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Turan S.,Harvard University | Turan S.,Marmara University | Fernandez-Rebollo E.,Harvard University | Fernandez-Rebollo E.,Institute dInvestigations Biomediques August Pi I Sunyer IDIBAPS | And 10 more authors.
Journal of Bone and Mineral Research | Year: 2014

Pseudohypoparathyroidism type-Ia (PHP-Ia), characterized by renal proximal tubular resistance to parathyroid hormone (PTH), results from maternal mutations of GNAS that lead to loss of α-subunit of the stimulatory G protein (Gαs) activity. Gαs expression is paternally silenced in the renal proximal tubule, and this genomic event is critical for the development of PTH resistance, as patients display impaired hormone action only if the mutation is inherited maternally. The primary clinical finding of PHP-Ia is hypocalcemia, which can lead to various neuromuscular defects including seizures. PHP-Ia patients frequently do not present with hypocalcemia until after infancy, but it has remained uncertain whether PTH resistance occurs in a delayed fashion. Analyzing reported cases of PHP-Ia with documented GNAS mutations and mice heterozygous for disruption of Gnas, we herein determined that the manifestation of PTH resistance caused by the maternal loss of Gαs, ie, hypocalcemia and elevated serum PTH, occurs after early postnatal life. To investigate whether this delay could reflect gradual development of paternal Gαs silencing, we then analyzed renal proximal tubules isolated by laser capture microdissection from mice with either maternal or paternal disruption of Gnas. Our results revealed that, whereas expression of Gαs mRNA in this tissue is predominantly from the maternal Gnas allele at weaning (3 weeks postnatal) and in adulthood, the contributions of the maternal and paternal Gnas alleles to Gαs mRNA expression are equal at postnatal day 3. In contrast, we found that paternal Gαs expression is already markedly repressed in brown adipose tissue at birth. Thus, the mechanisms silencing the paternal Gαs allele in renal proximal tubules are not operational during early postnatal development, and this finding correlates well with the latency of PTH resistance in patients with PHP-Ia. © 2014 American Society for Bone and Mineral Research. Source


Giugliano D.,The Second University of Naples | Maiorino M.I.,The Second University of Naples | Bellastella G.,The Second University of Naples | Petrizzo M.,Futura Medical | And 3 more authors.
Endocrine | Year: 2015

Current guidelines specify hemoglobin A1c (HbA1c) targets around or less than 7.0 %, with more (<6.5 %) or less (<8 %) stringent goals being appropriate for selected patients. The difficulty in setting a precise HbA1c target depends, at least in part, on the physician perception of the relative importance of the parameters to be considered when determining the target. Using the “a priori” approach, physicians set the HbA1c target first, then prescribe the appropriate antidiabetic drug in order to cover the distance from the target, i.e., the difference between the current HbA1c value of the patient and the individualized HbA1c target: calculating the distance from the target may also be useful as a predictor of therapeutic success. In the “a posteriori” approach, physicians first prescribe, then decide if the achieved HbA1c is an appropriate level for that patient. Attainment of the HbA1c target ultimately depends on which target the physician set: both approaches (“a priori” and “a posteriori”) may be useful for both physicians to make appropriate therapeutic decisions and patients to adhere to the best possible treatment. All this presumably will avoid unnecessary therapeutic inertia. © 2015, Springer Science+Business Media New York. Source


Partridge M.R.,Imperial College London | Miravitlles M.,Institute dInvestigations Biomediques August Pi I Sunyer IDIBAPS | Stahl E.,Astrazeneca | Karlsson N.,Astrazeneca | And 2 more authors.
European Respiratory Journal | Year: 2010

This report concerns the development and validation of two patient-reported outcomes questionnaires developed to assess chronic obstructive pulmonary disease (COPD) patients' ability to perform morning activities and to evaluate their morning symptoms. Based on interviews with COPD patients, the Capacity of Daily Living during the Morning (CDLM) questionnaire and the Global Chest Symptoms Questionnaire (GCSQ) were developed, linguistically validated and incorporated into two multicentre, randomised trials involving a total of 1,100 COPD patients; those trials were registered at ClinicalTrials.gov (NCT00496470 and NCT00542880). Data from these trials were used to determine the reliability, validity and responsiveness of the questionnaires and to derive estimates of minimal important differences (MIDs). Both questionnaires displayed good-to-high reliability (Cronbach's α 0.75-0.93). Analysis of convergent validity showed that CDLM and GCSQ scores correlated significantly (p<0.001) with symptoms, health-related quality of life (HRQoL) and use of rescue medication. In both trials, CDLM and GCSQ scores discriminated between patients with different levels of HRQoL, as assessed by the St George's Respiratory Questionnaire for COPD patients (SGRQ-C), but not with disease severity, as assessed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. A significant improvement in CDLM and GCSQ scores occurred in response to treatment. Estimations of MID scores, corresponding to an SGRQ-C MID of 4, were 0.20 for the CDLM questionnaire and 0.15 for the GCSQ. Both the CDLM questionnaire and the GCSQ are easy-to-use, reliable, responsive, self-administered questionnaires that report on patients' symptoms and ability to perform morning activities. Copyright©ERS 2010. Source


Malpique R.,Institute dInvestigations Biomediques August Pi I Sunyer IDIBAPS | Malpique R.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | Figueiredo H.,Institute dInvestigations Biomediques August Pi I Sunyer IDIBAPS | Figueiredo H.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas | And 20 more authors.
Diabetologia | Year: 2014

Aims/hypothesis: Comprehensive characterisation of the interrelation between the peripancreatic adipose tissue and the pancreatic islets promises novel insights into the mechanisms that regulate beta cell adaptation to obesity. Here, we sought to determine the main pathways and key molecules mediating the crosstalk between these two tissues during adaptation to obesity by the way of an integrated inter-tissue, multi-platform analysis. Methods: Wistar rats were fed a standard or cafeteria diet for 30 days. Transcriptomic variations by diet in islets and peripancreatic adipose tissue were examined through microarray analysis. The secretome from peripancreatic adipose tissue was subjected to a non-targeted metabolomic and proteomic analysis. Gene expression variations in islets were integrated with changes in peripancreatic adipose tissue gene expression and protein and metabolite secretion using an integrated inter-tissue pathway and network analysis. Results: The highest level of data integration, linking genes differentially expressed in both tissues with secretome variations, allowed the identification of significantly enriched canonical pathways, such as the activation of liver/retinoid X receptors, triacylglycerol degradation, and regulation of inflammatory and immune responses, and underscored interaction network hubs, such as cholesterol and the fatty acid binding protein 4, which were unpredicted through single-tissue analysis and have not been previously implicated in the peripancreatic adipose tissue crosstalk with beta cells. Conclusions/interpretation: The integrated analysis reported here allowed the identification of novel mechanisms and key molecules involved in peripancreatic adipose tissue interrelation with beta cells during the development of obesity; this might help the development of novel strategies to prevent type 2 diabetes. © 2014 Springer-Verlag Berlin Heidelberg. Source


Palau N.,Institute dInvestigations Biomediques August Pi I Sunyer IDIBAPS | Rebuffat S.A.,Institute dInvestigations Biomediques August Pi I Sunyer IDIBAPS | Rebuffat S.A.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asociadas Ciberdem | Altirriba J.,Institute dInvestigations Biomediques August Pi I Sunyer IDIBAPS | And 7 more authors.
Endocrinology | Year: 2012

In obesity an increase in β-cell mass occurs to cope with the rise in insulin demand. This β-cell plasticity is essential to avoid the onset of hyperglycemia, although the molecular mechanisms that regulate this process remain unclear. This study analyzed the role of adipose tissue in the control of β-cell replication. Using a diet-induced model of obesity, we obtained conditioned media from three different white adipose tissue depots. Only in the adipose tissue depot surrounding the pancreas did the diet induce changes that led to an increase in INS1E cells and the islet replication rate. To identify the factors responsible for this proliferative effect, adipose tissue gene expression analysis was conducted by microarrays and quantitative RT-PCR. Of all the differentially expressed proteins, only the secreted ones were studied. IGF binding protein 3 (Igfbp3) was identified as the candidate for this effect. Furthermore, in the conditioned media, although the blockage of IGFBP3 led to an increase in the proliferation rate, the blockage of IGF-I receptor decreased it. Taken together, these data show that obesity induces specific changes in the expression profile of the adipose tissue depot surrounding the pancreas, leading to a decrease in IGFBP3 secretion. This decrease acts in a paracrine manner, stimulating the β-cell proliferation rate, probably through an IGF-I-dependent mechanism. This cross talk between the visceral-pancreatic adipose tissue and β-cells is a novel mechanism that participates in the control of β-cell plasticity. Copyright © 2012 by The Endocrine Society. Source

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