owens-placentalrestriction-2012.pdf (416.81 kB)
Placental restriction reduces insulin sensitivity and expression of insulin signaling and glucose transporter genes in skeletal muscle, but not liver, in young sheep
journal contribution
posted on 2012-05-01, 00:00 authored by Miles J De Blasio, Kathryn L Gatford, M Lyn Harland, Jeffrey S Robinson, Julie OwensJulie OwensPoor growth before birth is associated with impaired insulin sensitivity later in life, increasing the risk of type 2 diabetes. The tissue sites at which insulin resistance first develops after intrauterine growth restriction (IUGR), and its molecular basis, are unclear. We have therefore characterized the effects of placental restriction (PR), a major cause of IUGR, on whole-body insulin sensitivity and expression of molecular determinants of insulin signaling and glucose uptake in skeletal muscle and liver of young lambs. Whole-body insulin sensitivity was measured at 30 d by hyperinsulinaemic euglycaemic clamp and expression of insulin signaling genes (receptors, pathways, and targets) at 43 d in muscle and liver of control (n = 15) and PR (n = 13) lambs. PR reduced size at birth and increased postnatal growth, fasting plasma glucose (+15%, P = 0.004), and insulin (+115%, P = 0.009). PR reduced whole-body insulin sensitivity (-43%, P < 0.001) and skeletal muscle expression of INSR (-36%), IRS1 (-28%), AKT2 (-44%), GLUT4 (-88%), GSK3α (-35%), and GYS1 (-31%) overall (each P < 0.05) and decreased AMPKγ3 expression in females (P = 0.030). PR did not alter hepatic expression of insulin signaling and related genes but increased GLUT2 expression (P = 0.047) in males. Whole-body insulin sensitivity correlated positively with skeletal muscle expression of IRS1, AKT2, HK, AMPKγ2, and AMPKγ3 in PR lambs only (each P < 0.05) but not with hepatic gene expression in control or PR lambs. Onset of insulin resistance after PR and IUGR is accompanied by, and can be accounted for by, reduced expression of insulin signaling and metabolic genes in skeletal muscle but not liver.
History
Journal
EndocrinologyVolume
153Issue
5Pagination
2142 - 2151Publisher
Oxford University PressLocation
Oxford, Eng.Publisher DOI
eISSN
1945-7170Language
engPublication classification
C1.1 Refereed article in a scholarly journalCopyright notice
2012, The Endocrine SocietyUsage metrics
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AnimalsBlood GlucoseFemaleFetal Growth RetardationGlucose Transport Proteins, FacilitativeInsulinLiverMuscle, SkeletalPlacentaPlacental InsufficiencyPregnancySheepScience & TechnologyLife Sciences & BiomedicineEndocrinology & MetabolismLOW-BIRTH-WEIGHTINTRAUTERINE GROWTH RESTRICTIONDEPENDENT DIABETES-MELLITUSACTIVATED PROTEIN-KINASEFOR-GESTATIONAL-AGEGLYCOGEN-SYNTHESISMETABOLIC SYNDROMEACTIVITY CONTRIBUTEPOSTNATAL-GROWTHFEEDING-ACTIVITY
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