Insulin-stimulated adiponectin secretion in pregnancy is mediated by inhibition of adiponectin ubiquitination and degradation and is impaired in obesity

ABSTRACTIn pregnancy, adiponectin serves as an endocrine link between maternal adipose tissue, placental function and fetal growth, with low adiponectin promoting placental function and fetal growth. Circulating adiponectin levels are decreased in obese pregnant women and in gestational diabetes, which is believed to contribute to the insulin resistance and increased risk of fetal overgrowth associated with these conditions. However, the molecular mechanisms governing adiponectin secretion from maternal adipose tissues in pregnancy are poorly understood. Using visceral adipose tissue from lean and obese pregnant mice, we show that obesity in pregnancy is associated with adipose tissue inflammation, ER stress, insulin resistance, increased adiponectin ubiquitination and decreased total abundance of adiponectin. Moreover, adiponectin ubiquitination was increased in visceral fat of obese pregnant women as compared to lean pregnant women. We further observed that insulin prevents, whereas ER stress and inflammation promote, adiponectin ubiquitination and degradation in differentiated 3T3-L1 adipocytes. We have identified key molecular pathways regulating adiponectin secretion in pregnancy. This information will help us better understand the mechanisms controlling maternal insulin resistance and fetal growth in pregnancy and may provide a foundation for the development of strategies aimed at improving adiponectin production in pregnant women with obesity or gestational diabetes.

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Insulin Increases Adipose Adiponectin in Pregnancy by Inhibiting Ubiquitination and Degradation: Impact of Obesity

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab680 ◽

2021 ◽

Author(s):

Irving L M H Aye ◽

Fredrick J Rosario ◽

Anita Kramer ◽

Oddrun Kristiansen ◽

Trond M Michelsen ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Gestational Diabetes ◽

Er Stress ◽

Pregnant Women ◽

Adipose Tissues ◽

Markers Of Inflammation ◽

Increased Risk ◽

Obesity In Pregnancy ◽

In Pregnancy

Abstract Context Circulating adiponectin levels are decreased in pregnant women with obesity or gestational diabetes, and this is believed to contribute to the insulin resistance and increased risk of fetal overgrowth associated with these conditions. However, the molecular mechanisms regulating adiponectin secretion from maternal adipose tissues in pregnancy are poorly understood. Objective We tested the hypothesis that obesity in pregnancy is associated with adipose tissue insulin resistance and increased adiponectin ubiquitination and degradation, caused by inflammation and endoplasmic reticulum (ER) stress. Methods Visceral adipose tissues were collected from lean and obese pregnant humans and mice. Total and ubiquitinated adiponectin, and markers of inflammation, ER stress, and insulin resistance were examined in adipose tissues. The role of insulin, inflammation, and ER stress in mediating adiponectin ubiquitination and degradation was examined using 3T3L-1 adipocytes. Results Obesity in pregnancy is associated with adipose tissue inflammation, ER stress, insulin resistance, increased adiponectin ubiquitination, and decreased total abundance of adiponectin. Adiponectin ubiquitination was increased in visceral fat of obese pregnant women as compared to lean pregnant women. We further observed that insulin prevents, whereas ER stress and inflammation promote, adiponectin ubiquitination and degradation in differentiated 3T3-L1 adipocytes. Conclusion We have identified adiponectin ubiquitination as a key mechanism by which obesity diminishes adiponectin secretion in pregnancy. This information will help us better understand the mechanisms controlling maternal insulin resistance and fetal growth in pregnancy and may provide a foundation for the development of strategies aimed at improving adiponectin production in pregnant women with obesity or gestational diabetes.

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Association between maternal triglycerides and disturbed glucose metabolism in pregnancy

Acta Diabetologica ◽

10.1007/s00592-020-01644-z ◽

2021 ◽

Author(s):

Daniel Eppel ◽

Michael Feichtinger ◽

Tina Lindner ◽

Grammata Kotzaeridi ◽

Ingo Rosicky ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Metabolism ◽

Gestational Diabetes ◽

Pregnant Women ◽

Early Pregnancy ◽

Early Gestation ◽

Glucose Levels ◽

Increased Risk ◽

Mean Glucose ◽

In Pregnancy

Abstract Aims Dyslipidemia in pregnancy is associated with adverse pregnancy outcomes as elevated triglycerides might be considered as a risk factor for hyperglycemia and gestational diabetes. As only a few studies have addressed the association between maternal triglycerides and glucose metabolism, we aimed to explore the pathophysiologic associations of moderate hypertriglyceridemia and maternal glucose metabolism in pregnancy. Methods Sixty-seven pregnant women received a detailed metabolic characterization at 12+0–22+6 weeks of gestation by an extended 2h-75g OGTT (oral glucose tolerance test); with measurements of glucose, insulin and C-peptide at fasting and every 30 min after ingestion and assessment of triglycerides at fasting state. All examinations were repeated at 24+0–27+6 weeks of gestation. Results Elevated triglycerides in early gestation were associated with insulin resistance and β-cell dysfunction. Mean glucose concentrations during the OGTT in early pregnancy were already higher in women with hypertriglyceridemia as compared to women with triglycerides in the normal range. A higher degree of insulin resistance and increased OGTT glucose levels were also observed when metabolic assessments were repeated between 24 and 28 weeks of gestation. Of note, elevated triglycerides at early gestation were associated with development of gestational diabetes by logistic regression (odds ratio: 1.16, 95%CI: 1.03–1.34, p=0.022 for an increase of 10 mg/dl). Conclusions Hypertriglyceridemia at the start of pregnancy is closely related to impaired insulin action and β-cell function. Women with hypertriglyceridemia have higher mean glucose levels in early- and mid-gestation. Pregnant women with elevated triglycerides in early pregnancy are at increased risk of developing gestational diabetes.

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The consequences of obesity and excess weight gain in pregnancy

Proceedings of The Nutrition Society ◽

10.1017/s0029665111003077 ◽

2011 ◽

Vol 70 (4) ◽

pp. 450-456 ◽

Cited By ~ 81

Author(s):

Jane E. Norman ◽

Rebecca Reynolds

Keyword(s):

Insulin Resistance ◽

Weight Gain ◽

Gestational Diabetes ◽

Pregnant Women ◽

Postpartum Haemorrhage ◽

Maternal Obesity ◽

Adverse Pregnancy Outcome ◽

Operative Delivery ◽

Adverse Pregnancy ◽

In Pregnancy

The prevalence of obesity in pregnancy is rising exponentially; about 15–20% of pregnant women now enter pregnancy with a BMI which would define them as obese. This paper provides a review of the strong links between obesity and adverse pregnancy outcome which operate across a range of pregnancy complications. For example, obesity is associated with an increased risk of maternal mortality, gestational diabetes mellitus, thromboembolism, pre-eclampsia and postpartum haemorrhage. Obesity also complicates operative delivery; it makes operative delivery more difficult, increases complications and paradoxically increases the need for operative delivery. The risk of the majority of these complications is amplified by excess weight gain in pregnancy and increases in proportion to the degree of obesity, for example, women with extreme obesity have OR of 7·89 for gestational diabetes and 3·84 for postpartum haemorrhage compared to their lean counterparts. The consequences of maternal obesity do not stop once the baby is born. Maternal obesity programmes a variety of long-term adverse outcomes, including obesity in the offspring at adulthood. Such an effect is mediated at least in part via high birthweight; a recent study has suggested that the odds of adult obesity are two-fold greater in babies weighing more than 4 kg at birth. The mechanism by which obesity causes adverse pregnancy outcome is uncertain. This paper reviews the emerging evidence that hyperglycaemia and insulin resistance may both play a role: the links between hyperglycaemia in pregnancy and both increased birthweight and insulin resistance have been demonstrated in two large studies. Lastly, we discuss the nature and rationale for possible intervention strategies in obese pregnant women.

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Differential Expression of MicroRNAs in Omental Adipose Tissue From Gestational Diabetes Mellitus Subjects Reveals miR-222 as a Regulator of ERα Expression in Estrogen-Induced Insulin Resistance

Endocrinology ◽

10.1210/en.2013-2046 ◽

2014 ◽

Vol 155 (5) ◽

pp. 1982-1990 ◽

Cited By ~ 69

Author(s):

Zhonghua Shi ◽

Chun Zhao ◽

Xirong Guo ◽

Hongjuan Ding ◽

Yugui Cui ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Adipose Tissue ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Differential Expression ◽

Molecular Mechanisms ◽

Expression Patterns ◽

Luciferase Assay ◽

Omental Adipose Tissue

Omental adipose tissue plays a central role in insulin resistance in gestational diabetes mellitus (GDM), and the molecular mechanisms leading to GDM remains vague. Evidence demonstrates that maternal hormones, such as estradiol, contribute to insulin resistance in GDM. In this study we determined the differential expression patterns of microRNAs (miRNAs) in omental adipose tissues from GDM patients and pregnant women with normal glucose tolerance using AFFX miRNA expression chips. MiR-222, 1 of 17 identified differentially expressed miRNAs, was found to be significantly up-regulated in GDM by quantitative real-time PCR (P < .01), and its expression was closely related with serum estradiol level (P < .05). Furthermore, miR-222 expression was significantly increased in 3T3-L1 adipocytes with a high concentration of 17β-estradiol stimulation (P < .01), whereas the expressions of estrogen receptor (ER)-α protein and insulin-sensitive membrane transporter glucose transporter 4 (GLUT4) protein (P < .01) were markedly reduced. In addition, ERα was shown to be a direct target of miR-222 in 3T3-L1 adipocytes by using the luciferase assay. Finally, antisense oligonucleotides of miR-222 transfection was used to silence miR-222 in 3T3-L1 adipocytes. The results showed that the expressions of ERα and GLUT4, the insulin-stimulated translocation of GLUT4 from the cytoplasm to the cell membrane and glucose uptake in mature adipocytes were dramatically increased (P < .01). In conclusion, miR-222 is a potential regulator of ERα expression in estrogen-induced insulin resistance in GDM and might be a candidate biomarker and therapeutic target for GDM.

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Diabetes in Pregnancy and Risk of Antepartum Depression: A Systematic Review and Meta-Analysis of Cohort Studies

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph17113767 ◽

2020 ◽

Vol 17 (11) ◽

pp. 3767 ◽

Cited By ~ 1

Author(s):

Kai Wei Lee ◽

Siew Mooi Ching ◽

Navin Kumar Devaraj ◽

Seng Choi Chong ◽

Sook Yee Lim ◽

...

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Cohort Studies ◽

Pregnant Women ◽

Meta Analysis ◽

Diabetes In Pregnancy ◽

Antepartum Depression ◽

Increased Risk ◽

In Pregnancy

Previous literature has reported that patients with diabetes in pregnancy (DIP) are at risk of developing antepartum depression but the results have been inconsistent in cohort studies. We conducted a systematic review and performed a meta-analysis to quantify the association between DIP and risk of antepartum depression in cohort studies. Medline, Cinahl, and PubMed databases were searched for studies investigating DIP involving pregnant women with pre-existing diabetes and gestational diabetes mellitus and their risk of antepartum depression that were published in journals from inception to 27 December 2019. We derived the summary estimates using a random-effects model and reported the findings as pooled relative risks (RR) and confidence interval (CI). Publication bias was assessed using a funnel plot and was quantified by Egger and Begg’s tests. Ten studies, involving 71,036 pregnant women were included in this meta-analysis. The pooled RR to develop antepartum depression was (RR = 1.430, 95% CI: 1.251–1.636) among women with gestational diabetes mellitus. Combining pregnant women with pre-existing diabetes mellitus and gestational diabetes mellitus, they had a significant increased risk of developing antepartum depression (RR = 1.431, 95% CI: 1.205–1.699) compared with those without it. In comparison, we found no association between pre-existing diabetes mellitus in pregnancy (RR = 1.300, 95% CI: 0.736–2.297) and the risk of developing antepartum depression. This study has a few limitations: first, different questionnaire and cut-off points were used in evaluation of depression across the studies. Second, there was a lack of data on history of depression prior to pregnancy, which lead to confounding bias that could not be solved by this meta-analysis. Third, data were dominated by studies in Western countries; this is due to the studies from Eastern countries failing to meet our inclusion criteria for statistical analysis. Women with gestational diabetes mellitus have an increased risk of developing antepartum depression compared to those without the disease. Therefore, more attention on the mental health status should be given on pregnant women diagnosed with pre-existing diabetes mellitus and gestational diabetes mellitus.

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Iron Status from Early Through Late Pregnancy and Neonatal Anthropometric Measures: Friend or Foe?

Current Developments in Nutrition ◽

10.1093/cdn/nzaa054_075 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1003-1003

Author(s):

Anisa Holloman ◽

Jing Wu ◽

Mengying Li ◽

Shristi Rawal ◽

Ellen Francis ◽

...

Keyword(s):

Iron Deficiency ◽

Pregnant Women ◽

Fetal Growth ◽

Gestational Age ◽

Chronic Conditions ◽

Iron Status ◽

Late Pregnancy ◽

Increased Risk ◽

Maternal Iron ◽

In Pregnancy

Abstract Objectives Although iron status in pregnancy is an important factor for fetal growth, associations between maternal iron status and neonatal size are highly conflicting. Further, studies with longitudinal measures of iron status in pregnancy are scarce. This study investigated maternal iron status from early through late pregnancy using comprehensive measures of iron biomarkers (ferritin, hepcidin, soluble transferrin receptor [sTfR], and sTfR: ferritin ratio) in relation to neonatal size. Methods This study included 321 pregnant women without major chronic conditions before pregnancy who were enrolled in the NICHD Fetal Growth Study- Singletons (n = 2802). Plasma iron biomarkers (i.e., ferritin, sTfR, hepcidin) were measured at 4 visits (10–14, 15–26, 23–31, and 33–39 gestational weeks [GW]). We used linear and Poisson regression models adjusted for covariates including pre-pregnancy BMI and C-reactive protein to estimate the association of tertiles (T) of iron biomarkers and clinically defined iron status with neonatal anthropometry, such as birthweight (BW), risk of large and small-for-gestational age (LGA, SGA) and macrosomia. Results Iron deficiency (i.e., ferritin <12 ug/L) at 10–14 GW was related to increased risk of macrosomia and LGA; adjusted RR (95% confidence interval (CI)) were 3.64 (1.45, 9.17), and 14.2 (5.49, 36.4), respectively. At 15–26 GW, iron deficiency was also related to increased risk of LGA with a RR of 3.58 (1.13, 11.4). In contrast, at 33–39 GW, iron deficiency was related to lower risk of macrosomia with a RR of 0.06 (0.01, 0.36). The CIs were wide, largely due to small sample size of macrosomia cases. In addition, at 10–14 GW, lower iron status (indicated by higher sTfR levels) was related to greater BW; highest vs. lowest T mean BW was 3385 g vs. 3251 g with an adjusted p-value for difference <0.05. Conclusions Our findings among U.S. pregnant women without major chronic conditions before pregnancy suggest that the relation of maternal iron status to neonatal size may vary by gestational age and lower iron status in early pregnancy is generally related to heavier neonates. Funding Sources Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/National Institutes of Health (NIH).

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First trimester uric acid level: a reliable marker for gestational diabetes mellitus

International Journal of Reproduction Contraception Obstetrics and Gynecology ◽

10.18203/2320-1770.ijrcog20192430 ◽

2019 ◽

Vol 8 (6) ◽

pp. 2358

Author(s):

Suvarna Jyothi Ganta ◽

Sunanda R. Kulkarni

Keyword(s):

Diabetes Mellitus ◽

Uric Acid ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Pregnant Women ◽

Serum Uric Acid ◽

First Trimester ◽

Family History Of Diabetes ◽

Increased Risk ◽

In Pregnancy

Background: The prevalence of diabetes mellitus (DM) is increasing worldwide and more in developing countries like India. The diabetic epidemic experienced in India can be due to strong genetic factors coupled with increasing urbanization, sedentary lifestyle, changes in the dietary patterns and increasing obesity. Indians are at an 11-fold increased risk of developing gestational glucose intolerance and hence universal screening is essential. Uric acid is a known marker of oxidative stress. Hyperuricemia in early pregnancy may be an indicator of the existing metabolic disturbance which can hinder the maternal physiological adaptations generally seen in pregnancy thus making the pregnant women more vulnerable to the development of gestational diabetes mellitus. The objective of this study was to investigate the association between elevated uric acid levels in the first trimester of pregnancy with gestational diabetes.Methods: This prospective observational study was conducted in Chinmaya mission hospital, Bangalore from June 2016 to March 2017 (10 months). Three hundred and twelve (312) pregnant women of gestational age less than 12 weeks who attended the OBG outpatient department within this time of period for regular antenatal check-up were enrolled in the study. Along with the other antenatal investigations serum uric acid levels were estimated before 12 weeks and also between 24-28 weeks. At 24-28 weeks screening for GDM was done by OGCT using 75 gms of glucose (IADPISG criteria). Other parameters like age, parity, BMI, family history of diabetes was noted and compared.Results: In our study, among the 312 pregnant women, 88 (28%) developed GDM. Of these 74 Women (84%) with GDM had uric acid levels above 3.5 mg/dl and 14 women (15.9%) with GDM had uric acid levels below 3.5 mg/dl. Women with higher BMI showed high uric acid levels.Conclusions: Elevated serum uric acid in the first trimester has a significant correlation with development of GDM. In present study; the cut-off level of maternal serum uric acid of 3.5 mg/dl in the first trimester appears to have a good sensitivity and specificity in identifying those patients who are most likely to develop GDM later in pregnancy.

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Obesity, insulin resistance and comorbidities ? Mechanisms of association

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/0004-2730000003223 ◽

2014 ◽

Vol 58 (6) ◽

pp. 600-609 ◽

Cited By ~ 91

Author(s):

Ana Valeria B. Castro ◽

Cathryn M. Kolka ◽

Stella P. Kim ◽

Richard N. Bergman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Molecular Mechanisms ◽

Metabolic Diseases ◽

Polycystic Ovary ◽

Bone Fragility ◽

The Body ◽

Ectopic Fat ◽

Increased Risk ◽

Fat Liver

Overall excess of fat, usually defined by the body mass index, is associated with metabolic (e.g. glucose intolerance, type 2 diabetes mellitus (T2DM), dyslipidemia) and non-metabolic disorders (e.g. neoplasias, polycystic ovary syndrome, non-alcoholic fat liver disease, glomerulopathy, bone fragility etc.). However, more than its total amount, the distribution of adipose tissue throughout the body is a better predictor of the risk to the development of those disorders. Fat accumulation in the abdominal area and in non-adipose tissue (ectopic fat), for example, is associated with increased risk to develop metabolic and non-metabolic derangements. On the other hand, observations suggest that individuals who present peripheral adiposity, characterized by large hip and thigh circumferences, have better glucose tolerance, reduced incidence of T2DM and of metabolic syndrome. Insulin resistance (IR) is one of the main culprits in the association between obesity, particularly visceral, and metabolic as well as non-metabolic diseases. In this review we will highlight the current pathophysiological and molecular mechanisms possibly involved in the link between increased VAT, ectopic fat, IR and comorbidities. We will also provide some insights in the identification of these abnormalities. Arq Bras Endocrinol Metab. 2014;58(6):600-9

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Gestational Diabetes Mellitus and Infant Adiposity at Birth: A Systematic Review and Meta-Analysis of Therapeutic Interventions

Journal of Clinical Medicine ◽

10.3390/jcm10040835 ◽

2021 ◽

Vol 10 (4) ◽

pp. 835

Author(s):

Manoja P. Herath ◽

Jeffrey M. Beckett ◽

Andrew P. Hills ◽

Nuala M. Byrne ◽

Kiran D. K. Ahuja

Keyword(s):

Diabetes Mellitus ◽

Adipose Tissue ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Fat Mass ◽

Metabolic Disorders ◽

Later Life ◽

Therapeutic Interventions ◽

Increased Risk ◽

The Impact

Exposure to untreated gestational diabetes mellitus (GDM) in utero increases the risk of obesity and type 2 diabetes in adulthood, and increased adiposity in GDM-exposed infants is suggested as a plausible mediator of this increased risk of later-life metabolic disorders. Evidence is equivocal regarding the impact of good glycaemic control in GDM mothers on infant adiposity at birth. We systematically reviewed studies reporting fat mass (FM), percent fat mass (%FM) and skinfold thicknesses (SFT) at birth in infants of mothers with GDM controlled with therapeutic interventions (IGDMtr). While treating GDM lowered FM in newborns compared to no treatment, there was no difference in FM and SFT according to the type of treatment (insulin, metformin, glyburide). IGDMtr had higher overall adiposity (mean difference, 95% confidence interval) measured with FM (68.46 g, 29.91 to 107.01) and %FM (1.98%, 0.54 to 3.42) but similar subcutaneous adiposity measured with SFT, compared to infants exposed to normal glucose tolerance (INGT). This suggests that IGDMtr may be characterised by excess fat accrual in internal adipose tissue. Given that intra-abdominal adiposity is a major risk factor for metabolic disorders, future studies should distinguish adipose tissue distribution of IGDMtr and INGT.

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Prenatal electrocardiogram testing and postpartum depression: A population-based cohort study

Obstetric Medicine ◽

10.1177/1753495x211012502 ◽

2021 ◽

pp. 1753495X2110125

Author(s):

Jonathan S Zipursky ◽

Deva Thiruchelvam ◽

Donald A Redelmeier

Keyword(s):

Cohort Study ◽

Postpartum Depression ◽

Pregnant Women ◽

Odds Ratio ◽

Population Based ◽

Relative Increase ◽

Organic Disease ◽

Increased Risk ◽

Clinical Clue ◽

In Pregnancy

Background Cardiovascular symptoms in pregnancy may be a clue to psychological distress. We examined whether electrocardiogram testing in pregnant women is associated with an increased risk of subsequent postpartum depression. Methods We conducted a population-based cohort study of pregnant women who delivered in Ontario, Canada comparing women who received a prenatal ECG to women who did not. Results In total, 3,238,218 women gave birth during the 25-year study period of whom 157,352 (5%) received an electrocardiogram during prenatal care. Receiving an electrocardiogram test was associated with a one-third relative increase in the odds of postpartum depression (odds ratio 1.34; 95% confidence interval 1.29–1.39, p < 0.001). Conclusion The association between prenatal electrocardiogram testing and postpartum depression suggests a possible link of organic disease with mental illness, and emphasizes that cardiovascular symptoms may be a clinical clue to the presence of an underlying mood disorder.

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