21 research outputs found
Osteoglycin as a Potential Biomarker of Mild Kidney Function Impairment in Type 2 Diabetes Patients
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 (14.45â23.27) ng/mL vs. 8.74 (7.03â12.35) 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 (12.13â20.48) ng/mL; mildly impaired kidney function: 19.15 (15.78â25.90)
ng/mL; moderate impaired kidney function: 21.80 (15.06â29.22) 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
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 55â75 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
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
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 âmandatory damageâ in the development of microvascular
complications and only âintroductory damageâ 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
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
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>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
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 â 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-
5âČ-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 (âŒ40 %).
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
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-5âČ-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
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 âInstituto de Salud Carlos IIIâ (ISCIII) (Spain)
3D DXA Hip Differences in Patients with Acromegaly or Adult Growth Hormone Deficiency
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