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1.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572712

RESUMO

Adiponectin is an adipocyte-derived hormone that plays a critical role in energy homeostasis, mainly attributed to its insulin-sensitizing properties. Accumulating studies have reported that adiponectin concentrations are decreased during metabolic diseases, such as obesity and type 2 diabetes, with an emerging body of evidence providing support for its use as a biomarker for pregnancy complications. The identification of maternal factors that could predict the outcome of compromised pregnancies could act as valuable tools that allow the early recognition of high-risk pregnancies, facilitating close follow-up and prevention of pregnancy complications in mother and child. In this review we consider the role of adiponectin as a potential biomarker of disorders associated with pregnancy. We discuss common disorders associated with pregnancy (gestational diabetes mellitus, preeclampsia, preterm birth and abnormal intrauterine growth) and highlight studies that have investigated the potential of adiponectin to serve as biomarkers for these disorders. We conclude the review by recommending strategies to consider for future research.


Assuntos
Adiponectina/sangue , Complicações na Gravidez/sangue , Adiponectina/metabolismo , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Diabetes Gestacional/sangue , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/metabolismo , Feminino , Humanos , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/metabolismo , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/metabolismo , Resultado da Gravidez , Nascimento Prematuro/sangue , Nascimento Prematuro/diagnóstico , Nascimento Prematuro/metabolismo , Transdução de Sinais
2.
Metabolism ; 116: 154704, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33421507

RESUMO

BACKGROUND: Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are associated with a high-risk for developing metabolic complications later in life and in their offspring. In contrast, exercise is recognized as a non-pharmacological strategy against metabolic dysfunctions associated to lifestyle disorders. Therefore, we investigated whether gestational exercise delays the development of metabolic alterations in GDM mothers later in life, but also protects 6-week-old male offspring from adverse effects of maternal diet. METHODS: Female Sprague-Dawley rats were fed with either control (C) or high-fat high-sucrose (HFHS) diet to induce GDM and submitted to gestational exercise during the 3 weeks of pregnancy. Male offspring were sedentary and fed with C-diet. RESULTS: Sedentary HFHS-fed dams exhibited increased gestational body weight gain (p < 0.01) and glucose intolerance (p < 0.01), characteristic of GDM. Their offspring had normal glucose metabolism, but increased early-age body weight, which was reverted by gestational exercise. Gestational exercise also reduced offspring hepatic triglycerides accumulation (p < 0.05) and improved liver mitochondrial respiration capacity (p < 0.05), contributing to the recovery of liver bioenergetics compromised by maternal HFHS diet. Interestingly, liver mitochondrial respiration remained increased by gestational exercise in HFHS-fed dams despite prolonged HFHS consumption and exercise cessation. CONCLUSIONS: Gestational exercise can result in liver mitochondrial adaptations in GDM animals, which can be preserved even after the exercise program cessation. Exposure to maternal GDM programs liver metabolic setting of male offspring, whereas gestational exercise appears as an important preventive tool against maternal diet-induced metabolic alterations.


Assuntos
Dieta Hiperlipídica , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Condicionamento Físico Animal/fisiologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Sacarose/administração & dosagem , Animais , Respiração Celular/efeitos dos fármacos , Diabetes Gestacional/metabolismo , Diabetes Gestacional/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Carboidratos da Dieta/efeitos adversos , Feminino , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Mitocôndrias Hepáticas/efeitos dos fármacos , Mães , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-Dawley
3.
Eur J Endocrinol ; 184(3): R69-R83, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33434155

RESUMO

Bile acids are lipid-solubilising molecules that also regulate metabolic processes. Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) are two bile acid receptors with key metabolic roles. FXR regulates bile acid synthesis in the liver and influences bile acid uptake in the intestine. TGR5 is mainly involved in regulation of signalling pathways in response to bile acid uptake in the gut and therefore prandial response. Both FXR and TGR5 have potential as therapeutic targets for disorders of glucose and/or lipid homeostasis. Gestation is also known to cause small increases in bile acid concentrations, but physiological hypercholanaemia of pregnancy is usually not sufficient to cause any clinically relevant effects. This review focuses on how gestation alters bile acid homeostasis, which can become pathological if the elevation of maternal serum bile acids is more marked than physiological hypercholanaemia, and on the influence of FXR and TGR5 function in pregnancy on glucose and lipid metabolism. This will be discussed with reference to two gestational disorders: intrahepatic cholestasis of pregnancy (ICP), a disease where bile acids are pathologically elevated, and gestational diabetes mellitus (GDM), characterised by hyperglycaemia during pregnancy.


Assuntos
Ácidos e Sais Biliares/metabolismo , Desenvolvimento Fetal/fisiologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Colestase Intra-Hepática/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Humanos , Gravidez , Complicações na Gravidez/metabolismo
4.
Biochim Biophys Acta Mol Basis Dis ; 1867(1): 165967, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32920120

RESUMO

Both obesity and gestational diabetes mellitus (GDM) lead to poor maternal and fetal outcomes, including pregnancy complications, fetal growth issues, stillbirth, and developmental programming of adult-onset disease in the offspring. Increased placental oxidative/nitrative stress and reduced placental (trophoblast) mitochondrial respiration occur in association with the altered maternal metabolic milieu of obesity and GDM. The effect is particularly evident when the fetus is male, suggesting a sexually dimorphic influence on the placenta. In addition, obesity and GDM are associated with inflexibility in trophoblast, limiting the ability to switch between usage of glucose, fatty acids, and glutamine as substrates for oxidative phosphorylation, again in a sexually dimorphic manner. Here we review mechanisms underlying placental mitochondrial dysfunction: its relationship to maternal and fetal outcomes and the influence of fetal sex. Prevention of placental oxidative stress and mitochondrial dysfunction may improve pregnancy outcomes. We outline pathways to ameliorate deficient mitochondrial respiration, particularly the benefits and pitfalls of mitochondria-targeted antioxidants.


Assuntos
Diabetes Gestacional/metabolismo , Mitocôndrias/metabolismo , Obesidade/metabolismo , Estresse Oxidativo , Trofoblastos/metabolismo , Diabetes Gestacional/patologia , Feminino , Humanos , Mitocôndrias/patologia , Obesidade/patologia , Gravidez , Trofoblastos/patologia
6.
Nature ; 589(7842): 442-447, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33361811

RESUMO

Successful pregnancies rely on adaptations within the mother1, including marked changes within the immune system2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (Treg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic Treg cells through RANK in a manner that depends on AIRE+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural Treg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of Treg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of Treg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of Treg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic Treg cells during pregnancy, and expand the functional role of maternal Treg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.


Assuntos
Diabetes Gestacional/imunologia , Morte Fetal/etiologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Linfócitos T Reguladores/imunologia , Timo/imunologia , Adipócitos/patologia , Animais , Proliferação de Células , Diabetes Gestacional/etiologia , Diabetes Gestacional/metabolismo , Diabetes Gestacional/patologia , Células Epiteliais/imunologia , Feminino , Feto/imunologia , Feto/metabolismo , Feto/patologia , Glucose/metabolismo , Intolerância à Glucose/genética , Humanos , Gordura Intra-Abdominal/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Placenta/imunologia , Placenta/patologia , Gravidez , Receptor Ativador de Fator Nuclear kappa-B/deficiência , Receptor Ativador de Fator Nuclear kappa-B/genética , Linfócitos T Reguladores/citologia , Timo/citologia , Fatores de Transcrição/metabolismo
7.
Int J Mol Sci ; 21(24)2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321877

RESUMO

Adipocytokines are hormonally active molecules that are believed to play a key role in the regulation of crucial biological processes in the human body. Numerous experimental studies established significant alterations in the adipokine secretion patterns throughout pregnancy. The exact etiology of various gestational complications, such as gestational diabetes, preeclampsia, and fetal growth abnormalities, needs to be fully elucidated. The discovery of adipokines raised questions about their potential contribution to the molecular pathophysiology of those diseases. Multiple studies analyzed their local mRNA expression and circulating protein levels. However, most studies report conflicting results. Several adipokines such as leptin, resistin, irisin, apelin, chemerin, and omentin were proposed as potential novel early markers of heterogeneous gestational complications. The inclusion of the adipokines in the standard predictive multifactorial models could improve their prognostic values. Nonetheless, their independent diagnostic value is mostly insufficient to be implemented into standard clinical practice. Routine assessments of adipokine levels during pregnancy are not recommended in the management of both normal and complicated pregnancies. Based on the animal models (e.g., apelin and its receptors in the rodent preeclampsia models), future implementation of adipokines and their receptors as new therapeutic targets appears promising but requires further validation in humans.


Assuntos
Adipocinas/metabolismo , Diabetes Gestacional/metabolismo , Pré-Eclâmpsia/metabolismo , Animais , Biomarcadores/metabolismo , Diabetes Gestacional/patologia , Feminino , Humanos , Pré-Eclâmpsia/patologia , Gravidez
8.
Ecotoxicol Environ Saf ; 205: 111154, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32810643

RESUMO

The study focused on the toxicological effect of Di-n-butyl phthalate (DBP) on the expression of Phosphorylated signal transducer and activator of transcription 1 (pSTAT1) -regulated Forkhead box protein M1 (FoxM1), which might provide a new understanding of gestational diabetes mellitus (GDM) development and a potential target for treatment. Streptozotocin (STZ) (40 mg/kg) was introduced in maternal rats by intraperitoneal injection on gestation day 0 (GD 0) in the STZ and STZ + DBP groups. DBP was introduced in maternal rats by oral feeding in the STZ + DBP group over the following 3 days (750 mg/kg/day). The changes in fasting blood glucose level in rats were detected on GD 1 and GD 5. The insulin levels in maternal rats and PIBCs were measured on GD 18. The Oral Glucose Tolerance Test (OGTT) test was performed on GD 18 to check the stability of the GDM model. The primary islet ß cells (PIBCs) were established for in vitro experiments. We examined the FoxM1 and pSTAT1 expression in pancreas by immunohistochemistry. Real-time PCR and Western blot were used to detect the pSTAR1 and FoxM1 protein and mRNA gene expression levels in PIBCs. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis was used to test the viability and apoptosis of cells. The results showed that the STZ + DBP group had higher glucose and lower insulin secretion levels than the other groups by both fasting test and OGTT. FoxM1 was significantly suppressed while pSTAT1 was highly expressed after DBP exposure. FoxM1 could be regulated by pSTAT1. DBP can influence the progression of GDM through its toxicological effect, which significantly increases the expression of pSTAT1 and suppresses FoxM1, causing a decline in ß cell viability.


Assuntos
Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Gestacional/induzido quimicamente , Dibutilftalato/toxicidade , Disruptores Endócrinos/toxicidade , Proteína Forkhead Box M1/metabolismo , Exposição Materna/efeitos adversos , Fator de Transcrição STAT1/metabolismo , Animais , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Proteína Forkhead Box M1/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Masculino , Fosforilação , Gravidez , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT1/genética , Transdução de Sinais
9.
Diabetes Res Clin Pract ; 167: 108353, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32739381

RESUMO

AIMS: We assessed how altered diagnostic processes and criteria for gestational diabetes mellitus (GDM) recommended by the United Kingdom (UK), Canada and Australia for use during the COVID-19 pandemic would affect both GDM frequency and related adverse outcomes. METHODS: Secondary analysis of 5974 HAPO study women with singleton pregnancies who underwent 75 g OGTTs and HbA1c assays between 24 and 32 weeks' gestation and who received no treatment for GDM. RESULTS: All post COVID-19 modified pathways reduced GDM frequency - UK (81%), Canada (82%) and Australia (25%). Canadian women whose GDM would remain undetected post COVID-19 (missed GDMs) displayed similar rates of pregnancy complications to those with post COVID-19 GDM. Using UK modifications, the missed GDM group were at slightly lower risk whilst the women missed using the Australian modifications were at substantially lower risk. CONCLUSIONS: The modifications in GDM diagnosis proposed for the UK, Canada and Australia result in differing reductions of GDM frequency. Each has both potential benefits in terms of reduction in potential exposure to COVID-19 and costs in terms of missed opportunities to influence pregnancy and postpartum outcomes. These factors should be considered when deciding which protocol is most appropriate for a particular context.


Assuntos
Glicemia/metabolismo , Infecções por Coronavirus/prevenção & controle , Diabetes Gestacional/diagnóstico , Teste de Tolerância a Glucose/métodos , Diagnóstico Ausente/estatística & dados numéricos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Complicações Infecciosas na Gravidez/prevenção & controle , Adulto , Austrália , Betacoronavirus , Canadá , Diabetes Gestacional/metabolismo , Jejum , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Guias de Prática Clínica como Assunto , Gravidez , Resultado da Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Reino Unido
10.
Am J Clin Nutr ; 112(2): 284-292, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32537643

RESUMO

BACKGROUND: Lower carbohydrate diets have the potential to improve glycemia but may increase ketonemia in women with gestational diabetes (GDM). We hypothesized that modestly lower carbohydrate intake would not increase ketonemia. OBJECTIVE: To compare blood ketone concentration, risk of ketonemia, and pregnancy outcomes in women with GDM randomly assigned to a lower carbohydrate diet or routine care. METHODS: Forty-six women aged (mean ± SEM) 33.3 ± 0.6 y and prepregnancy BMI 26.8 ± 0.9 kg/m2 were randomly assigned at 28.5 ± 0.4 wk to a modestly lower carbohydrate diet (MLC, ∼135 g/d carbohydrate) or routine care (RC, ∼200 g/d) for 6 wk. Blood ketones were ascertained by finger prick test strips and 3-d food diaries were collected at baseline and end of the intervention. RESULTS: There were no detectable differences in blood ketones between completers in the MLC group compared with the RC group (0.1 ± 0.0 compared with 0.1 ± 0.0 mmol/L, n = 33, P = 0.31, respectively), even though carbohydrate and total energy intake were significantly lower in the intervention group (carbohydrate 165 ± 7 compared with 190 ± 9 g, P = 0.04; energy 7040 ± 240 compared with 8230 ± 320 kJ, P <0.01, respectively). Only 20% of participants in the MLC group met the target intake compared with 65% in the RC group (P <0.01). There were no differences in birth weight, rate of large-for-gestational-age infants, percent fat mass, or fat-free mass between groups. CONCLUSIONS: An intervention to reduce carbohydrate intake in GDM did not raise ketones to clinical significance, possibly because the target of 135 g/d was difficult to achieve in pregnancy. Feeding studies with food provision may be needed to assess the benefits and risks of low-carbohydrate diets. This trial was registered at www.anzctr.org.au as ACTRN12616000018415.


Assuntos
Diabetes Gestacional/dietoterapia , Dieta com Restrição de Carboidratos , Adulto , Glicemia/metabolismo , Índice de Massa Corporal , Diabetes Gestacional/metabolismo , Carboidratos da Dieta/análise , Carboidratos da Dieta/metabolismo , Ingestão de Energia , Feminino , Índice Glicêmico , Humanos , Gravidez
11.
Eur J Endocrinol ; 183(3): 307-316, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32570208

RESUMO

Objective: Low circulating prolactin is a potential marker of metabolic risk during pregnancy. We aimed to investigate associations between prolactin and glucose status in pregnant women with and without gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS). Design: Prospective observational cohort study. From the Odense Child Cohort, 1497 pregnant women were included. Methods: Blood samples were assessed during first, second (prolactin, hemoglobin A1c (HbA1c)) and third trimester (fasting prolactin, testosterone, HbA1c, insulin, glucose). Oral glucose tolerance test (OGTT) was performed around gestation week 28 in 350 women with risk factors for GDM and in 272 randomly included women. GDM was defined by 2-h plasma glucose ≥9.0 mmol/L. Results: The median (IQR) prolactin increased from 633 (451-829) mIU/L in first-second trimester to 5223 (4151-6127) mIU/L at third trimester. Prolactin was inversely associated with HbA1c in first (r = -0.19, P < 0.001) and third trimester (r = -0.07, P = 0.014). In third trimester, women with GDM (n = 37; 6.0%) had lower prolactin compared to women without GDM (4269 vs 5072 mIU/L, P = 0.004). Third trimester prolactin multiple of the median (MoM) was inversely associated with risk of GDM in multivariate regression analysis (OR 0.30, P = 0.034). PCOS was diagnosed in 10.0% (n = 146). Early pregnancy prolactin MoM was positively associated to PCOS diagnosis (OR 1.38, P = 0.051). Conclusions: Low prolactin levels during pregnancy were associated with higher HbA1c and risk of GDM. A diagnosis of PCOS was associated with higher early pregnancy prolactin levels.


Assuntos
Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/metabolismo , Prolactina/sangue , Glicemia/metabolismo , Estudos de Coortes , Diabetes Gestacional/sangue , Diabetes Gestacional/metabolismo , Feminino , Teste de Tolerância a Glucose , Hemoglobina A Glicada/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Gravidez , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos
12.
Nat Rev Cardiol ; 17(11): 718-731, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32518358

RESUMO

Cardiovascular disease complicates 1-4% of pregnancies - with a higher prevalence when including hypertensive disorders - and is the leading cause of maternal death. In women with known cardiovascular pathology, such as congenital heart disease, timely counselling is possible and the outcome is fairly good. By contrast, maternal mortality is high in women with acquired heart disease that presents during pregnancy (such as acute coronary syndrome or aortic dissection). Worryingly, the prevalence of acquired cardiovascular disease during pregnancy is rising as older maternal age, obesity, diabetes mellitus and hypertension become more common in the pregnant population. Management of cardiovascular disease in pregnancy is challenging owing to the unique maternal physiology, characterized by profound changes to multiple organ systems. The presence of the fetus compounds the situation because both the cardiometabolic disease and its management might adversely affect the fetus. Equally, avoiding essential treatment because of potential fetal harm risks a poor outcome for both mother and child. In this Review, we examine how the physiological adaptations during pregnancy can provoke cardiometabolic complications or exacerbate existing cardiometabolic disease and, conversely, how cardiometabolic disease can compromise the adaptations to pregnancy and their intended purpose: the development and growth of the fetus.


Assuntos
Fenômenos Fisiológicos Cardiovasculares , Diabetes Gestacional/metabolismo , Hipertensão Induzida pela Gravidez/fisiopatologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Gravidez/fisiologia , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/fisiopatologia , Síndrome Coronariana Aguda/terapia , Aneurisma Dissecante/diagnóstico , Aneurisma Dissecante/fisiopatologia , Aneurisma Dissecante/terapia , Anti-Hipertensivos/uso terapêutico , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/terapia , Aspirina/uso terapêutico , Débito Cardíaco , Cardiomiopatias/diagnóstico , Cardiomiopatias/fisiopatologia , Cardiomiopatias/terapia , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/terapia , Progressão da Doença , Endocardite/diagnóstico , Endocardite/fisiopatologia , Endocardite/terapia , Feminino , Humanos , Hipertensão/fisiopatologia , Hipertensão Induzida pela Gravidez/diagnóstico , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Idade Materna , Obesidade Materna/metabolismo , Obesidade Materna/fisiopatologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Pré-Eclâmpsia/fisiopatologia , Pré-Eclâmpsia/prevenção & controle , Pré-Eclâmpsia/terapia , Gravidez/metabolismo , Complicações Cardiovasculares na Gravidez/diagnóstico , Complicações Cardiovasculares na Gravidez/terapia , Complicações Infecciosas na Gravidez/diagnóstico , Complicações Infecciosas na Gravidez/fisiopatologia , Complicações Infecciosas na Gravidez/terapia , Gravidez em Diabéticas/metabolismo , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/fisiopatologia
14.
PLoS Med ; 17(5): e1003112, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433647

RESUMO

BACKGROUND: Women with a history of gestational diabetes mellitus (GDM) have a 7-fold higher risk of developing type 2 diabetes (T2D) during midlife and an elevated risk of developing hypertension and cardiovascular disease. Glucose tolerance reclassification after delivery is recommended, but fewer than 40% of women with GDM are tested. Thus, improved risk stratification methods are needed, as is a deeper understanding of the pathology underlying the transition from GDM to T2D. We hypothesize that metabolites during the early postpartum period accurately distinguish risk of progression from GDM to T2D and that metabolite changes signify underlying pathophysiology for future disease development. METHODS AND FINDINGS: The study utilized fasting plasma samples collected from a well-characterized prospective research study of 1,035 women diagnosed with GDM. The cohort included racially/ethnically diverse pregnant women (aged 20-45 years-33% primiparous, 37% biparous, 30% multiparous) who delivered at Kaiser Permanente Northern California hospitals from 2008 to 2011. Participants attended in-person research visits including 2-hour 75-g oral glucose tolerance tests (OGTTs) at study baseline (6-9 weeks postpartum) and annually thereafter for 2 years, and we retrieved diabetes diagnoses from electronic medical records for 8 years. In a nested case-control study design, we collected fasting plasma samples among women without diabetes at baseline (n = 1,010) to measure metabolites among those who later progressed to incident T2D or did not develop T2D (non-T2D). We studied 173 incident T2D cases and 485 controls (pair-matched on BMI, age, and race/ethnicity) to discover metabolites associated with new onset of T2D. Up to 2 years post-baseline, we analyzed samples from 98 T2D cases with 239 controls to reveal T2D-associated metabolic changes. The longitudinal analysis tracked metabolic changes within individuals from baseline to 2 years of follow-up as the trajectory of T2D progression. By building prediction models, we discovered a distinct metabolic signature in the early postpartum period that predicted future T2D with a median discriminating power area under the receiver operating characteristic curve of 0.883 (95% CI 0.820-0.945, p < 0.001). At baseline, the most striking finding was an overall increase in amino acids (AAs) as well as diacyl-glycerophospholipids and a decrease in sphingolipids and acyl-alkyl-glycerophospholipids among women with incident T2D. Pathway analysis revealed up-regulated AA metabolism, arginine/proline metabolism, and branched-chain AA (BCAA) metabolism at baseline. At follow-up after the onset of T2D, up-regulation of AAs and down-regulation of sphingolipids and acyl-alkyl-glycerophospholipids were sustained or strengthened. Notably, longitudinal analyses revealed only 10 metabolites associated with progression to T2D, implicating AA and phospholipid metabolism. A study limitation is that all of the analyses were performed with the same cohort. It would be ideal to validate our findings in an independent longitudinal cohort of women with GDM who had glucose tolerance tested during the early postpartum period. CONCLUSIONS: In this study, we discovered a metabolic signature predicting the transition from GDM to T2D in the early postpartum period that was superior to clinical parameters (fasting plasma glucose, 2-hour plasma glucose). The findings suggest that metabolic dysregulation, particularly AA dysmetabolism, is present years prior to diabetes onset, and is revealed during the early postpartum period, preceding progression to T2D, among women with GDM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01967030.


Assuntos
Aminoácidos/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Gestacional/metabolismo , Metabolismo dos Lipídeos , Adulto , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Período Pós-Parto/metabolismo , Gravidez , Fatores de Risco , Adulto Jovem
15.
PLoS One ; 15(5): e0232297, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407388

RESUMO

BACKGROUND AND AIMS: Genetic variants involved in vitamin D metabolism have been associated with diabetes and related syndromes/diseases. We wanted to investigate possible associations of polymorphisms in genes involved in vitamin D metabolism with indices of insulin resistance and insulin secretion, and also with development of diabetes after gestational diabetes mellitus (GDM). MATERIALS AND METHODS: We have studied 376 women with previous GDM. Eight single nucleotide polymorphisms (SNPs) in the genes for vitamin D receptor (VDR) [rs731236, rs7975232, rs10735810, and rs1544410], vitamin D binding protein (DBP) [rs7041 and rs4588], and cytochrome P450 family 27 subfamily B member 1 (CYP27B1) [rs10877012 and rs4646536] were genotyped by TaqMan Allelic Discrimination Assay using the Quantstudio 7 Flex system. A 75-g oral glucose tolerance test (OGTT) was performed 1-2 years postpartum. The homeostasis model assessment of insulin resistance (HOMA-IR) and the disposition index [(insulinogenic index: I30/G30)/HOMA-IR] were used to calculate insulin resistance and insulin secretion, respectively. Serum samples for determination of 25(OH)D3 were collected at the time of the OGTT. Manifestation of diabetes was followed up to five years postpartum. RESULTS: After adjustment for BMI, age, and ethnicity, the A-allele of the VDR rs1544410 polymorphism was found to be associated with increased disposition index (difference per allele = 3.56, 95% CI: 0.4567-6.674; p = 0.03). The A-allele of the DBP rs7041 polymorphism was found to be associated with 25(OH)D3 levels (difference [in nmol/L] per allele = -5.478, 95% CI: -8.315 to -2.641; p = 0.0002), as was the T-allele of the DBP rs4588 polymorphism (OR = -6.319, 95% CI: -9.466 to -3.171; p = 0.0001). None of the SNPs were significantly associated with HOMA-IR or postpartum diabetes. CONCLUSIONS: This study provides evidence that the rs1544410 polymorphism of the VDR gene may be associated with increased insulin secretion in women after pregnancy complicated by GDM. Further studies in other populations are needed to confirm the results.


Assuntos
Diabetes Gestacional/genética , Diabetes Gestacional/metabolismo , Secreção de Insulina/genética , Polimorfismo de Nucleotídeo Único , Receptores de Calcitriol/genética , Feminino , Seguimentos , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Gravidez
16.
PLoS One ; 15(4): e0230658, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240196

RESUMO

BACKGROUND AND PURPOSE: Excess insulin resistance is considered the predominant pathophysiological mechanism in obese women who develop gestational diabetes (GDM). We hypothesised that obese women requiring differing treatment modalities for GDM may have diverse underlying metabolic pathways. METHODS: In this secondary analysis of the UK pregnancies Better Eating and Activity Trial (UPBEAT) we studied women from the control arm with complete biochemical data at three gestational time points; at 15-18+6 and 27-28+6 weeks (before treatment), and 34-36+0 weeks (after treatment). A total of 89 analytes were measured (plasma/serum) using a targeted nuclear magnetic resonance (NMR) platform and conventional assays. We used linear regression with appropriate adjustment to model metabolite concentration, stratified by treatment group. MAIN FINDINGS: 300 women (median BMI 35kg/m2; inter quartile range 32.8-38.2) were studied. 71 developed GDM; 28 received dietary treatment only, 20 metformin, and 23 received insulin. Prior to the initiation of treatment, multiple metabolites differed (p<0.05) between the diet and insulin-treated groups, especially very large density lipoprotein (VLDL) and high density lipoprotein (HDL) subclasses and constituents, with some differences maintained at 34-36 weeks' gestation despite treatment. Gestational lipid profiles of the diet treatment group were indicative of a lower insulin resistance profile, when compared to both insulin-treated women and those without GDM. At 28 weeks' the diet treatment group had lower plasma fasting glucose and insulin than women treated with insulin, yet similar to those without GDM, consistent with a glycaemic mechanism independent of insulin resistance. CONCLUSIONS/INTERPRETATION: This exploratory study suggests that GDM pathophysiological processes may differ amongst obese women who require different treatment modalities to achieve glucose control and can be revealed using metabolic profiling.


Assuntos
Biomarcadores/sangue , Glicemia/análise , Diabetes Gestacional/fisiopatologia , Dieta/métodos , Hipoglicemiantes/uso terapêutico , Obesidade/fisiopatologia , Triglicerídeos/sangue , Adulto , Diabetes Gestacional/tratamento farmacológico , Diabetes Gestacional/metabolismo , Feminino , Humanos , Insulina/uso terapêutico , Resistência à Insulina , Metformina/uso terapêutico , Obesidade/metabolismo , Gravidez
17.
Clin Sci (Lond) ; 134(6): 571-592, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32129440

RESUMO

Gestational diabetes mellitus (GDM) is a global health issue, whereby pregnant women are afflicted with carbohydrate intolerance with first onset during pregnancy. GDM is characterized by maternal peripheral insulin resistance, thought to be driven by low-grade maternal inflammation. Nobiletin, a polymethoxylated flavonoid, possesses potent glucose-sensitizing and anti-inflammatory properties; however, its effects in GDM have not been assessed. The present study aimed to determine the effects of nobiletin on glucose metabolism and inflammation associated with GDM in both in vitro human tissues and an in vivo animal model of GDM. In vitro, treatment with nobiletin significantly improved TNF-impaired glucose uptake in human skeletal muscle, and suppressed mRNA expression and protein secretion of pro-inflammatory cytokines and chemokines in human placenta and visceral adipose tissue (VAT). Mechanistically, nobiletin significantly inhibited Akt and Erk activation in placenta, and NF-κB activation in VAT. In vivo, GDM mice treated with 50 mg/kg nobiletin daily via oral gavage from gestational day (gd) 1-17 or via i.p. injections from gd 10-17 significantly improved glucose tolerance. Pregnant GDM mice treated with nobiletin from either gd 1-17 or gd 10-17 exhibited significantly suppressed mRNA expression of pro-inflammatory cytokines and chemokines in placenta, VAT and subcutaneous adipose tissue (SAT). Using a quantitative mass spectrometry approach, we identified differentially abundant proteins associated with the effect of nobiletin in vivo. Together, these studies demonstrate that nobiletin improves glucose metabolism and reduces inflammation associated with GDM and may be a novel therapeutic for the prevention of GDM.


Assuntos
Anti-Inflamatórios/administração & dosagem , Diabetes Gestacional/tratamento farmacológico , Flavonas/administração & dosagem , Hipoglicemiantes/administração & dosagem , Animais , Citocinas/imunologia , Diabetes Gestacional/genética , Diabetes Gestacional/imunologia , Diabetes Gestacional/metabolismo , Modelos Animais de Doenças , Feminino , Glucose/metabolismo , Humanos , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Placenta/efeitos dos fármacos , Placenta/imunologia , Placenta/metabolismo , Gravidez , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo
18.
In Vivo ; 34(2): 517-525, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32111749

RESUMO

AIM: To identify differentially expressed proteins (DEPs) in 1st trimester maternal plasma between pregnant women at risk for gestational diabetes mellitus (GDM) and uncomplicated controls. MATERIALS AND METHODS: First-trimester plasma from five women who developed GDM and five from non-diabetic ones were analyzed using isobaric tag for relative and absolute quantitation - labeled proteomics. Enzyme-linked immunosorbent assay was further applied in an independent cohort of 25 GDM cases and 25 controls for verification. RESULTS: Prenylcysteine oxidase 1 (PCYOX1), beta-ala-his dipeptidase (CNDP1), extracellular matrix protein 1 (ECM1), basement membrane-specific heparan sulfate proteoglycan core protein (HSPG2), thrombospondin-4 (TSP-4) demonstrated significant differences in expression between the two groups (p<0.05). DEPs are mainly associated with complement and coagulation cascades. CONCLUSION: The reported plasma proteomic changes represent potential biomarkers for the early identification of women at risk for GDM. Future studies using larger and more diverse cohorts are necessary to assess the clinical utility of these findings.


Assuntos
Biomarcadores , Diabetes Gestacional/diagnóstico , Diabetes Gestacional/metabolismo , Proteômica , Adulto , Proteínas Sanguíneas , Estudos de Casos e Controles , Cromatografia Líquida , Biologia Computacional/métodos , Diabetes Gestacional/sangue , Diagnóstico Precoce , Feminino , Ontologia Genética , Humanos , Gravidez , Prognóstico , Proteoma , Proteômica/métodos , Curva ROC , Espectrometria de Massas em Tandem
19.
Artigo em Inglês | MEDLINE | ID: mdl-32144130

RESUMO

INTRODUCTION: Gestational diabetes mellitus (GDM), a common pregnancy disorder, increases the risk of fetal overgrowth and later metabolic morbidity in the offspring. The placenta likely mediates these sequelae, but the exact mechanisms remain elusive. Mitochondrial dynamics refers to the joining and division of these organelles, in attempts to maintain cellular homeostasis in stress conditions or alterations in oxygen and fuel availability. These remodeling processes are critical to optimize mitochondrial function, and their disturbances characterize diabetes and obesity. METHODS AND RESULTS: Herein we show that placental mitochondrial dynamics are tilted toward fusion in GDM, as evidenced by transmission electron microscopy and changes in the expression of key mechanochemical enzymes such as OPA1 and active phosphorylated DRP1. In vitro experiments using choriocarcinoma JEG-3 cells demonstrated that increased exposure to insulin, which typifies GDM, promotes mitochondrial fusion. As placental ceramide induces mitochondrial fission in pre-eclampsia, we also examined ceramide content in GDM and control placentae and observed a reduction in placental ceramide enrichment in GDM, likely due to an insulin-dependent increase in ceramide-degrading ASAH1 expression. CONCLUSIONS: Placental mitochondrial fusion is enhanced in GDM, possibly as a compensatory response to maternal and fetal metabolic derangements. Alterations in placental insulin exposure and sphingolipid metabolism are among potential contributing factors. Overall, our results suggest that GDM has profound impacts on placental mitochondrial dynamics and metabolism, with plausible implications for the short-term and long-term health of the offspring.


Assuntos
Diabetes Gestacional/fisiopatologia , Dinâmica Mitocondrial , Placenta/fisiopatologia , Linhagem Celular , Ceramidas/metabolismo , Diabetes Gestacional/metabolismo , Feminino , Homeostase , Humanos , Insulina/administração & dosagem , Insulina/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/metabolismo , Placenta/metabolismo , Placenta/ultraestrutura , Gravidez
20.
Artigo em Inglês | MEDLINE | ID: mdl-32179515

RESUMO

OBJECTIVES: Abdominal obesity is more closely associated with diabetes than general obesity in adults, however, it is unknown which kind of obesity is more closely associated with abnormal glucose metabolism in children. RESEARCH DESIGN AND METHODS: We recruited 973 children (aged 3.08±1.06) of mothers with prior gestational diabetes mellitus (GDM). Children's height, weight, waist circumstance, fasting glucose and insulin were measured using standardized methods. Logistic regression models were used to assess the single and joint associations of general and abdominal obesity with the risks of hyperglycemia (the upper quartile of fasting glucose), insulin resistance (the upper quartile of homeostatic model assessment of insulin resistance (HOMA-IR)), and ß-cell dysfunction (the lower quartile of HOMA-%ß). RESULTS: Compared with normal weight children, children with general overweight/obesity had higher levels of HOMA-IR and HOMA-%ß, higher ORs for hyperglycemia (1.56, 95% CI 1.06 to 2.30) and insulin resistance (3.44, 95% CI 2.32 to 5.09), but a lower OR for ß-cell dysfunction (0.65, 95% CI 0.41 to 1.04). Children with abdominal obesity had an increased risk of insulin resistance (2.54, 95% CI 1.71 to 3.76) but not hyperglycemia and ß-cell dysfunction compared with children with normal waist circumstance. In the joint analyses, general overweight children with and without abdominal obesity had an increased risk of hyperglycemia and insulin resistance compared with normal weight children. CONCLUSIONS: General obesity was more closely associated with abnormal glucose metabolism than abdominal obesity in children of mothers with GDM.


Assuntos
Diabetes Gestacional/metabolismo , Glucose/metabolismo , Obesidade Abdominal/metabolismo , Obesidade/metabolismo , Pré-Escolar , Feminino , Humanos , Hiperglicemia/metabolismo , Resistência à Insulina , Masculino , Gravidez
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