21 research outputs found

    Osteoglycin as a Potential Biomarker of Mild Kidney Function Impairment in Type 2 Diabetes Patients

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    Osteoglycin (OGN) could be a biomarker of mild kidney function impairment in type 2 diabetes (T2D). Our study aimed to determine the association between serum OGN and impaired kidney function risk in T2D patients and to analyze its potential role as an estimator of kidney disturbances in this population. This cross-sectional study included 147 T2D patients (65 ± 8 years, 58.5% males), and 75 healthy controls (63 ± 10 years, 36% males). Circulating OGN levels were determined by ELISA. Linear regression modeling was performed to determine the variables influencing circulating OGN, and an ROC curve was plotted to assess the usefulness of OGN as an estimator of diabetic kidney disease risk. Circulating OGN was significantly increased in T2D patients compared to controls (18.41 (14.45–23.27) ng/mL vs. 8.74 (7.03–12.35) ng/mL; p < 0.001). We found a progressive increase in serum OGN according to the severity of kidney impairment in T2D patients (normal kidney function: 16.14 (12.13–20.48) ng/mL; mildly impaired kidney function: 19.15 (15.78–25.90) ng/mL; moderate impaired kidney function: 21.80 (15.06–29.22) ng/mL; p = 0.006). Circulating OGN was an independent estimator of mildly impaired kidney function risk in T2D patients. We suggest that serum OGN could act as an albuminuria-independent biomarker of incipient kidney dysfunction in T2D patients.Junta de AndalucĂ­a grants (PI-0207-2016 and PI0268-2019)Instituto de Salud Carlos III grants (PI18-00803 and PI18-01235)European Regional Development Fund (FEDER)Instituto de Salud Carlos III (FI19/00118; CD20/00022

    Circulating Undercarboxylated Osteocalcin as Estimator of Cardiovascular and Type 2 Diabetes Risk in Metabolic Syndrome Patients

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    Undercarboxylated osteocalcin (ucOC) could be a biomarker of glucose disturbances and cardiovascular risk. Our study aimed to determine the association between serum levels of ucOC and cardiovascular risk in metabolic syndrome (MetS) patients and to analyse its potential role as estimator of type 2 diabetes (T2D) risk in this population. This cross-sectional study included 235 patients with MetS, 53.2% women, aged 55–75 years. Circulating ucOC levels were measured by ELISA. Cardiovascular risk was determined as Z-score of the diagnostic criteria for MetS (CV-ZS). Linear regression model was performed to analyse the association between circulating ucOC and CV-ZS. A receiver operating curve (ROC) was performed to analyse the usefulness of ucOC as T2D risk estimator. Patients above the CV-ZS median showed signifcant lower ucOC levels. We found an inverse association between ucOC levels and CV-ZS in MetS patients without T2D. Patients with ucOC levels below the 25th percentile showed worse cardiometabolic profle and higher cardiovascular and T2D risk. The area under the curve performed better when ucOC levels were included along with the classic T2D risk factors. The measurement of circulating ucOC could be a useful tool to identify increased cardiovascular and T2D risk in MetS patients without T2D.Junta de Andalucia PI-0207-2016European Union (EU) PI18-00803 PI18-0123

    Exploring the Role of Sclerostin as a Biomarker of Cardiovascular Disease and Mortality: A Scoping Review

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    Sclerostin is most recognized for its role in controlling bone formation; however, it is also expressed in the heart, aorta, coronary, and peripheral arteries. Human studies have associated high circulating sclerostin levels with the presence of different cardiovascular diseases (CVD), surrogate CVD markers, and a high risk of cardiovascular events in some populations. However, this is still a matter of scientific debate, as the results have been very heterogeneous among studies. In the present review, the association between serum sclerostin levels and CVD and/or cardiovascular mortality was analyzed. For this purpose, a scoping review was performed in which articles measuring serum sclerostin levels and cardiovascular risk in patients were selected. Eleven articles answered the research question; of these articles, 8/11 evaluated the association between sclerostin and CVD, of which 4/8 found a positive association, 2/8 found a negative association, and 2/8 found no association between variables. Five (5/11) of the articles included in the study evaluated cardiovascular mortality, of which 3/5 found a positive association, 1/5 found a negative association, and 1/5 found no association between variables. In conclusion, we did not find sufficient results to be able to demonstrate an association between elevated sclerostin levels and the development of CVD and/or cardiovascular mortality in the general population due to heterogeneity in the results. However, there seems to be a tendency to consider increased sclerostin levels as a risk factor for both the development of cardiovascular events and cardiovascular mortality in specific populations. Further studies in this field will help to solve some of the inconsistencies found during this scoping review and allow for the future use of sclerostin measurement as a strategy in the prevention and diagnosis of CVD and/or cardiovascular mortality.Instituto de Salud Carlos III European Commission PI18-00803 PI21/01069 PI18-01235 CD20/00022European CommissionJunta de Andalucia PI-0268-2019 RH-0069-2021Instituto de Salud Carlos IIIUniversity of Granada FI19/00118European Commission 811

    The Contribution of Wnt Signaling to Vascular Complications in Type 2 Diabetes Mellitus

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    Vascular complications are the leading cause of morbidity and mortality among patients with type 2 diabetes mellitus (T2DM). These vascular abnormalities result in a chronic hyperglycemic state, which influences many signaling molecular pathways that initially lead to increased oxidative stress, increased inflammation, and endothelial dysfunction, leading to both microvascular and macrovascular complications. Endothelial dysfunction represents the initial stage in both types of vascular complications; it represents “mandatory damage” in the development of microvascular complications and only “introductory damage” in the development of macrovascular complications. Increasing scientific evidence has revealed an important role of the Wnt pathway in the pathophysiology of the vascular wall. It is well known that the Wnt pathway is altered in patients with T2DM. This review aims to be an update of the current literature related to the Wnt pathway molecules that are altered in patients with T2DM, which may also be the cause of damage to the vasculature. Both microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) are analyzed. This review aims to concisely concentrate all the evidence to facilitate the view on the vascular involvement of the Wnt pathway and its components by highlighting the importance of exploring possible therapeutic strategy for patients with T2DM who develop vascular pathologies.Instituto de Salud Carlos III European Commission PI18-00803 PI21-01069 PI18-01235 CD20/00022 FI19/00118European CommissionJunta de Andalucia PI-0268-2019University of GranadaEuropean Commission 811

    Undercarboxylated Osteocalcin: A Promising Target for Early Diagnosis of Cardiovascular and Glycemic Disorders in Patients with Metabolic Syndrome: A Pilot Study

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    Lifestyle changes are causing an exponential increase in the prevalence of obesity and metabolic syndrome (MetS) worldwide. The most frequent complications of these are the development of diabetes (T2D) and cardiovascular disease (CVD). Accurate tools are needed to classify the cardiovascular risk (CVR) in the MetS population. In recent years, numerous biomarkers of bone metabolism have been associated with CVR. The aim of this study was to determine the levels of undercarboxylated osteocalcin (ucOC) in a cohort of patients with MetS and to analyse its association with MetS parameters and CVR as well as with T2D prevalence. A longitudinal study was conducted in which a MetS population was followed for one year. Weight change, adherence to the Mediterranean diet (MedDiet), ucOC levels, MetS parameters and CVR were analysed and CVR was calculated using different scores. Our results showed a decrease of CVR associated with a better adherence to the MetDiet resulting in higher HDL-C and ucOC levels though the improvement of MetS risk factors. This bone protein appeared as a potential biomarker to classify CVR in the MetS population, especially for MetS patients without prevalent T2D. Furthermore, ucOC serum levels could be good predictors of T2D prevalence.Instituto de Salud Carlos III European Commission PI18-00803 PI21/01069 PI18-01235 FI19/00118 CD20/00022European CommissionJunta de Andalucia CD20/00022 PI-0268-2019 RH-0069202

    Systemic effects of hypophosphatasia characterization of two novel variants in the ALPL gene

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    IntroductionHypophosphatasia (HPP) is an inborn metabolic error caused by mutations in the ALPL gene encoding tissue non-specific alkaline phosphatase (TNSALP) and leading to decreased alkaline phosphatase (ALP) activity. Although the main characteristic of this disease is bone involvement, it presents a great genetic and clinical variability, which makes it a systemic disease.MethodsPatients were recruited based on biochemical assessments. Diagnosis was made by measuring serum ALP and pyridoxal 5-phosphate levels and finally by Sanger sequencing of the ALPL gene from peripheral blood mononuclear cells. Characterization of the new variants was performed by transfection of the variants into HEK293T cells, where ALP activity and cellular localization were measured by flow cytometry. The dominant negative effect was analyzed by co-transfection of each variant with the wild-type gene, measuring ALP activity and analyzing cellular localization by flow cytometry.ResultsTwo previously undescribed variants were found in the ALPL gene: leucine 6 to serine missense mutation (c.17T&gt;C, L6S) affecting the signal peptide and threonine 167 deletion (c.498_500delCAC, T167del) affecting the vicinity of the active site. These mutations lead mainly to non-pathognomonic symptoms of HPP. Structural prediction and modeling tools indicated the affected residues as critical residues with important roles in protein structure and function. In vitro results demonstrated low TNSALP activity and a dominant negative effect in both mutations. The results of the characterization of these variants suggest that the pleiotropic role of TNSALP could be involved in the systemic effects observed in these patients highlighting digestive and autoimmune disorders associated with TNSALP dysfunction.ConclusionsThe two new mutations have been classified as pathogenic. At the clinical level, this study suggests that both mutations not only lead to pathognomonic symptoms of the disease, but may also play a role at the systemic level

    Mild hypophosphatasia may be twice as prevalent as previously estimated: an effective clinical algorithm to detect undiagnosed cases

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    Objectives: Since the prevalence of hypophosphatasia (HPP), a rare genetic disease, seems to be underestimated in clinical practice, in this study, a new diagnostic algorithm to identify missed cases of HPP was developed and implemented. Methods: Analytical determinations recorded in the Clinical Analysis Unit of the Hospital Universitario ClĂ­nico San Cecilio in the period June 2018 – December 2020 were reviewed. A new clinical algorithm to detect HPP-misdiagnosed cases was used including the following steps: confirmation of persistent hypophosphatasemia, exclusion of secondary causes of hypophosphatasemia, determination of serum pyridoxal- 5â€Č-phosphate (PLP) and genetic study of ALPL gene. Results: Twenty-four subjects were selected to participate in the study and genetic testing was carried out in 20 of them following clinical algorithm criteria. Eighty percent of patients was misdiagnosed with HPP following the current standard clinical practice. Extrapolating these results to the current Spanish population means that there could be up to 27,177 cases of undiagnosed HPP in Spain. In addition, we found a substantial proportion of HPP patients affected by other comorbidities, such as autoimmune diseases (∌40 %). Conclusions: This new algorithm was effective in detecting previously undiagnosed cases ofHPP, which appears to be twice as prevalent as previously estimated for the European population. In the near future, our algorithm could be globally applied routinely in clinical practice to minimize the underdiagnosis of HPP. Additionally, some relevant findings, such as the high prevalence of autoimmune diseases in HPP-affected patients, should be investigated to better characterize this disorder.Instituto de Salud Carlos III grants PI21-01069 co-funded by the European Regional Development Fund (FEDER) and by Junta de AndalucĂ­a grant PI-0268-2019Operational Programme for Youth Employment of the Junta de AndalucĂ­a with Ref: POEJ_04/2022-12Instituto de Salud Carlos III with co-funding by FEDER (CD20/00022)(FI19/00118 and CM21/00221) from Instituto de Salud CarlosPostdoctoral fellowship from the Junta de AndalucĂ­a (RH-0141-2020

    Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene

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    Hypophosphatasia (HPP) is a genetic disease caused by one or several mutations in ALPL gene encoding the tissue-nonspecific alkaline phosphatase affecting the mineralization process. Due to its low prevalence and lack of recognition, this metabolic disorder is generally confused with other more frequent bone disorders. An assessment of serum total alkaline phosphatase (ALP) levels was performed in 78,590 subjects. Pyridoxal-5â€Č-phosphate (PLP) concentrations were determined and ALPL gene was sequenced in patients potentially affected by HPP. Functional validation of the novel mutations found was performed using a cell-based assay. Our results showed persistently low serum ALP levels in 0.12% of subjects. Among the studied subjects, 40% presented with HPP-related symptoms. Nine of them (~28%) had a history of fractures, 5 (~16%) subjects showed chondrocalcinosis and 4 (~13%) subjects presented with dental abnormalities. Eleven subjects showed increased PLP concentrations. Seven of them showed ALPL gene mutations (2 of the mutations corresponded to novel genetic variants). In summary, we identified two novel ALPL gene mutations associated with adult HPP. Using this protocol, almost half of the studied patients were diagnosed with HPP. Based on these results, the estimated prevalence of mild HPP in Spain could be up to double than previously reported.Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (with support from NIH P41-GM103311)grants from Alexion and FEIOMM, by Instituto de Salud Carlos III (grants PI18-00803 and PI18-01235)co-funding from FEDER and by Junta de AndalucĂ­a (grant PI-0207-2016)GM-N is supported by the predoctoral program from Instituto de Salud Carlos III (FI17/00178) and by the Research Initiation Grants for Official Master Students program from the University of Granada (2017)PJR is a Ramon y Cajal Researcher from the MINECO (RYC-2015-18383) at GENyO and University of Granada

    Tocilizumab in refractory Caucasian Takayasu's arteritis: a multicenter study of 54 patients and literature review

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    Objective: To assess the efficacy and safety of tocilizumab (TCZ) in Caucasian patients with refractory Takayasu's arteritis (TAK) in clinical practice. Methods: A multicenter study of Caucasian patients with refractory TAK who received TCZ. The outcome variables were remission, glucocorticoid-sparing effect, improvement in imaging techniques, and adverse events. A comparative study between patients who received TCZ as monotherapy (TCZMONO) and combined with conventional disease modifying anti-rheumatic drugs (cDMARDs) (TCZCOMBO) was performed. Results: The study comprised 54 patients (46 women/8 men) with a median [interquartile range (IQR)] age of 42.0 (32.5-50.5) years. TCZ was started after a median (IQR) of 12.0 (3.0-31.5) months since TAK diagnosis. Remission was achieved in 12/54 (22.2%), 19/49 (38.8%), 23/44 (52.3%), and 27/36 (75%) patients at 1, 3, 6, and 12 months, respectively. The prednisone dose was reduced from 30.0 mg/day (12.5-50.0) to 5.0 (0.0-5.6) mg/day at 12 months. An improvement in imaging findings was reported in 28 (73.7%) patients after a median (IQR) of 9.0 (6.0-14.0) months. Twenty-three (42.6%) patients were on TCZMONO and 31 (57.4%) on TCZCOMBO: MTX (n = 28), cyclosporine A (n = 2), azathioprine (n = 1). Patients on TCZCOMBO were younger [38.0 (27.0-46.0) versus 45.0 (38.0-57.0)] years; difference (diff) [95% confidence interval (CI) = -7.0 (-17.9, -0.56] with a trend to longer TAK duration [21.0 (6.0-38.0) versus 6.0 (1.0-23.0)] months; diff 95% CI = 15 (-8.9, 35.5), and higher c-reactive protein [2.4 (0.7-5.6) versus 1.3 (0.3-3.3)] mg/dl; diff 95% CI = 1.1 (-0.26, 2.99). Despite these differences, similar outcomes were observed in both groups (log rank p = 0.862). Relevant adverse events were reported in six (11.1%) patients, but only three developed severe events that required TCZ withdrawal. Conclusion: TCZ in monotherapy, or combined with cDMARDs, is effective and safe in patients with refractory TAK of Caucasian origin.Funding: This work was partially supported by RETICS Programs, RD08/0075 (RIER), RD12/0009/0013 and RD16/0012 from “Instituto de Salud Carlos III” (ISCIII) (Spain)

    3D DXA Hip Differences in Patients with Acromegaly or Adult Growth Hormone Deficiency

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    The skeleton is regulated by and responds to pituitary hormones, especially when the circulating levels are perturbed in disease. This study aims to analyse the between-group differences in 3D dual-energy X-ray absorptiometry (DXA) parameters at the hip site among patients with acromegaly or adult growth hormone deficiency (AGHD) and a healthy control group. The current cross-sectional study includes data for 67 adults, 20 with acromegaly, 14 with AGHD and 33 healthy controls. We obtained the areal bone mineral density (aBMD) outcomes using DXA and cortical and trabecular parameters using 3D-DXA software (3D-SHAPER). The mean-adjusted 3D-DXA parameters did not differ between acromegaly patients and the controls (p > 0.05); however, we found cortical bone impairment (-7.3% to -8.4%; effect size (ES) = 0.78) in AGHD patients (p < 0.05). Differences in the cortical bone parameters were more evident when comparing AGHD patients (-8.5% to -16.2%; ES = 1.22 to 1.24) with acromegaly patients (p < 0.05). In brief, the 3D mapping highlighted the trochanter as the site with greater cortical bone differences between acromegaly patients and the controls. Overall, AGHD patients displayed lower cortical parameters at the trochanter, femoral neck and intertrochanter compared to the controls and acromegaly patients. To sum up, 3D-DXA provided useful information about the characteristics of bone involvement in growth hormone (GH)-related disorders. Patients with AGHD showed distinct involvement of the cortical structure.Instituto de Salud Carlos IIIEuropean Commission PI18/01235La Caixa Foundation within the Junior Leader fellowship programme 100010434 LCF/BQ/PR19/1170000
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