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      Circulating Irisin in Children and Adolescents With Prader-Willi Syndrome: Relation With Glucose Metabolism

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          Abstract

          Irisin is a myokine involved in the browning of white adipose tissue and regulation of energy expenditure, glucose homeostasis and insulin sensitivity. Debated evidence exists on the metabolic role played by irisin in children with overweight or obesity, while few information exist in children with Prader Willi Syndrome (PWS), a condition genetically prone to obesity. Here we assessed serum irisin in relation to the metabolic profile and body composition in children and adolescents with and without PWS. In 25 PWS subjects [age 6.6-17.8y; body mass index standard deviation score (BMI SDS) 2.5 ± 0.3] and 25 age, and BMI-matched controls (age 6.8-18.0y; BMI SDS, 2.8 ± 0.1) we assessed irisin levels and metabolic profile inclusive of oral glucose tolerance test (OGTT), and body composition by dual-energy X-ray absorptiometry (DXA). In PWS, we recorded lower levels of fat-free mass (FFM) (p <0.05), fasting (p<0.0001) and 2h post-OGTT insulin (p<0.05) and lower insulin resistance as expressed by homeostatic model of insulin resistance (HOMA-IR) (p<0.0001). Irisin levels were significantly lower in PWS group than in controls with common obesity (p<0.05). In univariate correlation analysis, positive associations linked irisin to insulin OGTT 0 (p<0.05), insulin OGTT 120 (p<0.005), HOMA-IR (p<0.05) and fasting C-peptide (p<0.05). In stepwise multivariable regression analysis, irisin levels were independently predicted by insulin OGTT 120. These results suggest a link between irisin levels and insulin sensitivity in two divergent models of obesity.

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          Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.

          The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees beta-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient beta-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and beta-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p less than 0.0001), the fasting insulin concentration (Rs = 0.81, p less than 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p less than 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient beta-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p less than 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p less than 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for beta-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
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            A PGC1α-dependent myokine that drives browning of white fat and thermogenesis

            Exercise benefits a variety of organ systems in mammals, and some of the best-recognized effects of exercise on muscle are mediated by the transcriptional coactivator PGC1α Here we show that PGC1α expression in muscle stimulates an increase in expression of Fndc5, a membrane protein that is cleaved and secreted as a new hormone, irisin. Irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 expression and a broad program of brown fat-like development. Irisin is induced with exercise in mice and humans, and mildly increased irisin levels in blood cause an increase in energy expenditure in mice with no changes in movement or food intake. This results in improvements in obesity and glucose homeostasis. Irisin could be a protein therapeutic for human metabolic disease and other disorders that are improved with exercise.
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              Establishing a standard definition for child overweight and obesity worldwide: international survey.

              To develop an internationally acceptable definition of child overweight and obesity, specifying the measurement, the reference population, and the age and sex specific cut off points. International survey of six large nationally representative cross sectional growth studies. Brazil, Great Britain, Hong Kong, the Netherlands, Singapore, and the United States. 97 876 males and 94 851 females from birth to 25 years of age. Body mass index (weight/height(2)). For each of the surveys, centile curves were drawn that at age 18 years passed through the widely used cut off points of 25 and 30 kg/m(2) for adult overweight and obesity. The resulting curves were averaged to provide age and sex specific cut off points from 2-18 years. The proposed cut off points, which are less arbitrary and more internationally based than current alternatives, should help to provide internationally comparable prevalence rates of overweight and obesity in children.
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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                14 June 2022
                2022
                : 13
                : 918467
                Affiliations
                [1] 1 Laboratory of Metabolic Research, Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Giuseppe Hospital, Piancavallo , Verbania, Italy
                [2] 2 Reference Center for Prader Willi Syndrome, Research Institute, Bambino Gesù Children’s Hospital , Rome, Italy
                [3] 3 Division of Endocrinology, Department of Translational Medicine, University of Piemonte Orientale , Novara, Italy
                [4] 4 Division of Auxology, Istituto Auxologico Italiano, IRCCS, San Giuseppe Hospital, Piancavallo , Verbania, Italy
                [5] 5 Department of Clinical Sciences and Community Health, University of Milan , Milan, Italy
                Author notes

                Edited by: Marwan El Ghoch, Beirut Arab University, Lebanon

                Reviewed by: Giuseppe Petito, University of Campania Luigi Vanvitelli, Italy; Andrea P. Rossi, Ca’ Foncello Hospital, Italy

                *Correspondence: Stefania Mai, s.mai@ 123456auxologico.it

                This article was submitted to Obesity, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2022.918467
                9238350
                54a2229e-4f97-4049-8998-31fff36c1fbd
                Copyright © 2022 Mai, Fintini, Mele, Convertino, Bocchini, Grugni, Aimaretti, Vietti, Scacchi, Crinò and Marzullo

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 12 April 2022
                : 09 May 2022
                Page count
                Figures: 1, Tables: 4, Equations: 0, References: 57, Pages: 8, Words: 4921
                Categories
                Endocrinology
                Original Research

                Endocrinology & Diabetes
                irisin,pws,obesity,glucose metabolism,children,adolescents
                Endocrinology & Diabetes
                irisin, pws, obesity, glucose metabolism, children, adolescents

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