The effect of an in utero high fat diet on the expression of transcription factors and glucose sensing in the developing rat pancreas

[摘要] ENGLISH ABSTRACT:A high fat diet (HFD) reduces beta-cell mass, impairs glucose signalling and isinvolved in the development of Type 2 diabetes. Malnutrition during gestation ishypothesized to irreversibly damage beta-cell development. The transcriptionfactors Pdx-1 and Pax 4 are involved in islet cell development. Pdx-1 is reportedto regulate expression of GLUT-2, glucokinase (GK) and the insulin gene.AimsThe aim of this study is to investigate, in the neonatal and weanling rat, the effectof exposure to a HFD in utero and/or lactation on weight, glucose and insulinconcentrations, islet cell development, pancreatic transcription factors andglucose sensing genes.MethodsNeonatal and weanling rats were exposed to a maternal HFD for defined periodsof gestation and/or lactation. After termination, pups were weighed and glucoseand insulin concentrations determined. mRNA expression of Pdx-1, Pax 4,GLUT-2 and GK was quantified by LightCycler PCR. Pancreatic sections wereimmunostained for insulin and glucagon (islet cell development), and for Pdx-1,GLUT-2 and GK (beta-cell function) followed by image analysis.Results:Exposure to an in utero HFD throughout gestation resulted in hyperglycaemicpups with reduced beta-cell volume and number, Pdx-1 and GKimmunoreactivity. In contrast the alpha-cell volume, number and size wereaugmented in neonates exposed to a HFD throughout gestation.Most weanlings were hyperglycaemic and hypoinsulinaemic. In some weanlings,reduced beta-cell number and beta- and alpha-cell size was observed. Pdx-1mRNA was overexpressed in weanlings exposed to a maternal HFD for the finalweek of gestation or throughout both gestation and lactation, but reduced inthose only exposed throughout lactation. Pax 4 mRNA was reduced in weanlingsexposed to a maternal HFD for the first or final week of gestation, throughoutgestation or throughout lactation. In most of the weanlings, GLUT-2 mRNAexpression was reduced whereas immunoreactivity for GLUT-2 was increased.Both GK mRNA expression and immunoreactivity were reduced in most of theweanlings.Conclusions• Exposure to an in utero HFD throughout gestation inducedhyperglycaemia in neonates. The reduced Pdx-1 expression appears toplay a role in the compromised beta-cell development, and concomitantwith the reduced GK levels, contributes to the hyperglycaemia in theseneonates and may make them susceptible to beta-cell failure.•In most weanlings exposed to a HFD in utero and/or during lactation thehyperglycaemia and hypoinsulinaemia suggest compromised beta-cellfunction. The GK mRNA expression and immunoreactivity were reducedthereby impairing glycolysis which would result in reduced insulinsecretion contributing to the hyperglycaemia. Furthermore, beta-celldevelopment is adversely affected by the HFD in some weanlings. Thiswould contribute to reduced beta-cell function and may eventually result inbeta-cell failure. GLUT-2 immunoreactivity was increased in some,suggesting a compensatory adaptative mechanism to restore glucosehomeostasis.• A maternal HFD has adverse effects both in neonates and weanlings onbeta-cell development, transcription factor and glucose sensing geneexpression and induced hyperglycaemia and hypoinsulinaemia in some ofthe offspring. Ways to ameliorate the HFD-induced attenuation of keybeta-cell genes to ensure normal beta-cell function are important for futureresearch in Type 2 diabetes.

[发布机构] Stellenbosch University