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1.
Biochim Biophys Acta ; 1842(9): 1783-93, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24984282

RESUMO

INTRODUCTION/OBJECTIVES: The role of the placenta in diabetic mothers on fetal development and programming is unknown. Prolactin (PRL) produced by decidual endometrial cells may have an impact. Although full-length PRL is angiogenic, the processed form by bone morphogenetic protein-1 (BMP-1) and/or cathepsin D (CTSD) is antiangiogenic. The objectives were to investigate the involvement of decidual PRL and its antiangiogenic fragments in placentas from type-1 diabetic women (T1D) and from pregnant diabetic rats with lower offspring weights than controls. METHODS: PRL, BMP-1, and CTSD gene expressions and PRL protein level were assessed in T1D placentas (n=8) at delivery and compared to controls (n=5). Wistar rats received, at day 7 of pregnancy, streptozotocin (STZ) (n=5) or nicotinamide (NCT) plus STZ (n=9) or vehicle (n=9). Placental whole-genome gene expression and PRL western blots were performed at birth. RESULTS: In human placentas, PRL (p<0.05) and BMP-1 (p<0.01) gene expressions were increased with a higher amount of cleaved PRL (p<0.05) in T1D than controls. In rats, diabetes was more pronounced in STZ than in NCT-STZ group with intra-uterine growth restriction. Decidual prolactin-related protein (Dprp) (p<0.01) and Bmp-1 (p<0.001) genes were up-regulated in both diabetic groups, with an increased cleaved PRL amount in the STZ (p<0.05) and NCT-STZ (p<0.05) groups compared to controls. No difference in CTSD gene expression was observed in rats or women. CONCLUSIONS: Alterations in the levels of the PRL family are associated with maternal diabetes in both rats and T1D women suggesting that placental changes in these hormones impact on fetal development.


Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Placenta/metabolismo , Prolactina/metabolismo , Adulto , Animais , Western Blotting , Proteína Morfogenética Óssea 1/genética , Proteína Morfogenética Óssea 1/metabolismo , Estudos de Casos e Controles , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Feminino , Desenvolvimento Fetal , Humanos , Técnicas Imunoenzimáticas , Pâncreas/metabolismo , Pâncreas/patologia , Placenta/patologia , Gravidez , Prolactina/genética , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
2.
Diabetologia ; 56(6): 1306-16, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23508304

RESUMO

AIMS/HYPOTHESIS: We previously identified the G6PC2 locus as a strong determinant of fasting plasma glucose (FPG) and showed that a common G6PC2 intronic single nucleotide polymorphism (SNP) (rs560887) and two common G6PC2 promoter SNPs (rs573225 and rs13431652) are highly associated with FPG. However, these promoter SNPs have complex effects on G6PC2 fusion gene expression, and our data suggested that only rs13431652 is a potentially causative SNP. Here we examine the effect of rs560887 on G6PC2 pre-mRNA splicing and the contribution of an additional common G6PC2 promoter SNP, rs2232316, to the association signal. METHODS: Minigene analyses were used to characterise the effect of rs560887 on G6PC2 pre-mRNA splicing. Fusion gene and gel retardation analyses characterised the effect of rs2232316 on G6PC2 promoter activity and transcription factor binding. The genetic association of rs2232316 with FPG variation was assessed using regression adjusted for age, sex and BMI in 4,220 Europeans with normal FPG. RESULTS: The rs560887-G allele was shown to enhance G6PC2 pre-mRNA splicing, whereas the rs2232316-A allele enhanced G6PC2 transcription by promoting Foxa2 binding. Genetic analyses provide evidence for association of the rs2232316-A allele with increased FPG (ß = 0.04 mmol/l; p = 4.3 × 10(-3)) as part of the same signal as rs560887, rs573225 and rs13431652. CONCLUSIONS/INTERPRETATION: As with rs13431652, the in situ functional data with rs560887 and rs2232316 are in accord with the putative function of G6PC2 in pancreatic islets, and suggest that all three are potentially causative SNPs that contribute to the association between G6PC2 and FPG.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus/genética , Glucose-6-Fosfatase/genética , Polimorfismo de Nucleotídeo Único , Alelos , Diabetes Mellitus/sangue , Jejum , Feminino , Regulação da Expressão Gênica , Genótipo , Células HeLa , Humanos , Masculino , Regiões Promotoras Genéticas , Splicing de RNA , RNA Mensageiro/metabolismo
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