Pregnancy induces longitudinal changes in urinary C-peptide creatinine ratio in women with type 1 diabetes.

AIMS: Changes in maternal serum C-peptide have been described during pregnancy in women with Type 1 diabetes. We aimed to determine whether in these women, C-peptide, as measured by the urinary C-peptide creatinine ratio (UCPCR), display changes during the course of pregnancy and in the postpartum period. METHODS: In this longitudinal study including 26 women, UCPCR was measured in the first, second, and third trimester of pregnancy, and postpartum, using a high sensitivity two-step chemiluminescent microparticle immunoassay. RESULTS: UCPCR was detectable in 7/26 (26.9%) participants in the first trimester, 10/26 (38.4%) in the second trimester, and 18/26 (69.2%) in the third trimester. Changes in UCPCR concentrations were observed throughout pregnancy, significantly increasing from first to third trimester. UCPCR concentration in the three trimesters was associated with a shorter duration of diabetes and in the third trimester also with first trimester UCPCR. CONCLUSION: UCPCR detects longitudinal changes during pregnancy in women with type 1 diabetes mellitus, more marked in those with shorter diabetes duration.

Impact of gestational diabetes mellitus treatment on medium/long-term outcomes after pregnancy: A systematic review and meta-analysis.

AIM: We aimed to evaluate the effect of gestational diabetes mellitus (GDM) treatment on medium/long-term outcomes both the mother and offspring. METHODS: We performed a systematic review on randomized clinical trials addressing specific treatment of women with GDM versus usual care and its impact on maternal and offspring outcomes at medium/long-term. MEDLINE, EMBASE and CENTRAL were searched from inception to 8 October 2021. OUTCOME VARIABLES: maternal (diabetes, metabolic syndrome, 12 secondary); offspring (diabetes, impaired fasting glucose, impaired glucose tolerance, high body mass index, 15 secondary). Risk of bias was assessed with Cochrane tool and aggregation performed with Revman 5.4. RESULTS: We included five studies (1140 women, 767 offspring) with follow-up ranging 4-16 years after delivery. GDM treatment likely does not reduce risk of maternal diabetes (RR 1.00; [95% CI 0.82-1.23]) and may not reduce that of metabolic syndrome (RR 0.93; [95% CI 0.71-1.22]). We obtained very uncertain evidence that treatment may increase maternal HDL-cholesterol. Findings showed that GDM treatment may not have an impact on infants' outcomes (RRs 0.79; [95% CI 0.39-1.69] for impaired fasting glucose; RR 0.91; [95% CI 0.74-1.12] for body mass index >85th centile and 0.89; [95% CI 0.65-1.22] for body mass index >95th centile respectively). CONCLUSIONS: With current evidence is uncertain if specific treatment of women with GDM has an impact on medium/long-term metabolic outcomes either in the mother or in the offspring. These results add evidence to the recommendation of systematically reevaluating mother and offspring after delivery. REGISTRATION: OSF, DOI 10.17605/OSF.IO/KFN79.

Association between inadequate weight gain according to the institute of medicine 2009 guidelines and pregnancy outcomes in women with thyroid disorders.

PURPOSE: Gestational weight gain (GWG) is an important contributor to pregnancy outcomes in the general obstetric population and different subgroups. The corresponding information in women with thyroid conditions is limited. We aimed to evaluate the relationship between GWG according to institute of medicine (IOM) and pregnancy outcomes in women with thyroid disorders. METHODS: We performed a retrospective analysis of 620 pregnant women either treated with levothyroxine (N = 545) or attended because of hyperthyroidism during pregnancy (N = 75). RESULTS: The associations between GWG according to IOM and pregnancy outcomes were present both in women treated with thyroid hormone and women followed by hyperthyroidism, most of them related to the fetal outcomes. In women treated with levothyroxine, insufficient GWG was associated with gestational diabetes mellitus (GDM) (odds ratio (OR) 2.32, 95% confidence interval (CI) 1.18, 4.54), preterm birth (OR 2.31, 95% CI 1.22, 4.36), small-for-gestational age newborns (OR 2.38, 95% CI 1.09, 5.22) and respiratory distress (OR 6.89, 95% CI 1.46, 32.52). Excessive GWG was associated with cesarean delivery (OR 1.66, 95% CI 1.10, 2.51) and macrosomia (OR 2.75, 95% CI 1.38, 5.49). Large-for-gestational age newborns were associated with both insufficient GWG (OR 0.25, 95% CI 0.11, 0.58) and excessive GWG (OR 1.80, 95% CI 1.11, 2.92). In women followed by hyperthyroidism, excessive GWG was associated with large-for-gestational age newborns (OR 5.56, 95% CI 1.03, 29.96). CONCLUSION: GWG according to IOM is associated with pregnancy outcomes both in women treated with thyroid hormone and women followed by hyperthyroidism.

Low-Density Lipoprotein Receptor Is a Key Driver of Aggressiveness in Thyroid Tumor Cells.

We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the presence of BRAF V600E mutation is associated with more aggressive PTC. Although the link between MAPK cascade and LDL receptor (LDLR) expression has been previously described, it is unknown whether LDL can potentiate the adverse effects of PTC through it. We aimed to investigate whether the presence of LDL might accelerate the oncogenic processes through MAPK pathway in presence or absence of BRAF V600E in two thyroid cell lines: TPC1 and BCPAP (wild-type and BRAF V600E, respectively). LDLR, PI3K-AKT and RAS/RAF/MAPK (MEK)/ERK were analyzed via Western blot; cell proliferation was measured via MTT assay, cell migration was studied through wound-healing assay and LDL uptake was analyzed by fluorometric and confocal analysis. TPC1 demonstrated a time-specific downregulation of the LDLR, while BCPAP resulted in a receptor deregulation after LDL exposition. LDL uptake was increased in BCPAP over-time, as well as cell proliferation (20% higher) in comparison to TPC1. Both cell lines differed in migration pattern with a wound closure of 83.5 ± 9.7% after LDL coculture in TPC1, while a loss in the adhesion capacity was detected in BCPAP. The siRNA knockdown of LDLR in LDL-treated BCPAP cells resulted in a p-ERK expression downregulation and cell proliferation modulation, demonstrating a link between LDLR and MAPK pathway. The modulation of BRAF-V600E using vemurafenib-impaired LDLR expression decreased cellular proliferation. Our results suggest that LDLR regulation is cell line-specific, regulating the RAS/RAF/MAPK (MEK)/ERK pathway in the LDL-signaling cascade and where BRAF V600E can play a critical role. In conclusion, targeting LDLR and this downstream signaling cascade, could be a new therapeutic strategy for PTC with more aggressive behavior, especially in those harboring BRAF V600E.

LDL, HDL and endocrine-related cancer: From pathogenic mechanisms to therapies.

Cholesterol is essential for a variety of functions in endocrine-related cells, including hormone and steroid production. We have reviewed the progress to date in research on the role of the main cholesterol-containing lipoproteins; low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and their impact on intracellular cholesterol homeostasis and carcinogenic pathways in endocrine-related cancers. Neither LDL-cholesterol (LDL-C) nor HDL-cholesterol (HDL-C) was consistently associated with endocrine-related cancer risk. However, preclinical studies showed that LDL receptor plays a critical role in endocrine-related tumor cells, mainly by enhancing circulating LDL-C uptake and modulating tumorigenic signaling pathways. Although scavenger receptor type BI-mediated uptake of HDL could enhance cell proliferation in breast, prostate, and ovarian cancer, these effects may be counteracted by the antioxidant and anti-inflammatory properties of HDL. Moreover, 27-hydroxycholesterol a metabolite of cholesterol promotes tumorigenic processes in breast and epithelial thyroid cancer. Furthermore, statins have been reported to reduce the incidence of breast, prostate, pancreatic, and ovarian cancer in large clinical trials, in part because of their ability to lower cholesterol synthesis. Overall, cholesterol homeostasis deregulation in endocrine-related cancers offers new therapeutic opportunities, but more mechanistic studies are needed to translate the preclinical findings into clinical therapies.

Breastfeeding effect on glucose tolerance assessment in women with previous gestational diabetes mellitus: A randomized controlled trial.

AIMS: To test whether breastfeeding during the oral glucose tolerance test (OGTT) affects glucose and insulin outcomes (main outcome: 120 min plasma glucose). METHODS: A randomized crossover trial was conducted in 20 women with prior gestational diabetes mellitus. Each woman undertook two OGTTs in the first 3 months after delivery, breastfeeding the infant in one and avoiding breastfeeding in the other. Glucose and insulin were measured at 0, 30, 60 and 120 min. Statistics included: T-test for paired data, general linear model (GLM) for repeated measures. Analysis of covariance (ANCOVA) was used to adjust for glucose and insulin values at 0 min. Statistical dispersion for GLM and ANCOVA outcomes is expressed as standard error. RESULTS: In the OGTTs with breastfeeding, higher values were observed for overall glucose and insulin concentrations, glucose and insulin peaks and individual time points of glucose (at 0, 30 and 60 min) and insulin (at 0 and 60 min) but without differences at 120 min (glucose 6.7 ± 0.3 vs. 6.9 ± 0.3 mmol/L, p = 0.506). The rate of abnormal tests was not different. ANCOVA confirmed higher postchallenge glucose values in the OGTT with breastfeeding and similar glucose values at 120 min. CONCLUSIONS: According to the results of this randomized trial, we conclude that breastfeeding during the OGTT resulted in similar 120 min glucose concentration and glycaemic status categorization. However, breastfeeding during the OGTT led to clear differences in glucose and insulin values in the first hour, that warrant further studies.

Hypopituitarism and pregnancy: clinical characteristics, management and pregnancy outcome.

PURPOSE: To describe the clinical characteristics, management and pregnancy outcome of women with prepregnancy hypopituitarism (HYPO) that received care at our center. METHODS: Retrospective study describing 12 pregnancies in women with prepregnancy HYPO (two or more pituitary hormonal deficiencies under replacement treatment) that received care during pregnancy at Hospital Santa Creu i Sant Pau. Clinical characteristics, management and pregnancy outcome were systematically collected. RESULTS: Average patients' age was 35 years and HYPO duration at the beginning of pregnancy was 19 years. The most frequent cause of HYPO was surgical treatment of a sellar mass (8 pregnancies). Eight pregnancies were in primigravid women and 10 required assisted reproductive techniques. The hormonal deficits before pregnancy were as follows: GH in 12 women, TSH in 10, gonadotropin in 9, ACTH in 5 and ADH in 2. All deficits were under hormonal substitution except for GH deficit in 4 pregnancies. During pregnancy, 4 new deficits were diagnosed. The dosage of replacement treatment for TSH, ACTH and ADH deficits was increased and GH was stopped. Average gestational age at birth was 40 weeks, gestational weight gain was excessive in 9 women, 8 patients required induction/elective delivery and cesarean section was performed in 6. Average birthweight was 3227 g. No major complications were observed. Five women were breastfeeding at discharge. CONCLUSIONS: In this group of women with long-standing HYPO, with careful clinical management (including treatment of new-onset hormonal deficits) pregnancy outcome was satisfactory but with a high rate of excessive gestational weight gain and cesarean section.

Less sedentary time is associated with a more favourable glucose-insulin axis in obese pregnant women-a secondary analysis of the DALI study.

BACKGROUND/OBJECTIVES: Obese pregnant women are at high risk of developing gestational diabetes mellitus (GDM), which might be reduced by sufficient physical activity (PA) and reduced sedentary time (ST). We assessed whether PA and ST are longitudinally associated with the glucose-insulin axis in obese pregnant women. SUBJECTS/METHODS: In this secondary analysis of the DALI (vitamin D And Lifestyle Intervention for gestational diabetes mellitus prevention) study, pregnant women, <20 weeks gestation, with a pre-pregnancy body mass index (BMI) ≥ 29 kg/m2, without GDM on entry were included. Time spent in moderate-to-vigorous PA (MVPA) and ST were measured objectively with accelerometers at <20 weeks, 24-28 weeks and 35-37 weeks of gestation. Fasting glucose (mmol/l) and insulin (mU/l), insulin resistance (HOMA-IR) and first-phase and second-phase insulin release (Stumvoll first and second phase) were assessed at the same time. Linear mixed regression models were used to calculate between-participant differences and within-participant changes over time. Analyses were adjusted for gestational age, randomisation, pre-pregnancy BMI, education and age. MVPA, Insulin, HOMA-IR and Stumvoll first and second phase were log-transformed for analyses due to skewness. RESULTS: 232 women were included in the analysis. Concerning differences between participants, more ST was associated with higher fasting glucose (Estimate: 0.008; 95% CI: 0.002, 0.014), fasting insulin (0.011; 0.002, 0.019), HOMA-IR (0.012; 0.004, 0.021) and Stumvoll first and second phase (0.008; 0.001, 0.014 and 0.007; 0.001, 0.014). Participants with more MVPA had lower Stumvoll first and second phase (-0.137; -0.210, -0.064 and -0.133; -0.202, -0.063). Concerning changes over time, an increase in ST during gestation was associated with elevated Stumvoll first and second phase (0.006; 0.000, 0.011). CONCLUSIONS: As the glucose-insulin axis is more strongly associated with ST than MVPA in our obese population, pregnant women could be advised to reduce ST in addition to increasing MVPA. Moreover, our findings suggest that behaviour change interventions aiming at GDM risk reduction should start in early or pre-pregnancy.

The importance of maternal insulin resistance throughout pregnancy on neonatal adiposity.

BACKGROUND: Although previous studies evaluated the association of maternal health parameters with neonatal adiposity, little is known regarding the complexity of the relationships among different maternal health parameters throughout pregnancy and its impact on neonatal adiposity. OBJECTIVES: To evaluate the direct and indirect associations between maternal insulin resistance during pregnancy, in women with obesity, and neonatal adiposity. In addition, associations between maternal fasting glucose, triglycerides (TG), non-esterified fatty acids (NEFA), and neonatal adiposity were also assessed. METHODS: This is a longitudinal, secondary analysis of the DALI study, an international project conducted in nine European countries with pregnant women with obesity. Maternal insulin resistance (HOMA-IR), fasting glucose, TG, and NEFA were measured three times during pregnancy (<20, 24-28, and 35-37 weeks of gestation). Offspring neonatal adiposity was estimated by the sum of four skinfolds. Structural equation modelling was conducted to evaluate the direct and indirect relationships among the variables of interest. RESULTS: Data on 657 mother-infant pairs (50.7% boys) were analysed. Neonatal boys exhibited lower mean sum of skinfolds compared to girls (20.3 mm, 95% CI 19.7, 21.0 vs 21.5 mm, 95% CI 20.8, 22.2). In boys, maternal HOMA-IR at <20 weeks was directly associated with neonatal adiposity (ß = 0.35 mm, 95% CI 0.01, 0.70). In girls, maternal HOMA-IR at 24-28 weeks was only indirectly associated with neonatal adiposity, which implies that this association was mediated via maternal HOMA-IR, glucose, triglycerides, and NEFA during pregnancy (ß = 0.26 mm, 95% CI 0.08, 0.44). CONCLUSIONS: The timing of the role of maternal insulin resistance on neonatal adiposity depends on fetal sex. Although the association was time-dependent, maternal insulin resistance was associated with neonatal adiposity in both sexes.

Which growth standards should be used to identify large- and small-for-gestational age infants of mothers with type 1 diabetes? A pre-specified analysis of the CONCEPTT trial.

BACKGROUND: Offspring of women with type 1 diabetes are at increased risk of fetal growth patterns which are associated with perinatal morbidity. Our aim was to compare rates of large- and small-for-gestational age (LGA; SGA) defined according to different criteria, using data from the Continuous Glucose Monitoring in Type 1 Diabetes Pregnancy Trial (CONCEPTT). METHODS: This was a pre-specified analysis of CONCEPTT involving 225 pregnant women and liveborn infants from 31 international centres ( ClinicalTrials.gov NCT01788527; registered 11/2/2013). Infants were weighed immediately at birth and GROW, INTERGROWTH and WHO centiles were calculated. Relative risk ratios, sensitivity and specificity were used to assess the different growth standards with respect to perinatal outcomes, including neonatal hypoglycaemia, hyperbilirubinaemia, respiratory distress, neonatal intensive care unit (NICU) admission and a composite neonatal outcome. RESULTS: Accelerated fetal growth was common, with mean birthweight percentiles of 82.1, 85.7 and 63.9 and LGA rates of 62, 67 and 30% using GROW, INTERGROWTH and WHO standards respectively. Corresponding rates of SGA were 2.2, 1.3 and 8.9% respectively. LGA defined according to GROW centiles showed stronger associations with preterm delivery, neonatal hypoglycaemia, hyperbilirubinaemia and NICU admission. Infants born > 97.7th centile were at highest risk of complications. SGA defined according to INTERGROWTH centiles showed slightly stronger associations with perinatal outcomes. CONCLUSIONS: GROW and INTERGROWTH standards performed similarly and identified similar numbers of neonates with LGA and SGA. GROW-defined LGA and INTERGROWTH-defined SGA had slightly stronger associations with neonatal complications. WHO standards underestimated size in preterm infants and are less applicable for use in type 1 diabetes. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov . number NCT01788527 . Trial registered 11/2/2013.

Both glycaemic control and insulin dose during pregnancy in women with type 1 diabetes are associated with neonatal anthropometric measures and placental weight.

BACKGROUND: To investigate longitudinal associations of maternal glucose/HbA1c and insulin dose with birthweight-related outcomes in women with type 1 diabetes. METHODS: We performed a cohort study including 473 pregnant women with type 1 diabetes with singleton pregnancies. We investigated maternal self-monitored blood glucose (SMBG, mmol/L), HbA1c (%, mmol/mol) and insulin dose (IU/kg/day) in the three trimesters as potential independent variables, while adjusting for potential confounders. Outcomes of interest were birthweight, birthweight SD score, neonatal length, weight/length index, ponderal index and placental weight. Multiple linear regression analysis was performed with separate analyses for SMBG and HbA1c . RESULTS: Maternal glucose and insulin dose were independently associated with birthweight-related outcomes. In the main analysis, in the first trimester most associations were positive for insulin dose, in the second the associations were positive for glucose and inverse for insulin while in the third there were no associations. Most sensitivity analyses produced consistent results. In a sensitivity analysis splitting the first trimester in two periods, positive associations of maternal insulin with birthweight-related outcomes were observed in weeks 0+ to 6+. CONCLUSIONS: Early in pregnancy in women with type 1 diabetes, maternal insulin dose is positively associated with birthweight-related outcomes, whereas in the second trimester, a positive association with SMBG emerges and the association with maternal insulin becomes inverse. If confirmed in other cohorts, these results would have implications in the management of women with type 1 diabetes.

Correction to: The Effects of Lifestyle and/or Vitamin D Supplementation Interventions on Pregnancy Outcomes: What Have we Learned from the DALI Studies?

The original version of this review article unfortunately contained a mistake.

Intensive Insulin Therapy (Basal-Bolus).

BACKGROUND: Intensive insulin therapy (IIT) aims at achieving near-normal glycemic control and usually uses a basal-bolus (BB) schema to mimic physiologic insulin secretion. AREAS OF UNCERTAINTY: The treatment burden of IIT should be outweighed by improved glycemic control and reduction of chronic complications, but reviews summarizing the effects of IIT in subjects with T1DM and T2DM in glycated hemoglobin, hypoglycemia, insulin doses, and weight are limited. DATA SOURCES: We performed a PubMed search to identify relevant randomized control trials (RCTs) comparing IIT and conventional insulin treatment in T1DM and T2DM subjects and addressing glycated hemoglobin, hypoglycemia, insulin requirements, and weight. THERAPEUTIC ADVANCES: We have identified 11 RCTs in T1DM subjects, published years ago and very heterogenous in design. Throughout the studies there was a consistent superiority of IIT in glycated hemoglobin reduction, a higher rate of severe hypoglycemia and more weight gain in the IIT group without a clear effect on insulin doses. We have identified 2 RCTs in T2DM subjects, only one of them using a definite BB schema in the IIT group. IIT induced more hypoglycemia and better HbA1c, but not more weight gain. CONCLUSIONS: IIT is the best option for treatment of subjects with T1DM in HbA1c reduction with a cost in the rate of hypoglycemia and weight gain. In subjects with T2DM, IIT also yields improvement in HbA1c versus conventional treatment, also at the cost of more hypoglycemic episodes, but not of higher weight gain. RCT treatment arms did not only differ in the insulin schema, but also in treatment goals, therapeutic education, and frequency of clinical visits among other characteristics. However, most evidence was gained using a BB insulin schema in the intensive arm and it is likely that the insulin schema had a relevant contribution in the results.

A reduction in sedentary behaviour in obese women during pregnancy reduces neonatal adiposity: the DALI randomised controlled trial.

AIMS/HYPOTHESIS: Offspring of obese women are at increased risk of features of the metabolic syndrome, including obesity and diabetes. Lifestyle intervention in pregnancy might reduce adverse effects of maternal obesity on neonatal adiposity. METHODS: In the Vitamin D And Lifestyle Intervention for Gestational Diabetes Mellitus (GDM) Prevention (DALI) lifestyle trial, 436 women with a BMI ≥29 kg/m2 were randomly assigned to counselling on healthy eating (HE), physical activity (PA) or HE&PA, or to usual care (UC). In secondary analyses of the lifestyle trial, intervention effects on neonatal outcomes (head, abdominal, arm and leg circumferences and skinfold thicknesses, estimated fat mass, fat percentage, fat-free mass and cord blood leptin) were assessed using multilevel regression analyses. Mediation of intervention effects by lifestyle and gestational weight gain was assessed. RESULTS: Outcomes were available from 334 neonates. A reduction in sum of skinfolds (-1.8 mm; 95% CI -3.5, -0.2; p = 0.03), fat mass (-63 g; 95% CI -124, -2; p = 0.04), fat percentage (-1.2%; 95% CI -2.4%, -0.04%; p = 0.04) and leptin (-3.80 µg/l; 95% CI -7.15, -0.45; p = 0.03) was found in the HE&PA group, and reduced leptin in female neonates in the PA group (-5.79 µg/l; 95% CI -11.43, -0.14; p = 0.05) compared with UC. Reduced sedentary time, but not gestational weight gain, mediated intervention effects on leptin in both the HE&PA and PA groups. CONCLUSIONS/INTERPRETATION: The HE&PA intervention resulted in reduced adiposity in neonates. Reduced sedentary time seemed to drive the intervention effect on cord blood leptin. Implications for future adiposity and diabetes risk of the offspring need to be elucidated. TRIAL REGISTRATION: ISRCTN70595832.

The Effects of Lifestyle and/or Vitamin D Supplementation Interventions on Pregnancy Outcomes: What Have We Learned from the DALI Studies?

PURPOSE OF REVIEW: The DALI (vitamin D and lifestyle intervention in the prevention of gestational diabetes mellitus (GDM)) study aimed to prevent GDM with lifestyle interventions or Vitamin D supplementation (1600 IU/day). This review summarizes the learnings from the DALI studies among pregnant women with a BMI ≥ 29 kg/m2. RECENT FINDINGS: Women diagnosed with GDM earlier in pregnancy had a worse metabolic profile than those diagnosed later. A combined physical activity (PA) and healthy eating (HE) lifestyle intervention improved both behaviours, limited gestational weight gain (GWG) and was cost-effective. Although GDM risk was unchanged, neonatal adiposity was reduced due to less sedentary time. Neither PA nor HE alone limited GWG or GDM risk. Fasting glucose was higher with HE only intervention, and lower with Vitamin D supplementation. Our combined intervention did not prevent GDM, but was cost-effective, limited GWG and reduced neonatal adiposity.

Cross-Talk between Inflammatory Mediators and the Epithelial Mesenchymal Transition Process in the Development of Thyroid Carcinoma.

There is strong association between inflammatory processes and their main metabolic mediators, such as leptin, adiponectin secretion, and low/high-density lipoproteins, with the cancer risk and aggressive behavior of solid tumors. In this scenario, cancer cells (CCs) and cancer stem cells (CSCs) have important roles. These cellular populations, which come from differentiated cells and progenitor stem cells, have increased metabolic requirements when it comes to maintaining or expanding the tumors, and they serve as links to some inflammatory mediators. Although the molecular mechanisms that are involved in these associations remain unclear, the two following cellular pathways have been suggested: 1) the mesenchymal-epithelial transition (MET) process, which permits the differentiation of adult stem cells throughout the acquisition of cell polarity and the adhesion to epithelia, as well to new cellular lineages (CSCs); and, 2) a reverse process, termed the epithelial-mesenchymal transition (EMT), where, in pathophysiological conditions (tissue injury, inflammatory process, and oxidative stress), the differentiated cells can acquire a multipotent stem cell-like phenotype. The molecular mechanisms that regulate both EMT and MET are complex and poorly understood. Especially, in the thyroid gland, little is known regarding MET/EMT and the role of CCs or CSCs, providing an exciting, new area of knowledge to be investigated. This article reviews the progress to date in research on the role of inflammatory mediators and metabolic reprogramming during the carcinogenesis process of the thyroid gland and the EMT pathways.

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research.

Cost-effectiveness of healthy eating and/or physical activity promotion in pregnant women at increased risk of gestational diabetes mellitus: economic evaluation alongside the DALI study, a European multicenter randomized controlled trial.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with perinatal health risks to both mother and offspring, and represents a large economic burden. The DALI study is a multicenter randomized controlled trial, undertaken to add to the knowledge base on the effectiveness of interventions for pregnant women at increased risk for GDM. The purpose of this study was to evaluate the cost-effectiveness of the healthy eating and/or physical activity promotion intervention compared to usual care among pregnant women at increased risk of GDM from a societal perspective. METHODS: An economic evaluation was performed alongside a European multicenter-randomized controlled trial. A total of 435 pregnant women at increased risk of GDM in primary and secondary care settings in nine European countries, were recruited and randomly allocated to a healthy eating and physical activity promotion intervention (HE + PA intervention), a healthy eating promotion intervention (HE intervention), or a physical activity promotion intervention (PA intervention). Main outcome measures were gestational weight gain, fasting glucose, insulin resistance (HOMA-IR), quality adjusted life years (QALYs), and societal costs. RESULTS: Between-group total cost and effect differences were not significant, besides significantly less gestational weight gain in the HE + PA group compared with the usual care group at 35-37 weeks (-2.3;95%CI:-3.7;-0.9). Cost-effectiveness acceptability curves indicated that the HE + PA intervention was the preferred intervention strategy. At 35-37 weeks, it depends on the decision-makers' willingness to pay per kilogram reduction in gestational weight gain whether the HE + PA intervention is cost-effective for gestational weight gain, whereas it was not cost-effective for fasting glucose and HOMA-IR. After delivery, the HE + PA intervention was cost-effective for QALYs, which was predominantly caused by a large reduction in delivery-related costs. CONCLUSIONS: Healthy eating and physical activity promotion was found to be the preferred strategy for limiting gestational weight gain. As this intervention was cost-effective for QALYs after delivery, this study lends support for broad implementation. TRIAL REGISTRATION: ISRCTN ISRCTN70595832 . Registered 2 December 2011.

Epidemiology of gestational diabetes mellitus according to IADPSG/WHO 2013 criteria among obese pregnant women in Europe.

AIMS/HYPOTHESIS: Accurate prevalence estimates for gestational diabetes mellitus (GDM) among pregnant women in Europe are lacking owing to the use of a multitude of diagnostic criteria and screening strategies in both high-risk women and the general pregnant population. Our aims were to report important risk factors for GDM development and calculate the prevalence of GDM in a cohort of women with BMI ≥29 kg/m2 across 11 centres in Europe using the International Association of the Diabetes and Pregnancy Study Groups (IADPSG)/WHO 2013 diagnostic criteria. METHODS: Pregnant women (n = 1023, 86.3% European ethnicity) with a BMI ≥29.0 kg/m2 enrolled into the Vitamin D and Lifestyle Intervention for GDM Prevention (DALI) pilot, lifestyle and vitamin D studies of this pan-European multicentre trial, attended for an OGTT during pregnancy. Demographic, anthropometric and metabolic data were collected at enrolment and throughout pregnancy. GDM was diagnosed using IADPSG/WHO 2013 criteria. GDM treatment followed local policies. RESULTS: The number of women recruited per country ranged from 80 to 217, and the dropout rate was 7.1%. Overall, 39% of women developed GDM during pregnancy, with no significant differences in prevalence across countries. The prevalence of GDM was high (24%; 242/1023) in early pregnancy. Despite interventions used in the DALI study, a further 14% (94/672) had developed GDM when tested at mid gestation (24-28 weeks) and 13% (59/476) of the remaining cohort at late gestation (35-37 weeks). Demographics and lifestyle factors were similar at baseline between women with GDM and those who maintained normal glucose tolerance. Previous GDM (16.5% vs 7.9%, p = 0.002), congenital malformations (6.4% vs 3.3%, p = 0.045) and a baby with macrosomia (31.4% vs 17.9%, p = 0.001) were reported more frequently in those who developed GDM. Significant anthropometric and metabolic differences were already present in early pregnancy between women who developed GDM and those who did not. CONCLUSIONS/INTERPRETATION: The prevalence of GDM diagnosed by the IADPSG/WHO 2013 GDM criteria in European pregnant women with a BMI ≥29.0 kg/m2 is substantial, and poses a significant health burden to these pregnancies and to the future health of the mother and her offspring. Uniform criteria for GDM diagnosis, supported by robust evidence for the benefits of treatment, are urgently needed to guide modern GDM screening and treatment strategies.