrow mesenchymal stem cell (BMSCs), type 2 diabetes mellitus (T2DM) induces metabolic and functional disorders, leading to imbalanced bone resorption and formation and bone loss. Brain and muscle ARNT-like protein 1 (BMAL1) is involved in regulating T2DM-related suppression of BMSCs osteogenesis and bone formation. However, the relationship between BMAL1 and bone remodelling, especially bone resorption in T2DM, is unclear. We investigated the antergic role played by BMAL1 in T2DM-prompted imbalance in BMSCs osteogenic-osteoclastic function. BMAL1 was inhibited and the receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio was increased in diabetic BMSCs. Inhibitor κB (IκB) expression was decreased, whereas phosphorylated-p65 (p-p65), caspase-3, and p-IκB expression were increased in diabetic BMSCs. BMAL1 overexpression recovered the osteogenesis ability and suppressed osteoclastic induction capability of BMSCs to improve bone metabolism and function, which was partially due to NF-κB pathway activity inhibition. Our results provide evidence about the role of BMAL1 in T2DM-prompted BMSCs differentiation dysfunction, i.e. partially decreasing NF-κB pathway expression. In T2DM, it might be possible to use overexpressed BMAL1 to re-establish the homeostasis of bone metabolism.

Topics: Animals; ARNTL Transcription Factors; Bone Marrow Cells; Bone Resorption; Cell Differentiation; Cell Proliferation; Cells, Cultured; Diabetes Mellitus, Type 2; Male; Mesenchymal Stem Cells; NF-kappa B; Osteoclasts; Osteogenesis; Osteoprotegerin; RANK Ligand; Rats; Rats, Wistar; Signal Transduction; Stromal Cells

This study aims to compare the levels of osteoprotegerin (OPG) and 25-hydroxy vitamin D (25(OH)D) in patients with diabetic foot and patients with newly diagnosed type 2 diabetes mellitus (DM) and to investigate the prevalence and severity of 25(OH)D insufficiency in patients with diabetic foot.. This prospective study was conducted on 105 patients including 58 patients with diabetic foot (42 males, 16 females; mean age 63.6 years; range, 31 to 90 years), who applied to our hospital between June 2014 and May 2015, and 47 newly diagnosed type 2 DM patients (27 males, 20 females; mean age 51.4 years; range, 29 to 85 years) (control group). 25(OH)D and osteoprotegerin serum levels in both groups were measured and compared.. Osteoprotegerin levels in diabetic foot group were significantly higher than the control group (p<0.05). The 25(OH)D levels in diabetic foot group were significantly lower than the control group (p<0.05). There were positive correlations between OPG levels and C-reactive protein (CRP) and creatinine levels in patients with diabetic foot.. Elevated levels of OPG in patients with diabetic foot may display the severity of the clinical status due to its positive correlation with CRP and creatinine. We detected severe 25(OH)D deficiency in the majority of diabetic foot patients. Vitamin D supplementation may be required in diabetic foot patients to prevent unfavorable immunologic alterations.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Creatinine; Diabetes Mellitus, Type 2; Diabetic Foot; Female; Humans; Male; Middle Aged; Osteoprotegerin; Prospective Studies; Vitamin D

Although vascular calcification (VC) is prevalent in Type 2 diabetes mellitus (T2DM), underlying mechanisms remain unclear. Neither is it known whether T2DM confers calcific potential (CP) on serum, enabling it to induce VC outside the disease milieu. We, therefore, investigated the CP of serum from controls and subjects with T2DM with and without

Topics: Aged; Calcium-Binding Proteins; Case-Control Studies; Diabetes Mellitus, Type 2; Extracellular Matrix Proteins; Female; Glomerular Filtration Rate; Humans; Male; Matrix Gla Protein; Middle Aged; Myocytes, Smooth Muscle; Osteoprotegerin; Vascular Calcification

to evaluate the role of clinical characteristics, functional markers of vasodilation, inflammatory response, and atherosclerosis in predicting wound healing in diabetic foot ulcer.. a cohort study (February - October 2010) was conducted from 40 subjects with acute diabetic foot ulcer at clinical ward of Dr. Cipto Mangunkusumo National Central General Hospital, Jakarta, Indonesia. Each subject underwent at least two variable measurements, i.e. during inflammatory phase and proliferation phase. The studied variables were clinical characteristics, complete peripheral blood count (CBC) and differential count, levels of HbA1c, ureum, creatinine, lipid profile, fasting blood glucose (FBG), marker of endothelial dysfunction (asymmetric dimethylarginine/ADMA, endothelin-1/ET-1, and flow-mediated dilation/FMD of brachial artery), and marker of vascular calcification (osteoprotegerin/OPG).. median of time achieving 50% granulation tissue in our study was 21 days. There were nine factors that contribute in the development of 50% granulation tissue, i.e. family history of diabetes mellitus (DM), previous history of wound, wound area, duration of existing wound, captopril and simvastatin medications, levels of ADMA, ET-1, and OPG. There were three out of the nine factors that significantly correlated with wound healing, i.e. wound area, OPG levels, and simvastatin medications.. in acute diabetic foot ulcers, wound area and OPG levels had positive correlation with wound healing, whereas simvastatin medications had negative correlation with wound healing.

Topics: Aged; Biomarkers; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Foot; Endothelin-1; Female; Humans; Indonesia; Kaplan-Meier Estimate; Linear Models; Male; Middle Aged; Multivariate Analysis; Osteoprotegerin; Tertiary Care Centers; Vascular Calcification; Wound Healing

Replacement of missing teeth by dental implants is one of the most common methods employed these days. Because of significant advancement in the design of implants and modifications in the procedure of dental implant surgery, the survival rate of the dental implants has reached up to approximately 95%. Osseointegration is one of the important factors affecting the survival of dental implants. Apart from these, the body's physiologic alterations can also predispose the dental implants for failure. Diabetes is one such metabolic disease characterized by abnormal or delayed wound healing. Hence, we assessed the clinicomicrobial and salivary profile of diabetic patients undergoing rehabilitation by dental implants.. This study included diabetic patients who underwent dental implant surgeries for prosthetic rehabilitation. Follow-up records of the patients' up to 1 year were maintained. Various clinicoradiographic and periodontal parameters were measured at various time intervals during follow-up time; 25 mL of salivary and blood sample was taken from all the subjects and was sent to the laboratories for assessment of various salivary biomarkers. All the results were analyzed by Statistical Package for the Social Sciences software.. The mean level of interleukin-p at baseline time was found to be 2.38 and 2.21 in diabetic group and control group respectively. While comparing the levels of osteoprotegerin in both study groups, a significant correlation was obtained. In diabetic and control group, 62 and 61 years was the mean age of the patients respectively. No significant correlation was obtained while comparing the microbial flora of diabetic and control group.. In both diabetic and nondiabetic patients, similar microbial, salivary marker, and clinicoradiological patterns were seen.. Diabetic patients who maintain their body's metabolic rate show similar success rate of dental implants as seen in nondiabetic patients.

Topics: Adult; Biomarkers; Dental Implantation, Endosseous; Dental Implants; Dental Restoration Failure; Diabetes Mellitus, Type 2; Female; Humans; Interleukins; Longitudinal Studies; Male; Matrix Metalloproteinases; Middle Aged; Osseointegration; Osteoprotegerin; Saliva; Survival Analysis

The OPG/RANKL/RANK (osteoprotegerin/receptor-activator of nuclear factor κB ligand/receptor-activator of nuclear factor κB) axis has been recently linked to the development of atherosclerosis and plaque destabilization. We have investigated whether polymorphism rs2073618 of the OPG gene is associated with subclinical markers of carotid atherosclerosis in subjects with type 2 diabetes mellitus (T2DM).. 595 subjects with T2DM were enrolled in the cross-sectional study. Subclinical markers of carotid atherosclerosis (carotid intima media thickness, plaque thickness, and plaques presence) were assessed with ultrasound at the time of recruitment. Genotyping for rs2073618 (a missense variant located in exon I of the OPG gene) was performed, and OPG serum levels were determined by ELISA.. Compared to the GG genotype, the CC genotype of the rs2073618 polymorphism had a significantly increased risk for the presence of carotid plaque (OR = 2.54, 95 % CI = 1.22-5.28, p = 0.01). No statistically significant difference could be detected (p = 0.68) upon comparing median values of serum OPG levels among studied genotype groups in subjects with T2DM. Multivariable linear regression analyses in T2DM subjects demonstrated that GC and CC genotypes (p = 0.03 and p = 0.003), together with statin therapy (p = 0.009), were independent predictors of the number of carotid segments with plaques.. Despite the fact that OPG rs2073618 genotypes failed to predict the serum OPG levels as there was no statistical difference among compared genotypes, our results demonstrate that the rs2073618 polymorphism could be a possible genetic marker for the prediction of increased risk for carotid plaque burden as a measure of advanced subclinical atherosclerosis in T2DM subjects.

Topics: Aged; Asymptomatic Diseases; Carotid Artery Diseases; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Osteoprotegerin; Phenotype; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors; Slovenia; White People

Osteoprotegerin (OPG) is closely related to insulin resistance and bone remodeling. However, no studies have examined the role of OPG in postmenopausal women with coexistent impaired glucose and bone regulation. The present study investigated the relationship of OPG to glucose homeostasis and insulin resistance in postmenopausal osteoporotic women with different types of glucose tolerance.. In all, 114 postmenopausal osteoporotic women were divided into three groups according to glucose tolerance status: 51 with normal glucose tolerance (NGT, group 1), 31 with impaired glucose tolerance (IGT, group 2), and 32 with type 2 diabetes mellitus (DM, group 3). Study participants were evaluated for metabolic parameters, OPG, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), and bone mineral density parameters.. The OPG levels differed significantly across groups and increased from group 1 to group 3 in a continuous fashion (analysis of variance, P < 0.0001). In post-hoc analysis, OPG was significantly lower in osteoporotic women with NGT, than participants with IGT and DM (P < 0.05 and P < 0.0001, respectively). OPG was positively associated with HOMA-IR (P < 0.0001). No association between serum OPG levels and measures of BMD was observed. In a multiple regression analysis, OPG emerged as an independent predictor of HOMA-IR even after controlling for age, body mass index, and creatinine.. OPG is significantly higher in postmenopausal osteoporotic women with impaired glucose regulation (IGT and DM) than women with NGT. OPG was independently associated with insulin resistance assessed by HOMA-IR. Thus, measurement of OPG may potentially be considered as a prediabetic state screening in postmenopausal osteoporotic women.

Topics: Aged; Bone Density; Case-Control Studies; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Osteoporosis, Postmenopausal; Osteoprotegerin

High mobility group box-1 (HMGB-1) is a nuclear protein also acting as inflammatory mediator, whilst osteoprotegerin (OPG), member of tumor necrosis factor receptor superfamily, is indicated as marker of vascular calcification. Peripheral artery disease (PAD) and type 2 diabetes (T2D) are clinical conditions characterized by elevated serum inflammatory markers and vascular calcification enhancement. The aim of this study was to investigate the potential role of HMGB-1, OPG and several inflammatory mediators such as C-reactive protein (HsCRP), tumor necrosis factor-alpha and interleukin-6 (IL-6) on the presence and severity of peripheral artery disease in patients with T2D.. In this retrospective observational study, we have analyzed HMGB-1, OPG and inflammatory cytokines serum levels in 1393 type 2 diabetic patients with PAD and without PAD (WPAD).. HMGB-1 (7.89 ± 15.23 ng/mL), OPG (6.54 ± 7.76 pmol/L), HsCRP (15.6 ± 14.4 mg/L) and IL-6 (56.1 ± 28.6 pg/mL) serum levels were significantly higher in patients with PAD than in those WPAD (3.02 ± 8.12 ng/mL, P ˂ 0.001; 2.98 ± 2.01 pmol/L, P < 0.001; 7.05 ± 4.4 mg/L, P < 0.001; 37.5 ± 20.2 pg/mL, P < 0.001 respectively). Moreover HMGB-1 (P < 0.001), OPG (P < 0.001), HsCRP (P < 0.001) and IL-6 (P < 0.001) serum levels were positively correlated with clinical severity of PAD. HMGB-1 (adjusted OR 12.32; 95% CI 3.56-23.54, P = 0.023) and OPG (adjusted OR 3.53; 95% CI 1.54-6.15, P = 0.019) resulted independent determinants of PAD in patients with T2D after adjusting for the conventional cardiovascular risk factor and established inflammatory mediators.. In T2D patients HMGB-1 and OPG serum levels are higher in patients affected by PAD and independently associated with its occurrence and clinical severity.

Topics: Aged; Biomarkers; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; HMGB1 Protein; Humans; Male; Middle Aged; Osteoprotegerin; Peripheral Arterial Disease; Retrospective Studies; Risk Factors; Tumor Necrosis Factor-alpha; Vascular Calcification

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

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

The aim of the present study is to evaluate the serum receptor activator of nuclear factor-κβ ligand (RANKL)/osteoprotegerin (OPG) system in patients with chronic periodontitis (CP) and type 2 diabetes mellitus (T2DM) and its changes after periodontal intervention.. Thirty-five patients with CP + T2DM, 35 systemically healthy patients with CP, and 35 healthy controls were enrolled, and serum levels of RANKL and OPG were measured at baseline. Then the CP + T2DM group was divided into a well-controlled subgroup and a poorly controlled subgroup according to their hemoglobin A1c (HbA1c), and initial periodontal therapy was performed. After 3 months, patients in both subgroups were recalled, and serum RANKL and OPG levels were tested again and compared with the baseline.. At baseline, serum levels of OPG in the T2DM + CP group were much lower than in the CP group and healthy controls (197.41 ± 57.05 pg/mL versus 232.60 ± 70.85 pg/mL [CP group] or 244.96 ± 85.13 pg/mL [healthy controls], P <0.05), whereas their RANKL levels were much higher than in the other two groups (324.35 ± 87.62 pg/mL versus 284.52 ± 90.35 pg/mL [CP group] or 163.01 ± 45.24 pg/mL [healthy control], P <0.05), as was the RANKL/OPG (R/O) ratio (1.68 ± 0.33 versus 1.26 ± 0.35 [CP group] or 0.72 ± 0.25 [healthy control], P <0.001). Serum levels of OPG in both disease groups had significant negative correlations with HbA1C, and serum levels of RANKL in all participants had significant positive correlations with periodontal parameters. After periodontal intervention, both the well-controlled and poorly controlled subgroups exhibited significant increases in OPG and decreases in RANKL in serum, and the R/O ratio was also notably reduced. Additionally, the poorly controlled subgroup exhibited a greater reduction in HbA1c and a greater increase in OPG than the well-controlled subgroup.. The changing trend in the serum RANKL/OPG system in patients with T2DM + CP was similar to that seen in CP patients and may be even more pronounced. Periodontal intervention effectively improved glucose metabolism and changed the serum RANKL/OPG system regardless of whether patients' HbA1c was well-controlled or poorly controlled over the 3-month observation period.

Topics: Chronic Periodontitis; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Osteoprotegerin; RANK Ligand

Osteopontin (OPN) and osteoprotegerin (OPG) are bone metabolism biomarkers potentially associated with nerve function. We evaluated the association of cardiovascular autonomic nerve function, OPN, and OPG in 50 individuals with type 2 diabetes mellitus (T2DM).. RR-variation during deep breathing (i.e., mean circular resultant (MCR) and expiration/inspiration (E/I) ratio) was used to assess parasympathetic nerve function. Participants' demographics, HbA1c, 25-hydroxyvitamin D (25(OH)D), BMI, HOMA-IR, calcium, parathyroid hormone, creatinine, OPN, and OPG were determined.. Using stepwise multiple linear regression analysis with MCR or E/I ratio as the dependent variable, OPN was independently associated with reduced autonomic function. A previous report showed a significant association of cardiovascular autonomic function with age, 25(OH)D insufficiency, and the interaction of age×25(OH)D insufficiency. Here we report a novel association for OPN and its interaction with age indicating that for those who are younger, elevated OPN levels are related to a greater loss of autonomic function (MCR model R2=0.598, p<0.001; E/I model R2=0.594, p<0.001).. Our results suggest that OPN is associated with reduced parasympathetic function, particularly in younger individuals with T2DM. Further studies are needed to determine if OPN is neuroprotective, involved in the pathogenesis of autonomic dysfunction, or a bystander.

Topics: Adult; Autonomic Nervous System; Biomarkers; Cardiovascular System; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Osteopontin; Osteoprotegerin; Respiration; Young Adult

Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor (TNF) receptor superfamily, is a decoy receptor for the receptor activator of nucleus factor-κB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). OPG has an effect on systemic insulin sensitivity and glucose homeostasis. The objective of this study was to evaluate the relationship between plasma osteoprotegerin (OPG) levels and nonalcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes.. A case-control study was performed with 746 patients with type 2 diabetes. Of the study population, 367 patients had B-mode ultrasound-proven NAFLD and 379 were controls. The plasma OPG levels were measured using ELISA methods. NAFLD was diagnosed by hepatic ultrasound after the exclusion of alcohol abuse and other liver diseases.. The OPG levels were significantly decreased in patients with NAFLD (2.3±1.1μg/L vs. 2.8±1.3μg/L, p=3.75×10(5)) compared to controls. Pearson correlation analysis showed that the OPG levels were associated with age and systolic blood pressure (both p<0.05). The participants in the lowest OPG quartile had a significantly increased risk for NAFLD (OR=3.49, 95% CI 1.86-6.94) after adjusting for potential cofounders.. The plasma OPG level is negatively associated with NAFLD independent of potential cofounders.

Topics: Age Factors; Aged; Asian People; Blood Pressure; Case-Control Studies; China; Diabetes Mellitus, Type 2; Female; Humans; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Osteoprotegerin; Ultrasonography

Receptor activator of nuclear factor-kappa B ligand (RANKL), its receptor activator of nuclear factor-kappa B (RANK), and decoy receptor osteoprotegerin (OPG) are three major proteins of the RANKL/RANK/OPG signaling pathway encoded by TNFSF11, TNFRSF11A, and TNFRSF11B, respectively. This pathway plays a critical role in bone remodeling and may have a role in the pathogenesis of type 2 diabetes mellitus (T2DM). The aim of this study was to investigate the relationship between gene polymorphisms in the RANKL/RANK/OPG pathway and T2DM in Southern Han Chinese women.. A total of 1233 participants, including 514 T2DM patients and 719 healthy control subjects, were enrolled in this case-control study. Twenty-one single-nucleotide polymorphisms (SNPs) of TNFSF11, TNFRSF11A, and TNFRSF11B were genotyped using an improved multiplex ligation detection reaction technique.. Two SNPs of TNFRSF11B (rs11573819 and rs2073618) were significantly associated with T2DM (p = 0.04 and p = 0.009, respectively). Subjects with the GA genotype of rs11573819 had a lower risk of T2DM (odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.51-0.88, p = 0.005) compared with subjects with the GG genotype. The GG genotype of rs2073618 was associated with increased risk for T2DM (OR = 1.94, 95% CI = 1.14-3.30, p = 0.01) compared with the CC genotype.. This study suggests that TNFRSF11B but not TNFSF11 and TNFRSF11A genetic polymorphisms are associated with T2DM in Southern Han Chinese women. These findings provide preliminary support for the potential role of the RANKL/RANK/OPG pathway in T2DM.

Topics: Aged; Alleles; Asian People; Case-Control Studies; China; Diabetes Mellitus, Type 2; Ethnicity; Female; Gene Frequency; Genetic Association Studies; Humans; Middle Aged; Osteoprotegerin; Polymorphism, Single Nucleotide; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of osteoporotic fracture. Several factors have been identified as being potentially responsible for this risk, such as alterations in bone remodelling that may have been induced by changes in circulating glucose or/and by the presence of non-oxidative end products of glycosylation (AGEs). The aim of this study is to assess whether such variations generate a change in the gene expression related to the differentiation and osteoblast activity (OPG, RANKL, RUNX2, OSTERIX, and AGE receptor) in primary cultures of human osteoblast-like cells (hOB).. We recruited 32 patients; 10 patients had osteoporotic hip fractures (OP group), 12 patients had osteoporotic hip fractures with T2DM (T2DM group), and 10 patients had hip osteoarthritis (OA group) with no osteoporotic fractures and no T2DM. The gene expression was analyzed in hOB cultures treated with physiological glucose concentration (4.5 mM) as control, high glucose (25 mM), and high glucose plus AGEs (2 μg/ml) for 24 h.. The hOB cultures from patients with hip fractures presented slower proliferation. Additionally, the hOB cultures from the T2DM group were the most negatively affected with respect to RUNX2 and OSX gene expression when treated solely with high glucose or with high glucose plus AGEs. Moreover, high levels of glucose induced a major decrease in the RANKL/OPG ratio when comparing the OP and the T2DM groups to the OA group.. Our data indicates an altered bone remodelling rate in the T2DM group, which may, at least partially, explain the reduced bone strength and increased incidence of non-traumatic fractures in diabetic patients.

Topics: Aged; Aged, 80 and over; Biomarkers; Bone and Bones; Bone Remodeling; Core Binding Factor Alpha 1 Subunit; Diabetes Mellitus, Type 2; Female; Gene Expression; Glucose; Glycation End Products, Advanced; Hip Fractures; Humans; Male; Osteoarthritis, Hip; Osteoblasts; Osteoporotic Fractures; Osteoprotegerin; Primary Cell Culture; RANK Ligand; Sp7 Transcription Factor

Angiogenesis is involved in the pathogenesis of diabetic retinopathy. Osteoprotegerin, a recently identified glycoprotein belonging to the tumour necrosis factor receptor superfamily, has been implicated to be correlated with angiogenesis. This study aims to determine whether serum and vitreous concentrations of osteoprotegerin are associated with diabetic retinopathy.. This study consisted of 254 diabetic patients (100 without diabetic retinopathy, 64 with non-proliferative diabetic retinopathy and 90 with proliferative diabetic retinopathy) and 62 control subjects. Serum and vitreous concentrations of osteoprotegerin were evaluated using enzyme-linked immunosorbent assay method.. Serum and vitreous osteoprotegerin concentrations in proliferative diabetic retinopathy patients were significantly elevated compared with those of the other three groups. Non-proliferative diabetic retinopathy patients showed elevated concentrations of serum and vitreous osteoprotegerin compared with patients without diabetic retinopathy. In addition, control subjects had significantly lower serum and vitreous osteoprotegerin concentrations compared with diabetic patients without retinopathy, non-proliferative diabetic retinopathy patients and proliferative diabetic retinopathy patients.. Serum and vitreous osteoprotegerin concentrations are associated with the presence and severity of diabetic retinopathy.

Topics: Asian People; Biomarkers; China; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Enzyme-Linked Immunosorbent Assay; Female; Hospitals, University; Humans; Male; Middle Aged; Osteoprotegerin; Severity of Illness Index; Up-Regulation; Vitreous Body

Coronary artery calcification (CAC) is a prominent feature of atherosclerosis and is associated with cardiovascular events. In vitro studies have suggested that osteoprotegerin (OPG) and osteocalcin (OC) exert anticalcification potential in the vessel wall. The objective of this study was to investigate the association of CAC and serum bone biomarkers in persons with type 2 diabetes.. We examined 50 individuals with type 2 diabetes. CAC imaging was performed by multidetector computed tomography. CAC scores ≥10, expressed in Agatston units, were considered abnormal. OC, undercarboxylated OC (ucOC), and OPG levels were determined by enzyme-linked immunosorbent assay.. Abnormal CAC scores were found for 64% of the study cohort. OPG levels were significantly elevated (5.5 ± 2.0 pmol/L vs. 4.2 ± 1.7 pmol/L; P = .026) for those with abnormal CAC scores. No univariate differences were found for OC or ucOC. Logistic regression analyses revealed that an increase in serum OPG level was significantly associated with an increase in CAC score (odds ratio, 3.324; 95% confidence interval, 1.321 to 8.359; P = .011). Longer duration of diabetes was a significant covariate (P = .026), whereas nonsignificant covariates in the final model were age, gender, systolic blood pressure, body mass index, insulin resistance determined by the homeostasis model assessment for insulin resistance, leptin, adiponectin, and glycemic control. The Nagelkerke R2 for the model was 0.66. Neither OC nor ucOC were significantly associated with elevated CAC scores.. Our results suggest that OPG is a more useful serum biomarker than OC or ucOC for identifying those at increased risk of arterial calcification in type 2 diabetes.

Topics: Aged; Biomarkers; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Humans; Insulin Resistance; Logistic Models; Male; Middle Aged; Osteocalcin; Osteoprotegerin; Vascular Calcification

To investigate the plasma osteoprotegerin level and osteoprotegerin expression in renal biopsy tissue in type 2 diabetes with nephropathy.. Plasma osteoprotegerin level was measured by enzyme-linked immunoassay in 48 type 2 diabetes with normoalbuminuria, 48 patients with microalbuminuria, 44 patients with macroalbuminuria and 40 healthy persons. Part of diabetes patients with nephropathy were performed kidney biopsy by ultrasound guide. The osteoprotegerin expression in kidney biopsy tissue is examined by immunohistochemistry.. The plasma osteoprotegerin levels were significantly elevated in patients with microalbuminuria (3.73±0.75 ng/l) and macroalbuminuria (4.68±0.82 ng/l) as compared with patients with normoalbuminuria (2.71±0.69 ng/l) and control subjects (2.11±0.42 ng/l). And the plasma osteoprotegerin level in macroalbuminuric group was also higher than that in microalbuminuria group. The plasma osteoprotegerin level had a positive correlation with the fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), glycohemoglobinA1c (HbA1C), high sensitive C-reactive protein (hsCRP) and log(UAER). Multivariate regression analysis revealed that plasma osteoprotegerin level was an independent factor associated with albuminuria in type 2 diabetes. The immunohistochemistry results showed that positive immunostaining for osteoprotegerin was observed in the renal tubule cells of biopsy and not in glomerulus, and the osteoprotegerin expression was higher in macroalbuminuria group than that in microalbuminuria group.. The plasma osteoprotegerin level and the osteoprotegerin expression in renal tubule cells of biopsy tissue were increased in nephropathy of type 2 diabetes. This finding supports the growing concept that osteoprotegerin may act as an important regulatory molecule in the angiopathy, and particularly, that it may be involved in the occurrence and development of nephropathy in type 2 diabetes.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Kidney; Male; Middle Aged; Osteoprotegerin

Vascular calcification (VC) is inhibited by the glycoprotein osteoprotegerin (OPG). It is unclear whether treatments for type 2 diabetes are capable of promoting or inhibiting VC. The present study examined the effects of insulin and liraglutide on i) the production of OPG and ii) the emergence of VC, both in vitro in human aortic smooth muscle cells (HASMCs) and in vivo in type 2 diabetes.. HASMCs were exposed to insulin glargine or liraglutide, after which OPG production, alkaline phosphatase (ALP) activity and levels of Runx2, ALP and bone sialoprotein (BSP) mRNA were measured. A prospective, nonrandomised human subject study was also conducted, in which OPG levels and coronary artery calcification (CAC) were measured in a type 2 diabetes population before and 16 months after the commencement of either insulin or liraglutide treatment and in a control group that took oral hypoglycemics only.. Exposure to insulin glargine, but not liraglutide, was associated with significantly decreased OPG production (11 913±1409 pg/10(4) cells vs 282±13 pg/10(4) cells, control vs 10 nmol/l insulin, P<0.0001), increased ALP activity (0.82±0.06 IU/10(4) cells vs 2.40±0.16 IU/10(4) cells, control vs 10 nmol/l insulin, P<0.0001) and increased osteogenic gene expression by HASMCs. In the clinical study (n=101), insulin treatment was associated with a significant reduction in OPG levels and, despite not achieving full statistical significance, a trend towards increased CAC in patients.. Exogenous insulin down-regulated OPG in vitro and in vivo and promoted VC in vitro. Although neither insulin nor liraglutide significantly affected CAC in the present pilot study, these data support the establishment of randomised trials to investigate medications and VC in diabetes.

Topics: Aged; Alkaline Phosphatase; Cells, Cultured; Core Binding Factor Alpha 1 Subunit; Coronary Vessels; Diabetes Mellitus, Type 2; Endpoint Determination; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; In Vitro Techniques; Insulin Glargine; Insulin, Long-Acting; Liraglutide; Male; Metformin; Middle Aged; Muscle, Smooth, Vascular; Osteoprotegerin; Pilot Projects; Prospective Studies; Sialoglycoproteins; Vascular Calcification

Growing evidence suggests the presence of a complex interplay between hypertension as well as type 2 diabetes mellitus (DM) and osteoporosis. The present study was designed to investigate a possible effect of type 2 DM on bone remodelling markers such as osteoprotegerin and N-terminal propeptide of type 1 collagen (P1NP) in hypertensive patients.. The 100 study participants were divided into three groups according to the presence of DM and hypertension: group one included diabetic hypertensive subjects, group 2 included hypertensive subjects without diabetes and group 3 included subjects without hypertension and without DM (controls). Blood sampling for metabolic parameters, including osteoprotegerin, P1NP, adiponectin, fasting glucose, HbA1c , CRP, homeostasis model assessment-insulin resistance, homeostasis model assessment-beta function was performed.. Circulating P1NP increased from group 1 to group 3 in a continuous fashion. P1NP was significantly lower in hypertensive subjects with DM (group 1), than in groups 2 and 3 (p < 0.0001). P1NP, was marginally lower in diabetic hypertensive subjects as compared with nondiabetic subjects with hypertension (p = 0.079). Circulating osteoprotegerin did not differ significantly between groups (p = 0.593).. In the present study, bone formation marker, P1NP, was significantly lower in diabetic hypertensive subjects as compared with nondiabetic subjects with and without hypertension. P1NP was inversely associated with parameters of glucose homeostasis such as fasting glucose, HbA1c and positively with homeostasis model assessment-beta cell function. Type 2 DM was associated with an adverse effect on bone formation independently of age, sex and exposure to anti-diabetic drugs.

Topics: Adiponectin; Aged; Biomarkers; Blood Glucose; Bone and Bones; Bone Remodeling; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Osteoporosis; Osteoprotegerin; Peptide Fragments; Procollagen

This study evaluated the influence of type 2 diabetes mellitus (T2DM) on the gene expression of bone-related factors in alveolar bone tissue from sites designated to receive dental implants. Bone biopsies were harvested from sites of planned implants for 19 systemically healthy patients and 35 patients with T2DM (17 with better-controlled T2DM (glycated haemoglobin (HbA1c) levels ≤8%) and 18 with poorly controlled T2DM (HbA1c levels >8%)). The mRNA levels of tumour necrosis factor alpha, transforming growth factor beta, receptor activator of the nuclear factor kappa B ligand (RANKL), osteoprotegerin (OPG), runt-related transcription factor 2, alkaline phosphatase, bone sialoprotein (BSP), type I collagen (COL-I), and osteocalcin were evaluated by quantitative real-time polymerase chain reaction. T2DM up-regulates RANKL levels and the ratio of RANKL/OPG, whereas it down-regulates COL-I and BSP expression (P<0.05). Higher mRNA levels of RANKL/OPG were observed in the poorly controlled T2DM patients compared to those with better-controlled T2DM and systemically healthy patients (P<0.05). A lower amount of COL-I and BSP was detected in the biopsies from individuals with poorly controlled T2DM compared to systemically healthy patients (P<0.05). In conclusion, RANKL, RANKL/OPG, COL-I, and BSP are negatively affected in diabetics. Additionally, the patient's glycaemic status appears to modulate bone-related genes in a different manner.

Topics: Adult; Aged; Alkaline Phosphatase; Alveolar Process; Biomarkers; Biopsy; Collagen Type I; Core Binding Factor Alpha 1 Subunit; Dental Implants; Diabetes Mellitus, Type 2; Female; Gene Expression; Humans; Integrin-Binding Sialoprotein; Male; Middle Aged; Osteoprotegerin; RANK Ligand; Real-Time Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

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 member of the tumor necrosis factor receptor superfamily and suggested as a marker of atherosclerosis. However, little is known about the association between plasma OPG levels and lower extremity arterial disease. We investigated whether plasma OPG levels were associated with the presence and severity of lower extremity arterial disease in patients with type 2 diabetes.. This was a study of 712 patients with type 2 diabetes aged 40 years or older. Plasma OPG was measured using ELISA. The lower extremity arterial disease was diagnosed by high-frequency color Doppler ultrasonic.. Of 712 patients, 505 (70.9 %) had lower extremity arterial stenosis. OPG levels were significantly increased in patients with lower extremity arterial stenosis [1.89 (1.48-2.41) vs. 2.39 (1.82-3.33) ng/mL, p < 0.001]. Plasma OPG levels increased gradually with increasing severity of lower extremity arterial stenosis (p < 0.001 for trend), 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(SBP). The risk of lower extremity arterial disease was increased (OR = 1.17, 95 % CI 1.09 -1.28, p < 0.001) with each standard deviation (SD) higher level of OPG in patients with type 2 diabetes after adjustment for traditional CVD risk factors.. Plasma OPG levels were significantly associated with the presence and severity of lower extremity arterial disease. Our results suggest that OPG is an important plasma biomarker of lower extremity arterial disease in type 2 diabetes.

Topics: Adiponectin; Adult; Aged; C-Reactive Protein; Cohort Studies; Constriction, Pathologic; Diabetes Mellitus, Type 2; Female; Humans; Lower Extremity; Male; Middle Aged; Osteoprotegerin; Peripheral Arterial Disease; Prospective Studies; Severity of Illness Index; Ultrasonography, Doppler, Color

Serum adiponectin levels have been suggested to be predictors of type 2 diabetes mellitus in diverse populations. However, the relationship between circulating adiponectin levels and the risk of development of type 2 diabetes in postmenopausal women has not been investigated.A total of 382 healthy postmenopausal women who participated in a prospective cohort study were followed for 5.8 years. Type 2 diabetes mellitus was defined according to the criteria set out by the American Diabetes Association. Adiponectin, osteoprotegerin (OPG), and high-sensitivity C-reactive protein (hs-CRP) levels were measured using ELISA.Of 195 women who did not have diabetes at baseline and who were reexamined in the second phase of the study for diabetic status, 35 subjects (17.9%) developed type 2 diabetes mellitus during the 5.8 years follow-up period. The women with type 2 diabetes had lower adiponectin levels than the healthy postmenopausal women. Multiple regression analysis showed that, after adjustments were made for age, cardiovascular risk factors, OPG, and hs-CRP levels, higher baseline adiponectin levels were associated with a lower relative risk (RR) of having type 2 (RR = 0.07, confidence interval [CI]: 0.01-0.66, P = 0.021).Higher baseline adiponectin levels functioned as a predictor of a lower risk of developing type 2 diabetes mellitus among postmenopausal women during a 5.8 years follow-up study. Therefore, it is suggested that elevated adiponectin levels may offer protection against the development of type 2 diabetes mellitus after the menopause.

Topics: Adiponectin; C-Reactive Protein; Diabetes Mellitus, Type 2; Female; Humans; Iran; Middle Aged; Osteoprotegerin; Postmenopause; Protective Factors; Risk Assessment; Risk Factors

Chronic kidney disease (CKD) is often observed among patients with type 2 diabetes mellitus (T2DM) and diabetic foot (DF) leading to end stage renal disease. The aim of this pilot study was to determine genetic and environmental factors involved in the etiology of CKD among patients with DF. The following polymorphisms were studied: rs1800469, rs759853, rs1553005, rs1799983, rs1801133, rs3134069, rs2073618, rs8192678, rs6330, rs11466112, rs121917832 in terms of alleles distribution in patients with DF and T2DM, with or without CKD. The study includes 101 patients with T2DM and DF. Studied groups were divided into 39 individuals with CKD (cases) and 62 controls, depending on the presence of kidney failure defined as eGFR < 60ml/min/1.73m(2) and coexistence of microalbuminuria > 30 mg/dl in at least 3 urine samples. Cases and controls were matched according to mean age, gender, mean duration of T2DM, mean duration of insulin therapy, mean duration of DF cholesterol levels and smoking frequencies. The study showed that CKD risk factors were the following variables: creatinine level, body weight, hips circumference, ischemic heart disease, hypertension and diabetic retinopathy. Moreover, the results suggest the protective role of the allele C of rs3134069 polymorphism in CKD development in patients with T2DM and DF in the following allelic variants: [AA] vs. [AC] and [AA] vs. [AC + CC]. The allele C was observed to be less frequent than the allele A in patients with T2DM and DF. None of the other following polymorphisms was observed to be a potential risk factor of CKD in T2DM and DF population: rs6330, rs759853, rs1553005, rs1799983, rs1801133, rs1800469, rs8192678, rs11466112, rs121917832. We concluded that the rs3134069 polymorphism seems to be the most likely protective genetic factor in CKD development in patients with T2DM and DF.

Topics: Aged; Alleles; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Foot; Female; Genetic Predisposition to Disease; Humans; Hypoglycemic Agents; Insulin; Male; Middle Aged; Osteoprotegerin; Pilot Projects; Polymorphism, Single Nucleotide; Renal Insufficiency, Chronic; Risk Factors

High osteoprotegerin (OPG) has been reported in association with insulin resistance and type 2 diabetes. We aimed to evaluate the association of serum OPG with impaired glucose regulation (IGR) and microalbuminuria among middle-aged and older Chinese.. Serum OPG was measured in 599 individuals with normal glucose regulation, 730 with impaired glucose regulation and 327 newly diagnosed patients with diabetes. Serum OPG was measured using ELISA methods and urine albumin/creatinine ratio was used to determine the urinary albumin excretion.. Serum OPG levels were significantly higher in subjects with isolated impaired fasting glucose, isolated impaired glucose tolerance, combined impaired fasting glucose/impaired glucose tolerance and diabetes than in those with normal glucose regulation, whereas serum OPG levels were not different in the four groups with dysregulation of glucose metabolism. OPG was associated with a higher risk for IGR (OR 1.108 for each 0.1 μg/l increase in OPG, 95% CI 1.009-1.117, p = 0.01) after adjustment for gender, age, BMI, current smoking and alcohol intake, family history of diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profile; the corresponding OR of combined impaired glucose regulation and type 2 diabetes was 1.121 (95% CI 1.101-1.141, p = 0.0005). OPG was associated with the risk of microalbuminuria (OR 1.025, 95% CI 1.006-1.044, p = 0.02) after adjustment for gender, age, current smoking, current alcohol intake, family history of diabetes, BMI, waist/hip ratio, HOMA-IR, eGFR and lipid profile.. Serum OPG level is closely and independently associated with IGR and is an independent risk factor for microalbuminuria.

Topics: Aged; Albuminuria; Biomarkers; C-Reactive Protein; China; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Insulin Resistance; Longitudinal Studies; Male; Middle Aged; Osteoprotegerin; Prediabetic State

Type 2 diabetes is known to affect bone metabolism. In this study, we aimed to determine the effects of type 2 diabetes on bone remodeling during orthodontic tooth movement.. The 48 rats were divided into 4 groups: Wistar control group (n = 8), Goto-Kakizaki (GK) control group (n = 8), Wistar appliance group (n = 16), and GK appliance group (n = 16). The distances between the teeth were measured weekly. On day 42, maxillary alveolar bone specimens were obtained for histologic evaluation and determination of the gene expression levels of the receptor activator of nuclear factor ҡB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG).. No significant difference was observed in the levels of tooth movement between the 2 appliance groups. After orthodontic force application, the alveolar bone volume and osteoblast surface in the GK rats were diminished compared with those in the Wistar rats. The increase in the osteoclast surface relative to the control groups was 2.4-fold greater in the GK rats than in the Wistar rats. Significant upregulations of the RANK and OPG gene expression levels in the Wistar appliance group were observed. The RANKL/OPG ratio was increased in the GK appliance group compared with the Wistar appliance group.. Diminished bone formation and slightly increased bone resorption were observed during orthodontic tooth movement in the rats with type 2 diabetes.

Topics: Alveolar Process; Animals; Bone Remodeling; Bone Resorption; Diabetes Mellitus, Type 2; Disease Models, Animal; Incisor; Maxilla; Molar; Organ Size; Orthodontic Wires; Osteoblasts; Osteoclasts; Osteogenesis; Osteoprotegerin; RANK Ligand; Rats; Rats, Inbred Strains; Rats, Wistar; Receptor Activator of Nuclear Factor-kappa B; Tooth Movement Techniques; Up-Regulation

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

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

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

Calcification of the arterial wall in diabetes contributes to the arterial occlusive process occurring below the knee. The osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL) system is suspected to be involved in the calcification process.. The aim of the study was to investigate whether there is a link between arterial calcification in type 2 diabetes and 1) conventional cardiovascular risk factors, 2) serum RANKL and OPG levels, and 3) neuropathy.. We objectively scored, in a cross-sectional study, infrapopliteal vascular calcification using computed tomography scanning in 198 patients with type 2 diabetes, a high cardiovascular risk, and a glomerular filtration rate >30 mL/min. Color duplex ultrasonography was performed to assess peripheral arterial occlusive disease, and mediacalcosis. Peripheral neuropathy was defined by a neuropathy disability score >6. RANKL and OPG were measured in the serum by routine chemistry.. Below-knee arterial calcification was associated with arterial occlusive disease. In multivariate logistic regression analysis, the variables significantly and independently associated with the calcification score were age (odds ratio [OR] = 1.08; 95% confidence interval [CI] = 1.04-1.13; P < .0001), male gender (OR = 3.53; 95% CI = 1.54-8.08; P = .003), previous cardiovascular disease (OR = 2.78; 95% CI = 1.39-5.59; P = .005), and neuropathy disability score (per 1 point, OR = 1.21; 95% CI = 1.05-1.38; P = .006). The association with ln OPG, significantly associated with calcification score in univariate analysis (OR = 3.14; 95% CI = 1.05-9.40; P = .045), was no longer significant in multivariate analysis. RANKL and OPG/RANKL were not significantly associated with the calcification score.. Below-knee arterial calcification severity is clearly correlated with peripheral neuropathy severity and with several usual cardiovascular risk factors, but not with serum RANKL level.

Topics: Aged; Arterial Occlusive Diseases; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Humans; Male; Middle Aged; Osteoprotegerin; RANK Ligand; Severity of Illness Index; Vascular Calcification

The aim of this paper was to investigate the association of circulating osteoprotegerin (OPG) and receptor activator of the nuclear factor kB ligand (RANKL) levels with carotid intima-media thickness (CIMT) in type 2 diabetes mellitus (T2DM).. We performed a cross-sectional community-based study including 40 T2DM postmenopausal women and 40 healthy controls. CIMT was measured by B-mode ultrasound. Serum OPG and RANKL were measured by solid-phase enzyme-linked immunosorbent assay (ELISA).. Serum OPG levels were higher in T2DM than in controls (median 2.9 vs 2.0 pmol/liter; P<0.001), significantly associated with CIMT in T2DM (P<0.001). RANKL levels were lower in T2DM than in controls (median 0.45 vs 0.60 pmol/liter; P<0.0001), however no association was found with CIMT. Serum OPG levels were associated with cross-sectional measure of CIMT in T2DM.. The data would support the role of an increased OPG/RANKL ratio as a possible marker of progression of vascular dysfunction in diabetes.

Topics: Adult; Age Factors; Aged; Body Mass Index; Carotid Arteries; Carotid Intima-Media Thickness; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Disease Progression; Enzyme-Linked Immunosorbent Assay; Female; Humans; Middle Aged; Osteoprotegerin; Postmenopause; RANK Ligand; Reproducibility of Results; Sex Factors; Ultrasonography; Vascular Diseases

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

Vascular calcification and atherosclerosis play a vital role in the development of cardiovascular morbidity and mortality in diabetic patients, especially when complications of diabetic nephropathy occur. Osteoprotegerin (OPG) and fetuin-A are two markers of vascular calcification. We evaluated the association between these vascular markers and urinary albumin excretion in diabetic patients.. Three groups were arranged containing 40 patients: normoalbuminuric (Group 1), microalbuminuric (Group 2), and macroalbuminuric (Group 3). In addition to the obtained data, levels of hs-CRP (high sensitivity-CRP) and homocysteine were examined.. OPG levels of patients in Group 2 were higher than in Group 1 (p = 0.058). OPG levels in Group 3 were lower than in Groups 1 or 2 (p = 0.014 and 0.000, respectively). Levels of fetuin-A in Group 2 were determined to be lower than in Groups 1 and 3 (p = 0.001 and 0.000, respectively). Carotid intima media thickness (CIMT) in Group 3 was higher than in Group 1 (p = 0.002). CIMT in Group 2 was also higher than in Group 1 (p = 0.039). A positive correlation between fetuin-A and OPG was found (p = 0.012, r = 0.393). Additionally, a positive correlation between hs-CRP and fetuin-A in Group 2 (p = 0.020, r = 0.367) and a negative correlation between hs-CRP and OPG in Group 3 (p = 0.036, r = -0.333) were observed.. The differences found between albuminuria and OPG or fetuin-A may be due to the different doses and variety of medications the patients received, in addition to genetic and racial factors. So far, in our country, polymorphisms related to OPG and fetuin-A have not been defined. Further detailed studies about polymorphisms will have additional value.

Topics: Aged; Albuminuria; alpha-2-HS-Glycoprotein; Biomarkers; C-Reactive Protein; Carotid Intima-Media Thickness; Diabetes Mellitus, Type 2; Female; Homocysteine; Humans; Male; Middle Aged; Osteoprotegerin

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

Today the prevalence of type 2 diabetes reached an epidemic level. It is known that type 2 diabetes could only be prevented before the manifestation, during the "prediabetic" state, urging the development of diagnostic tests to recognize the group at risk in time.. The authors explored metabolic differences between healthy, normal glucose tolerant, normal insulin resistant females having first degree relatives with and without type 2 diabetes.. Healthy, normal insulin sensitive females without (n = 26) and with (n = 18) type 2 diabetic relatives were investigated.. Healthy females with first degree diabetic relatives had lower low density lipoproteins and higher high density lipoproteins as well as higher glucose and insulin levels at the 120 min of oral glucose test as compared to those without first degree diabetic relatives.. These results suggest that the appearance of insulin resistance is preceded by hepatic insulin resistance and impaired lipid metabolism in the symptom-free prediabetic period of genetically susceptible females.. Bevezetés: A 2-es típusú cukorbetegség ma már „világjárvány”, megelőzése csak a „praediabetes” idején eredményes, ezért olyan szűrővizsgálatokra van szükség, amelyek a cukorbetegség várományosait időben felfedik. Célkitűzés: A szerzők célul tűzték ki egészséges, negatív családi anamnézisű (genetikailag nem diabeteses) és elsőfokú cukorbeteg rokonokkal rendelkező (genetikailag diabeteses), normális szénhidrát-toleranciájú és inzulinérzékenységű nőkben a diagnosztikai értékű anyagcsere-eltérések feltárását. Módszer: A klemp vizsgálatok során normális inzulinérzékenységű, genetikailag nem diabeteses (n = 26) és genetikailag diabeteses (n = 18) önkéntesek adatait elemezték. Eredmények: Genetikailag diabeteses, egészséges nőkben az orális cukorterhelés 120. percében magasabb glükóz- és inzulinkoncentrációt, valamint nagyobb magas denzitású és kisebb alacsony denzitású lipidszintet találtak a genetikailag nem diabeteses egészséges nőkben mért értékekhez képest. Következtetések: Az eredmények szerint genetikailag diabeteses, egészséges nőkben a kialakuló inzulinrezisztenciát megelőzi a hepaticus inzulinrezisztencia és a zsíranyagcsere zavara. A szerzők nem kaptak választ arra a kérdésre, hogy a cukorbetegséghez és az elhízáshoz vezető energiafelesleg miért okoz genetikailag diabeteses nőkben korán zsíranyagcsere-zavart és hyperinsulinaemiát, továbbá arra sem, hogy az elhízás miért nem társul mindig inzulinrezisztenciával. Orv. Hetil., 2013, 154, 1747–1753.

Topics: Adipokines; Adult; Aged; Biomarkers; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Family; Female; Follicle Stimulating Hormone; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Interleukin-6; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Obesity; Osteocalcin; Osteoprotegerin; Prediabetic State; Triglycerides; Tumor Necrosis Factor-alpha

Recent studies indicate that osteoprotegerin (OPG) acts as an important regulatory molecule in the vasculature. Also, a strong association was observed between circulation OPG and microvascular complication. By considering the possible role of OPG in diabetic retinopathy (DR) we examined two of the most studied polymorphisms of the OPG genes rs2073618 (located in exon I) and rs3134069 (located in the promoter region) and their relation to DR in Slovenian patients with type 2 diabetes. Logistic regression analysis demonstrated that the carriers of the CC genotype had a 2.2 higher risk for DR than those with either the CG genotype or the GG genotype (codominant model for rs2073618). Furthermore, the combined effect of single nucleotide polymorphisms (SNPs) rs2073618 and rs3134069 on the DR was stronger than that of each SNP alone. The odds ratio (OR) for individuals with CC genotype (rs2073618) and AA genotype (rs3134069) compared with carriers of CG/GG (rs2073618) + AA (rs3134069) was 2.54 (95% CI = 1.26-5.13, P = 0.01). To conclude, these results indicate that SNPs in the OPG gene may be implicated in the pathogenesis of DR.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Osteoprotegerin; Polymorphism, Single Nucleotide; Risk Factors

The role of osteoprotegerin (OPG) as a marker of cardiovascular disease (CVD) in Type 2 diabetes (T2DM) is not well established. Moreover, the relationship between OPG, osteoporosis, and vertebral fractures in T2DM remains to be elucidated.. To determine the role of serum OPG in the prediction of CVD and bone disease in T2DM males.. Cross-sectional study with 68 males, 43 with T2DM and 25 subjects without diabetes. We measured: serum OPG by inmunoassay, the presence of CVD (coronary heart disease, cerebrovascular and peripheral artery disease), surrogate markers of CVD [intima- media thickness (IMT) and aortic calcification] and bone disease (bone mineral density and prevalent vertebral fractures).. OPG serum levels (in pmol/l) were significantly higher in T2DM males with abnormal IMT (5.12 ± 1.59 vs 3.76 ± 1.98), carotid plaque (5.46 ± 1.67 vs 4.20 ± 1.81), aortic calcification (5.91 ± 1.39 vs 4.07 ± 1.76), hypertension (5.11 ± 1.86 vs 3.81 ± 1.47), and peripheral artery disease (6.24 ± 1.64 vs 4.21 ± 1.63, p < 0.05 for all comparisons). In the logistic regression analysis (after adjustment for age and main cardiovascular risk factors), serum OPG (per 1 pmol/l increase in OPG) was associated with increased risk of abnormal IMT [odds ratio (OR) 1.84, confidence interval (CI) 1.21-2.79, p = 0.004), carotid plaque (OR 1.71, CI 1.13-2.58, p = 0.012), aortic calcification (OR 2.21, CI 1.27-3.84, p = 0.05) and peripheral artery disease (OR 4.02, CI 1.65-9.8 p = 0.002). However, OPG were not related to bone mass or vertebral fractures.. Our results suggest that in T2DM males OPG serum concentrations constitute a marker of CVD, but not a marker of bone disease.

Topics: Absorptiometry, Photon; Biomarkers; Blood Pressure Determination; Bone Density; Bone Diseases; Cardiovascular Diseases; Carotid Intima-Media Thickness; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Osteoprotegerin; Prognosis; Risk Factors

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

Amylin displays osteogenic features, but its role in diabetic osteopenia is unclear. We examined the possible osteogenic action of amylin infusion for 3days into fructose-induced insulin-resistant (IR) and streptozotocin-induced type 2 diabetic (T2D) and normal (N) rats. Amylin failed to affect glycaemia or parathyroid hormone levels in any group, but reduced hyperinsulinemia in IR rats. In N rats, amylin increased bone formation rate and reduced osteoclast surface and erosive surface in the femoral metaphysis, and increased osteoprotegerin (OPG)/receptor activator of NFκB ligand (RANKL) mRNA ratio in the tibia. In T2D rats, amylin normalized trabecular structure parameters and increased osteoblast number and osteocalcin (OC) expression in long bones. In contrast, in IR rats, no apparent osteogenic effect of amylin in the femur was observed, although both OC and OPG/RANKL ratio were increased in the tibia. Our findings demonstrate a different osteogenic efficacy of amylin in two diabetic settings.

Topics: Animals; Bone Density Conservation Agents; Bone Diseases, Metabolic; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Femur; Gene Expression; Islet Amyloid Polypeptide; Male; Osteocalcin; Osteogenesis; Osteoprotegerin; Radiography; RANK Ligand; Rats; Rats, Wistar; Tibia

 Diabetic foot is a severe diabetic complication, which may result in ulcerations that are unresponsive to treatment and in lower limb amputation. Osteoprotegerin is a protein that is involved in the pathogenesis of diabetic foot..  The aim of the study was to evaluate the frequency of alleles in the TNFRSF11B gene rs2073617, rs2073618, and rs3134069 polymorphisms in patients with diabetic foot, diabetes, and healthy controls.. The study comprised 877 patients, including 122 with diabetic foot, 293 with type 2 diabetes without diabetic foot, and 462 healthy controls.. In the rs2073618 polymorphism, the C allele was a risk factor for diabetic foot in patients with diabetes in the allelic variants [CC] vs. [CG + GG] (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.03-2.86; P = 0.035), and in men in the following allelic variants: CC vs. GG (OR, 3.16; 95% CI, 1.27-7.87; P = 0.011), CC vs. CG (OR, 3.33; 95% CI, 1.47-7.54; P = 0.002), and [CC] vs. [CG + GG] (OR, 3.28; 95% CI, 1.48-7.24; P = 0.002). A similar association was observed between men with diabetic foot and those only with diabetes in the following allelic variants: CC vs. GG (OR, 2.30; 95% CI, 0.91-5.85; P = 0.076), CC vs. CG (OR, 2.69; 95% CI, 1.16-6.22; P = 0.018) and [CC] vs. [CG + GG] (OR, 2.56; 95% CI, 1.13-5.77; P = 0.02). For patients with neuropathic diabetic foot, the association was demonstrated in variant CC vs. CG (OR, 2.5; 95% CI, 1.00-6.23; P = 0.044) and only for men in the following allelic variants: [CC] vs. [CG + GG] (OR, 3.17; 95% CI, 1.07-9.38; P = 0.029) and CC vs. CG (OR, 3.49; 95% CI, 1.15-10.58; P = 0.02). The A allele of the rs2073617 polymorphism protected women in variant AA vs. AG against diabetic foot compared with controls (OR, 0.45; 95% CI, 1.00-4.92; P = 0.045). The rs3134069 polymorphism was not observed to be a risk factor for diabetic foot..  The analysis of the TNFRSF11B gene may be used to assess the risk of diabetic foot and neuropathic diabetic foot in patients with type 2 diabetes.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Foot; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Osteoprotegerin; Polymorphism, Genetic

Osteoprotegerin is a member of the tumor necrosis factor-related family and inhibits RANK stimulation of osteoclast formation as a soluble decoy receptor. The goal of this study was to determine the relationship of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes.. The subjects were 124 patients with type 2 diabetes mellitus, including 88 males and 36 females with a mean (± SD) age of 65.6 ± 8.2 years old. Serum levels of osteoprotegerin, osteocalcin, fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D3 and adiponectin were measured by ELISA. Vascular calcification in the cervical artery was examined by ultrasound sonography. The subjects were divided into 4 quartiles depending on serum osteoprotegerin levels.. Vascular calcification was significantly higher in the 4th quartile and significantly lower in the 1st quartile of serum osteoprotegerin levels, compared to other quartiles. There were no differences in serum osteoprotegerin and vascular calcification among patients with different stages of diabetic nephropathy, but serum FGF23 levels were elevated in those with stage 4 diabetic nephropathy. Simple regression analysis showed that serum osteoprotegerin levels had significant positive correlations with age, systolic blood pressure and serum adiponectin levels, and significant negative correlations with BMI and serum 25-hydroxyvitamin D3.. These findings suggest that elevated serum osteoprotegerin may be involved in vascular calcification independently of progression of diabetic nephropathy in patients with type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Diabetes Mellitus, Type 2; Female; Fibroblast Growth Factor-23; Humans; Male; Middle Aged; Osteoprotegerin; Up-Regulation; Vascular Calcification

The aim of this study is to evaluate the gene expression of immune-inflammatory markers in gingival biopsies of patients with type 2 diabetes with chronic periodontitis (CP).. Gingival biopsies were harvested from systemically and periodontally healthy patients (SPH), systemically healthy patients with CP (SHCP), and patients with better-controlled and poorly controlled diabetes and CP. The levels of mRNA of interleukin (IL)-17, IL-6, IL-23, IL-10, IL-4, interferon-γ, toll-like receptor (TLR)-2, TLR-4, osteoprotegerin, receptor activator of nuclear factor-kappa B ligand (RANKL), tumor necrosis factor-α, transforming growth factor-β, transcription factor forkhead box p3, transcription factor orphan nuclear receptor C2 (RORC2), and receptor of advanced glycation end products (RAGE) were evaluated by quantitative real-time polymerase chain reaction.. All CP groups presented higher levels of mRNA of TLR-2, TLR-4, IL-17, RANKL, and RAGE and a higher frequency of IL-17 and TLR-2 mRNA-positive biopsies when compared to SPH (P <0.05). There was a higher frequency of detection of RORC2 in the biopsies from both groups with diabetes compared to the other groups (P <0.05). The frequency of IL-4 mRNA-positive tissues was lower in patients with diabetes compared to SHCP (P <0.05).. CP, but not type 2 diabetes mellitus, significantly affected the expressions of the evaluated genes related to the innate and adaptive immune responses.

Topics: Adaptive Immunity; Adult; Biomarkers; Chronic Periodontitis; Cytokines; Diabetes Mellitus, Type 2; Female; Forkhead Transcription Factors; Gingiva; Humans; Immunity, Innate; Inflammation Mediators; Interferon-gamma; Interleukin-10; Interleukin-12; Interleukin-17; Interleukin-4; Interleukin-6; Male; Middle Aged; Nuclear Receptor Subfamily 1, Group F, Member 3; Osteoprotegerin; RANK Ligand; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Toll-Like Receptor 2; Toll-Like Receptor 4; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

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

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

Osteoprotegerin (OPG), a secreted member of the tumour necrosis factor receptor superfamily of cytokines, has been associated with endothelial dysfunction. We studied in type 2 diabetic and/or hypertensive patients the relationship between serum OPG and vascular alterations associated with these pathologies.. We analysed 191 consecutive patients (52 with type 2 diabetes and 139 hypertensive nondiabetic patients) and 54 healthy controls. We assessed the relationship of OPG serum levels measured by ELISA with basal glycaemia, glycosylated haemoglobin, blood pressure, endothelial dysfunction (assessed by pulse wave velocity), retinopathy (by Keith-Wagener classification), left ventricular hypertrophy (by Cornell index), cardiovascular risk and target organs (heart, vascular, kidney) damage.. Serum OPG levels were higher in either hypertensive or diabetic patients and in patients with non-dipper and riser circadian blood pressure patterns. We found significant correlations between OPG levels and age, height, glycaemia, systolic, diastolic and pulse blood pressure, pulse wave velocity and left ventricular hypertrophy in both hypertensive and diabetic patients. OPG levels were also higher in hypertensive patients with retinopathy, patients with high probability of 10-year cardiovascular risk, patients with three or more damaged target organs (heart, vessels, kidneys) and patients with previous episodes of ischaemic cardiopathy or hypercholesterolaemia.. Osteoprotegerin is an indicator of diabetes- and hypertension-associated vascular pathologies as endothelial dysfunction and cardiovascular risk.

Topics: Adult; Aged; Biomarkers; Blood Pressure; Cardiovascular Diseases; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypertension; Male; Middle Aged; Osteoprotegerin; Risk Factors; Time Factors

To determine predictors of prevalence and progression of peripheral vascular calcification (VC) in type 2 diabetes (DM) subjects with preserved kidney function.. Fifty-eight subjects (age 63 ± 11.6 years) with type 2 DM and serum creatinine <125 μmol/l were studied. A CT scan of femoral, posterior tibial and dorsalis pedis arteries was carried out at baseline and at one year. Serum osteoprotegerin (OPG) and RANKL were measured along with routine biochemistry.. Seventy-eight percent of patients had baseline VC, 47% with femoral VC, 49% with VC at two sites - femoral and foot, and 4% foot VC alone. Age, ethnicity, peripheral neuropathy and eGFR were independent predictors of baseline VC. Baseline calcification was the most important predictor of VC progression and was present in all subjects with progression compared to 35% of non-progressors (p < 0.001). Exclusion of demographic factors from models revealed neuropathy and serum OPG levels as independent predictors of both; baseline VC and progression.. Subjects with type 2 DM and well-preserved renal function had a high prevalence of VC, which was rapidly progressive especially in those with baseline VC. Age, ethnicity, neuropathy, smoking and eGFR were predictors of baseline VC and progression.

Topics: Aged; Creatinine; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Disease Progression; Female; Femoral Artery; Humans; Male; Middle Aged; Osteoprotegerin; Pilot Projects; Prevalence; Risk Factors; Smoking; Tibial Arteries; Tomography, X-Ray Computed; United Kingdom; Vascular Calcification

An increase in serum osteoprotegerin (OPG) is associated with type 2 diabetes mellitus, the severity of vascular calcification, and coronary artery disease. Obesity is a risk factor for diabetes and cardiovascular disease, but little is known about the relationship between OPG and obesity. The purpose of this study was to determine if changes in body mass index (BMI) and insulin sensitivity influence circulating OPG in healthy subjects. A total of 100 subjects (36 lean, 41 overweight, and 23 obese) with normal glucose tolerance, blood pressure, and electrocardiogram stress test result volunteered for this study. Insulin sensitivity was estimated using a 2-hour oral glucose tolerance test with oral glucose insulin sensitivity analysis. Osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL),soluble receptor activator of nuclear factor-κβ ligand (sRANKL), and adiponectin were analyzed using commercially available enzyme-linked immunosorbent assays. Osteoprotegerin (P < .01) and adiponectin (P < .001) were significantly decreased in the obese compared with lean subjects. There was no significant difference between BMI categories for TRAIL or sRANKL. Controlling for age and sex, there was a significant correlation between OPG and adiponectin (r = 0.391, P < .001), BMI (r = -0.331, P < .001), waist circumference (r = -0.268, P < .01), homeostasis model assessment of insulin resistance (r = -0.222, P < .05), and oral glucose insulin sensitivity (r = 0.221, P < .05). Both OPG and adiponectin were negatively correlated with body weight, BMI, waist circumference, and fasting plasma insulin while being positively correlated with insulin sensitivity (P < .05). Controlling for age, sex, and BMI, TRAIL was positively related to fat mass (r = 0.373, P < .001) and waist circumference (r = 0.257, P < .05). In contrast to patients with type 2 diabetes mellitus, circulating OPG is lower in obese, but otherwise healthy subjects and is positively correlated with indices of insulin sensitivity.

Topics: Adiponectin; Adult; Blood Pressure; Body Mass Index; Cohort Studies; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Osteoprotegerin; RANK Ligand; TNF-Related Apoptosis-Inducing Ligand; Waist Circumference

Osteoprotegerin (OPG) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have recently been reported to be associated with diabetic nephropathy in an in vitro study. However, the literature regarding serum OPG and TRAIL in type 2 diabetes mellitus patients is scarce. To investigate the role of OPG/TRAIL in diabetic nephropathy, we measured the serum concentrations of OPG and TRAIL in type 2 diabetes mellitus patients with different stages of nephropathy by enzyme-linked immunosorbent assay. One hundred seventy-nine subjects with type 2 diabetes mellitus were studied and stratified according to urinary microalbumin and serum creatinine measurements. The serum concentrations of OPG and TRAIL were significantly elevated in patients with microalbuminuria (OPG, 2154.2 ± 922.1 pg/mL; TRAIL, 80.2 ± 24.1 pg/mL) and macroalbuminuria (OPG, 2251.5 ± 925.7 pg/mL; TRAIL, 88.1 ± 23.8 pg/mL) as compared with patients with normoalbuminuria (OPG, 1690.1 ± 627.2 pg/mL; TRAIL, 70.7 ± 23.3 pg/mL). Serum OPG and TRAIL levels were increased in parallel and were significantly associated with each other. Using multivariate stepwise regression analysis, serum OPG was found to be an independent factor associated with the severity of diabetic nephropathy. Our results suggested that serum OPG may be a marker for the severity of diabetic nephropathy. Further studies are necessary to investigate the role of elevated serum OPG in the pathogenesis of diabetic nephropathy.

Topics: Aged; Albuminuria; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Insulin; Male; Middle Aged; Osteoprotegerin; Severity of Illness Index; TNF-Related Apoptosis-Inducing Ligand

Topics: Adipose Tissue; Aged; Atherosclerosis; Biomarkers; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Osteoprotegerin

This study compares the levels of cytokines and bone-related factors in the gingival crevicular fluid (GCF) of systemically healthy patients with chronic periodontitis (CP); and better-controlled, and poorly controlled patients with type 2 diabetes and CP.. Thirty-seven patients with type 2 diabetes and CP and 20 systemically healthy patients with CP were enrolled in this study. The patients with diabetes mellitus were categorized as better-controlled (n = 17; HbA(1c) levels ≤8%) or poorly controlled (n = 20; glycated hemoglobin values >8%). Levels of tumor necrosis factor-α, interleukin (IL)-4, interferon (IFN)-γ, IL-23, IL-17, soluble receptor activator of nuclear factor-kappa B ligand (sRANKL), and osteoprotegerin (OPG) in GCF of diseased sites were analyzed by enzyme-linked immunosorbent assay.. Type 2 diabetes mellitus, as a whole, upregulates the levels of OPG, sRANKL, IFN-γ, IL-17, and IL-23 and downregulates the production of IL-4 in sites with CP (P <0.05). Better-controlled individuals exhibited the highest levels of IFN-γ, whereas poorly controlled patients presented the highest levels of IL-17 (P <0.05). There were no differences in the levels of tumor necrosis factor-α, OPG, and IL-23 among systemically healthy, better-controlled, and poorly controlled patients with diabetes (P >0.05).. Increased levels of proinflammatory cytokines and RANKL were observed in the GCF of patients with type 2 diabetes with CP, compared to patients without diabetes. In addition, poor or good glycemic status seems to modulate osteo-immunoinflammatory mediators in a different manner.

Topics: Adult; Analysis of Variance; Blood Glucose; Case-Control Studies; Chronic Periodontitis; Cohort Studies; Cytokines; Diabetes Mellitus, Type 2; Female; Gingival Crevicular Fluid; Humans; Male; Middle Aged; Osteoprotegerin; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B; Reference Values; Statistics, Nonparametric

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

Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and cardiac function. The adipocytokine adiponectin (ADPN) is downregulated in type 2 diabetes mellitus (T2DM) and coronary artery disease and shows an inverse correlation with insulin sensitivity and cardiovascular disease risk. We assessed the relationship of plasma OPG and ADPN and arterial function, cardiac function and myocardial glucose metabolism in T2DM.. We included 78 asymptomatic men with uncomplicated, well-controlled T2DM, without inducible ischemia, assessed by dobutamine-stress echocardiography, and 14 age-matched controls. Cardiac function was measured by magnetic resonance imaging, myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography. OPG and ADPN levels were measured in plasma.. T2DM patients vs. controls showed lower aortic distensibility, left ventricular (LV) volumes, impaired LV diastolic function and MMRglu (all P < 0.05). In T2DM men vs. controls, OPG levels were higher (P = 0.02), whereas ADPN concentrations were decreased (P = 0.04). OPG correlated inversely with aortic distensibility, LV volumes and E/A ratio (diastolic function), and positively with LV mass/volume ratio (all P < 0.05). Regression analyses showed the associations with aortic distensibility and LV mass/volume ratio to be independent of age-, blood pressure- and glycated hemoglobin (HbA1c). However, the associations with LV volumes and E/A ratio were dependent of these parameters. ADPN correlated positively with MMRglu (P < 0.05), which, in multiple regression analysis, was dependent of whole-body insulin sensitivity, HbA1c and waist.. OPG was inversely associated with aortic distensibility, LV volumes and LV diastolic function, while ADPN was positively associated with MMRglu. These findings indicate that in asymptomatic men with uncomplicated T2DM, OPG and ADPN may be markers of underlying mechanisms linking the diabetic state to cardiac abnormalities.. Current Controlled Trials ISRCTN53177482.

Topics: Adiponectin; Aorta; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glucose; Glycated Hemoglobin; Heart; Humans; Hypertrophy, Left Ventricular; Insulin Resistance; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Osteoprotegerin; Positron-Emission Tomography; Ventricular Dysfunction, Left

Plasma osteoprotegerin (P-OPG) is an independent predictor of cardiovascular disease in diabetic and other populations. OPG is a bone-related glycopeptide produced by vascular smooth muscle cells and increased P-OPG may reflect arterial damage. We investigated the correlation between P-OPG and coronary artery disease (CAD) in asymptomatic type 2 diabetic patients with microalbuminuria.. P-OPG was measured in 200 asymptomatic diabetic patients without known cardiac disease. Patients with P-NT-proBNP >45.2 ng/l and/or coronary calcium score (CCS) ≥400 were stratified as high risk of CAD (n = 133), and all other patients as low risk patients (n = 67). High risk patients were examined by myocardial perfusion imaging (MPI; n = 109), and/or CT-angiography (n = 20), and/or coronary angiography (CAG; n = 86). Significant CAD was defined by presence of significant myocardial perfusion defects at MPI and/or >70% coronary artery stenosis at CAG.. Significant CAD was demonstrated in 70 of the high risk patients and of these 23 patients had >70% coronary artery stenosis at CAG. Among high risk patients, increased P-OPG was an independent predictor of significant CAD (adjusted odds ratio [CI] 3.11 [1.01-19.54] and 3.03 [1.00-9.18] for second and third tertile vs.first tertile P-OPG, respectively) and remained so after adjustments for NT-proBNP and CCS. High P-OPG was also associated with presence of >70% coronary artery stenosis(adjusted odds ratio 14.20 [1.35-148.92] for third vs. first tertile P-OPG), and 91% of patients with low (first tertile) P-OPG did not have >70% coronary artery stenosis.. Elevated P-OPG is an independent predictor of the presence of CAD in asymptomatic type 2 diabetic patients with microalbuminuria.

Topics: Adult; Aged; Albuminuria; Biomarkers; Calcium; Comorbidity; Coronary Angiography; Coronary Artery Disease; Coronary Vessels; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Natriuretic Peptide, Brain; Osteoprotegerin; Peptide Fragments; Predictive Value of Tests; Retrospective Studies; Risk Factors

Cardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes.. Type 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured.. The prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia.. Increased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown.

Topics: Adult; Aged; Biomarkers; Blood Pressure; Carotid Arteries; Carotid Artery Diseases; Diabetes Mellitus, Type 2; Female; Humans; Logistic Models; Male; Middle Aged; Myocardial Ischemia; Osteoprotegerin; Perfusion Imaging; Peripheral Arterial Disease; Prevalence; Retrospective Studies; Risk Factors; Ultrasonography

In patients with type 2 diabetes, high serum levels of osteoprotegerin (OPG) have been associated with a greater risk of cardiovascular events. However, it remains unclear how well OPG performs when compared with traditional biomarkers of cardiovascular risk such as high-sensitivity C-reactive protein (hsCRP). Furthermore, OPG levels are also high in the presence of diabetes-related microvascular disease, and it is unclear whether OPG can distinguish microvascular disease from large-vessel atherosclerosis. The first aim of this study was to compare OPG levels against other biomarkers of cardiovascular risk in the identification of patients with documented multivessel coronary artery disease (CAD). The second aim was to compare OPG levels in patients with microvascular complications (microalbuminuria) against those with established CAD.. Three groups of male patients with type 2 diabetes were recruited: patients without microvascular complications or large-vessel atherosclerosis (n = 24), patients with microalbuminuria only (n = 23), and patients with microalbuminuria and documented multivessel CAD (n = 25). OPG, hsCRP, interleukin 6, urate, and pulse wave velocity were measured.. Serum OPG levels were significantly higher in patients with a combination of microalbuminuria and CAD than in those with microalbuminuria alone. There were no significant differences in any of the other biomarkers between the groups.. OPG was found to be superior to the other biomarkers studied in identifying patients with documented CAD. The presence of CAD was a greater determinant of serum OPG levels than microalbuminuria in our population. These findings support the use of OPG as a biomarker of cardiovascular risk.

Topics: Aged; Biomarkers; Blood Flow Velocity; Coronary Artery Disease; Diabetes Mellitus, Type 2; Humans; Male; Middle Aged; Osteoprotegerin; Risk Factors

Because T2DM increases the risk of coronary atherosclerosis and CAD and new noninvasive techniques to assess CVD risk have gained considerable popularity, it is important to know how these tools relate to each other. The aim of this study was to evaluate the relationship between the extent of coronary artery calcification measured by MDCT, plasma OPG levels, baPWV and the established cardiovascular risk factors in Korean patients with T2DM. From November 2006 to December 2007, 110 asymptomatic Korean patients with T2DM without prior evidence of CAD were assessed (mean age 57.2 years). CAC imaging was performed using a 40-slice MDCT. Serum OPG levels were measured by an enzyme-linked immunosorbent assay (Oscotec, Korea) from the serum samples of each subject. We measured the baPWV as an index of arterial stiffness. In addition, we measured fasting glucose, HbA(1)C, hsCRP and lipid profiles. A total of 74 patients (67.3%) had minimal or insignificant CAC (<10). The CACS, OPG and baPWV showed significant positive correlations with each other. The CACS was significantly associated with the baPWV, smoking and use of a statin. The baPWV was significantly associated with age, duration of DM, total cholesterol and CACS by multiple linear regression models of the dependent variables of CACS or baPWV. CAC and baPWV were significant predictors of each other (r = 0.359, P = 0.014 and r = 0.361, P = 0.004). The results of this study showed that CAC, baPWV and serum OPG levels were significantly correlated with each other in asymptomatic Korean patients with T2DM. Furthermore, our results suggest that arterial stiffness, as determined by baPWV, may predict the extent of coronary calcification by MDCT.

Topics: Aged; Calcinosis; Coronary Artery Disease; Coronary Vessels; Diabetes Mellitus, Type 2; Humans; Male; Middle Aged; Osteoprotegerin; Republic of Korea; Vascular Resistance

Osteoprotegerin (OPG) is an inhibitor of bone resorption. Circulating levels of OPG seem to be elevated in patients with cardiovascular disorders and diabetes. The relationship between OPG and the metabolic syndrome has never been studied in postmenopausal women. In a population-based study, 382 Iranian postmenopausal women were randomly selected. Cardiovascular risk factors, high-sensitivity C-reactive protein, and OPG were measured. The diabetes classification and the metabolic syndrome definition were based on the criteria of the American Diabetes Association and the National Cholesterol Education Program-Adult Treatment Panel III, respectively. The mean serum OPG level was higher in those with type 2 diabetes mellitus than those without diabetes (4.33 +/- 1.70 vs 3.84 +/- 1.76 pmol/L, P = .016). In multiple logistic regression analysis, type 2 diabetes mellitus showed a significant association with serum OPG levels when adjustments were made for age, high-sensitivity C-reactive protein, and cardiovascular risk factors (odds ratio = 2.21; confidence interval, 1.34-3.66; P = .002). No significant difference was found between the mean serum OPG levels of those with the metabolic syndrome and those without the metabolic syndrome. Mean OPG levels did not differ significantly between subjects with and without hypertension, dyslipidemia, glucose intolerance, or abdominal obesity according to the National Cholesterol Education Program-Adult Treatment Panel III criteria. In conclusion, circulating OPG levels are significantly associated with diabetes, independent of cardiovascular risk factors in postmenopausal women. However, OPG levels have no correlation with the metabolic syndrome or its components. Further studies are warranted to determine the pathophysiologic origin of elevated OPG in type 2 diabetes mellitus.

Topics: Aged; Aged, 80 and over; Blood Pressure; C-Reactive Protein; Cholesterol; Diabetes Mellitus, Type 2; Female; Humans; Metabolic Syndrome; Middle Aged; Osteoprotegerin; Postmenopause; Statistics, Nonparametric; Triglycerides

Human bone marrow mesenchymal stem cells (MSCs) are pleiotrophic cells that differentiate to either adipocytes or osteoblasts as a result of crosstalk by specific signaling pathways including heme oxygenase (HO)-1/-2 expression. We examined the effect of inducers of HO-1 expression and inhibitors of HO activity on MSC differentiation to the osteoblast and following high glucose exposure. MSC cultured in osteogenic medium increased expression of osteonectin, Runt-related transcription factor 2 (RUNX-2), osteocalcin, and alkaline phosphatase. HO-1 expression during differentiation was initially decreased and then followed by a rebound increase after 15 days of culture. Additionally, the effect of HO-1 on osteoblasts appears different to that seen in adipocyte stem cells. On addition of a cobalt compound, the resultant induction of HO-1 decreases adipogenesis. Moreover, glucose (30 mM) inhibited osteoblast differentiation, as evidenced by decreased bone morphogenetic protein (BMP)-2, osteonectin, osteocalcin, and osteoprotegerin (OPG). In contrast, MSC-derived adipocytes were increased by glucose. Increased HO-1 expression increased the levels of osteonectin, OPG, and BMP-2. Inhibition of HO activity prevented the increase in osteonectin and potentiated the decrease of osteocalcin and OPG in cells exposed to high glucose levels. Furthermore, targeting HO-1 expression increased pAMPK and endothelial nitric oxide synthase (eNOS) and restored osteoblastic markers. Our findings suggest that targeting HO-1 gene expression attenuates the hyperglycemia-mediated decrease in MSC-derived osteoblast differentiation. Finally, the mechanism underlying the HO-1-specific cell effect on osteoblasts and adipocytes is yet to be explored. Thus, the targeting of HO-1 gene expression presents a portal to increase osteoblast function and differentiation and attenuate osteoporosis by promoting bone formation.

Topics: Adipogenesis; AMP-Activated Protein Kinases; Biomarkers; Bone Diseases, Metabolic; Cell Differentiation; Cells, Cultured; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Heme Oxygenase-1; Humans; Hyperglycemia; Mesenchymal Stem Cells; Nitric Oxide Synthase Type III; Osteoblasts; Osteocalcin; Osteogenesis; Osteoporosis; Osteoprotegerin; RNA, Messenger; Time Factors

We investigated whether gene polymorphisms of Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and matrix metalloproteinase 3 (MMP3) are associated with increased vascular calcification in patients with type 2 diabetes (T2D) and evaluated whether serum MMP3 and osteoprotegerin (OPG) levels are related to calcification.. This study included 464 subjects: 269 patients with T2D and 195 healthy controls in South Korea. We genotyped subjects for four single nucleotide polymorphisms (SNPs): ENPP1 K121Q, ENPP1 A/G+1044TGA, MMP3 -709A>G and MMP3 -1475G>A. The presence or absence of calcifications in the aortic arch was assessed by plain chest radiography.. The SNPs ENPP1 K121Q and MMP3 -709A>G showed significant associations with T2D (P=0.001 and P=0.004). The SNP ENPP1 K121Q showed a significant association with aortic arch calcification in T2D (P=0.036). Serum OPG levels were significantly higher in T2D patients than in the control group (P<0.001). However, serum MMP3 levels were significantly lower in T2D patients than in the control group (P<0.001).. Our study demonstrates that the ENPP1 K121Q and MMP3 -709A>G polymorphisms are associated with T2D, and that the ENPP1 Q allele is associated with increased aortic arch calcification in a Korean population.

Topics: Adult; Aged; Alleles; Analysis of Variance; Aortic Diseases; Asian People; Body Composition; Calcinosis; Chi-Square Distribution; Diabetes Mellitus, Type 2; Diet; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Humans; Male; Matrix Metalloproteinase 3; Middle Aged; Osteoprotegerin; Phosphoric Diester Hydrolases; Polymorphism, Single Nucleotide; Pyrophosphatases; Regression Analysis; Republic of Korea

Diabetes and periodontitis produce a protein discharge that can be reflected in saliva. This study evaluates the salivary concentrations of interleukin (IL)-6, matrix metalloproteinase (MMP)-8, and osteoprotegerin (OPG) in patients with periodontitis with type 2 diabetes.. Whole saliva samples were obtained from 90 subjects who were divided into four groups: healthy (control; n = 22), untreated periodontitis (UPD; n = 24), diabetes mellitus (DM; n = 20), and UPD + DM (n = 24) groups. Clinical and metabolic data were recorded. Salivary IL-6, MMP-8, and OPG concentrations were determined by a standard enzyme-linked immunosorbent assay.. The UPD and UPD + DM groups exhibited higher salivary IL-6 than the control and DM groups (P <0.01). The salivary MMP-8 concentrations in all diseased groups (UPD, DM, and UPD + DM) were higher than in the control group (P <0.01). The salivary OPG concentrations in the DM group were higher than in the UPD and control groups (P <0.05). In the UPD + DM group, salivary IL-6 was correlated with glycated hemoglobin (HbA1c) levels (r = 0.60; P <0.05). The regression analysis indicated that the number of remaining teeth, clinical attachment level, and IL-6 might have influenced the HbA1c levels in patients with diabetes.. Salivary IL-6 concentrations were elevated in patients with periodontitis with or without diabetes. Salivary MMP-8 and OPG concentrations were elevated regardless of periodontal inflammation in patients with diabetes. Therefore, periodontitis and diabetes are conditions that may interfere with protein expression and should be considered when using saliva for diagnoses.

Topics: Adult; Aged; Analysis of Variance; Case-Control Studies; Chronic Periodontitis; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Inflammation Mediators; Interleukin-6; Linear Models; Male; Matrix Metalloproteinase 8; Middle Aged; Osteoprotegerin; Salivary Proteins and Peptides; Statistics, Nonparametric

The aim of this study is to evaluate the levels of osteoclastogenesis-related factors (soluble receptor activator of nuclear factor-kappa B ligand [sRANKL] and osteoprotegerin [OPG]) in gingival crevicular fluid (GCF) from subjects with poorly and well-controlled type 2 diabetes and chronic periodontitis before and after periodontal therapy.. Eighteen subjects with well-controlled diabetes (glycated hemoglobin [HbA1c] levels ≤ 8%) and 20 subjects with poorly controlled diabetes (HbA1c levels >8%) were enrolled in this study. All subjects were submitted to non-surgical periodontal therapy. GCF sampling and clinical periodontal parameters were assessed at baseline and 3 and 6 months post-therapy. Total amounts and concentrations of sRANKL and OPG in GCF were analyzed by enzyme-linked immunosorbent assay (ELISA).. Total amounts and concentrations of sRANKL and RANKL/OPG ratios were higher in poorly controlled subjects than in well-controlled subjects at baseline and 3 and 6 months post-therapy (P <0.05). In addition, RANKL/OPG ratios decreased in well-controlled subjects (P <0.05) but not in poorly controlled subjects (P >0.05) at 3 months post-therapy. Almost all clinical parameters improved significantly for both groups post-treatment (P <0.05).. RANKL/OPG ratios in untreated and treated periodontitis sites may be negatively influenced by poor glycemic control in subjects with type 2 diabetes.

Topics: Adult; Aged; Analysis of Variance; Chi-Square Distribution; Chronic Periodontitis; Dental Plaque; Dental Scaling; Diabetes Mellitus, Type 2; Female; Gingival Crevicular Fluid; Glycated Hemoglobin; Humans; Male; Middle Aged; Osteoprotegerin; RANK Ligand; Statistics, Nonparametric

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

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

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

Plasma osteoprotegerin (OPG) is an emerging strong and independent predictor of cardiovascular disease (CVD) in high-risk populations. OPG is a bone-related glycopeptide produced by vascular smooth muscle cells, and increased plasma OPG levels may reflect arterial vascular damage. We aimed to investigate the prognostic value of OPG in relation to all-cause and cardiovascular mortality in a cohort of type 2 diabetic patients.. In a prospective observational follow-up study, 283 type 2 diabetic patients (172 men; aged 53.9 ± 8.8 years) were followed for a median of 16.8 years (range 0.2-23.0). Baseline plasma OPG concentrations were determined by immunoassay.. During follow-up, 193 (68%) patients died. High versus low levels of OPG predicted all-cause mortality (covariate-adjusted for urinary albumin excretion rate [UAER], estimated glomerular filtration rate, and conventional risk factors); hazard ratio (HR) 1.81 [95% CI 1.21-2.69]. The all-cause predictive effect of OPG was independent of NH(2)-terminal pro-brain natriuretic peptide (NT-proBNP) and was also useful within groups divided according to level of UAER. In total, 103 (73%) patients died because of CVD. High and medium versus low levels of OPG predicted cardiovascular mortality (unadjusted HR 1.86 [95% CI 1.07-3.23] and 3.51 [2.10-5.85], respectively). However, after adjustment for the covariates, HRs were no longer significant.. Elevated plasma OPG is a strong predictor of all-cause mortality in type 2 diabetic patients. The effect of OPG on all-cause mortality was independent of conventional cardiovascular risk factors, UAER, and NT-proBNP levels.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Osteoprotegerin; Prospective Studies

Peripheral arterial disease (PAD) and type 2 diabetes mellitus (DM) are both associated with excessive vascular calcification and elevated levels of inflammatory markers IL-6 and hsCRP. The recently identified Osteoprotegerin(OPG)/RANKL/TRAIL pathway has been implicated in vascular calcification, but data on levels in PAD and effect of co-existent DM are lacking.. 4 groups of patients were recruited - 26 with PAD and DM, 35 with DM alone, 22 with PAD alone, and 21 healthy individuals. Serum OPG, RANKL, TRAIL, hsCRP and IL-6 were measured using commercial ELISA assays. Presence and severity of PAD was defined using ankle brachial index (ABI).. Serum OPG (7.4±0.3 vs.5.8±0.2 pmol/l, p<0.0001), TRAIL (95.5±5.2 ng/ml vs. 76.2±4.4 ng/ml, p=0.006), hsCRP (2.6±0.3 vs. 1.8±0.3 mg/l, p=0.048), and IL-6 (4.1±0.4 vs. 2.9±0.4 pg/ml, p=0.06) were higher in patients with PAD. There was no difference in RANKL. Only OPG was significantly higher in PAD and DM (7.2±0.3 pmol/l) and PAD alone (7.7±0.4 pmol/l) compared to DM only (5.8±0.3 pmol/l) and healthy controls (5.6±0.4 pmol/l), p<0.01, but OPG was no higher in those with DM plus PAD versus those with PAD alone (p<0.3). Only OPG was associated with PAD severity, correlating negatively with ABI (r=-0.26, p=0.03), independent of age, gender, glycaemic status, hsCRP and IL-6.. PAD is associated with higher serum OPG, regardless of the co-existence of DM. This finding, in addition to its correlation with severity of PAD, suggests that OPG may be a novel marker for the presence and severity of PAD, possibly by reflecting the degree of underlying vascular calcification.

Topics: Aged; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Osteoprotegerin; Peripheral Arterial Disease

To investigate the association of plasma osteoprotegerin (OPG) levels with diabetic neuropathy.. Forty-two diabetic patients (21 female and 21 male) and twenty-four non-diabetic healthy control subjects (12 female and 12 male) were included in the study. All consecutive diabetic patients who came for routine follow-up at our outpatient clinic were invited to participate in this clinical study. We studied EMG and neuropathy symptom score in all study subjects. Fasting plasma glucose, HbA1 C, hs-CRP, OPG levels and lipid profile were measured for each subject.. Serum fasting glucose, HbA1c, HOMA-IR, total cholesterol, triglyserid, LDL-Cholesterol, HDL-Cholesterol, lipoprotein (a), apolipoprotein-b, hs-CRP, OPG levels, and neuropathy symptom score were statistically higher in diabetic patients than in healthy control subjects. Plasma OPG levels was statistically higher in diabetic patients than it was in nondiabetic control subjects. However, plasma OPG levels were not significantly different between diabetic patients without neuropathy and healthy control subjects. On the other hand, OPG levels were statistically higher in diabetic patients with neuropathy than in patients without neuropathy. In addition to that serum fasting glucose, HbA1c, hs-CRP, diabetes duration, neuropathy symptom score were statistically higher in diabetic patients with neuropathy than they were in patients without neuropathy. In total group of subjects, plasma OPG levels were correlated significantly with age, diabetes duration, HbA1c, total cholesterol, HDL-cholesterol, lipoprotein (a), apolipoprotein b, hs-CRP. In diabetic patients, plasma OPG correlated significantly with age, diabetes duration, neuropathy symptom score, HbA1c, lipoprotein (a), apolipoprotein b levels.. The major findings of this study were that the plasma OPG concentrations were higher in type 2 diabetic patients than OPG concentrations in healthy control subjects and they were positively correlated with diabetic neuropathy. This finding supports the growing concept that OPG acts as an important regulator in the development of vascular dysfunction in diabetes.

Topics: Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Female; Health; Humans; Male; Middle Aged; Osteoprotegerin

It has been suggested that hormones released after nutrient absorption, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 2 (GLP-2), could be responsible for changes in bone resorption. However, information about the role of GLP-1 in this regard is scanty. Diabetes-related bone loss occurs as a consequence of poor control of glucose homeostasis, but the relationship between osteoporosis and type 2 diabetes remains unclear. Since GLP-1 is decreased in the latter condition, we evaluated some bone characteristics in streptozotocin-induced type 2 diabetic (T2D) and fructose-induced insulin-resistant (IR) rat models compared to normal (N) and the effect of GLP-1 or saline (control) treatment (3 days by osmotic pump). Blood was taken before and after treatment for plasma measurements; tibiae and femora were collected for gene expression of bone markers (RT-PCR) and structure (microCT) analysis. Compared to N, plasma glucose and insulin were, respectively, higher and lower in T2D; osteocalcin (OC) and tartrate-resistant alkaline phosphatase 5b were lower; phosphate in IR showed a tendency to be higher; PTH was not different in T2D and IR; all parameters were unchanged after GLP-1 infusion. Bone OC, osteoprotegerin (OPG) and RANKL mRNA were lower in T2D and IR; GLP-1 increased OC and OPG in all groups and RANKL in T2D. Compared to N, trabecular bone parameters showed an increased degree of anisotropy in T2D and IR, which was reduced after GLP-1. These findings show an insulin-independent anabolic effect of GLP-1 and suggest that GLP-1 could be a useful therapeutic agent for improving the deficient bone formation and bone structure associated with glucose intolerance.

Topics: Acid Phosphatase; Animals; Bone and Bones; Bone Resorption; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucagon-Like Peptide 1; Glucose; Insulin; Insulin Resistance; Isoenzymes; Male; Osteocalcin; Osteoprotegerin; Parathyroid Hormone; Peptide Fragments; RANK Ligand; Rats; Rats, Wistar; Tartrate-Resistant Acid Phosphatase

Osteoprotegerin (OPG) is a soluble tumour necrosis factor-receptor-like molecule present in connective tissues, especially bone and vasculature. It is known to accumulate in the arterial wall in diabetes. As its synthesis in vascular cells is decreased by insulin, we wanted to elucidate the acute effects of insulin on plasma OPG concentrations in individuals with type 2 diabetes and obese individuals compared with lean controls.. The study population consisted of ten type 2 diabetic, ten obese subjects, and ten lean subjects with no family history of diabetes.. All subjects underwent a 4-h euglycemic-hyperinsulinemic clamp. Plasma OPG, insulin, lactate, HbA1c, cholesterol, triglycerides, free fatty acids (FFA), and glucose disposal rate were measured before and at the end of the clamp.. Baseline OPG concentrations did not differ significantly between groups. Insulin infusion decreased plasma OPG concentrations in all groups (P<0.01); however, the fall in OPG was 50% less in obese and type 2 diabetic individuals (P=0.007). Baseline OPG correlated with fasting insulin, baseline lactate, and low density lipoprotein cholesterol in the diabetic group, and with baseline FFA in the lean group. The relative change of OPG in response to insulin correlated inversely with HbA1c and baseline FFA in the lean group.. Acute hyperinsulinemia decreases plasma OPG, but with diminished effect in individuals with type 2 diabetes and obesity. Increased levels of OPG in arteries and plasma in diabetes together with the capability of plasma OPG as a cardiovascular risk predictor may be related to the described effects of insulin.

Topics: Acute Disease; Body Weight; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Insulin; Male; Middle Aged; Obesity; Osteoprotegerin; Risk Factors

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

Presented here is a first-person account of the evolution of the practice of surgical neurootology to that of medical neurootology shaped mainly by results of treatment directed at underlying otosclerosis-like lesions of the otic capsule and metabolic factors. With new technologies and rapidly evolving concepts, the changing treatment algorithms did not remain constant to provide the usual evidence-based outcome analyses. However, the majority of the patients presenting with neurootological symptoms had undergone previous medical or surgical treatment before undergoing the medical management herein described. The underlying ongoing basic science findings over this period were linked to the clinical observations. On the basis of the more effective results of treating neurootological disorders, recommendations are made for future areas of investigation-mostly basic science-into developing an investigative foundation for future effective management of patients with a variety of neurootological disorders.

Topics: Animals; Blood Glucose; Bone Density Conservation Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Diabetes Mellitus, Type 2; Diphosphonates; Evidence-Based Medicine; Hair Cells, Auditory; Hearing Loss, Sensorineural; Humans; Insulin Resistance; Labyrinth Diseases; Meniere Disease; Mice; Mice, Knockout; Migraine Disorders; Osteoclasts; Osteoprotegerin; Otosclerosis; Tinnitus; Tumor Necrosis Factor-alpha

Our objective of this study is to investigate the relationship between plasma osteoprotegerin (OPG) levels in type 2 diabetes and its relationship with the insulin resistance, HbA(1c), CRP, and TNF-alpha levels.. In a cross-sectional study, levels of OPG were determined in 50 subjects with type 2 diabetes and 59 control subjects without diabetes. The OPG levels between the groups were compared and their correlation with insulin resistance, glycemia and inflammatory markers CRP and TNF-alpha was determined.. OPG levels were elevated in subjects with diabetes (6.8+/-0.27 pmol/l), compared to control subjects (5.7+/-0.26 pmol/l). OPG levels significantly correlate with insulin, insulin resistance, CRP, and TNF-alpha.. OPG levels are significantly correlated with insulin resistance and may reflect the proinflammatory state in type 2 diabetes.

Topics: C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Insulin Resistance; Male; Middle Aged; Osteoprotegerin; Tumor Necrosis Factor-alpha

Topics: Age Factors; Aged; Blood Pressure; Body Mass Index; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Myocardial Ischemia; Osteoprotegerin; Sex Factors; Thiazolidinediones; Triglycerides

To investigate the effect of oral glucose on bone resorption and osteoprotegerin (OPG) in subjects with varying degrees of glucose tolerance.. In a cross-sectional study, 163 postmenopausal women aged 50-88 years without previous history of diabetes, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) were recruited. All subjects underwent a 75-g oral glucose tolerance test (OGTT) and were then classified as having normal glucose tolerance (NGT), IFG, IGT or diabetes according to American Diabetes Association (ADA) criteria.. Plasma glucose, serum insulin, C-terminal telopeptide of type I collagen (CTX-I) and OPG were measured.. Fasting insulin levels increased progressively from subjects with NGT, IFG/IGT to diabetes. After adjusted for age and body mass index (BMI), there was no significant difference in fasting CTX-I and OPG levels across the various degrees of glucose tolerance. After oral glucose, there was a significant decrease in serum CTX-I and OPG (P < 0.001) except for serum OPG in diabetic subjects. In addition, the percentages of change from baseline for both serum CTX-I and OPG were significantly less in diabetic subjects when compared to those in NGT subjects (-40.9% and 0.6% for diabetes and -50.2% and -10.6% for NGT, respectively).. Oral glucose intake causes suppression of serum CTX-I and OPG in postmenopausal women. The effect is attenuated in women with type 2 diabetes.

Topics: Aged; Aged, 80 and over; Bone Resorption; Collagen Type I; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin; Middle Aged; Osteoprotegerin; Peptides

We analyzed the relation of osteoprotegerin (OPG) with insulin sensitivity, lipid profile, serum glutamic pyruvic transaminase (SGPT), adipocytokines, and C-reactive protein (CRP) in obese and non-obese subjects.. In the study, 170 subjects (106 obese and 64 non-obese, sex ratio female/male=2.03) were included. Thirty-two obese subjects were reevaluated 6 months after the weight loss induced by bariatric surgery.. OPG did not differ between obese and non-obese subjects (respective mean values 5.17 and 4.96 pmol/l) or according to gender, but was positively correlated with age (P<0.0001 for both groups). OPG was statistically higher in 18 obese diabetic subjects compared with non-diabetics (P=0.03). After adjustment for age, no significant correlation was found between OPG and body mass index (BMI), waist, systolic and diastolic blood pressure, cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol, leptin, and adiponectin in both the obese and non-obese subjects. However, OPG was positively correlated with homeostasis model assessment (HOMA) index and SGPT levels in obese subjects at baseline (r=0.295, r=0.20, P<0.05) and after adjustment for age (r=0.28, r=0.20, P<0.05). OPG was also significantly correlated with CRP; this correlation persisted after adjustment for age in obese subjects (r=0.30, P<0.01). In a multivariate analysis in the obese group, HOMA index and CRP were independent predictors of OPG while SGPT was not. Six months post-surgery, OPG did not change, despite a significant reduction in glucose, SGPT, cholesterol, triglycerides, CRP, and leptin values (P=0.02, P=0.006, P=0.007, P<0.001, P<0.001, P<0.001 respectively) and a significant increase in adiponectin and HDL values (P<0.001 for both variables).. Our results show that in obese subjects, OPG is not related to BMI. However, we describe new relationships between OPG and both HOMA index and CRP.

Topics: Adipokines; Adult; Alanine Transaminase; Bariatric Surgery; Body Weight; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, HDL; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Female; Homeostasis; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Osteoprotegerin; Regression Analysis; Risk Factors; Triglycerides; Weight Loss

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

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

This study prospectively evaluated the relationship between cardiovascular risk factors, selected biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin [IL]-6, and osteoprotegerin [OPG]), and the progression of coronary artery calcification (CAC) in type 2 diabetic subjects.. Coronary artery calcification is pathognomonic of coronary atherosclerosis. Osteoprotegerin is a signaling molecule involved in bone remodeling that has been implicated in the regulation of vascular calcification and atherogenesis.. Three hundred ninety-eight type 2 diabetic subjects without prior coronary disease or symptoms (age 52 +/- 8 years, 61% male, glycated hemoglobin [HbA(1)c] 8 +/- 1.5) were evaluated serially by CAC imaging (mean follow-up 2.5 +/- 0.4 years). Progression/regression of CAC was defined as a change > or =2.5 between the square root transformed values of baseline and follow-up volumetric CAC scores. Demographic data, risk factors, glycemic control, medication use, serum hs-CRP, IL-6, and plasma OPG levels were measured at baseline and follow-up.. Two hundred eleven patients (53%) had CAC at baseline. One hundred eighteen patients (29.6%) had CAC progression, whereas 3 patients (0.8%) had regression. Age, male gender, hypertension, baseline CAC, HbA(1)c >7, waist-hip ratio, IL-6, OPG, use of beta-blockers, calcium channel antagonists, angiotensin-converting enzyme (ACE) inhibitors, statins, and Framingham/UKPDS (United Kingdom Prospective Diabetes Study) risk scores were univariable predictors of CAC progression. In the multivariate model, baseline CAC (odds ratio [OR] for CAC >400 = 6.38, 95% confidence interval [CI] 2.63 to 15.5, p < 0.001), HbA(1)c >7 (OR 1.95, CI 1.08 to 3.52, p = 0.03), and statin use (OR 2.27, CI 1.38 to 3.73, p = 0.001) were independent predictors of CAC progression.. Baseline CAC severity and suboptimal glycemic control are strong risk factors for CAC progression in type 2 diabetic subjects.

Topics: Adult; Aged; Biomarkers; C-Reactive Protein; Calcinosis; Cohort Studies; Coronary Artery Disease; Diabetes Mellitus, Type 2; Disease Progression; Female; Glycated Hemoglobin; Humans; Interleukin-6; Male; Middle Aged; Osteoprotegerin; Risk Factors; Severity of Illness Index; Tomography, X-Ray Computed

This study sought to prospectively evaluate the relationship between plasma osteoprotegerin (OPG), inflammatory biomarkers (high-sensitivity C-reactive protein [hs-CRP], interleukin-6 [IL-6], coronary artery calcification (CAC), and cardiovascular events in patients with type 2 diabetes.. Arterial calcification is a prominent feature of atherosclerosis and is associated with an increased risk of cardiovascular events. Osteoprotegerin is a cytokine that has recently been implicated in the regulation of vascular calcification.. A total of 510 type 2 diabetic patients (53 +/- 8 years; 61% male) free of symptoms of cardiovascular disease were evaluated by CAC imaging. Risk factors, hs-CRP, IL-6, and OPG levels were measured. Patients were followed up for cardiovascular events (cardiac death, myocardial infarction, acute coronary syndrome, late revascularization, and nonhemorrhagic stroke).. Significant CAC (>10 Agatston units) was seen in 236 patients (46.3%); OPG was significantly elevated in patients with increased CAC. In multivariable analyses, OPG retained a strong association with elevated CAC scores after adjustment for age, gender, and other risk factors (odds ratio = 2.84, 95% confidence interval 2.2 to 3.67; p < 0.01). Sixteen cardiovascular events occurred during a mean follow-up of 18 +/- 5 months. The waist-to-hip ratio, United Kingdom Prospective Diabetes Study (UKPDS) risk score, OPG level, and CAC score were significant predictors of time to cardiovascular events in a univariate Cox proportional hazards model. In the multivariate model, the CAC score was the only independent predictor of adverse events. Levels of hs-CRP and IL-6 were related to neither the extent of CAC nor short-term events.. A high proportion of asymptomatic diabetic patients have significant subclinical atherosclerosis. Of the biomarkers studied, only OPG predicted both subclinical disease and near-term cardiovascular events. Therefore, measurement of OPG merits further investigation as a simple test for identifying high-risk type 2 diabetic patients.

Topics: Biomarkers; C-Reactive Protein; Calcinosis; Cardiovascular Diseases; Coronary Artery Disease; Diabetes Mellitus, Type 2; Female; Glycoproteins; Humans; Interleukin-6; Male; Middle Aged; Osteoprotegerin; Prognosis; Proportional Hazards Models; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Risk Factors; Sensitivity and Specificity; Survival Rate

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 is a recently identified inhibitor of bone resorption. Recent studies indicate that osteoprotegerin also acts as an important regulatory molecule in the vasculature. The purpose of this study was to investigate the relationship between plasma osteoprotegerin levels and endothelium-dependent arterial dilation in type 2 diabetic patients. The study subjects included 40 newly diagnosed type 2 diabetic patients and 46 healthy subjects. All patients were given insulin therapy for 6 months. Plasma osteoprotegerin concentration was measured in duplicate by a sandwich enzyme-linked immunosorbent assay method, and high-resolution ultrasound was used to measure brachial artery diameter at rest, after reactive hyperemia, and after sublingual glyceryltrinitrate. The plasma osteoprotegerin level in patients before treatment was 3.36 +/- 0.32 ng/l, which was significantly higher than that in control subjects (2.38 +/- 0.25 ng/l, P < 0.001). After 6 months of treatment, osteoprotegerin levels decreased markedly (2.83 +/- 0.34 ng/l, P < 0.001). Flow-mediated endothelium-dependent arterial dilation in patients before treatment was 3.21 +/- 0.52%, which was significantly lower than that in control subjects (4.46 +/- 0.56%, P < 0.01), and it improved markedly after 6 months of treatment (4.03 +/- 0.49%, P < 0.01). In multivariate analysis, osteoprotegerin was significantly associated with endothelium-dependent arterial dilation, fasting blood glucose (FBG), HbA(1c) (A1C), and ultrasensitive C-reactive protein (CRP) at baseline (P < 0.01). The absolute changes in osteoprotegerin showed significant correlation with changes in endothelium-dependent arterial dilation, FBG, A1C, and CRP in diabetic patients during the course of treatment (P < 0.01). This study shows that plasma osteoprotegerin levels are elevated in newly diagnosed diabetic patients and are significantly associated with endothelial function.

Topics: Adult; Arteries; Blood Glucose; C-Reactive Protein; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Glycated Hemoglobin; Glycoproteins; Humans; Male; Middle Aged; Osteoprotegerin; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Reference Values; Vasodilation

Endothelial dysfunction (ED) is associated with the presence of atherosclerosis. However, ED is also considered a sign of the early vascular changes preceding atherosclerosis. By measuring flow-mediated vasodilation (FMD) and circulating markers of endothelial function we sought to explore whether impaired endothelial function is already present in healthy subjects at increased risk of developing type 2 diabetes mellitus. Furthermore, we aimed to assess the impact of short-term lifestyle intervention (10 weeks endurance exercise) on the potentially primary defects of endothelial function. Twenty-nine healthy but insulin-resistant first-degree relatives of patients diagnosed with type 2 diabetes mellitus (33 +/- 5 years; body mass index, 26.3 +/- 1.6 kg/m2) were compared with 19 control subjects without a family history of diabetes mellitus (31 +/- 5 years; body mass index, 25.8 +/- 3.0 kg/m2). At baseline the von Willebrand factor was significantly increased in the relatives (P < .05). Furthermore, mannose-binding lectin (P = .06), soluble intercellular adhesion molecule 1 (P = .08), and osteoprotegerin (P = .08) tended to be increased in relatives. The following markers of endothelial function were comparable at baseline: FMD, C-reactive protein, plasminogen activator inhibitor 1, and soluble vascular cell adhesion molecule 1. Exercise training resulted in a decrease in mannose-binding lectin (P = .02) and osteoprotegerin (P < .01) in relatives only, whereas other biochemical markers were unaffected in both groups. Moreover, the relatively high-intensity exercise training tended weakly to reduce FMD in the relatives (P = .15). In conclusion, healthy subjects predisposed for type 2 diabetes mellitus show only minor signs of endothelial dysfunction. Under these almost normal vascular conditions, exercise training has little effect on endothelial function.

Topics: Adult; C-Reactive Protein; Diabetes Mellitus, Type 2; Endothelium, Vascular; Exercise; Female; Genetic Predisposition to Disease; Humans; Intercellular Adhesion Molecule-1; Male; Mannose-Binding Lectin; Osteoprotegerin; Plasminogen Activator Inhibitor 1; Statistics, Nonparametric; Vascular Cell Adhesion Molecule-1; Vasodilation; von Willebrand Factor

Serum osteoprotegerin (OPG) is significantly increased in diabetic patients, prompting expanded investigation of the correlation between OPG production/release and glycemic levels. Serum levels of OPG, but not of its cognate ligand receptor activator of nuclear factor-kappaB ligand (RANKL), were significantly increased in type 2 diabetes mellitus patients compared with healthy blood donors. Serum OPG was also significantly elevated in a subgroup of recently diagnosed diabetic patients (within 2 years). The relationship between serum OPG and diabetes mellitus onset was next investigated in apoE-null and littermate mice. Serum OPG increased early after diabetes induction in both mouse strains and showed a positive correlation with blood glucose levels and an inverse correlation with the levels of free (OPG-unbound) RANKL. The in vitro addition of tumor necrosis factor-alpha to human vascular endothelial cells, but not human peripheral blood mononuclear cells, markedly enhanced OPG release in culture. In contrast, high glucose concentrations did not modulate OPG release when used alone or in association with tumor necrosis factor-alpha. Moreover, the ability of soluble RANKL to activate the extracellular signal-regulated kinase/mitogen-activated protein kinase and endothelial nitric-oxide synthase pathways in endothelial cells was neutralized by preincubation with recombinant OPG. Altogether, these findings suggest that increased OPG production represents an early event in the natural history of diabetes mellitus, possibly contributing to disease-associated endothelial cell dysfunction.

Topics: Aged; Animals; Aorta; Apolipoproteins E; Blood Glucose; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endothelium, Vascular; Female; Glucose; Humans; Male; Mice; Mice, Inbred C57BL; Middle Aged; Osteoprotegerin; RANK Ligand; Signal Transduction; Time Factors

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

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

To clarify the pathogenesis of altered bone metabolism in diabetic state and its underlying mechanisms, the bone mineral content and fasting levels of serum intact parathyroid hormone (i-PTH), intact osteocalcin (i-OC), tartrate-resistant acid phosphatase (TRAP) and osteoclastgenesis inhibitory factor/osteoprotegerin (OCIF/OPG) were measured in male type 2 diabetic patients and their age-matched controls. In addition, urine levels of osteoclastic markers, C-telopeptide of type I collagen (CTx), deoxypyridinoline (DPD), and N-telopeptide of type I collagen (NTx) were simultaneously determined. Serum levels of i-PTH and i-OC in diabetic patients were significantly lower than those in the controls. Conversely, serum concentrations of TRAP were significantly elevated in diabetic patients. However, no clear correlation was observed between serum i-OC and TRAP. It was also observed that urinary excretion of CTx, DPD, and NTx was significantly increased in the diabetics as compared with the controls. Unexpectedly, serum levels of OCIF/OPG tended to be higher in the diabetic group, and these values exhibited a significantly positive correlation with those of serum TRAP. There was found a significantly negative correlation between serum TRAP and bone mineral density (BMD) and also between serum OCIF/OPG and bone mineral density. It seems probable that OCIF/OPG has a suppressive role on the increased bone resorption to prevent further loss of the skeletal bone mass in type 2 diabetic patients.

Topics: Acid Phosphatase; Amino Acids; Biomarkers; Bone Density; C-Peptide; Calcitriol; Calcium; Collagen; Collagen Type I; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Glycoproteins; Humans; Insulin; Isoenzymes; Magnesium; Male; Middle Aged; Osteocalcin; Osteoclasts; Osteoprotegerin; Parathyroid Hormone; Peptides; Phosphorus; Receptors, Cytoplasmic and Nuclear; Receptors, Tumor Necrosis Factor; Sex Factors; Tartrate-Resistant Acid Phosphatase

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