Publications by authors named "Jesús Argente"

221 Publications

Digital Health for Supporting Precision Medicine in Pediatric Endocrine Disorders: Opportunities for Improved Patient Care.

Front Pediatr 2021 29;9:715705. Epub 2021 Jul 29.

Department of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine & Dentistry, London, United Kingdom.

Digitalization of healthcare delivery is rapidly fostering development of precision medicine. Multiple digital technologies, known as telehealth or eHealth tools, are guiding individualized diagnosis and treatment for patients, and can contribute significantly to the objectives of precision medicine. From a basis of "one-size-fits-all" healthcare, precision medicine provides a paradigm shift to deliver a more nuanced and personalized approach. Genomic medicine utilizing new technologies can provide precision analysis of causative mutations, with personalized understanding of mechanisms and effective therapy. Education is fundamental to the telehealth process, with artificial intelligence (AI) enhancing learning for healthcare professionals and empowering patients to contribute to their care. The Gulf Cooperation Council (GCC) region is rapidly implementing telehealth strategies at all levels and a workshop was convened to discuss aspirations of precision medicine in the context of pediatric endocrinology, including diabetes and growth disorders, with this paper based on those discussions. GCC regional investment in AI, bioinformatics and genomic medicine, is rapidly providing healthcare benefits. However, embracing precision medicine is presenting some major new design, installation and skills challenges. Genomic medicine is enabling precision and personalization of diagnosis and therapy of endocrine conditions. Digital education and communication tools in the field of endocrinology include chatbots, interactive robots and augmented reality. Obesity and diabetes are a major challenge in the GCC region and eHealth tools are increasingly being used for management of care. With regard to growth failure, digital technologies for growth hormone (GH) administration are being shown to enhance adherence and response outcomes. While technical innovations become more affordable with increasing adoption, we should be aware of sustainability, design and implementation costs, training of HCPs and prediction of overall healthcare benefits, which are essential for precision medicine to develop and for its objectives to be achieved.
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http://dx.doi.org/10.3389/fped.2021.715705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358399PMC
July 2021

Adult height and long-term outcomes after rhIGF-1 therapy in two patients with PAPP-A2 deficiency.

Growth Horm IGF Res 2021 Jul 25;60-61:101419. Epub 2021 Jul 25.

Hospital Infantil Universitario Niño Jesús, Departments of Pediatrics & Pediatric Endocrinology, Research Institute "La Princesa", Madrid, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain; Universidad Autónoma de Madrid, Department of Pediatrics, Madrid, Spain; IMDEA, Food Institute, CEIUAM+CSI, Cantoblanco, Madrid, Spain. Electronic address:

PAPP-A2 deficiency is a novel syndrome characterized by short stature due to low IGF bioactivity, skeletal abnormalities and decreased bone mineral density (BMD). Treatment with recombinant human IGF-1 (rhIGF-1) for 1 year demonstrated to increase growth velocity and BMD, without reported adverse effects, but data regarding the long-term efficacy and safety of rhIGF-1 administration in this entity has not yet been reported. Two Spanish siblings with short stature due to a homozygous loss-of-function mutation in the PAPP-A2 gene (p.D643fs25*) were treated with rhIGF-1 twice daily for six years. Growth velocity continued to increase and both patients achieved their target height. Free IGF-1 concentrations increased notably after rhIGF-1 administration, with serum IGFBP-3, IGFBP-5 and ALS levels also being higher during treatment. BMD was progressively normalized and an increase in lean mass was also noted during treatment. No episodes of hypoglycemia or any other adverse effects were documented. An increase in the growth of kidney and spleen length was observed in one of the patients.
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http://dx.doi.org/10.1016/j.ghir.2021.101419DOI Listing
July 2021

Milestones of Precision Medicine: An Innovative, Multidisciplinary Overview.

Mol Diagn Ther 2021 09 30;25(5):563-576. Epub 2021 Jul 30.

Department of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-UAM, Madrid, Spain.

Although the concept of precision medicine, in which healthcare is tailored to the molecular and clinical characteristics of each individual, is not new, its implementation in clinical practice has been heterogenous. In some medical specialties, precision medicine has gone from being just a promise to a reality that achieves better patient outcomes. This is a fact if we consider, for example, the great advances made in the genetic diagnosis and subsequent treatment of countless hereditary diseases, such as cystic fibrosis, which have improved the life expectancy of many of the affected children. In the field of oncology, the development of targeted therapies has prolonged the survival of patients with breast, lung, colorectal, melanoma, and hematological malignancies. In other disciplines, clinical milestones are perhaps less well known, but no less important. The current challenge is to expand and generalize the use of technologies that are central to precision medicine, such as massively parallel sequencing, to improve the management (prevention and treatment) of complex conditions such as cardiovascular, kidney, or autoimmune diseases. This process requires investment in specialized expertise, multidisciplinary collaboration, and the nationwide organization of genetic laboratories for diagnosis of specific diseases.
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http://dx.doi.org/10.1007/s40291-021-00544-4DOI Listing
September 2021

Short stature with low insulin-like growth factor 1 availability due to pregnancy-associated plasma protein A2 deficiency in a Saudi family.

Clin Genet 2021 Jul 17. Epub 2021 Jul 17.

Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.

In 2016 a new syndrome with postnatal short stature and low IGF1 bioavailability caused by biallelic loss-of-function mutations in the gene encoding the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) was described in two families. Here we report two siblings of a third family from Saudi Arabia with postnatal growth retardation and decreased IGF1 availability due to a new homozygous nonsense mutation (p.Glu886* in exon 7) in PAPPA2. The two affected males showed progressively severe short stature starting around 8 years of age, moderate microcephaly, decreased bone mineral density, and high circulating levels of total IGF1, IGFBP3, and the IGF acid-labile subunit (IGFALS), with decreased free IGF1 concentrations. Interestingly, circulating IGF2 and IGFBP5 were not increased. An increase in growth velocity and height was seen in the prepuberal patient in response to rhIGF1. These patients contribute to the confirmation of the clinical picture associated with PAPP-A2 deficiency and that the PAPPA2 gene should be studied in all patients with short stature with this characteristic phenotype. Hence, pediatric endocrinologists should measure circulating PAPP-A2 levels in the study of short stature as very low or undetectable levels of this protein can help to focus the diagnosis and treatment.
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http://dx.doi.org/10.1111/cge.14030DOI Listing
July 2021

Effects of Maternal Resveratrol Intake on the Metabolic Health of the Offspring.

Int J Mol Sci 2021 Apr 30;22(9). Epub 2021 Apr 30.

Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, 28009 Madrid, Spain.

Maternal nutritional imbalances, in addition to maternal overweight and obesity, can result in long-term effects on the metabolic health of the offspring, increasing the risk of common non-communicable disorders such as obesity, diabetes and cardiovascular disease. This increased disease risk may also be transmitted across generations. Unfortunately, lifestyle interventions have shown reduced compliancy and limited efficacy. Resveratrol is a natural polyphenolic compound reported to have pleiotropic beneficial actions including a possible protective effect against the metabolic programming induced by poor dietary habits during development. However, studies to date are inconclusive regarding the potential metabolic benefits of maternal resveratrol supplementation during pregnancy and lactation on the offspring. Moreover, the responses to metabolic challenges are suggested to be different in males and females, suggesting that the effectiveness of treatment strategies may also differ, but many studies have been performed only in males. Here we review the current evidence, both in humans and animal models, regarding the possible beneficial effects of maternal resveratrol intake on the metabolic health of the offspring and highlight the different effects of resveratrol depending on the maternal diet, as well as the differential responses of males and females.
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http://dx.doi.org/10.3390/ijms22094792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124273PMC
April 2021

Recombinant IGF-1 Induces Sex-Specific Changes in Bone Composition and Remodeling in Adult Mice with Deficiency.

Int J Mol Sci 2021 Apr 14;22(8). Epub 2021 Apr 14.

Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29071 Málaga, Spain.

Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. mice (both sexes) had reduced body and bone length. Male mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in , (resorption) and (formation) characterized the bone of females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in mice (both sexes). rmIGF-1 treatment in females also increased collagen maturity, and , , and expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair.
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http://dx.doi.org/10.3390/ijms22084048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070906PMC
April 2021

Precocious sexual maturation: Unravelling the mechanisms of pubertal onset through clinical observations.

J Neuroendocrinol 2021 Apr 26:e12979. Epub 2021 Apr 26.

Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain.

Puberty is a crucial biological process normally occurring at a specific time during the lifespan, during which sexual and somatic maturation are completed, and reproductive capacity is reached. Pubertal timing is not only determined by genetics, but also by endogenous and environmental cues, including nutritional and metabolic signals. During the last decade, we have learned much regarding the essential roles of kisspeptins and the neuropeptide pathways that converge on these neurones to modulate kisspeptin signalling, as well as neurokinin B and dynorphin, the co-transmitters of Kiss1 neurones in the arcuate nucleus, and the effects of melanocortins on puberty. Indeed, melanocortins are involved in transmitting the regulatory actions of metabolic cues on pubertal maturation. Intracellular metabolic sensors, such as the AMP-activated protein kinase and the fuel-sensing deacetylase SIRT1, have been shown to contribute to puberty. Further understanding of these signals and regulatory circuits will help uncover the intimacies of the central control of puberty, as well as how alterations in metabolic status, ranging from undernutrition to obesity, affect the pubertal process. Precocious puberty is rare and has a clear female predominance. Central precocious puberty (CPP) is diagnosed when premature activation of the hypothalamic-pituitary axis occurs. Its causes are heterogeneous, with alterations of the central nervous system being of special interest, and with environmental factors also playing a role in some cases. During the last decade, several mutations in different genes (including KISS1, KISS1R, MKRN3 and DLK1) that cause CPP have been discovered. Loss-of-function mutations in MKRN3 are the most common monogenic cause of CPP known to date. Here, we review and update what is known regarding the genotype-phenotype relationship in patients with CPP.
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http://dx.doi.org/10.1111/jne.12979DOI Listing
April 2021

Difference in Insulin Resistance Assessment between European Union and Non-European Union Obesity Treatment Centers (ESPE Obesity Working Group Insulin Resistance Project).

Horm Res Paediatr 2020 26;93(11-12):622-633. Epub 2021 Apr 26.

Division of Pediatrics, Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

Introduction: The obesity epidemic has become one of the most important public health issues of modern times. Impaired insulin sensitivity seems to be the cornerstone of multiple obesity related comorbidities. However, there is no accepted definition of impaired insulin sensitivity.

Objective: We hypothesize that assessment of insulin resistance differs between centers.

Methods: The ESPE Obesity Working Group (ESPE ObWG) Scientific Committee developed a questionnaire with a focus on the routine practices of assessment of hyperinsulinemia and insulin resistance, which was distributed through Google Docs platform to the clinicians and researchers from the current ESPE ObWG database (n = 73). Sixty-one complete responses (84% response rate) from clinicians and researchers were analyzed: 32 from European Union (EU) centers (representatives of 14 countries) and 29 from Non-EU centers (representatives from 10 countries). Standard statistics were used for the data analysis.

Results: The majority of respondents considered insulin resistance (IR) as a clinical tool (85.2%) rather than a research instrument. For the purpose of IR assessment EU specialists prefer analysis of the oral glucose tolerance test (OGTT) results, whereas non-EU ones mainly use Homeostatic Model Assessment of Insulin Resistance (HOMA-IR; p = 0.032). There was no exact cutoff for the HOMA-IR in either EU or non-EU centers. A variety of OGTT time points and substances measured per local protocol were reported. Clinicians normally analyzed blood glucose (88.52% of centers) and insulin (67.21%, mainly in EU centers, p = 0.0051). Furthermore, most participants (70.5%) considered OGTT insulin levels as a more sensitive parameter of IR than glucose. Meanwhile, approximately two-thirds (63.9%) of the centers did not use any cutoffs for the insulin response to the glucose load.

Conclusions: Since there is no standard for the IR evaluation and uniform accepted indication of performing, an OGTT the assessment of insulin sensitivity varies between EU and non-EU centers. A widely accepted standardized protocol is needed to allow comparison between centers.
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http://dx.doi.org/10.1159/000515730DOI Listing
April 2021

Bone Mineral Density, Body Composition, and Metabolic Health of Very Low Birth Weight Infants Fed in Hospital Following Current Macronutrient Recommendations during the First 3 Years of Life.

Nutrients 2021 Mar 20;13(3). Epub 2021 Mar 20.

Department of Neonatology, Hospital Universitario La Paz, Department of Pediatrics, Universidad Autonoma de Madrid, 28046 Madrid, Spain.

The present study longitudinally evaluated growth, bone mineral density, body composition, and metabolic health outcome in very low birth weight (VLBW) infants whose in-hospital target nutrient intake was within recent recommendations. From six months to three years, bone mineral density (dual-energy X-ray absorptiometry, DXA), body composition, and metabolic health outcome were compared with a reference group of term infants. The aim was to test whether in-hospital achieved weight gain until 36 weeks of gestation (light or appropriate for term equivalent age; LTEA or ATEA) predicts later growth, bone mineral density (BMD), abdominal obesity, or metabolic health outcomes such as insulin resistance, relative to term infants, during the first three years of life. Target in-hospital energy and protein intake was not achieved. Growth in weight, length and head circumference, mid arm circumference, adiposity, fat free mass (FFM), and bone mineralization in VLBW infants was less than those in term infants and influenced by nutritional status at discharge. Preterm infants had poorer motor and cognitive outcomes. Post-discharge body composition patterns indicate FFM proportional to height but lower fat mass index in LTEA preterm infants than term infants, with no evidence of increased truncal fat in preterm infants. The hypothesis of early BMD catch-up in VLBW infants after discharge was not supported by the present data. The clinical significance of these findings is unclear. The data may suggest a reduced obesity risk but an increased osteoporosis risk. Since postnatal growth restriction may have permanent negative health effects, LTEA VLBW infants would especially appear to benefit from targeted preventive interventions. Further follow-up of the infants is required.
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http://dx.doi.org/10.3390/nu13031005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003951PMC
March 2021

Cerebral Insulin Bolus Revokes the Changes in Hepatic Lipid Metabolism Induced by Chronic Central Leptin Infusion.

Cells 2021 03 6;10(3). Epub 2021 Mar 6.

Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, E-28009 Madrid, Spain.

Central actions of leptin and insulin on hepatic lipid metabolism can be opposing and the mechanism underlying this phenomenon remains unclear. Both hormones can modulate the central somatostatinergic system that has an inhibitory effect on growth hormone (GH) expression, which plays an important role in hepatic metabolism. Using a model of chronic central leptin infusion, we evaluated whether an increase in central leptin bioavailability modifies the serum lipid pattern through changes in hepatic lipid metabolism in male rats in response to an increase in central insulin and the possible involvement of the GH axis in these effects. We found a rise in serum GH in leptin plus insulin-treated rats, due to an increase in pituitary GH mRNA levels associated with lower hypothalamic somatostatin and pituitary somatostatin receptor-2 mRNA levels. An augment in hepatic lipolysis and a reduction in serum levels of non-esterified fatty acids (NEFA) and triglycerides were found in leptin-treated rats. These rats experienced a rise in lipogenic-related factors and normalization of serum levels of NEFA and triglycerides after insulin treatment. These results suggest that an increase in insulin in leptin-treated rats can act on the hepatic lipid metabolism through activation of the GH axis.
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http://dx.doi.org/10.3390/cells10030581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8000796PMC
March 2021

Leptin Modulates the Response of Brown Adipose Tissue to Negative Energy Balance: Implication of the GH/IGF-I Axis.

Int J Mol Sci 2021 Mar 11;22(6). Epub 2021 Mar 11.

Department of Endocrinology, Instituto de Investigación La Princesa, Hospital Infantil Universitario Niño Jesús, E-28009 Madrid, Spain.

The growth hormone (GH)/insulin-like growth factor I (IGF-I) axis is involved in metabolic control. Malnutrition reduces IGF-I and modifies the thermogenic capacity of brown adipose tissue (BAT). Leptin has effects on the GH/IGF-I axis and the function of BAT, but its interaction with IGF-I and the mechanisms involved in the regulation of thermogenesis remains unknown. We studied the GH/IGF-I axis and activation of IGF-I-related signaling and metabolism related to BAT thermogenesis in chronic central leptin infused (L), pair-fed (PF), and control rats. Hypothalamic somatostatin mRNA levels were increased in PF and decreased in L, while pituitary GH mRNA was reduced in PF. Serum GH and IGF-I concentrations were decreased only in PF. In BAT, the association between suppressor of cytokine signaling 3 and the IGF-I receptor was reduced, and phosphorylation of the IGF-I receptor increased in the L group. Phosphorylation of Akt and cyclic AMP response element binding protein and glucose transporter 4 mRNA levels were increased in L and mRNA levels of uncoupling protein-1 (UCP-1) and enzymes involved in lipid anabolism reduced in PF. These results suggest that modifications in UCP-1 in BAT and changes in the GH/IGF-I axis induced by negative energy balance are dependent upon leptin levels.
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http://dx.doi.org/10.3390/ijms22062827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001882PMC
March 2021

Primary Dwarfism, Microcephaly, and Chorioretinopathy due to a PLK4 Mutation in Two Siblings.

Horm Res Paediatr 2020 23;93(9-10):567-572. Epub 2021 Mar 23.

Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Research Institute "La Princesa,", Madrid, Spain,

Introduction: Primary autosomal recessive microcephalies (MCPHs) are characterized by primary dwarfism with MCPH and may present delayed psychomotor development and visual impairment. Biallelic loss of function variants in the PLK4 gene, which encodes the polo-like kinase 4 protein involved in centriole biogenesis, has been recently identified in several patients with MCPH and various ethnic backgrounds.

Case Presentation: Here, we describe 2 siblings of different sex from Equatorial Guinea harboring a homozygous frameshift mutation in PLK4 (c.1299_1303del, p.Phe433Leufs*6). A Seckel syndrome spectrum phenotype was present in both siblings, with short stature, severe MCPH, reduced brain volume, and distinctive facial features. They also presented severe intellectual disability, lissencephaly/pachygyria, subependymal heterotopia, and ophthalmological impairment. One of them suffered from deafness, and scoliosis was observed in the other.

Discussion/conclusion: Biallelic variants in PLK4 lead to a syndrome where severe short stature, MCPH, and cognitive impairment are constant features. However, ocular, skeletal, and other neurological manifestations can vary upon the same genetic basis.
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http://dx.doi.org/10.1159/000514280DOI Listing
March 2021

Amyloid-β differentially stimulates proliferation, activation of oxidative stress and inflammatory responses in male and female hippocampal astrocyte cultures.

Mech Ageing Dev 2021 04 17;195:111462. Epub 2021 Feb 17.

Department of Paediatrics, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo, 4, Madrid, 28029, Spain; Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Av. Menéndez Pelayo, 65, Madrid, 28009, Spain; Instituto de Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5 Pabellón 11, Planta 0, Madrid, 28029, Spain. Electronic address:

Alzheimer's disease (AD) is the most common form of dementia and has a higher incidence in women. The main component of the senile plaques characteristic of AD is amyloid-beta (Aβ), with surrounding astrocytes contributing to the degenerative process. We hypothesized that the sex difference in the incidence of AD could be partially due to differential astrocytic responses to Aβ. Thus, the effect of Aβ on cell viability, the inflammatory response, and oxidative status was studied in cultures of hippocampal astrocytes from male and female rats. Aβ increased astrocyte viability in both female and male cultures by activating proliferation and survival pathways. Pro-inflammatory and anti-inflammatory responses were induced in astrocytes from both sexes. Aβ did not affect endoplasmic reticulum stress although it induced oxidative stress in male and female astrocytes. Interestingly, male astrocytes had an increase in cell number and significantly lower cell death in response to Aβ. Conversely, astrocytes from females displayed a greater inflammatory response after the Aβ challenge. These results suggest that the inflammatory and oxidative environment induced by Aβ in female astrocytes may contribute to enhance the vulnerability to AD and warrants further studies to unveil the mechanisms underlying sex differences in astrocytic responses.
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http://dx.doi.org/10.1016/j.mad.2021.111462DOI Listing
April 2021

Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations.

J Clin Endocrinol Metab 2021 03;106(4):1041-1050

Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.

Context: Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP).

Objective: To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects.

Methods: Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group.

Results: Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher follicle-stimulating hormone levels than ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement than patients with missense mutations (2.3 ± 1.6 vs 1.6 ± 1.4 years, P = .048), and had higher basal luteinizing hormone levels (2.2 ± 1.8 vs 1.1 ± 1.1 UI/L, P = .018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization.

Conclusion: Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.
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http://dx.doi.org/10.1210/clinem/dgaa955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993586PMC
March 2021

Effectiveness and equity of continuous subcutaneous insulin infusions in pediatric type 1 diabetes: A systematic review and meta-analysis of the literature.

Diabetes Res Clin Pract 2021 Feb 31;172:108643. Epub 2020 Dec 31.

Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid/IdiPAZ, Madrid, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain; IMDEA Food Institute, CEIUAM+CSI, Madrid, Spain. Electronic address:

Aims: We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) and non-randomized studies (NRS) to assess the effectiveness and equity of continuous subcutaneous insulin infusions (CSII) versus multiple-daily injections (MDI) on glycemic outcomes.

Methods: Searches were conducted between 2000 and 2019 in MEDLINE, CENTRAL, EMBASE and HTA. Included studies compared the CSII vs MDI in children and young people (CYP) ≤ 20 years with type 1 diabetes. Two independent reviewers screened the articles, extracted the data, assessed the risk of bias, evaluated the quality of evidence, and identified equity data. Results were pooled with a random-effects model.

Results: Of the 578 articles screened, 16 RCT (545 CYP on CSII) and 70 NRS (73253 on CSII) were included in the meta-analysis. There was moderate-level evidence that the CSII lower HbA in RCT (pooled mean difference [MD]: -0.22%; 95% confidence interval [CI]: -0.33, -0.11%; I:34%) and insufficient in NRS (pooled MD: -0.45%; 95%CI: -0.52, -0.38%; I:99%). The pooled incidence rate ratio of severe hypoglycemia on CSII vs MDI in RCT was 0.87 (95%CI: 0.55, 1.37; I:0%; low-level evidence), and 0.71 (95%CI: 0.63, 0.81; I:57%, insufficient evidence) in NRS. Health-related quality of life presented insufficient evidence. Equity data were scarcely reported.

Conclusions: CSII modestly lower HbA when compared with MDI. Current literature does not provide adequate data on other glycemic outcomes. Future assessment on diabetes technology should include individual and area-level socioeconomic data. The study protocol was pre-registered in PROSPERO (CRD42018116474).
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http://dx.doi.org/10.1016/j.diabres.2020.108643DOI Listing
February 2021

Impact of Long-Term HFD Intake on the Peripheral and Central IGF System in Male and Female Mice.

Metabolites 2020 Nov 13;10(11). Epub 2020 Nov 13.

Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, E-28009 Madrid, Spain.

The insulin-like growth factor (IGF) system is responsible for growth, but also affects metabolism and brain function throughout life. New IGF family members (i.e., pappalysins and stanniocalcins) control the availability/activity of IGFs and are implicated in growth. However, how diet and obesity modify this system has been poorly studied. We explored how intake of a high-fat diet (HFD) or commercial control diet (CCD) affects the IGF system in the circulation, visceral adipose tissue (VAT) and hypothalamus. Male and female C57/BL6J mice received HFD (60% fat, 5.1 kcal/g), CCD (10% fat, 3.7 kcal/g) or chow (3.1 % fat, 3.4 kcal/g) for 8 weeks. After 7 weeks of HFD intake, males had decreased glucose tolerance ( 0.01) and at sacrifice increased plasma insulin ( 0.05) and leptin ( 0.01). Circulating free IGF1 ( 0.001), total IGF1 ( 0.001), IGF2 ( 0.05) and IGFBP3 ( 0.01) were higher after HFD in both sexes, with CCD increasing IGFBP2 in males ( 0.001). In VAT, HFD reduced mRNA levels of IGF2 ( 0.05), PAPP-A ( 0.001) and stanniocalcin (STC)-1 ( 0.001) in males. HFD increased hypothalamic IGF1 ( 0.01), IGF2 ( 0.05) and IGFBP5 ( 0.01) mRNA levels, with these changes more apparent in females. Our results show that diet-induced changes in the IGF system are tissue-, sex- and diet-dependent.
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http://dx.doi.org/10.3390/metabo10110462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698111PMC
November 2020

Congenital hypopituitarism in two brothers with a duplication of the 'acrogigantism gene' GPR101: clinical findings and review of the literature.

Pituitary 2021 Apr 13;24(2):229-241. Epub 2020 Nov 13.

Department of Internal Medicine, Section of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Purpose: Congenital hypopituitarism (CH) can cause significant morbidity or even mortality. In the majority of patients, the etiology of CH is unknown. Understanding the etiology of CH is important for anticipation of clinical problems and for genetic counselling. Our previous studies showed that only a small proportion of cases have mutations in the known 'CH genes'. In the current project, we present the results of SNP array based copy number variant analysis in a family with unexplained congenital hypopituitarism.

Methods: DNA samples of two affected brothers with idiopathic CH and their mother were simultaneously analyzed by SNP arrays for copy number variant analysis and Whole Exome Sequencing (WES) for mutation screening. DNA of the father was not available.

Results: We found a 6 Mb duplication including GPR101 and SOX3 on the X-chromosome (Xq26.2-q27.1) in the two siblings and their mother, leading to 2 copies of this region in the affected boys and 3 copies in the mother. Duplications of GPR101 are associated with X-linked acrogigantism (the phenotypic 'opposite' of the affected brothers), whereas alterations in SOX3 are associated with X-linked hypopituitarism.

Conclusion: In our patients with hypopituitarism we found a 6 Mb duplication which includes GPR101, a gene associated with X- linked gigantism, and SOX3, a gene involved in early pituitary organogenesis that is associated with variable degrees of hypopituitarism. Our findings show that in duplications containing both GPR101 and SOX3, the growth hormone deficiency phenotype is dominant. This suggests that, if GPR101 is duplicated, it might not be expressed phenotypically when early patterning of the embryonic pituitary is affected due to SOX3 duplication. These results, together with the review of the literature, shed a new light on the role of GPR101 and SOX3 in pituitary function.
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http://dx.doi.org/10.1007/s11102-020-01101-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7966638PMC
April 2021

The pubertal growth spurt is diminished in children with severe obesity.

Pediatr Res 2021 Jul 10;90(1):184-190. Epub 2020 Nov 10.

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: At the population level, there is a negative linear correlation between childhood body mass index (BMI) and pubertal height gain. However, in children with obesity, there are no studies showing whether the severity of obesity affects pubertal height gain. Moreover, how obesity in childhood affects pubertal timing is controversial, especially in boys. We aimed to investigate the impact of severe obesity in childhood on the pubertal growth spurt in both sexes.

Methods: The study group consisted of 68 patients (32 boys) with childhood onset obesity followed in a Spanish university hospital. The QEPS growth model was used to calculate pubertal growth function estimates for each individual. The highest individual prepubertal BMI SDS value was related to the age at onset of pubertal growth and pubertal height gain. Results were compared to analyses from individuals in a community-based setting (n = 1901) with different weight status.

Results: A higher peak BMI in childhood was associated with less specific pubertal height gain in children with moderate-to-extreme obesity. For boys, the higher the BMI, the earlier the onset of pubertal growth. For girls with obesity, this correlation was not linear.

Conclusions: Obesity in childhood impairs the pubertal growth spurt in a severity-related fashion.

Impact: The higher the BMI in childhood, the lower the pubertal height gain in children with moderate-to-extreme obesity. For boys with obesity, the higher the BMI, the earlier the onset of pubertal growth. The results contribute to the research field of how weight status in childhood is related to pubertal timing and pubertal growth. The results have implications for understanding how childhood obesity is related to further growth.
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http://dx.doi.org/10.1038/s41390-020-01234-3DOI Listing
July 2021

Ethnicity Strongly Influences Body Fat Distribution Determining Serum Adipokine Profile and Metabolic Derangement in Childhood Obesity.

Front Pediatr 2020 9;8:551103. Epub 2020 Oct 9.

Departments of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.

Body fat content and distribution in childhood is influenced by sex and puberty, but interethnic differences in the percentage and distribution of body fat also exist. The abdominal visceral/subcutaneous fat ratio has been the main feature of body fat distribution found to associate with the serum adipokine profile and metabolic derangement in adulthood obesity. This has also been assumed for childhood obesity despite the known singularities of this disease in the pediatric age in comparison to adults. We aimed to investigate the effect of ethnicity, together with sex and pubertal status, on body fat content and distribution, serum adipokine profile, metabolic impairment and liver steatosis in children and adolescents with obesity. One hundred and fifty children with obesity (50% Caucasians/50% Latinos; 50% males/50% females) were studied. Body fat content and distribution were studied by whole body DXA-scan and abdominal magnetic resonance, and their relationships with liver steatosis (as determined by ultrasonography), glycemia, insulinemia, lipid metabolism, uric acid, total and HMW-adiponectin, leptin, leptin-receptor, and sex steroid levels were explored. Latino patients had more severe truncal obesity (higher trunk/lower limb fat ratio, odds ratio 10.00; < 0.05) and higher prevalence of liver steatosis than Caucasians regardless of sex or pubertal status, but there were no difference in the visceral/subcutaneous abdominal fat ratio, except for pubertal females. A higher trunk/lower limb fat ratio, but not the visceral/subcutaneous abdominal fat ratio, was associated with adipokine profile impairment (higher free leptin index and lower adiponectin levels), insulin resistance and dyslipidemia, and was further enhanced when liver steatosis was present ( < 0.05). A higher abdominal visceral/subcutaneous fat ratio was observed in prepubertal children ( < 0.01), except for Latino females, whereas predominant subcutaneous fat deposition was observed in adolescents. Ethnicity is one of the main determinants of increased trunk body fat accumulation in Latino children with obesity, which is best estimated by the trunk/lower limb fat ratio and related to the development of metabolic derangement and liver steatosis.
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http://dx.doi.org/10.3389/fped.2020.551103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581788PMC
October 2020

Severity in pediatric type 1 diabetes mellitus debut during the COVID-19 pandemic.

J Pediatr Endocrinol Metab 2020 Dec 5;33(12):1601-1603. Epub 2020 Nov 5.

Endocrinology Department, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.

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http://dx.doi.org/10.1515/jpem-2020-0481DOI Listing
December 2020

Insulin Resistance in Obese Children: What Can Metabolomics and Adipokine Modelling Contribute?

Nutrients 2020 Oct 29;12(11). Epub 2020 Oct 29.

Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, 28009 Madrid, Spain.

The evolution of obesity and its resulting comorbidities differs depending upon the age of the subject. The dramatic rise in childhood obesity has resulted in specific needs in defining obesity-associated entities with this disease. Indeed, even the definition of obesity differs for pediatric patients from that employed in adults. Regardless of age, one of the earliest metabolic complications observed in obesity involves perturbations in glucose metabolism that can eventually lead to type 2 diabetes. In children, the incidence of type 2 diabetes is infrequent compared to that observed in adults, even with the same degree of obesity. In contrast, insulin resistance is reported to be frequently observed in children and adolescents with obesity. As this condition can be prerequisite to further metabolic complications, identification of biological markers as predictive risk factors would be of tremendous clinical utility. Analysis of obesity-induced modifications of the adipokine profile has been one classic approach in the identification of biomarkers. Recent studies emphasize the utility of metabolomics in the analysis of metabolic characteristics in children with obesity with or without insulin resistance. These studies have been performed with targeted or untargeted approaches, employing different methodologies. This review summarizes some of the advances in this field while emphasizing the importance of the different techniques employed.
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http://dx.doi.org/10.3390/nu12113310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692749PMC
October 2020

Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials.

Lancet Diabetes Endocrinol 2020 12 30;8(12):960-970. Epub 2020 Oct 30.

Institute for Experimental Pediatric Endocrinology, Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address:

Background: The melanocortin 4 receptor (MC4R), a component of the leptin-melanocortin pathway, plays a part in bodyweight regulation. Severe early-onset obesity can be caused by biallelic variants in genes that affect the MC4R pathway. We report the results from trials of the MC4R agonist setmelanotide in individuals with severe obesity due to either pro-opiomelanocortin (POMC) deficiency obesity or leptin receptor (LEPR) deficiency obesity.

Methods: These single-arm, open-label, multicentre, phase 3 trials were done in ten hospitals across Canada, the USA, Belgium, France, Germany, the Netherlands, and the UK. Participants aged 6 years or older with POMC or LEPR deficiency obesity received open-label setmelanotide for 12 weeks. Participants with at least 5 kg weight loss (or ≥5% if weighing <100 kg at baseline) entered an 8-week placebo-controlled withdrawal sequence (including 4 weeks each of blinded setmelanotide and placebo treatment) followed by 32 additional weeks of open-label treatment. The primary endpoint, which was assessed in participants who received at least one dose of study medication and had a baseline assessment (full analysis set), was the proportion of participants with at least 10% weight loss compared with baseline at approximately 1 year. A key secondary endpoint was mean percentage change in the most hunger score of the 11-point Likert-type scale at approximately 1 year on the therapeutic dose, which was assessed in a subset of participants aged 12 years or older in the full analysis set who demonstrated at least 5 kg weight loss (or ≥5% in paediatric participants if baseline bodyweight was <100 kg) over the 12-week open-label treatment phase and subsequently proceeded into the placebo-controlled withdrawal sequence, regardless of later disposition. These studies are registered with ClinicalTrials.gov, NCT02896192 and NCT03287960.

Findings: Between Feb 14, 2017, and Sept 7, 2018, ten participants were enrolled in the POMC trial and 11 participants were enrolled in the LEPR trial, and included in the full analysis and safety sets. Eight (80%) participants in the POMC trial and five (45%) participants in the LEPR trial achieved at least 10% weight loss at approximately 1 year. The mean percentage change in the most hunger score was -27·1% (n=7; 90% CI -40·6 to -15·0; p=0·0005) in the POMC trial and -43·7% (n=7; -54·8 to -29·1; p<0·0001) in the LEPR trial. The most common adverse events were injection site reaction and hyperpigmentation, which were reported in all ten participants in the POMC trial; nausea was reported in five participants and vomiting in three participants. In the LEPR trial, the most commonly reported treatment-related adverse events were injection site reaction in all 11 participants, skin disorders in five participants, and nausea in four participants. No serious treatment-related adverse events occurred in both trials.

Interpretation: Our results support setmelanotide for the treatment of obesity and hyperphagia caused by POMC or LEPR deficiency.

Funding: Rhythm Pharmaceuticals.
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http://dx.doi.org/10.1016/S2213-8587(20)30364-8DOI Listing
December 2020

Rasmussen's encephalitis and central precocious puberty. Neuroendocrinological characterization of three cases.

Seizure 2020 Dec 12;83:139-142. Epub 2020 Oct 12.

Department of Neuropediatrics, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; Member of the Clinical Group linked (GCV14/ER/6) to the Networked Biomedical Research Centre for Rare Diseases (CIBERER), Carlos III Health Institute, Madrid, Spain.

Purpose: Rasmussen's encephalitis (RE) is a chronic neurological disorder characterized by inflammation of the cerebral cortex, mainly unilateral, that leads to drug-resistant epilepsy and progressive neurological impairment. Central Precocious Puberty (CPP) is uncommon, albeit increased in frequency in patients with neurological conditions and the physiopathological bases of these associations remains unclear in most cases. Epilepsy has been proposed to play a role, as well as the accumulation of substances produced as a result of metabolism or tissue degeneration in some neurodegenerative diseases. However, CPP has not been previously described in patients with RE.

Methods: From a series of patients affected by RE followed-up at a referral center, an in-depth review of the characteristics of those who developed CCP was carried out.

Results: Three cases were identified, representing a relative frequency of 21.4 % for CPP. They were girls, of Caucasian ethnicity, without family history of CPP or any image-identified abnormalities in the hypothalamic area. In two cases CPP manifested immediately before the onset of the epilepsy (prior to the diagnosis of RE) and in the other, after epilepsy onset but coinciding with a worsening of the seizures. A GnRH test with pubertal response confirmed CPP in the three cases.

Conclusion: The high proportion of CPP in patients affected by RE suggested a plausible relationship between these two entities. Various factors involved, including neuroinflammation, are hypothesized in the present study. However, further studies are needed to elucidate the pathophysiological bases, which could provide insight in the understanding of both entities.
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http://dx.doi.org/10.1016/j.seizure.2020.10.008DOI Listing
December 2020

Adiponectin Signaling and Impaired GTPase Rab5 Expression in Adipocytes of Adolescents with Obesity.

Horm Res Paediatr 2020 19;93(5):287-296. Epub 2020 Oct 19.

Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics, University of Patras School of Medicine, Patras, Greece,

Introduction: Abnormalities in adipose tissue AdipoR1; adaptor protein, phosphotyrosine interaction, PH domain, and leucine zipper containing 1 (APPL1); GTPase Rab5; adiponectin; leptin; and visfatin in adults with obesity have been associated with metabolic disturbances.

Objective: The objective of this study was to examine whether pediatric obesity disrupts elements of the adiponectin signaling pathway and GTPase Rab5 in adipose tissue.

Methods: Primary adipocyte cultures of subcutaneous abdominal tissue were obtained from 96 lean and 66 children and adolescents with obesity (AO). AdipoR1, APPL1, and GTPase Rab5 mRNA levels were measured by RT-PCR and their protein content by Western immunoblotting. Serum total and high-molecular-weight adiponectin, leptin, leptin soluble receptor (sOB-R), and visfatin were measured by ELISA.

Results: The mRNA expression and protein content of AdipoR1 and APPL1 did not differ significantly with obesity, age, or puberty. However, GTPase Rab5 protein was increased in the adipocytes of younger prepubertal children with obesity but decreased in AO. Leptin was increased in AO compared to lean adolescents (AL) and in older prepubertal lean (OPL) children and AL compared to younger prepubertal lean and obese children. sOB-R was higher in OPL children and in the AL and AO. Serum visfatin was increased in the younger prepubertal children and AO.

Conclusions: In contrast to adults, obesity did not change the expression of AdipoR1 and APPL1 in cultured adipocytes from biopsies of subcutaneous abdominal adipose tissue of children and adolescents. Similar to adipose tissue studies in adults with obesity and metabolic dysfunction, the AO in our study showed reduced adipocyte GTPase Rab5 expression.
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http://dx.doi.org/10.1159/000510851DOI Listing
October 2020

Maternal hypercaloric diet affects factors involved in lipid metabolism and the endogenous cannabinoid systems in the hypothalamus of adult offspring: sex-specific response of astrocytes to palmitic acid and anandamide.

Nutr Neurosci 2020 Sep 21:1-14. Epub 2020 Sep 21.

Department of Endocrinology, Fundación Investigación Biomédica del Hospital Infantil Universitario Niño Jesús, Instituto de Investigación Biomédica la Princesa, Madrid, Spain.

We aimed to investigate whether maternal malnutrition during gestation/lactation induces long-lasting changes on inflammation, lipid metabolism and endocannabinoid signaling in the adult offspring hypothalamus and the role of hypothalamic astrocytes in these changes. We analyzed the effects of a free-choice hypercaloric palatable diet (P) during (pre)gestation, lactation and/or post-weaning on inflammation, lipid metabolism and endogenous cannabinoid signaling in the adult offspring hypothalamus. We also evaluated the response of primary hypothalamic astrocytes to palmitic acid and anandamide. Postnatal exposure to a P diet induced factors involved in hypothalamic inflammation ( and ) and gliosis ( and ) in adult offspring, being more significant in females. In contrast, maternal P diet reduced factors involved in astrogliosis (), fatty acid oxidation () and monounsaturated fatty acid synthesis (). These changes were accompanied by an increase in the expression of the genes for the cannabinoid receptor () and an enzyme involved in endocannabinoid synthesis, in females and a decrease in the endocannabinoid degradation enzyme in males. These changes suggest that the maternal P diet results in sex-specific alterations in hypothalamic endocannabinoid signaling and lipid metabolism. This hypothesis was tested in hypothalamic astrocyte cultures, where palmitic acid (PA) and the polyunsaturated fatty acid N-arachidonoylethanolamine (anandamide or AEA) were found to induce similar changes in the endocannabinoid system (ECS) and lipid metabolism. These results stress the importance of both maternal diet and sex in long term metabolic programming and suggest a possible role of hypothalamic astrocytes in this process.
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http://dx.doi.org/10.1080/1028415X.2020.1821519DOI Listing
September 2020

A combination of circulating chemokines as biomarkers of obesity-induced insulin resistance at puberty.

Pediatr Obes 2021 02 27;16(2):e12711. Epub 2020 Aug 27.

Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.

Background: In obesity adipose tissue undergoes structural re-modelling leading to a chronic low-grade inflammatory state linked to insulin resistance (IR).

Objective: We aimed to develop a clinically relevant biomarker model for stratifying IR in adolescents with obesity.

Methods: Cytokines [tumour cell derived factor 1α, monocyte chemoattract protein (MCP) 1, eotaxin and fractalkine], growth factors [brain-derived neurotrophic factor, pro-fibrotic platelet-derived growth factor (PDGF-BB) and insulin-like growth factor 1] and biochemical/metabolic factors were analysed in serum of 143 pubertal patients with obesity (50% IR; 50% non-IR) and 33 controls. Factor analysis, correlation, binary logistic regression and receiver operating characteristic analysis were used to evaluate combinations of these biomarkers as possible diagnostic tools for IR.

Results: Two biomarker IR models combining levels of triglycerides (TG)/HDL, eotaxin, MCP-1 and PDGF-BB in pubertal patients with obesity of both sexes were defined. Altered levels of MCP-1, eotaxin, and PDGF-BB constitute a main component that determines 27.7% of the variance explaining IR. Growth and inflammatory factors comprise two other components linked to the first, together accounting for 59.2% of the variance determining IR.

Conclusions: PDGF-BB, MCP-1, eotaxin, TG and cholesterol concentrations constitute a solid panel of biomarkers associated with IR in pubertal children with obesity that could be useful in their stratification in a clinical setting for stratification.
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http://dx.doi.org/10.1111/ijpo.12711DOI Listing
February 2021

Short-Term Diet Induced Changes in the Central and Circulating IGF Systems Are Sex Specific.

Front Endocrinol (Lausanne) 2020 11;11:513. Epub 2020 Aug 11.

Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain.

Insulin-like growth factor (IGF) 1 exerts a wide range of functions in mammalians participating not only in the control of growth and metabolism, but also in other actions such as neuroprotection. Nutritional status modifies the IGF system, although little is known regarding how diet affects the newest members of this system including pregnancy-associated plasma protein-A (PAPP-A) and PAPP-A2, proteases that liberate IGF from the IGF-binding proteins (IGFBPs), and stanniocalcins (STCs) that inhibit PAPP-A and PAPP-A2 activity. Here we explored if a 1-week dietary change to either a high-fat diet (HFD) or a low-fat diet (LFD) modifies the central and peripheral IGF systems in both male and female Wistar rats. The circulating IGF system showed sex differences in most of its members at baseline. Males had higher levels of both free ( < 0.001) and total IGF1 ( < 0.001), as well as IGFBP3 ( < 0.001), IGFBP5 ( < 0.001), and insulin ( < 0.01). In contrast, females had higher serum levels of PAPP-A2 ( < 0.05) and IGFBP2 ( < 0.001). The responses to a short-term dietary change were both diet and sex specific. Circulating levels of IGF2 increased in response to LFD intake in females ( < 0.001) and decreased in response to HFD intake in males ( < 0.001). In females, LFD intake also decreased circulating IGFBP2 levels ( < 0.001). In the hypothalamus LFD intake increased IGF2 ( < 0.01) and IGFBP2 mRNA ( < 0.001) levels, as well as the expression of NPY ( < 0.001) and AgRP ( < 0.01), but only in males. In conclusion, short-term LFD intake induced more changes in the peripheral and central IGF system than did short-term HFD intake. Moreover, these changes were sex-specific, with IGF2 and IGFBP2 being more highly affected than the other members of the IGF system. One of the main differences between the commercial LFD employed and the HFD or normal rodent chow is that the LFD has a significantly higher sucrose content, suggesting that this nutrient could be involved in the observed responses.
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http://dx.doi.org/10.3389/fendo.2020.00513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431666PMC
June 2021

Aldosterone deficiency with a hormone profile mimicking pseudohypoaldosteronism.

J Pediatr Endocrinol Metab 2020 Nov;33(11):1501-1505

Departments of Pediatrics & Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain.

Background Aldosterone deficiency (hypoaldosteronism) or aldosterone resistance (pseudohypoaldosteronism) both result in defective aldosterone activity. Case presentation A 42-day-old man presented with failure to thrive, hyponatremia, high urine sodium output, severe hyperkalemia and high plasma renin activity and aldosterone levels. NR3C2, SCNN1A, B and G sequencing showed no variants. Exclusive sodium supplementation resulted in clinical stabilization and growth normalization. His younger sibling had similar clinical and laboratory features, except for low-normal aldosterone. Both patients showed compound heterozygous mutations in CYP11B2 (c.C554T/2802pbE1-E2del). The younger patient needed transient fludrocortisone treatment and higher sodium supplementation, recuperating his weight and a normal growth velocity, although below his brother's and target height (c.10th vs. c.50th). Conclusions On a suggestive clinical picture, high aldosterone plasma levels in early infancy do not rule out aldosterone insufficiency and might mislead differential diagnosis with pseudohypoaldosteronism. Therapeutic requests and growth impairment in hypoaldosteronism vary even with a common genetic background.
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http://dx.doi.org/10.1515/jpem-2020-0239DOI Listing
November 2020
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