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1.
Clin Perinatol ; 46(2): 257-272, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31010559

RESUMO

Diabetes is a common complication of pregnancy associated with both short- and long-term adverse maternal and offspring effects. All types of diabetes in pregnancy are increasing in prevalence. Treatment of diabetes in pregnancy, targeting glycemic control, improves both maternal and offspring outcomes, albeit imperfectly for many women. Pharmacologic treatment recommendations differ between pregestational and gestational diabetes. Improved treatment of diabetes in pregnancy will need to consider maternal disease heterogeneity and comorbidities as well as long-term offspring outcomes. In this review, the authors summarize recent clinical studies to highlight established pharmacologic treatments for diabetes in pregnancy and provide suggestions for further research.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Gestacional/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Gravidez em Diabéticas/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/uso terapêutico , Metformina/uso terapêutico , Planejamento de Assistência ao Paciente , Gravidez , Gravidez em Diabéticas/metabolismo
2.
Diabetologia ; 62(2): 249-258, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30421138

RESUMO

AIMS/HYPOTHESIS: This study aimed to examine the association of maternal diabetes, being large for gestational age (LGA) and breast-feeding with being overweight or obese in pre-school-aged children. METHODS: Data on height and weight at the time of their pre-school (age 4-6 years) immunisation visit between January 2009 and August 2017, as well as breast-feeding status in the first 5 months of life, for 81,226 children born between January 2005 and August 2013 were linked with maternal hospitalisation and outpatient records and birth registry data. Children were grouped into six categories based on maternal diabetes status during pregnancy (no diabetes, gestational diabetes or pre-existing diabetes) and birthweight (appropriate for gestational age [AGA] or LGA). WHO criteria were used to identify children who were overweight or obese. RESULTS: There were 69,506 children in the no diabetes/AGA group (control), 5926 in the no diabetes/LGA group, 4563 in the gestational diabetes/AGA group, 573 in the gestational diabetes/LGA group, 480 in the pre-existing diabetes/AGA group and 178 in the pre-existing diabetes/LGA group. The rate of being overweight/obese at pre-school age ranged from 20.5% in the control group to 42.9% in the gestational diabetes/LGA group. The adjusted attributable risk per cent for LGA alone (39.4%) was significantly higher than that for maternal gestational diabetes (16.0%) or pre-existing diabetes alone (15.1%); the risk for the combinations of gestational diabetes/LGA and pre-existing diabetes/LGA were 50.1% and 39.1%, respectively. Further stratification of the pre-existing diabetes groups found the prevalence of being overweight/obese was 21.2% in the type 1/AGA group, 31.4% in the type 1/LGA group (similar to those in the no diabetes groups), 26.7% in the type 2/AGA group and 42.5% in the type 2/LGA group. Breast-feeding was associated with a lower likelihood of being overweight/obese in childhood in all groups except gestational diabetes/LGA and pre-existing diabetes/LGA (both type 1 and type 2). CONCLUSION/INTERPRETATION: LGA is a stronger marker for risk of being overweight/obese in early childhood, compared with maternal diabetes during pregnancy. Rates of being overweight/obese in childhood were highest in LGA children born to mothers with gestational diabetes or pre-existing type 2 diabetes. Breast-feeding was associated with a lower risk of being overweight/obese in childhood in the majority of children; however, this association was not maintained in LGA children of mothers with diabetes.


Assuntos
Aleitamento Materno , Diabetes Mellitus Tipo 2/complicações , Diabetes Gestacional/metabolismo , Macrossomia Fetal/etiologia , Sobrepeso/etiologia , Obesidade Pediátrica/etiologia , Índice de Massa Corporal , Criança , Pré-Escolar , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Recém-Nascido , Masculino , Sobrepeso/metabolismo , Obesidade Pediátrica/metabolismo , Gravidez , Gravidez em Diabéticas/metabolismo , Fatores de Risco
3.
Acta Diabetol ; 56(1): 73-85, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30167870

RESUMO

AIMS: Maternal type 2 diabetes (T2D) can result in adverse pathological outcomes to both the mother and fetus. The present study aimed to investigate the pathological effects of maternal T2D on the gene expression patterns and functions of fetal human umbilical vein endothelial cells (HUVECs), a representative of fetal vascular cells. METHODS: Cell proliferation, apoptosis, mitochondrial ROS production and cell cycle were measured using flowcytometry. Genome-wide expression was measured using Affymetrix microarray. Gene expression of CCND2, STAT1, ITGB8, ALDH2, and ADAMTS5 was measured using real-time PCR. RESULTS: HUVECs derived from T2D mothers (T2D-HUVECs) showed elevated levels of mitochondrial superoxide anions, reduced cell proliferation, and increased apoptosis rates relative to HUVECs derived from healthy control mothers (C.HUVECs). In addition , T2D-HUVECs showed a decreased proportion of cells in G0/G1 and cell cycle arrest at the S phases relative to controls. Interestingly, microarray experiments revealed significant differences in genome-wide expression profiles between T2D-HUVECs and C.HUVECs. In particular, the analysis identified 90 upregulated genes and 42 downregulated genes. The upregulated genes CCND2, STAT1, ITGB8, ALDH2, and ADAMTS5 were validated as potential biomarkers for fetal endothelial dysfunction. Functional network analysis revealed that these genes are the important players that participate in the pathogenesis of endothelial dysfunction, which in turn influences the inflammatory response, cellular movement, and cardiovascular system development and function. CONCLUSION: Sustained alterations in the overall function of T2D-HUVEC and gene expression profiles provided insights into the role of maternal T2D on the pathophysiology of the fetal endothelial dysfunction.


Assuntos
Diabetes Mellitus Tipo 2/genética , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Células Endoteliais da Veia Umbilical Humana/fisiologia , Gravidez em Diabéticas/genética , Adulto , Apoptose/genética , Estudos de Casos e Controles , Proliferação de Células/genética , Células Cultivadas , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Perfilação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Análise em Microsséries , Gravidez , Gravidez em Diabéticas/metabolismo , Gravidez em Diabéticas/patologia
4.
BMC Pregnancy Childbirth ; 18(1): 468, 2018 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-30526530

RESUMO

BACKGROUND: Resistance to thyroid hormone beta (RTHß) results in symptoms of both increased and decreased thyroid hormone action. The effect of thyroid hormone changes in different types of autoimmune thyroid disease (AITD) in RTHß is dynamic. CASE PRESENTATION: A 25-year-old Asian female had a RTHß Y321C mutation with Hashimoto's thyroiditis and type 2 diabetes mellitus. She was followed-up through gestation and two years postpartum, revealing development of postpartum thyroiditis (PPT) with characteristic wide fluctuations in serum thyrotropin levels, and of spontaneous recovery from an episode of transient hypothyroidism. The presence of RTHß did not prolong thyroiditis duration nor progressed toward permanent hypothyroidism. Prenatal genetic analysis was not performed on the unaffected fetus, and did not result in congenital hypothyroidism, possibly because maternal free thyroxine (FT4) levels were mildly elevated at less than 50% above the reference range in early gestation and gradually decreased to less than 20% after the 28th gestational week. CONCLUSION: In RTHß patients with autoimmune thyroid disease, episodes of thyroid dysfunction can significantly alter thyrotropin levels. During pregnancy, mildly elevated maternal free thyroxine levels less than 20% above the upper limit may not be harmful to unaffected fetuses. Unnecessary thyroid hormone control and fetal genetic testing was avoided during the gestational period with monthly follow-up.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Doença de Hashimoto/metabolismo , Hipotireoidismo/metabolismo , Tireoidite Pós-Parto/metabolismo , Complicações na Gravidez/metabolismo , Gravidez em Diabéticas/metabolismo , Síndrome da Resistência aos Hormônios Tireóideos/metabolismo , Adulto , Diabetes Mellitus Tipo 2/complicações , Feminino , Doença de Hashimoto/complicações , Humanos , Hipotireoidismo/etiologia , Mutação , Gravidez , Receptores beta dos Hormônios Tireóideos/genética , Síndrome da Resistência aos Hormônios Tireóideos/complicações , Tireoidite Autoimune , Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo
5.
Cytokine ; 111: 41-48, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30114628

RESUMO

This study was based on the hypothesis that IL-1ß and its central regulator, the inflammasome, may play a role in the inflammatory condition exhibited by placental tissues from mothers with different gestational hyperglycemia levels. Pregnant women were classified according to the glycemic reference as non-diabetic (n = 15), mild gestational hyperglycemia (n = 15), gestational diabetes mellitus (n = 15) and type 2 diabetes mellitus (n = 15). We investigated levels of pro-inflammatory factors in maternal plasma and placental tissues (by ELISA or immunohistochemistry) and, NFKB activity (by electrophoretic mobility shift assay) and inflammasome protein expression (by Western blot) in chorionic villous. Maternal plasma and placental levels of inflammatory factors (IL-1ß, IL-6, and MCP-1) were increased during all hyperglycemic conditions. Villous stroma cells showed strong immunoreactivity to CD68. In addition, with syncytiotrophoblast, the villous stroma cells were also stained to detect iNOS, MCP-1, TLR2, and TLR4. Although the levels of protein had fluctuated in the groups, NLRP1, NLRP3, ASC, and Caspase 1 were up-regulated in all hyperglycemic groups suggesting the inflammasome may be assembled in these pregnant women. The NFKB activity also exhibited higher levels in hyperglycemic groups, which might imply in pro-inflammatory cytokines production. In summary, increased maternal glucose levels during pregnancy changed systemic and placental inflammatory patterns, which occurred in parallel with the expression of inflammasome factors and processing and secretion of the pro-inflammatory cytokine IL-1ß. These results suggest an inflammatory condition in all gestational hyperglycemic conditions, even in hyperglycemia that is less severe than gestational or overt diabetes, likely associated with inflammasome activation and inflammatory cytokine secretion. Inflammasome activation as a possible source of inflammatory factors may be an important target to be considered while managing hyperglycemia and preventing adverse pregnancy outcomes.


Assuntos
Vilosidades Coriônicas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Gestacional/metabolismo , Hiperglicemia/metabolismo , Mediadores da Inflamação/metabolismo , Gravidez em Diabéticas/metabolismo , Adulto , Vilosidades Coriônicas/patologia , Diabetes Mellitus Tipo 2/patologia , Diabetes Gestacional/patologia , Feminino , Humanos , Hiperglicemia/patologia , Gravidez , Gravidez em Diabéticas/patologia
6.
Diab Vasc Dis Res ; 15(6): 528-540, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30130976

RESUMO

BACKGROUND: There is clinical and experimental evidence for altered adenosine signalling in the fetoplacental circulation in pregnancies complicated by diabetes, leading to adenosine accumulation in the placenta. However, the consequence for fetoplacental vasocontractility is unclear. This study examined contractility to adenosine of chorionic vessels from type 1 diabetes mellitus, gestational diabetes mellitus and normal pregnancies. METHODS: Chorionic arteries and veins were isolated from human placenta from normal, gestational diabetes mellitus and type 1 diabetes mellitus pregnancies. Isometric tension recording measured responses to adenosine and the thromboxane A2 analogue U46619 (thromboxane A2 mediates fetoplacental vasoconstriction to adenosine). Adenosine and thromboxane prostanoid receptor protein expression was determined by immunoblotting. RESULTS: Adenosine elicited contractions in chorionic arteries and veins which were impaired in both gestational diabetes mellitus and type 1 diabetes mellitus. Contractions to potassium chloride were unchanged. Adenosine A2A and A2B receptor protein levels were not different in gestational diabetes mellitus and normal pregnancies. Contractions to U46619 were unaltered in gestational diabetes mellitus arteries and increased in type 1 diabetes mellitus arteries. Overnight storage of vessels restored contractility to adenosine in gestational diabetes mellitus arteries and normalized contraction to U46619 in type 1 diabetes mellitus arteries. CONCLUSION: These data are consistent with the concept of aberrant adenosine signalling in diabetes; they show for the first time that this involves impaired adenosine contractility of the fetoplacental vasculature.


Assuntos
Adenosina/farmacologia , Artérias/efeitos dos fármacos , Córion/irrigação sanguínea , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Gestacional/fisiopatologia , Gravidez em Diabéticas/fisiopatologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Veias/efeitos dos fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Artérias/metabolismo , Artérias/fisiopatologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/metabolismo , Feminino , Humanos , Gravidez , Gravidez em Diabéticas/diagnóstico , Gravidez em Diabéticas/metabolismo , Receptor A2A de Adenosina/metabolismo , Receptor A2B de Adenosina/metabolismo , Receptor A3 de Adenosina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Nascimento a Termo , Veias/metabolismo , Veias/fisiopatologia
7.
BMJ ; 362: k2638, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29976596

RESUMO

OBJECTIVE: To examine the association between maternal type 1 diabetes and the risk of major birth defects according to levels of glycated haemoglobin (HbA1C) within three months before or after estimated conception. DESIGN: Population based historical cohort study using nationwide health registers. SETTING: Sweden, 2003-15. PARTICIPANTS: 2458 singleton liveborn infants of mothers with type 1 diabetes and a glycated haemoglobin measurement within three months before or after estimated conception and 1 159 865 infants of mothers without diabetes. MAIN OUTCOME MEASURES: Major cardiac and non-cardiac birth defects according to glycated haemoglobin levels. RESULTS: 122 cases of major cardiac defects were observed among 2458 infants of mothers with type 1 diabetes. Compared with 15 cases of major cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 33 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 2.17, 95% confidence interval 1.37 to 3.42), 49 per 1000 for 6.5% to <7.8% (3.17, 2.45 to 4.11), 44 per 1000 for 7.8% to <9.1% (2.79, 1.90 to 4.12), and 101 per 1000 for ≥9.1% (6.23, 4.32 to 9.00). The corresponding adjusted risk differences were 17 (5 to 36), 32 (21 to 46), 26 (13 to 46), and 77 (49 to 118) cases of major cardiac defects per 1000 infants, respectively. 50 cases of major non-cardiac defects were observed among infants of mothers with type 1 diabetes. Compared with 18 cases of major non-cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 22 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 1.18, 0.68 to 2.07), 19 per 1000 for 6.5% to <7.8% (1.01, 0.66 to 1.54), 17 per 1000 for 7.8% to <9.1% (0.89, 0.46 to 1.69), and 32 per 1000 for ≥9.1% (1.68, 0.85 to 3.33). CONCLUSION: Among liveborn infants of mothers with type 1 diabetes, increasingly worse glycaemic control in the three months before or after estimated conception was associated with a progressively increased risk of major cardiac defects. Even with glycated haemoglobin within target levels recommended by guidelines (<6.5%), the risk of major cardiac defects was increased more than twofold. The risk of major non-cardiac defects was not statistically significantly increased at any of the four glycated haemoglobin levels examined; the study had limited statistical power for this outcome and was based on live births only.


Assuntos
Anormalidades Congênitas/epidemiologia , Diabetes Mellitus Tipo 1/epidemiologia , Gravidez em Diabéticas/epidemiologia , Adulto , Biomarcadores/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Lactente , Recém-Nascido , Gravidez , Gravidez em Diabéticas/metabolismo , Fatores de Risco , Suécia/epidemiologia
8.
Reprod Toxicol ; 80: 92-104, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29859881

RESUMO

We discuss the possibilities to prevent the post-exposure teratogenic effects of several teratogens: valproic acid (VPA), diabetes and alcohol. Co-administration of folic acid with VPA reduced the rate of Neural Tube Defects (NTD) and other anomalies in rodents, but apparently not in pregnant women. Antioxidants or the methyl donor S-adenosyl methionine prevented Autism Spectrum Disorder (ASD) like behavior in mice and rats. In vivo and in vitro studies demonstrated that antioxidants, arachidonic acid, myoinositol and nutritional agents may prevent diabetes-embryopathy. Prevention of alcohol-induced embryonic and fetal injuries and neurodevelopmental deficits was achieved by supplementation of zinc, choline, vasoactive intestinal proteins (VIP related peptides), antioxidants and folic acid. While the animal research described in this review is indicative of possible preventions of the different teratogenic effects, this is not yet the focus in human research. Future research should promote further knowledge where our current understanding is the vaguest, human prevention.


Assuntos
Anormalidades Induzidas por Medicamentos/prevenção & controle , Antioxidantes/administração & dosagem , Diabetes Gestacional , Ácido Fólico/administração & dosagem , Gravidez em Diabéticas , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Teratogênios/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Animais , Antioxidantes/uso terapêutico , Diabetes Gestacional/metabolismo , Etanol/toxicidade , Etil-Éteres , Feminino , Ácido Fólico/uso terapêutico , Antagonistas do Ácido Fólico/toxicidade , Humanos , Estresse Oxidativo , Gravidez , Gravidez em Diabéticas/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Compostos de Sulfidrila , Ácido Valproico/toxicidade
9.
Endocr J ; 65(9): 903-913, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-29925744

RESUMO

This paper aims to investigate the influence of lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor, darapladib, on insulin resistance (IR) in streptozotocin (STZ)-induced diabetic pregnant rats. The rat models were divided into Control (normal pregnancy), STZ + saline (STZ-induced diabetic pregnant rats), STZ + Low-dose and STZ + High-dose darapladib (STZ-induced diabetic pregnant rats treated with low-/high-dose darapladib) groups. Pathological changes were observed by Hematoxylin-eosin (HE) and Immunohistochemistry staining. Lp-PLA2 levels were determined by enzyme-linked immunosorbent assay (ELISA). An automatic biochemical analyzer was used to measure the serum levels of biochemical indicators, and homeostatic model assessment for insulin resistance (HOMA-IR) and insulin sensitivity index (ISI) were calculated. Western blot was applied to determine levels of inflammatory cytokines. Compared with Control group, rats in the STZ + saline group were significantly decreased in body weight, the number of embryo implantation, the number of insulin positive cells and pancreatic islet size as well as the islet endocrine cells, and high-density lipoprotein (HDL-C) level, but substantially increased in Lp-PLA2, low-density lipoprotein (LDL-C), fatty acids (FFA), serum total cholesterol (TC), triglyceride (TG) levels. Moreover, the increased fasting plasma glucose (FPG) and HOMA-IR and inflammatory cytokines but decreased fasting insulin (FINS) and ISI were also found in diabetic pregnant rats. On the contrary, rats in the darapladib-treated groups were just opposite to the STZ + saline group, and STZ + High-dose group improved better than STZ + Low-dose group. Thus, darapladib can improve lipid metabolism, and enhance insulin sensitivity of diabetic pregnant rats by regulating inflammatory cytokines.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , Benzaldeídos/farmacologia , Diabetes Mellitus Experimental/metabolismo , Inibidores Enzimáticos/farmacologia , Resistência à Insulina , Oximas/farmacologia , Gravidez em Diabéticas/metabolismo , Animais , Benzaldeídos/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Feminino , Insulina/sangue , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Oximas/uso terapêutico , Gravidez , Gravidez em Diabéticas/tratamento farmacológico , Gravidez em Diabéticas/patologia , Ratos , Ratos Sprague-Dawley , Estreptozocina
10.
Am J Obstet Gynecol ; 219(2): 191.e1-191.e6, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29750952

RESUMO

BACKGROUND: During labor, maintenance of maternal euglycemia is critical to decrease the risk of neonatal hypoglycemia and associated morbidities. When continuous intravenous insulin infusion is needed, standardized insulin dosing charts have been used for titration of insulin to maintain glucose in target range. The GlucoStabilizer software program (Indiana University Health Inc, Indianapolis, IN) is a software-guided insulin dosing system that calculates the dose of intravenous insulin that is needed based on metabolic parameters, target glucose concentration, and an individual's response to insulin. Although this tool has been validated and shown to reduce both hypoglycemia and errors in critical care settings, the utility of this software has not been examined in obstetrics. OBJECTIVE: The purpose of this study was to determine whether the use of intravenous insulin dosing software in women with pregestational or gestational diabetes mellitus that requires intrapartum insulin infusion can improve the rate of glucose concentration in target range (70-100 mg/dL; 3.9-5.5 mmol/L) at the time delivery. STUDY DESIGN: We performed a retrospective cohort study comparing laboring patients with diabetes mellitus that required insulin infusion who were dosed by standard insulin dosing chart vs the GlucoStabilizer software program from January 2012 to December 2017. The GlucoStabilizer software program, which was implemented in May 2016, replaced the standard intravenous insulin dosing chart. Inclusion criteria were women with pregestational or gestational diabetes mellitus who were treated with an intravenous insulin infusion intrapartum for at least 2 hours. Maternal characteristics, glucose values in labor, and neonatal outcomes were extracted from delivery and neonatal records. The primary outcome was the percentage of women who achieved the target glucose range (defined as a blood glucose between 70-100 mg/dL; 3.9-5.5 mmol/L) before delivery. Parametric and nonparametric statistics were used to compare both groups; a probability value of <.05 was considered statistically significant. RESULTS: We identified 22 patients who were dosed by a standard insulin dosing chart and 11 patients who were dosed by the GlucoStabilizer software program during intrapartum management. The GlucoStabilizer software program was superior in achieving glucose values in target range at delivery (81.8% vs 9.1%; P<.001) compared with standard insulin dosing without increasing maternal hypoglycemia (0% vs 4.3%; P=.99). Patients whose insulin dosing was managed by the GlucoStabilizer software program also had lower mean capillary blood glucose values compared with the standard insulin infusion (102.9±5.9 mg/dL [5.7±0.33 mmol/L] vs 121.7±5.9 mg/dL [6.8±0.33 mmol/L]; P=.02). Before the initiation of the infusion, both groups demonstrated mean capillary blood glucose values outside of target range (122.6±8.8 mg/dL [6.7±0.49 mmol/L] for the GlucoStabilizer software program vs 131.9±10.1 mg/dL [7.3±0.56 mmol/L] for standard insulin treatment group; P=not significant). There were no significant differences in baseline maternal characteristics between the groups or neonatal outcomes. CONCLUSION: This study is the first to demonstrate that the use of software-guided intravenous insulin dosing in obstetrics can improve intrapartum glycemic management without increasing hypoglycemia in women with both pregestational and gestational diabetes mellitus that is treated with an insulin infusion.


Assuntos
Diabetes Gestacional/tratamento farmacológico , Cálculos da Dosagem de Medicamento , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Trabalho de Parto , Gravidez em Diabéticas/tratamento farmacológico , Software , Adulto , Glicemia/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Humanos , Infusões Intravenosas , Gravidez , Gravidez em Diabéticas/metabolismo , Estudos Retrospectivos
11.
Am J Obstet Gynecol ; 219(2): 197.e1-197.e8, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29733843

RESUMO

BACKGROUND: Diabetes mellitus in early pregnancy increases the risk of birth defects in infants. Maternal hyperglycemia stimulates the expression of nitric oxide synthase 2, which can be regulated by transcription factors of the nuclear factor-κB family. Increases in reactive nitrogen species generate intracellular stress conditions, including nitrosative, oxidative, and endoplasmic reticulum stresses, and trigger programmed cell death (or apoptosis) in the neural folds, resulting in neural tube defects in the embryo. Inhibiting nitric oxide synthase 2 can reduce neural tube defects; however, the underlying mechanisms require further delineation. Targeting nitric oxide synthase 2 and associated nitrosative stress using naturally occurring phytochemicals is a potential approach to preventing birth defects in diabetic pregnancies. OBJECTIVE: This study aims to investigate the effect of quercetin-3-glucoside, a naturally occurring polyphenol flavonoid, in reducing maternal diabetes-induced neural tube defects in an animal model, and to delineate the molecular mechanisms underlying quercetin-3-glucoside action in regulating nitric oxide synthase 2 expression. STUDY DESIGN: Female mice (C57BL/6) were induced to develop diabetes using streptozotocin before pregnancy. Diabetic pregnant mice were administered quercetin-3-glucoside (100 mg/kg) daily via gavage feeding, introduction of drug to the stomach directly via a feeding needle, during neurulation from embryonic day 6.5-9.5. After treatment at embryonic day 10.5, embryos were collected and examined for the presence of neural tube defects and apoptosis in the neural tube. Expression of nitric oxide synthase 2 and superoxide dismutase 1 (an antioxidative enzyme) was quantified using Western blot assay. Nitrosative, oxidative, and endoplasmic reticulum stress conditions were assessed using specific biomarkers. Expression and posttranslational modification of factors in the nuclear factor-κB system were investigated. RESULTS: Treatment with quercetin-3-glucoside (suspended in water) significantly decreased neural tube defect rate and apoptosis in the embryos of diabetic mice, compared with those in the water-treated diabetic group (3.1% vs. 24.7%; P < .001). Quercetin-3-glucoside decreased the expression of nitric oxide synthase 2 and nitrosative stress (P < .05). It also increased the levels of superoxide dismutase 1 (P < .05), further increasing the antioxidative capacity of the cells. Quercetin-3-glucoside treatment also alleviated of endoplasmic reticulum stress in the embryos of diabetic mice (P < .05). Quercetin-3-glucoside reduced the levels of p65 (P < .05), a member of the nuclear factor-κB transcription factor family, but augmented the levels of the inhibitor of κBα (P < .05), which suppresses p65 nuclear translocation. In association with these changes, the levels of inhibitor of κB kinase-α and inhibitor of κBα phosphorylation were elevated (P < .05). CONCLUSION: Quercetin-3-glucoside reduces the neural tube defects rate in the embryos of diabetic dams. Quercetin-3-glucoside suppresses nitric oxide synthase 2 and increases superoxide dismutase 1 expression, leading to alleviation of nitrosative, oxidative, and endoplasmic reticulum stress conditions. Quercetin-3-glucoside may regulate the expression of nitric oxide synthase 2 via modulating the nuclear factor-κB transcription regulation system. Quercetin-3-glucoside, a naturally occurring polyphenol that has high bioavailability and low toxicity, is a promising candidate agent to prevent birth defects in diabetic pregnancies.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/metabolismo , Embrião de Mamíferos/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , NF-kappa B/efeitos dos fármacos , Neurulação/efeitos dos fármacos , Estresse Nitrosativo/efeitos dos fármacos , Quercetina/análogos & derivados , Animais , Western Blotting , Feminino , Camundongos , NF-kappa B/genética , NF-kappa B/metabolismo , Defeitos do Tubo Neural/embriologia , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/metabolismo , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Gravidez em Diabéticas/epidemiologia , Gravidez em Diabéticas/metabolismo , Quercetina/farmacologia , Superóxido Dismutase-1/efeitos dos fármacos , Superóxido Dismutase-1/metabolismo , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/metabolismo
12.
Endocrinology ; 159(5): 2186-2198, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29659791

RESUMO

Growth hormone (GH), an endocrine hormone, primarily secreted from the anterior pituitary, stimulates growth, cell reproduction, and regeneration and is a major regulator of postnatal growth. Humans have two GH genes that encode two versions of GH proteins: a pituitary version (GH-N/GH1) and a placental GH-variant (GH-V/GH2), which are expressed in the syncytiotrophoblast and extravillous trophoblast cells of the placenta. During pregnancy, GH-V replaces GH-N in the maternal circulation at mid-late gestation as the major circulating form of GH. This remarkable change in spatial and temporal GH secretion patterns is proposed to play a role in mediating maternal adaptations to pregnancy. GH-V is associated with fetal growth, and its circulating concentrations have been investigated across a range of pregnancy complications. However, progress in this area has been hindered by a lack of readily accessible and reliable assays for measurement of GH-V. This review will discuss the potential roles of GH-V in normal and pathological pregnancies and will touch on the assays used to quantify this hormone.


Assuntos
Hormônio do Crescimento/metabolismo , Hormônios Placentários/metabolismo , Complicações na Gravidez/metabolismo , Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Diabetes Gestacional/metabolismo , Síndrome de Down/metabolismo , Feminino , Retardo do Crescimento Fetal/metabolismo , Macrossomia Fetal/metabolismo , Doença Trofoblástica Gestacional/metabolismo , Humanos , Gravidez , Gravidez em Diabéticas/metabolismo , Gravidez Ectópica/metabolismo , Isoformas de Proteínas , Síndrome da Trissomía do Cromossomo 18/metabolismo
13.
Diabetes Obes Metab ; 20(7): 1642-1651, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29498473

RESUMO

AIMS: To evaluate the association between use of non-insulin antidiabetics in early pregnancy and the risk of miscarriages, stillbirths and major structural malformations. MATERIALS AND METHODS: A cohort of 1511 pregnant women with pre-gestational diabetes linked to live births was identified using electronic medical records from The Health Improvement Network (THIN) for the period 1995 to 2012. Information on prescriptions, foetal outcomes and potential confounders was ascertained from both codes and free text in the THIN database. Odds ratios (OR) and 95% confidence intervals (CI) of adverse foetal outcomes in women treated with non-insulin antidiabetics during the first trimester compared to those on insulin were estimated using logistic regression to adjust for type of diabetes, glycaemic control and other maternal characteristics. RESULTS: Among 311 pregnant women on non-insulin antidiabetics, 21.9% had a miscarriage and 1.6% a stillbirth; 1.9% of live births had major malformations. The corresponding frequencies for the 883 women on insulin were 13.3%, 1.7% and 9.6%. Insulin users more often had type 1 diabetes and poor glycaemic control. Compared to women with type 1 diabetes, those with type 2 diabetes had a higher risk of miscarriages (20.5% vs 12.8%) but a lower prevalence of malformations (4.0% vs 9.2%). Compared to women with HbA1c ≤7%, those with HbA1c >7% had a higher prevalence of malformations (12.6% vs 2.7%). After adjustment for diabetes type and glycaemic control, compared to insulin, non-insulin antidiabetic patients were associated with an OR for miscarriage of 1.19 (95% CI, 0.75-1.89), for stillbirths of 0.65 (95% CI, 0.16-2.58), and for major malformations of 0.25 (95% CI, 0.08-0.84). CONCLUSION: Among women with diabetes, use of non-insulin antidiabetics early in pregnancy was not associated with greater risks of foetal losses or major malformations than was insulin.


Assuntos
Aborto Espontâneo/epidemiologia , Anormalidades Congênitas/epidemiologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Gravidez em Diabéticas/tratamento farmacológico , Natimorto/epidemiologia , Adolescente , Adulto , Glicemia/metabolismo , Estudos de Coortes , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Razão de Chances , Gravidez , Primeiro Trimestre da Gravidez , Gravidez em Diabéticas/metabolismo , Prevalência , Estudos Retrospectivos , Fatores de Risco , Reino Unido/epidemiologia , Adulto Jovem
14.
J Pak Med Assoc ; 68(3): 490-493, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29540896

RESUMO

Management of hyperglycaemia is crucial during labour to improve outcomes both in the newborn and in the mother. This is particularly crucial in mothers with pregestational type 1 diabetes and in all mothers requiring insulin treatment during pregnancy. The use of antenatal steroids in mothers at risk of preterm delivery complicates management of hyperglycaemia in the immediate antepartum period and requires appropriate dosing adjustments of insulin therapy. Mothers are generally asked to be nil per orum during active labour. This requires appropriate fluid, glucose and insulin management in the hours leading on to the delivery of the baby. If the woman undergoes an operative delivery then patients continues to require glucose insulin infusion till patient is able to eat and drink normally. This review focuses on the management of hyperglycaemia during labour and in the immediate post partum period. A dosing schedule for women who receive steroids in the antepartum period is also discussed. The review suggests a practical glucose insulin regimen that can be followed during active labour in women who are nil orally. Lastly the review discusses immediate post partum management in these women as well.


Assuntos
Diabetes Gestacional/terapia , Hidratação/métodos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Trabalho de Parto , Metformina/uso terapêutico , Gravidez em Diabéticas/terapia , Corticosteroides/efeitos adversos , Glicemia/metabolismo , Parto Obstétrico , Diabetes Gestacional/metabolismo , Gerenciamento Clínico , Feminino , Glucose/uso terapêutico , Humanos , Hiperglicemia/induzido quimicamente , Hiperglicemia/metabolismo , Gravidez , Gravidez em Diabéticas/metabolismo , Nascimento Prematuro
15.
PLoS One ; 13(2): e0190698, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29470513

RESUMO

AIMS/HYPOTHESIS: We hypothesized that diabetes during pregnancy (DDP) alters genome-wide DNA methylation in placenta resulting in differentially methylated loci of metabolically relevant genes and downstream changes in RNA and protein expression. METHODS: We mapped genome-wide DNA methylation with the Infinium 450K Human Methylation Bead Chip in term fetal placentae from Native American and Hispanic women with DDP using a nested case-control design (n = 17 pairs). RNA expression and protein levels were assayed via RNA-Seq and Western Blot. RESULTS: Genome-wide DNA methylation analysis revealed 465 CpG sites with significant changes for male offspring, 247 for female offspring, and 277 for offspring of both sexes (p<0.001). Placentae from female offspring were 40% more likely to have significant gains in DNA methylation compared with placentae from male offspring exposed to DDP (p<0.001). Changes in DNA methylation corresponded to changes in RNA and protein levels for 6 genes: PIWIL3, CYBA, GSTM1, GSTM5, KCNE1 and NXN. Differential DNA methylation was detected at loci related to mitochondrial function, DNA repair, inflammation, oxidative stress. CONCLUSIONS/INTERPRETATION: These findings begin to explain mechanisms responsible for the increased risk for obesity and type 2 diabetes in offspring of mothers with DDP.


Assuntos
Metilação de DNA , Expressão Gênica , Placenta/metabolismo , Gravidez em Diabéticas/genética , Gravidez em Diabéticas/metabolismo , Adulto , Estudos de Casos e Controles , Ilhas de CpG , Diabetes Mellitus Tipo 2/etiologia , Feminino , Humanos , Recém-Nascido , Masculino , Obesidade/etiologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores Sexuais , Adulto Jovem
16.
Ginekol Pol ; 89(1): 20-24, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29411342

RESUMO

OBJECTIVES: The aim of the study is to determine the impact of the experimental diabetes and the chronic hypoxia on pregnancy development and rat fetal body weight. MATERIAL AND METHODS: The experiment was performed on female Wistar rats. Animals were divided into the experimen-tal groups. I - Controls, II - Untreated diabetes, III - Insulin-treated diabetes, IV - No diabetes with chronic hypoxia, V - Untreated diabetes and chronic hypoxia, VI - Insulin- treated diabetes and chronic hypoxia. Diabetes was induced in groups II, III, V and VI with intraperitoneal injection of streptozocin (STZ) at a dose of 40 mg/kg. Chronic hypoxia was induced by placing dams (groups IV, V and VI) in conditions of 10.5% oxygen and 89.5%. Insulin was administered subcutaneously at the dose of 9 IU/kg. Starting from the 6th day after STZ injection and chronic hypoxia conditions animals were caged together for 12 hours for 3 consecutive days to ensure fertilization. On day 21 of gestation the animals were decapitated, the fetuses were removed and weighted. RESULTS: Mean fetal body weight in separate groups were: I - 5.38 g, II - 6.04g, III - 5.32g, IV- 5.56 g, V - 3.45 g, VI - 6.23 g. CONCLUSIONS: Pre-existing type 1 diabetes does not affect fetal body weight compared to healthy newborn control rats. Pro-longed hypoxia does not impact on fetal body weight. Chronic hypoxia during pregnancy complicated with untreated type 1 diabetes mellitus leads to significant reduction of fetal body weight. Insulin treatment reversed the detrimental effect of chronic hypoxia on fetal development.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Desenvolvimento Fetal , Peso Fetal , Hipóxia/metabolismo , Gravidez em Diabéticas/metabolismo , Prenhez , Animais , Estudos de Casos e Controles , Diabetes Mellitus Experimental/fisiopatologia , Modelos Animais de Doenças , Feminino , Hipóxia/fisiopatologia , Gravidez , Gravidez em Diabéticas/fisiopatologia , Ratos , Ratos Wistar
17.
Am J Obstet Gynecol ; 218(1): 136.e1-136.e10, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29100869

RESUMO

BACKGROUND: Maternal diabetes induces neural tube defects, and oxidative stress is a causal factor for maternal diabetes-induced neural tube defects. The redox gene nuclear factor erythroid 2-related factor 2 is the master regulator of the cellular antioxidant system. OBJECTIVE: In this study, we aimed to determine whether maternal diabetes inhibits nuclear factor erythroid 2-related factor 2 expression and nuclear factor erythroid 2-related factor 2-controlled antioxidant genes through the redox-sensitive miR-27a. STUDY DESIGN: We used a well-established type 1 diabetic embryopathy mouse model induced by streptozotocin for our in vivo studies. Embryos at embryonic day 8.5 were harvested for analysis of nuclear factor erythroid 2-related factor 2, nuclear factor erythroid 2-related factor 2-controlled antioxidant genes, and miR-27a expression. To determine if mitigating oxidative stress inhibits the increase of miR-27a and the decrease of nuclear factor erythroid 2-related factor 2 expression, we induced diabetic embryopathy in superoxide dismutase 2 (mitochondrial-associated antioxidant gene)-overexpressing mice. This model exhibits reduced mitochondria reactive oxygen species even in the presence of hyperglycemia. To investigate the causal relationship between miR-27a and nuclear factor erythroid 2-related factor 2 in vitro, we examined C17.2 neural stem cells under normal and high-glucose conditions. RESULTS: We observed that the messenger RNA and protein levels of nuclear factor erythroid 2-related factor 2 were significantly decreased in embryos on embryonic day 8.5 from diabetic dams compared to those from nondiabetic dams. High-glucose also significantly decreased nuclear factor erythroid 2-related factor 2 expression in a dose- and time-dependent manner in cultured neural stem cells. Our data revealed that miR-27a was up-regulated in embryos on embryonic day 8.5 exposed to diabetes, and that high glucose increased miR-27a levels in a dose- and time-dependent manner in cultured neural stem cells. In addition, we found that a miR-27a inhibitor abrogated the inhibitory effect of high glucose on nuclear factor erythroid 2-related factor 2 expression, and a miR-27a mimic suppressed nuclear factor erythroid 2-related factor 2 expression in cultured neural stem cells. Furthermore, our data indicated that the nuclear factor erythroid 2-related factor 2-controlled antioxidant enzymes glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, and glutathione S-transferase A1 were down-regulated by maternal diabetes in embryos on embryonic day 8.5 and high glucose in cultured neural stem cells. Inhibiting miR-27a restored expression of glutamate-cysteine ligase catalytic subunit, glutamate-cysteine ligase modifier subunit, and glutathione S-transferase A1. Overexpressing superoxide dismutase 2 reversed the maternal diabetes-induced increase of miR-27a and suppression of nuclear factor erythroid 2-related factor 2 and nuclear factor erythroid 2-related factor 2-controlled antioxidant enzymes. CONCLUSION: Our study demonstrates that maternal diabetes-induced oxidative stress increases miR-27a, which, in turn, suppresses nuclear factor erythroid 2-related factor 2 and its responsive antioxidant enzymes, resulting in diabetic embryopathy.


Assuntos
MicroRNAs/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Gravidez em Diabéticas/metabolismo , Animais , Células Cultivadas , Feminino , MicroRNAs/genética , Mitocôndrias/genética , Modelos Animais , Fator 2 Relacionado a NF-E2/genética , Células-Tronco Neurais/metabolismo , Defeitos do Tubo Neural/metabolismo , Gravidez , Superóxido Dismutase/genética , Regulação para Cima
18.
J Diabetes Investig ; 9(4): 959-966, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29280333

RESUMO

AIMS/INTRODUCTION: To measure longitudinal changes in resting energy expenditure and body composition of Japanese pregnant women with or without diabetes. MATERIALS AND METHODS: The study population consisted of women who had delivered a live singleton neonate after 22 weeks' gestation at Okayama University Hospital from July 2013 to June 2017. Resting energy expenditure and body composition were measured in the first trimester, second trimester, third trimester and postpartum. RESULTS: A total of 144 women participated in this study: 103 with normal glucose tolerance and 41 with diabetes. The resting energy expenditure (kcal/day) of pregnant women with normal glucose tolerance was significantly higher in the third trimester (1,644 ± 234) than in the first (1,461 ± 215) and second trimesters (1,491 ± 219), and postpartum (1,419 ± 254), whereas that of pregnant women with diabetes did not significantly change during all periods (1,568 ± 404, 1,710 ± 332, 1,716 ± 251, 1,567 ± 249). The resting energy expenditure of women with good glycemic control was lower than that of women with poor control. Fat-free mass was closely correlated with resting energy expenditure. CONCLUSIONS: The resting energy expenditure of Japanese pregnant women with normal glucose tolerance was significantly increased in the third trimester. The resting energy expenditure of women with good glycemic control was lower than that of women with poor control. Resting energy expenditure and fat-free mass are potential indexes for medical nutrition therapy in pregnant women with diabetes.


Assuntos
Composição Corporal , Metabolismo Energético , Gravidez em Diabéticas/metabolismo , Adulto , Grupo com Ancestrais do Continente Asiático , Peso ao Nascer , Feminino , Teste de Tolerância a Glucose , Hemoglobina A Glicada/análise , Humanos , Japão , Estudos Longitudinais , Gravidez , Trimestres da Gravidez , Albumina Sérica/análise
19.
J Matern Fetal Neonatal Med ; 31(10): 1358-1363, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-28423959

RESUMO

OBJECTIVE: Docosahexaenoic acid (DHA) is vital for fetal development especially during the third trimester of gestation when the speed of fetal brain growth is at its peak. Diabetes modifies the maternal fatty acid profile, which may in turn change the quantity and/or quality of lipids transferred to the fetus. Neonates born to diabetic mothers might be more vulnerable to DHA deficiency leading to lower cognitive scores together with lower overall intellectual quotients when compared to control. We reviewed the influence of type 1 or type 2 pre-gestational (PGD) and gestational diabetes mellitus (GDM) on maternal and fetal DHA levels. METHOD: We searched MEDLINE articles about PGD and/or GDM and DHA published before October 2016. RESULTS: Maternal blood DHA level seems higher in those with diabetes than those without diabetes. However, DHA in cord plasma of neonates born to PGD and/or GDM mothers seem lower compared to neonates born to nondiabetic mothers. CONCLUSIONS: Altogether, these results suggest that the transfer of DHA from the mother to the fetus may be deficient or dysregulated in diabetic pregnancies. What remains to be understood is how placental lipid transport is regulated and whether there is a link with clinical neurodevelopmental phenotypes in the newborns.


Assuntos
Diabetes Mellitus/metabolismo , Diabetes Gestacional/metabolismo , Ácidos Docosa-Hexaenoicos/deficiência , Troca Materno-Fetal/fisiologia , Gravidez em Diabéticas/metabolismo , Diabetes Mellitus/fisiopatologia , Diabetes Gestacional/fisiopatologia , Ácidos Docosa-Hexaenoicos/sangue , Feminino , Sangue Fetal/química , Sangue Fetal/metabolismo , Desenvolvimento Fetal , Humanos , Recém-Nascido , Placenta/metabolismo , Gravidez , Terceiro Trimestre da Gravidez , Gravidez em Diabéticas/fisiopatologia
20.
Obes Res Clin Pract ; 12(Suppl 2): 90-100, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28111084

RESUMO

Metabolic disorders usually increase the level of reactive oxygen species (ROS) and damage mitochondrial function. The placenta supplies nutrients and hormonal signals to the fetus for regulating fetal metabolism, and is also prone to injury by oxidants. The aim of this study was to determine the effect of pre-existing maternal type 2 diabetes mellitus (DM) combined with obesity on placental mitochondrial function and metabolism disorders of offspring. The study included 96 pregnant women. The women were put into the following groups: healthy women (control, n=24), women with DM (DM, n=24), women with obesity (OB, n=24) and women with both DM and obesity (DM+OB, n=24). The ROS level, mitochondrial content, and the mitochondrial respiratory complex activities of the placenta were measured in the four groups. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) was detected by immunofluorescence staining and western blotting. In addition, serum levels of insulin, glucose, leptin, nonesterified fatty acid (NEFA), adiponectin and triglycerides of their offspring were also measured. Maternal DM combined with obesity markedly increased ROS level, reduced mitochondrial DNA (mtDNA) content and mitochondrial respiratory complex I, II-III activities in placenta compared to the placenta from the control group and the DM group. Maternal DM combined with obesity significantly decreased Nrf2 and HO-1 expression. Furthermore, maternal DM combined with obesity influenced the glucose and lipid metabolism in their offspring. In conclusion, women with both DM and obesity detrimentally alter placenta function in oxidative stress regulation, and the Nrf2/ARE (antioxidant responsive element) pathway is involved. This may increase metabolic disturbance susceptibility in their offspring.


Assuntos
Elementos de Resposta Antioxidante/genética , Diabetes Mellitus Tipo 2/complicações , Fator 2 Relacionado a NF-E2/fisiologia , Obesidade/complicações , Placenta/metabolismo , Gravidez em Diabéticas/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal , Adulto , Elementos de Resposta Antioxidante/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Recém-Nascido , Dinâmica Mitocondrial/fisiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Estresse Oxidativo , Gravidez , Gravidez em Diabéticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
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