{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T17:44:59Z","timestamp":1760204699195},"reference-count":44,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T00:00:00Z","timestamp":1630281600000},"content-version":"vor","delay-in-days":2697,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,5,1]]},"abstract":"<jats:p>Intrauterine growth restriction (IUGR) leads to development of type 2 diabetes (T2D) in adulthood. The mechanisms underlying this phenomenon have not been fully elucidated. Inflammation is associated with T2D; however, it is unknown whether inflammation is causal or secondary to the altered metabolic state. Here we show that the mechanism by which IUGR leads to the development of T2D in adulthood is via transient recruitment of T-helper 2 (Th) lymphocytes and macrophages in fetal islets resulting in localized inflammation. Although this immune response is short-lived, it results in a permanent reduction in islet vascularity and impaired insulin secretion. Neutralizing interleukin-4 antibody therapy given only in the newborn period ameliorates inflammation and restores vascularity and \u03b2-cell function into adulthood, demonstrating a novel role for Th2 immune responses in the induction and progression of T2D. In the neonatal stage, inflammation and vascular changes are reversible and may define an important developmental window for therapeutic intervention to prevent adult-onset diabetes.<\/jats:p>","DOI":"10.2337\/db13-1226","type":"journal-article","created":{"date-parts":[[2014,1,10]],"date-time":"2014-01-10T01:52:23Z","timestamp":1389318743000},"page":"1672-1684","update-policy":"http:\/\/dx.doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":25,"title":["Neutralizing Th2 Inflammation in Neonatal Islets Prevents \u03b2-Cell Failure in Adult IUGR Rats"],"prefix":"10.2337","volume":"63","author":[{"given":"Lane J.","family":"Jaeckle Santos","sequence":"first","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"},{"name":"The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changhong","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"},{"name":"The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paschalis-Thomas","family":"Doulias","sequence":"additional","affiliation":[{"name":"The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harry","family":"Ischiropoulos","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"},{"name":"The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G. Scott","family":"Worthen","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"},{"name":"The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca A.","family":"Simmons","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA"},{"name":"The Children\u2019s Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","published-online":{"date-parts":[[2014,4,12]]},"reference":[{"key":"2022031223163655600_B1","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.pcl.2009.03.004","article-title":"Developmental origins of adult disease","volume":"56","author":"Simmons","year":"2009","journal-title":"Pediatr Clin North Am"},{"key":"2022031223163655600_B2","doi-asserted-by":"crossref","first-page":"S60","DOI":"10.1016\/j.placenta.2009.12.015","article-title":"Review: placental programming of postnatal diabetes and impaired insulin action after IUGR","volume":"31","author":"Gatford","year":"2010","journal-title":"Placenta"},{"key":"2022031223163655600_B3","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.2337\/db05-1526","article-title":"Islet inflammation and fibrosis in a spontaneous model of type 2 diabetes, the GK rat","volume":"55","author":"Homo-Delarche","year":"2006","journal-title":"Diabetes"},{"key":"2022031223163655600_B4","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.bbrc.2003.12.180","article-title":"Chronological characterization of diabetes development in male Spontaneously Diabetic Torii rats","volume":"314","author":"Masuyama","year":"2004","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031223163655600_B5","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1007\/s00109-003-0450-y","article-title":"Inflammatory mediators and islet beta-cell failure: a link between type 1 and type 2 diabetes","volume":"81","author":"Donath","year":"2003","journal-title":"J Mol Med (Berl)"},{"key":"2022031223163655600_B6","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1007\/s00125-005-1764-9","article-title":"An immune origin of type 2 diabetes","volume":"48","author":"Kolb","year":"2005","journal-title":"Diabetologia"},{"key":"2022031223163655600_B7","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.lfs.2012.01.019","article-title":"Alteration in lymphocyte population and humoral immune response in type 2 diabetic Goto-Kakizaki rats","volume":"90","author":"Takeda","year":"2012","journal-title":"Life Sci"},{"key":"2022031223163655600_B8","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1042\/BJ20111708","article-title":"Role and function of macrophages in the metabolic syndrome","volume":"442","author":"Bhargava","year":"2012","journal-title":"Biochem J"},{"key":"2022031223163655600_B9","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/eji.200636910","article-title":"New vistas on macrophage differentiation and activation","volume":"37","author":"Mantovani","year":"2007","journal-title":"Eur J Immunol"},{"key":"2022031223163655600_B10","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nri1412","article-title":"Fibrotic disease and the T(H)1\/T(H)2 paradigm","volume":"4","author":"Wynn","year":"2004","journal-title":"Nat Rev Immunol"},{"key":"2022031223163655600_B11"},{"key":"2022031223163655600_B12","doi-asserted-by":"crossref","first-page":"551","DOI":"10.4049\/jimmunol.1103608","article-title":"Activation of invariant NKT cells in early phase of experimental autoimmune encephalomyelitis results in differentiation of Ly6Chi inflammatory monocyte to M2 macrophages and improved outcome","volume":"189","author":"Denney","year":"2012","journal-title":"J Immunol"},{"key":"2022031223163655600_B13","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.tem.2009.12.010","article-title":"Cytokine production by islets in health and diabetes: cellular origin, regulation and function","volume":"21","author":"Donath","year":"2010","journal-title":"Trends Endocrinol Metab"},{"key":"2022031223163655600_B14","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nri2925","article-title":"Type 2 diabetes as an inflammatory disease","volume":"11","author":"Donath","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"2022031223163655600_B15","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1056\/NEJMoa065213","article-title":"Interleukin-1-receptor antagonist in type 2 diabetes mellitus","volume":"356","author":"Larsen","year":"2007","journal-title":"N Engl J Med"},{"key":"2022031223163655600_B16","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.2337\/dc11-2219","article-title":"Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes","volume":"35","author":"Cavelti-Weder","year":"2012","journal-title":"Diabetes Care"},{"key":"2022031223163655600_B17","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.2337\/dc11-0357","article-title":"Effect of diacerein on insulin secretion and metabolic control in drug-naive patients with type 2 diabetes: a randomized clinical trial","volume":"34","author":"Ramos-Zavala","year":"2011","journal-title":"Diabetes Care"},{"key":"2022031223163655600_B18","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.2337\/diabetes.50.10.2279","article-title":"Intrauterine growth retardation leads to the development of type 2 diabetes in the rat","volume":"50","author":"Simmons","year":"2001","journal-title":"Diabetes"},{"key":"2022031223163655600_B19","doi-asserted-by":"crossref","first-page":"28785","DOI":"10.1074\/jbc.M505695200","article-title":"Progressive accumulation of mitochondrial DNA mutations and decline in mitochondrial function lead to beta-cell failure","volume":"280","author":"Simmons","year":"2005","journal-title":"J Biol Chem"},{"key":"2022031223163655600_B20","doi-asserted-by":"crossref","first-page":"734","DOI":"10.2337\/diabetes.52.3.734","article-title":"Neonatal exendin-4 prevents the development of diabetes in the intrauterine growth retarded rat","volume":"52","author":"Stoffers","year":"2003","journal-title":"Diabetes"},{"key":"2022031223163655600_B21","doi-asserted-by":"crossref","first-page":"5116","DOI":"10.1073\/pnas.091062498","article-title":"Significance analysis of microarrays applied to the ionizing radiation response","volume":"98","author":"Tusher","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022031223163655600_B22","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1203\/PDR.0b013e3181a282a5","article-title":"Exendin-4 normalizes islet vascularity in intrauterine growth restricted rats: potential role of VEGF","volume":"66","author":"Ham","year":"2009","journal-title":"Pediatr Res"},{"key":"2022031223163655600_B23","doi-asserted-by":"crossref","first-page":"R996","DOI":"10.1152\/ajpregu.00177.2011","article-title":"Reduction of TIP47 improves hepatic steatosis and glucose homeostasis in mice","volume":"302","author":"Carr","year":"2012","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2022031223163655600_B24","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/j.1600-065X.2008.00641.x","article-title":"The spectrum of complement alternative pathway-mediated diseases","volume":"223","author":"Holers","year":"2008","journal-title":"Immunol Rev"},{"key":"2022031223163655600_B25","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1164\/ajrccm.164.10.2010096","article-title":"Complement factors C3a and C5a are increased in bronchoalveolar lavage fluid after segmental allergen provocation in subjects with asthma","volume":"164","author":"Krug","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"2022031223163655600_B26","doi-asserted-by":"crossref","first-page":"8084","DOI":"10.1073\/pnas.0602357103","article-title":"Factor B of the alternative complement pathway regulates development of airway hyperresponsiveness and inflammation","volume":"103","author":"Taube","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022031223163655600_B27","first-page":"3328","article-title":"Leptin concentration in cord blood correlates with intrauterine growth","volume":"82","author":"Koistinen","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031223163655600_B28","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1080\/00313020600696256","article-title":"Insulin sensitivity and insulin secretion at birth in intrauterine growth retarded infants","volume":"38","author":"Setia","year":"2006","journal-title":"Pathology"},{"key":"2022031223163655600_B29","doi-asserted-by":"crossref","first-page":"26602","DOI":"10.1074\/jbc.M601284200","article-title":"Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance","volume":"281","author":"Kamei","year":"2006","journal-title":"J Biol Chem"},{"key":"2022031223163655600_B30","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.earlhumdev.2010.02.006","article-title":"Uteroplacental insufficiency increases visceral adiposity and visceral adipose PPARgamma2 expression in male rat offspring prior to the onset of obesity","volume":"86","author":"Joss-Moore","year":"2010","journal-title":"Early Hum Dev"},{"key":"2022031223163655600_B31","doi-asserted-by":"crossref","first-page":"2860","DOI":"10.1172\/JCI30910","article-title":"Disruption of leptin receptor expression in the pancreas directly affects beta cell growth and function in mice","volume":"117","author":"Morioka","year":"2007","journal-title":"J Clin Invest"},{"key":"2022031223163655600_B32"},{"key":"2022031223163655600_B33","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.bbrc.2009.04.121","article-title":"Leptin enhances CC-chemokine ligand expression in cultured murine macrophage","volume":"384","author":"Kiguchi","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031223163655600_B34","doi-asserted-by":"crossref","first-page":"21351","DOI":"10.1016\/S0021-9258(18)54642-1","article-title":"Interleukin-1 beta-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans. Role of nitric oxide in interleukin-1 beta-induced inhibition of insulin secretion","volume":"266","author":"Corbett","year":"1991","journal-title":"J Biol Chem"},{"key":"2022031223163655600_B35","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1210\/endo-129-6-3167","article-title":"Interleukin-1 beta-induced nitric oxide production in isolated rat pancreatic islets requires gene transcription and may lead to inhibition of the Krebs cycle enzyme aconitase","volume":"129","author":"Welsh","year":"1991","journal-title":"Endocrinology"},{"key":"2022031223163655600_B36","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1172\/JCI844","article-title":"IL-1 produced and released endogenously within human islets inhibits beta cell function","volume":"102","author":"Arnush","year":"1998","journal-title":"J Clin Invest"},{"key":"2022031223163655600_B37","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1111\/j.1365-2249.2006.03295.x","article-title":"Effect of interleukin-4 on vascular endothelial growth factor production in rheumatoid synovial fibroblasts","volume":"147","author":"Hong","year":"2007","journal-title":"Clin Exp Immunol"},{"key":"2022031223163655600_B38","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nri2922","article-title":"Immunometabolism: an emerging frontier","volume":"11","author":"Mathis","year":"2011","journal-title":"Nat Rev Immunol"},{"key":"2022031223163655600_B39","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/dmrr.568","article-title":"Inflammation and the etiology of type 2 diabetes","volume":"22","author":"Sj\u00f6holm","year":"2006","journal-title":"Diabetes Metab Res Rev"},{"key":"2022031223163655600_B40"},{"key":"2022031223163655600_B41","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/0167-5699(93)90235-D","article-title":"Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon","volume":"14","author":"Wegmann","year":"1993","journal-title":"Immunol Today"},{"key":"2022031223163655600_B42","doi-asserted-by":"crossref","first-page":"4730","DOI":"10.4049\/jimmunol.160.10.4730","article-title":"Transplacental priming of the human immune system to environmental allergens: universal skewing of initial T cell responses toward the Th2 cytokine profile","volume":"160","author":"Prescott","year":"1998","journal-title":"J Immunol"},{"key":"2022031223163655600_B43","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10654-012-9657-y","article-title":"Fetal and infant origins of asthma","volume":"27","author":"Duijts","year":"2012","journal-title":"Eur J Epidemiol"},{"key":"2022031223163655600_B44","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1097\/00001648-200003000-00018","article-title":"Low birth weight and preterm delivery as risk factors for asthma and atopic dermatitis in young adult males","volume":"11","author":"Steffensen","year":"2000","journal-title":"Epidemiology"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/63\/5\/1672\/578397\/1672.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/63\/5\/1672\/578397\/1672.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,9]],"date-time":"2023-07-09T18:21:15Z","timestamp":1688926875000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/63\/5\/1672\/34094\/Neutralizing-Th2-Inflammation-in-Neonatal-Islets"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,4,12]]},"references-count":44,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2014,4,12]]},"published-print":{"date-parts":[[2014,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db13-1226","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,4,12]]}}}