{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T06:19:22Z","timestamp":1779344362071,"version":"3.51.4"},"reference-count":40,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T00:00:00Z","timestamp":1696550400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>No data are available on insulin clearance (ClI) trends during the pubertal transition. The aim of this study was to investigate in 973 youths with obesity whether ClI in fasting and post-oral glucose challenge (OGTT) conditions varies at the pubertal transition in relation to the severity of obesity and the presence of steatosis liver disease (SLD). The severity of obesity was graded according to the Centers for Disease Control. SLD was graded as absent, mild and severe based on alanine amino transferase levels. ClI was defined as the molar ratio of fasting C-peptide to insulin and of the areas under the insulin to glucose curves during an OGTT. In total, 35% of participants were prepubertal, 72.6% had obesity class II, and 52.6% had mild SLD. Fasting ClI (nmol\/pmol \u00d7 10\u22122) was significantly lower in pubertal [0.11 (0.08\u20130.14)] than in prepubertal individuals [0.12 (0.09\u20130.16)] and higher in class III [0.15 (0.11\u20130.16)] than in class I obesity [0.11 (0.09\u20130.14)]. OGTT ClI was higher in boys [0.08 (0.06\u20130.10)] than in girls [0.07 (0.06\u20130.09)]; in prepubertal [0.08 (0.06\u20130.11)] than in pubertal individuals [0.07 (0.05\u20130.09)]; in class III [0.14 (0.08\u20130.17)] than in class I obesity [0.07 (0.05\u20130.10)]; and in severe SLD [0.09 (0.04\u20130.14)] than in no steatosis [0.06 (0.04\u20130.17)]. It was lower in participants with prediabetes [0.06 (0.04\u20130.07)]. OGTT ClI was lower in youths with obesity at puberty along with insulin sensitivity and greater secretion. The findings suggest that the initial increase in ClI in youth with severe obesity and SLD is likely to compensate for hyperinsulinemia and its subsequent decrease at the onset of prediabetes and other metabolic abnormalities.<\/jats:p>","DOI":"10.3390\/ijms241914963","type":"journal-article","created":{"date-parts":[[2023,10,7]],"date-time":"2023-10-07T14:03:03Z","timestamp":1696687383000},"page":"14963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Insulin Clearance at the Pubertal Transition in Youth with Obesity and Steatosis Liver Disease"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2230-7148","authenticated-orcid":false,"given":"Roberto","family":"Franceschi","sequence":"first","affiliation":[{"name":"Pediatric Department, S. Chiara Hospital of Trento, APSS, 38121 Trento, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danilo","family":"Fintini","sequence":"additional","affiliation":[{"name":"Diabetes and Growth Disorders Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3238-7807","authenticated-orcid":false,"given":"Lucilla","family":"Rav\u00e0","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7358-2529","authenticated-orcid":false,"given":"Michela","family":"Mariani","sequence":"additional","affiliation":[{"name":"Diabetes and Growth Disorders Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9216-8609","authenticated-orcid":false,"given":"Alessia","family":"Aureli","sequence":"additional","affiliation":[{"name":"Diabetes and Growth Disorders Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Inzaghi","sequence":"additional","affiliation":[{"name":"Diabetes and Growth Disorders Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefania","family":"Pedicelli","sequence":"additional","affiliation":[{"name":"Diabetes and Growth Disorders Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Deodati","sequence":"additional","affiliation":[{"name":"Diabetes and Growth Disorders Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5616-9185","authenticated-orcid":false,"given":"Carla","family":"Bizzarri","sequence":"additional","affiliation":[{"name":"Diabetes and Growth Disorders Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Cappa","sequence":"additional","affiliation":[{"name":"Research Unit, Innovative Therapies for Endocrinopathies, Scientific Directorate, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2580-8781","authenticated-orcid":false,"given":"Stefano","family":"Cianfarani","sequence":"additional","affiliation":[{"name":"Diabetes and Growth Disorders Unit, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, 00168 Rome, Italy"},{"name":"Department of Systems Medicine, University of Rome \u2018Tor Vergata\u2019, 00168 Rome, Italy"},{"name":"Department of Women\u2019s and Children\u2019s Health, Karolinska Institutet, 17177 Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6581-975X","authenticated-orcid":false,"given":"Melania","family":"Manco","sequence":"additional","affiliation":[{"name":"Research Unit of Predictive and Preventive Medicine, Bambino Ges\u00f9 Children\u2019s Hospital, 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E517","DOI":"10.1152\/ajpendo.1983.244.6.E517","article-title":"Splanchnic and Renal Metabolism of Insulin in Human Subjects: A Dose-Response Study","volume":"244","author":"Ferrannini","year":"1983","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.2337\/db15-1373","article-title":"Hepatic and Extrahepatic Insulin Clearance Are Differentially Regulated: Results From a Novel Model-Based Analysis of Intravenous Glucose Tolerance Data","volume":"65","author":"Polidori","year":"2016","journal-title":"Diabetes"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.2337\/db19-0098","article-title":"Hypothesis: Role of Reduced Hepatic Insulin Clearance in the Pathogenesis of Type 2 Diabetes","volume":"68","author":"Bergman","year":"2019","journal-title":"Diabetes"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Tric\u00f2, D., Natali, A., Arslanian, S., Mari, A., and Ferrannini, E. (2018). Identification, Pathophysiology, and Clinical Implications of Primary Insulin Hypersecretion in Nondiabetic Adults and Adolescents. JCI Insight, 3.","DOI":"10.1172\/jci.insight.124912"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3014","DOI":"10.2337\/diabetes.51.10.3014","article-title":"Hyperinsulinemia in African-American Children","volume":"51","author":"Arslanian","year":"2002","journal-title":"Diabetes"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1172\/JCI113338","article-title":"Quantitative Study of Insulin Secretion and Clearance in Normal and Obese Subjects","volume":"81","author":"Polonsky","year":"1988","journal-title":"J. Clin. Invest."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s00125-005-0109-z","article-title":"Ethnic Differences in Beta Cell Adaptation to Insulin Resistance in Obese Children and Adolescents","volume":"49","author":"Weiss","year":"2006","journal-title":"Diabetologia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2218","DOI":"10.1210\/jcem.87.5.8498","article-title":"Contribution of Insulin Secretion and Clearance to Glucose-Induced Insulin Concentration in African-American and Caucasian Children","volume":"87","author":"Gower","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"741114","DOI":"10.3389\/fendo.2021.741114","article-title":"Insulin Resistance, Secretion and Clearance \u2013Taming the Three Effector Encounter of Type 2 Diabetes","volume":"12","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1111\/dom.14076","article-title":"Intrahepatic Fat, Irrespective of Ethnicity, Is Associated with Reduced Endogenous Insulin Clearance and Hepatic Insulin Resistance in Obese Youths: A Cross-sectional and Longitudinal Study from the Y Ale P Ediatric NAFLD Cohort","volume":"22","author":"Galderisi","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.2337\/db19-0120","article-title":"Lower Insulin Clearance Parallels a Reduced Insulin Sensitivity in Obese Youths and Is Associated With a Decline in \u03b2-Cell Function Over Time","volume":"68","author":"Galderisi","year":"2019","journal-title":"Diabetes"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(03)14364-4","article-title":"Prediabetes in Obese Youth: A Syndrome of Impaired Glucose Tolerance, Severe Insulin Resistance, and Altered Myocellular and Abdominal Fat Partitioning","volume":"362","author":"Weiss","year":"2003","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/S2352-4642(17)30044-5","article-title":"Prediabetes in Youths: Mechanisms and Biomarkers","volume":"1","author":"Weiss","year":"2017","journal-title":"Lancet Child Adolesc. Health"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"The RISE Consortium, Ehrmann, D.A., Temple, K.A., Rue, A., Barengolts, E., Mokhlesi, B., Van Cauter, E., Sam, S., Miller, M.A., and Kahn, S.E. (2018). Metabolic Contrasts Between Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: I. Observations Using the Hyperglycemic Clamp. Diabetes Care, 41, 1696\u20131706.","DOI":"10.1530\/ey.16.12.3"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1203\/01.pdr.0000246097.73031.27","article-title":"Longitudinal Study of Physiologic Insulin Resistance and Metabolic Changes of Puberty","volume":"60","author":"Hannon","year":"2006","journal-title":"Pediatr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.2337\/dc20-0750","article-title":"The Measurement of Insulin Clearance","volume":"43","author":"Piccinini","year":"2020","journal-title":"Diabetes Care."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"377","DOI":"10.2337\/db19-1152","article-title":"Adaptation of Insulin Clearance to Metabolic Demand Is a Key Determinant of Glucose Tolerance","volume":"70","author":"Gastaldelli","year":"2021","journal-title":"Diabetes"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Koh, H.E., Cao, C., and Mittendorfer, B. (2022). Insulin Clearance in Obesity and Type 2 Diabetes. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020596"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1146\/annurev-physiol-031622-043133","article-title":"Insulin Clearance in Health and Disease","volume":"85","author":"Najjar","year":"2023","journal-title":"Annu. Rev. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"RISE Consortium (2018). Metabolic Contrasts between Youth Adults with Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: II. Observations Using the Oral Glucose Tolerance Test. Diabetes Care, 41, 1707\u20131716.","DOI":"10.1530\/ey.16.12.3"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1146\/annurev-physiol-021115-105331","article-title":"Pathophysiology and Mechanisms of Nonalcoholic Fatty Liver Disease","volume":"78","author":"Haas","year":"2016","journal-title":"Annu. Rev. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1053\/j.gastro.2016.12.051","article-title":"Adolescent Obesity and Insulin Resistance: Roles of Ectopic Fat Accumulation and Adipose Inflammation","volume":"152","author":"Caprio","year":"2017","journal-title":"Gastroenterology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.2337\/dc10-0284","article-title":"Central Role of Fatty Liver in the Pathogenesis of Insulin Resistance in Obese Adolescents","volume":"33","author":"Cali","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Koutny, F., Weghuber, D., Bollow, E., Greber-Platzer, S., Hartmann, K., K\u00f6rner, A., Reinehr, T., Roebl, M., Simic-Schleicher, G., and Wabitsch, M. (2020). Prevalence of Prediabetes and Type 2 Diabetes in Children with Obesity and Increased Transaminases in European German-speaking Countries. Analysis of the APV Initiative. Pediatr. Obes., 15.","DOI":"10.1111\/ijpo.12601"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1007\/s00109-009-0540-6","article-title":"Polymorphisms within Insulin-Degrading Enzyme (IDE) Gene Determine Insulin Metabolism and Risk of Type 2 Diabetes","volume":"87","author":"Rudovich","year":"2009","journal-title":"J. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2178","DOI":"10.1002\/hep.26988","article-title":"Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis","volume":"59","author":"Bril","year":"2014","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1053\/j.gastro.2008.03.021","article-title":"Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes","volume":"135","author":"Kotronen","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"155607","DOI":"10.1016\/j.metabol.2023.155607","article-title":"Hepatic insulin receptor: New views on the mechanisms of liver disease","volume":"145","author":"Lee","year":"2023","journal-title":"Metabolism"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3779","DOI":"10.2337\/dc12-1203","article-title":"Hepatic Insulin Clearance Is Closely Related to Metabolic Syndrome Components","volume":"36","author":"Pivovarova","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bergman, R.N., Kabir, M., and Ader, M. (2022). The Physiology of Insulin Clearance. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031826"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1111\/dom.14695","article-title":"A low n-6 to n-3 polyunsaturated fatty acid ratio diet improves hyperinsulinaemia by restoring insulin clearance in obese youth","volume":"24","author":"Galderisi","year":"2022","journal-title":"Diabetes Obes. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1053\/j.gastro.2009.12.052","article-title":"SAFETY Study: Alanine Aminotransferase Cutoff Values Are Set Too High for Reliable Detection of Pediatric Chronic Liver Disease","volume":"138","author":"Schwimmer","year":"2010","journal-title":"Gastroenterology"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pedicelli, S., Fintini, D., Rav\u00e0, L., Inzaghi, E., Deodati, A., Spreghini, M.R., Bizzarri, C., Mariani, M., Cianfarani, S., and Cappa, M. (2022). Prevalence of Prediabetes in Children and Adolescents by Class of Obesity. Pediatr. Obes., 17.","DOI":"10.1111\/ijpo.12900"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rav\u00e0, L., Fintini, D., Mariani, M., Deodati, A., Inzaghi, E., Pedicelli, S., Bizzarri, C., Cappa, M., Cianfarani, S., and Manco, M. (2022). High 1-h glucose in youths with obesity as marker of prediabetes and cardiovascular risk. J. Endocrinol. Invest., 19, ahead of print.","DOI":"10.1007\/s40618-023-02111-6"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1136\/adc.51.3.170","article-title":"Clinical Longitudinal Standards for Height, Weight, Height Velocity, Weight Velocity, and Stages of Puberty","volume":"51","author":"Tanner","year":"1976","journal-title":"Arch. Dis. Child."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/BF00280883","article-title":"Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentration in man","volume":"28","author":"Matthews","year":"1985","journal-title":"Diabetologia"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.2337\/diacare.22.9.1462","article-title":"Insulin Sensitivity Indices Obtained from Oral Glucose Tolerance Testing: Comparison with the Euglycemic Insulin Clamp","volume":"22","author":"Matsuda","year":"1999","journal-title":"Diabetes Care"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"89","DOI":"10.2337\/dc06-1519","article-title":"Muscle and Liver Insulin Resistance Indexes Derived From the Oral Glucose Tolerance Test","volume":"30","author":"Matsuda","year":"2007","journal-title":"Diabetes Care"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1111\/j.1464-5491.1994.tb00273.x","article-title":"Understanding Oral Glucose Tolerance: Comparison of Glucose or Insulin Measurements During the Oral Glucose Tolerance Test with Specific Measurements of Insulin Resistance and Insulin Secretion","volume":"11","author":"Phillips","year":"1994","journal-title":"Diabet. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"537","DOI":"10.2337\/diacare.20.4.537","article-title":"Effects of Diet and Exercise in Preventing NIDDM in People With Impaired Glucose Tolerance: The Da Qing IGT and Diabetes Study","volume":"20","author":"Pan","year":"1997","journal-title":"Diabetes Care"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14963\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:02:08Z","timestamp":1760130128000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,6]]},"references-count":40,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms241914963"],"URL":"https:\/\/doi.org\/10.3390\/ijms241914963","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,10,6]]}}}