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dc.contributor.authorBerends, Lindsey M
dc.contributor.authorDearden, Laura
dc.contributor.authorTung, Yi Chun L
dc.contributor.authorVoshol, Peter
dc.contributor.authorFernandez-Twinn, Denise S
dc.contributor.authorOzanne, Susan E
dc.date.accessioned2018-11-23T00:32:24Z
dc.date.available2018-11-23T00:32:24Z
dc.date.issued2018-10
dc.identifier.issn0012-186X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285817
dc.description.abstractAIMS: Intra-uterine growth restriction (IUGR) followed by accelerated postnatal growth is associated with an increased risk of obesity and type 2 diabetes. We aimed to determine central and peripheral insulin sensitivity in mice that underwent IUGR followed by postnatal catch-up growth and investigate potential molecular mechanisms underpinning their physiology. METHODS: We used a C57BL/6J mouse model of maternal diet-induced IUGR (maternal diet, 8% protein) followed by cross-fostering to a normal nutrition dam (maternal diet, 20% protein) and litter size manipulation to cause accelerated postnatal catch-up growth. We performed intracerebroventricular insulin injection and hyperinsulinaemic-euglycaemic clamp studies to examine the effect of this early nutritional manipulation on central and peripheral insulin resistance. Furthermore, we performed quantitative real-time PCR and western blotting to examine the expression of key insulin-signalling components in discrete regions of the hypothalamus. RESULTS: IUGR followed by accelerated postnatal growth caused impaired glucose tolerance and peripheral insulin resistance. In addition, these 'recuperated' animals were resistant to the anorectic effects of central insulin administration. This central insulin resistance was associated with reduced protein levels of the p110β subunit of phosphoinositide 3-kinase (PI3K) and increased serine phosphorylation of IRS-1 in the arcuate nucleus (ARC) of the hypothalamus. Expression of the gene encoding protein tyrosine phosphatase 1B (PTP1B; Ptpn1) was also increased specifically in this region of the hypothalamus. CONCLUSIONS/INTERPRETATION: Mice that undergo IUGR followed by catch-up growth display peripheral and central insulin resistance in adulthood. Recuperated offspring show changes in expression/phosphorylation of components of the insulin signalling pathway in the ARC. These defects may contribute to the resistance to the anorectic effects of central insulin, as well as the impaired glucose homeostasis seen in these animals.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherSpringer Science and Business Media LLC
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAdipose Tissue
dc.subjectAnimals
dc.subjectMice, Inbred C57BL
dc.subjectAnimals, Newborn
dc.subjectMice
dc.subjectFetal Growth Retardation
dc.subjectDiabetes Mellitus, Type 2
dc.subjectGlucose Intolerance
dc.subjectInsulin Resistance
dc.subjectObesity
dc.subjectDisease Models, Animal
dc.subjectBody Weight
dc.subjectInsulin
dc.subjectGlucose Tolerance Test
dc.subjectGlucose Clamp Technique
dc.subjectSignal Transduction
dc.subjectBody Composition
dc.subjectTime Factors
dc.subjectAnimal Feed
dc.subjectFemale
dc.subjectMale
dc.titleProgramming of central and peripheral insulin resistance by low birthweight and postnatal catch-up growth in male mice.
dc.typeArticle
prism.endingPage2234
prism.issueIdentifier10
prism.publicationDate2018
prism.publicationNameDiabetologia
prism.startingPage2225
prism.volume61
dc.identifier.doi10.17863/CAM.33161
dcterms.dateAccepted2018-06-13
rioxxterms.versionofrecord10.1007/s00125-018-4694-z
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-10
dc.contributor.orcidDearden, Laura [0000-0002-0804-074X]
dc.identifier.eissn1432-0428
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (089939/Z/09/Z)
pubs.funder-project-idMedical Research Council (MC_UU_12012/4)
pubs.funder-project-idWellcome Trust (106026/Z/14/Z)
pubs.funder-project-idMedical Research Council (MC_UU_12012/5)
cam.issuedOnline2018-07-24


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International