Medical comorbidities in bipolar disorder (BIPCOM): clinical validation of risk factors and biomarkers to improve prevention and treatment. Study protocol.

BACKGROUND: BIPCOM aims to (1) identify medical comorbidities in people with bipolar disorder (BD); (2) examine risk factors and clinical profiles of Medical Comorbidities (MC) in this clinical group, with a special focus on Metabolic Syndrome (MetS); (3) develop a Clinical Support Tool (CST) for the personalized management of BD and medical comorbidities. METHODS: The BIPCOM project aims to investigate MC, specifically MetS, in individuals with BD using various approaches. Initially, prevalence rates, characteristics, genetic and non-genetic risk factors, and the natural progression of MetS among individuals with BD will be assessed by analysing Nordic registers, biobanks, and existing patient datasets from 11 European recruiting centres across 5 countries. Subsequently, a clinical study involving 400 participants from these sites will be conducted to examine the clinical profiles and incidence of specific MetS risk factors over 1 year. Baseline assessments, 1-year follow-ups, biomarker analyses, and physical activity measurements with wearable biosensors, and focus groups will be performed. Using this comprehensive data, a CST will be developed to enhance the prevention, early detection, and personalized treatment of MC in BD, by incorporating clinical, biological, sex and genetic information. This protocol will highlight the study's methodology. DISCUSSION: BIPCOM's data collection will pave the way for tailored treatment and prevention approaches for individuals with BD. This approach has the potential to generate significant healthcare savings by preventing complications, hospitalizations, and emergency visits related to comorbidities and cardiovascular risks in BD. BIPCOM's data collection will enhance BD patient care through personalized strategies, resulting in improved quality of life and reduced costly interventions. The findings of the study will contribute to a better understanding of the relationship between medical comorbidities and BD, enabling accurate prediction and effective management of MetS and cardiovascular diseases. TRIAL REGISTRATION: ISRCTN68010602 at https://www.isrctn.com/ISRCTN68010602 . Registration date: 18/04/2023.

Real-world evidence of off-label use of commercially automated insulin delivery systems compared to multiple daily insulin injections in pregnancies complicated by type 1 diabetes.

AIMS: To compare glycemic control and maternal-fetal outcomes of women with type 1 diabetes (T1D) using hybrid closed loop (HCL) vs. multiple daily insulin injections (MDI) plus continuous glucose monitoring (CGM). METHODS: Multicenter prospective cohort study of pregnant women with T1D in Spain. We evaluated HbA1c and time spent within (TIR), below (TBR) and above (TAR) the pregnancy-specific glucose range 3.5-7.8 mmol/L. Adjusted models were performed for adverse pregnancy outcomes including baseline maternal characteristics and center. RESULTS: 112 women were included (HCL n=59). Women in the HCL group had a longer duration of diabetes and higher rates of prepregnancy care. There were no between-group differences in HbA1c in any trimester. However, in the second trimester, MDI users had a greater decrease in HbA1c (-6.12±9.06 vs. -2.16 ±7.42 mmol/mol, p=0.031). No differences in TIR (3.5-7.8 mmol/L) and TAR were observed between HCL and MDI users, but with a higher total insulin dose in the second trimester (+0.13 IU/Kg/d). HCL therapy was associated with increased maternal weight gain during pregnancy (ßadjusted 3.20 kg, 95%CI 0.90-5.50). Regarding neonatal outcomes, newborns of HCL users were more likely to have higher birthweight (ßadjusted 279.0 g, 95% CI 39.5-518.5) and macrosomia (ORadjusted 3.18, 95% CI 1.05-9.67) compared to MDI users. These associations disappeared when maternal weight gain or third trimester HbA1c were included in the models. CONCLUSIONS: In a real-world setting, HCL users gained more weight during pregnancy and had larger newborns than MDI users, while achieving similar glycemic control in terms of HbA1c and TIR.

COMPAR-EU Recommendations on Self-Management Interventions in Type 2 Diabetes Mellitus.

Self-management interventions (SMIs) offer a promising approach to actively engage patients in the management of their chronic diseases. Within the scope of the COMPAR-EU project, our goal is to provide evidence-based recommendations for the utilisation and implementation of SMIs in the care of adult individuals with type 2 diabetes mellitus (T2DM). A multidisciplinary panel of experts, utilising a core outcome set (COS), identified critical outcomes and established effect thresholds for each outcome. The panel formulated recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, a transparent and rigorous framework for developing and presenting the best available evidence for the formulation of recommendations. All recommendations are based on systematic reviews (SR) of the effects and of values and preferences, a contextual analysis, and a cost-effectiveness analysis. The COMPAR-EU panel is in favour of using SMIs rather than usual care (UC) alone (conditional, very low certainty of the evidence). Furthermore, the panel specifically is in favour of using ten selected SMIs, rather than UC alone (conditional, low certainty of the evidence), mostly encompassing education, self-monitoring, and behavioural techniques. The panel acknowledges that, for most SMIs, moderate resource requirements exist, and cost-effectiveness analyses do not distinctly favour either the SMI or UC. Additionally, it recognises that SMIs are likely to enhance equity, deeming them acceptable and feasible for implementation.

Gestational weight gain in women with type 1 and type 2 diabetes mellitus is related to both general and diabetes-related clinical characteristics.

PURPOSE: To assess predictors of gestational weight gain (GWG), according to the Institute of Medicine (IOM) 2009, in women with type 1 and type 2 diabetes. METHODS: This was a retrospective cohort study conducted at a tertiary center. GWG based on the IOM was assessed both uncorrected and corrected for gestational age. General and diabetes-related clinical characteristics were analyzed as predictors. RESULTS: We evaluated 633 pregnant women with type 1 and type 2 diabetes. GWG uncorrected for gestational age was inadequate (iGWG) in 20.4%, adequate in 37.1%, and excessive (eGWG) in 42.5% of the women. Predictors included general (height, prepregnancy body mass index category, and multiple pregnancy) and diabetes-related clinical characteristics. Neuropathy and follow-up length were associated with iGWG (odds ratio (OR) 3.00, 95% CI 1.22-7.37; OR 0.92, 95% CI 0.86-0.97, respectively), while pump use and third-trimester insulin dose were associated with eGWG (OR 1.68, 95% CI 1.07-2.66; OR 3.64, 95% CI 1.88-7.06, respectively). Independent predictors for corrected GWG and sensitivity analyses also included general and diabetes-related clinical characteristics. CONCLUSION: In this cohort of women with type 1 and type 2 diabetes, non-adequate GWG was common, mainly due to eGWG, and associated clinical characteristics were both general and diabetes-related. Current clinical care of these women during pregnancy may favor weight gain.

Ultrarapid Insulin Use Can Reduce Postprandial Hyperglycemia and Late Hypoglycemia, Even in Delayed Insulin Injections: A Connected Insulin Cap-Based Real-World Study.

Objectives: Reaching optimal postprandial glucose dynamics is a daily challenge for people with type 1 diabetes (T1D). This study aimed to analyze the postprandial hyperglycemic excursion (PHEs) and late postprandial hypoglycemia (LPH) risk according to prandial insulin time and type. Research Design and Methods: Real-world, retrospective study in T1D using multiple daily injections (MDI) analyzing 5 h of paired continuous glucose monitoring and insulin injections data collected from the connected cap Insulclock®. Meal events were identified using the rate of change detection methodology. Postprandial glucometrics and LPH (glucose <70 mg/dL 2-5 h after a meal) were evaluated according to insulin injection time and rapid (RI) or ultrarapid analog, Fiasp® (URI), use. Results: Meal glycemic excursions (n = 2488), RI: 1211, 48.7%; UR: 1277, 51.3%, in 82 people were analyzed according to injection time around the PHE: -45 to -15 min; -15 to 0 min; and 0 to +45 min. In 63% of the meals, insulin was injected after the PHE started. Lower PHE was observed with URI versus RI (glucose peak-baseline; mg/dL; mean ± standard deviation): 106.7 ± 35.2 versus 111.2 ± 40.3 (P = 0.003), particularly in 0/+45 injections: 111.6 ± 40.2 versus 118.1 ± 43.3; (P = 0.002). One third (29.1%) of participants added a second (correction) injection. The use of URI and avoiding a second injection were independently associated with less LPH risk, even in delayed injections (0/+45), (-36%, odds ratio [OR] 0.641; confidence interval [CI]: 0.462-0.909; P = 0.012) and -56% (OR 0.641; CI: 0.462-0.909 P = 0.038), respectively. Conclusions: URI analog use as prandial insulin reduces postprandial hyper- and hypoglycemia, even in delayed injections.

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.

Lenvatinib-Loaded Poly(lactic-co-glycolic acid) Nanoparticles with Epidermal Growth Factor Receptor Antibody Conjugation as a Preclinical Approach to Therapeutically Improve Thyroid Cancer with Aggressive Behavior.

BACKGROUND: Lenvatinib, a tyrosine kinase inhibitor (TKI) approved for the treatment of progressive and radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC), is associated with significant adverse effects that can be partially mitigated through the development of novel drug formulations. The utilization of nanoparticles presents a viable option, as it allows for targeted drug delivery, reducing certain side effects and enhancing the overall quality of life for patients. This study aimed to produce and assess, both in vitro and in vivo, the cytotoxicity, biodistribution, and therapeutic efficacy of lenvatinib-loaded PLGA nanoparticles (NPs), both with and without decoration using antibody conjugation (cetuximab), as a novel therapeutic approach for managing aggressive thyroid tumors. METHODS: Poly(lactic-co-glycolic acid) nanoparticles (NPs), decorated with or without anti-EGFR, were employed as a lenvatinib delivery system. These NPs were characterized for size distribution, surface morphology, surface charge, and drug encapsulation efficiency. Cytotoxicity was evaluated through MTT assays using two cellular models, one representing normal thyroid cells (Nthy-ori 3-1) and the other representing anaplastic thyroid cells (CAL-62). Additionally, an in vivo xenograft mouse model was established to investigate biodistribution and therapeutic efficacy following intragastric administration. RESULTS: The NPs demonstrated success in terms of particle size, polydispersity index (PDI), zeta potential, morphology, encapsulation efficiency, and cetuximab distribution across the surface. In vitro analysis revealed cytotoxicity in both cellular models with both formulations, but only the decorated NPs achieved an ID50 value in CAL-62 cells. Biodistribution analysis following intragastric administration in xenografted thyroid mice demonstrated good stability in terms of intestinal barrier function and tumor accumulation. Both formulations were generally well tolerated without inducing pathological effects in the examined organs. Importantly, both formulations increased tumor necrosis; however, decorated NPs exhibited enhanced parameters related to apoptotic/karyolytic forms, mitotic index, and vascularization compared with NPs without decoration. CONCLUSIONS: These proof-of-concept findings suggest a promising strategy for administering TKIs in a more targeted and effective manner.

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.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

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.

Breastfeeding is associated with a delayed decrease in postprandial maternal glucose concentration.

BACKGROUND: Breastfeeding has long-term benefits in reducing the risk of diabetes; however, information about the acute influence on maternal glucose profile is scarce. Thus, the aim of the study was to assess maternal glucose fluctuations associated with breastfeeding episodes in women with normal glucose status. METHODS: We performed an observational study of glucose fluctuations with breastfeeding episodes in 26 women with normal glucose status in fasting and postprandial state. Continuous glucose monitoring was performed using CGMS MiniMed Gold®/iPro2® (Medtronic, Dublin, Ireland) three months after delivery under real-life conditions. We compared fasting and postprandial periods of 150 minutes affected or not by a breastfeeding episode. RESULTS: Mean glucose concentration of postprandial periods affected by breastfeeding was lower than not affected (-6.31 mg/dL [95% CI: -11.17, -1.62] P<0.01). Glucose concentration was significantly lower between 50 and 105 minutes after meal initiation (maximum difference -9.19 mg/dL [95% CI: -16.03, -2.16] at 91-95 min). Mean glucose concentrations of fasting periods affected by breastfeeding were similar to those not affected (-0.18 mg/dL [95% CI: -2.7, 0] P=0.831). CONCLUSIONS: In women with normal glucose status, breastfeeding episodes are associated with a lower glucose concentration in the postprandial but not in the fasting state.

Hybrid closed-loop systems can help patients with extreme fear of hypoglycemia or hyperglycemia.

Fear of hypoglycemia and hyperglycemia can lead to inappropriate diabetes self-management and untoward health outcomes. We report two patients, representative of these opposite conditions, who benefited from hybrid closed-loop technology. In the patient with fear of hypoglycemia, time in range improved from 26 to 56% and the patient did not present with severe hypoglycemia. Meanwhile, the patient with hyperglycemia aversiveness had a drastic reduction in time below range, from 19 to 4%. We conclude that hybrid closed-loop technology was an effective tool for improvement of glucose values in two patients with fear of hypoglycemia and hyperglycemia aversiveness, respectively.

Insulin degludec versus insulin detemir, both in combination with insulin aspart, in the treatment of pregnant women with type 1 diabetes (EXPECT): an open­label, multinational, randomised, controlled, non-inferiority trial.

BACKGROUND: Insulin degludec (degludec) is a second-generation basal insulin with an improved pharmacokinetic-pharmacodynamic profile compared with first-generation basal insulins, but there are few data regarding its use during pregnancy. In this non-inferiority trial, we aimed to compare the efficacy and safety of degludec with insulin detemir (detemir), both in combination with insulin aspart (aspart), in pregnant women with type 1 diabetes. METHODS: This open-label, multinational, randomised, controlled, non-inferiority trial (EXPECT) was conducted at 56 sites (hospitals and medical centres) in 14 countries. Women aged at least 18 years with type 1 diabetes who were between gestational age 8 weeks (+0 days) and 13 weeks (+6 days) or planned to become pregnant were randomly assigned (1:1), via an interactive web response system, to degludec (100 U/mL) once daily or detemir (100 U/mL) once or twice daily, both with mealtime insulin aspart (100 U/mL), all via subcutaneous injection. Participants who were pregnant received the trial drug at randomisation, throughout pregnancy and until 28 days post-delivery (end of treatment). Participants not pregnant at randomisation initiated the trial drug before conception. The primary endpoint was the last planned HbA1c measurement before delivery (non-inferiority margin of 0·4% for degludec vs detemir). Secondary endpoints included efficacy, maternal safety, and pregnancy outcomes. The primary endpoint was assessed in all randomly assigned participants who were pregnant during the trial. Safety was assessed in all randomly assigned participants who were pregnant during the trial and exposed to at least one dose of trial drug. This study is registered with ClinicalTrials.gov, NCT03377699, and is now completed. FINDINGS: Between Nov 22, 2017, and Nov 8, 2019, from 296 women screened, 225 women were randomly assigned to degludec (n=111) or detemir (n=114). Mean HbA1c at pregnancy baseline was 6·6% (SD 0·6%; approximately 49 mmol/mol; SD 7 mmol/mol) in the degludec group and 6·5% (0·8%; approximately 48 mmol/mol; 9 mmol/mol) in the detemir group. Mean last planned HbA1c measurement before delivery was 6·2% (SE 0·07%; approximately 45 mmol/mol; SE 0·8 mmol/mol) in the degludec group and 6·3% (SE 0·07%; approximately 46 mmol/mol; SE 0·8 mmol/mol) in the detemir group (estimated treatment difference -0·11% [95% CI -0·31 to 0·08]; -1·2 mmol/mol [95% CI: -3·4 to 0·9]; pnon-inferiority<0·0001), confirming non-inferiority. Compared with detemir, no additional safety issues were observed with degludec. INTERPRETATION: In pregnant women with type 1 diabetes, degludec was found to be non-inferior to detemir. FUNDING: Novo Nordisk.

Gestational weight gain and pregnancy outcomes in women with type 1 and type 2 diabetes mellitus.

AIMS: We aimed to explore the relationship between gestational weight gain (GWG) after Institute of Medicine (IOM) and pregnancy outcomes in women with type 1 and type 2 diabetes. METHODS: Retrospective cohort study at a tertiary medical center (1981-2011). OUTCOME VARIABLES: 2 maternal and 14 fetal. Main exposure variable: GWG according to IOM. We calculated crude and adjusted ORs as well as population attributable (PAF) and preventable fractions (PPF) for significant positive and negative associations, respectively. RESULTS: We evaluated 633 pregnant women with type 1 or type 2 diabetes. GWG was insufficient (iGWG) in 16.7% and excessive (eGWG) in 50.7%. In the adjusted analysis, GWG according to IOM was significantly associated with maternal outcomes (pregnancy-induced hypertension and cesarean delivery) and four fetal outcomes (large-for-gestational age, macrosomia, small-for-gestational age and neonatal respiratory distress). The association with large-for-gestational age newborns was negative for iGWG (0.48, CI 95% 0.25-0.94) and positive for eGWG (1.76, CI 95% 1.18-2.63). In addition, iGWG was associated with a higher risk of small-for-gestational age newborns and respiratory distress and eGWG with a higher risk of pregnancy-induced hypertension, caesarean delivery and macrosomia. PAF and PPF ranged from the 20.4% PPF of iGWG for large-for-gestational age to 56.5% PAF of eGWG for macrosomia. CONCLUSION: In this cohort of women with type 1 or type 2 diabetes, inadequate GWG after IOM was associated with adverse pregnancy outcomes; associations were unfavorable for eGWG and mixed for iGWG. The attributable fractions were not moderate, pointing to the potential impact of modifying inadequate GWG.

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.

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.

Vitamin D3 Supplementation in Overweight/Obese Pregnant Women: No Effects on the Maternal or Fetal Lipid Profile and Body Fat Distribution-A Secondary Analysis of the Multicentric, Randomized, Controlled Vitamin D and Lifestyle for Gestational Diabetes Prevention Trial (DALI).

Vitamin D deficiency is a common finding in overweight/obese pregnant women and is associated with increased risk for adverse pregnancy outcome. Both maternal vitamin D deficiency and maternal obesity contribute to metabolic derangements in pregnancy. We aimed to assess the effects of vitamin D3 supplementation in pregnancy versus placebo on maternal and fetal lipids. Main inclusion criteria were: women <20 weeks' gestation, BMI ≥ 29 kg/m2. Eligible women (n = 154) were randomized to receive vitamin D3 (1600 IU/day) or placebo. Assessments were performed <20, 24−28 and 35−37 weeks and at birth. Linear regression models were used to assess effects of vitamin D on maternal and cord blood lipids. In the vitamin D group significantly higher total 25-OHD and 25-OHD3 levels were found in maternal and cord blood compared with placebo. Adjusted regression models did not reveal any differences in triglycerides, LDL-C, HDL-C, free fatty acids, ketone bodies or leptin between groups. Neonatal sum of skinfolds was comparable between the two groups, but correlated positively with cord blood 25-OH-D3 (r = 0.34, p = 0.012). Vitamin D supplementation in pregnancy increases maternal and cord blood vitamin D significantly resulting in high rates of vitamin D sufficiency. Maternal and cord blood lipid parameters were unaffected by Vitamin D3 supplementation.

The Weak Relationship between Vitamin D Compounds and Glucose Homeostasis Measures in Pregnant Women with Obesity: An Exploratory Sub-Analysis of the DALI Study.

Studies on the relationship between vitamin D (VitD) and glucose homeostasis usually consider either total VitD or 25OHD3 but not 25OHD2 and epimers. We aimed to evaluate the cross-sectional association of VitD compounds with glucose homeostasis measurements in pregnant women with overweight/obesity participating in the Vitamin D And Lifestyle Intervention for Gestational Diabetes Mellitus Prevention study. Methods: The analysis included 912 women. Inclusion criteria: <20 weeks gestation, body mass index ≥29 kg/m2 and information on exposure and outcome variables at baseline. Measurements: A 75 g OGTT at <20, 24−28 and 35−37 weeks gestation (except if previous diabetes diagnosis). Exposure variables: 25OHD2, 25OHD3 and C3-epimer. Outcome variables: fasting and post-challenge insulin sensitivity and secretion indices, corresponding disposition indices (DI), plasma glucose at fasting and 1 and 2 h, hyperglycemia in pregnancy (HiP). Statistics: Multivariate regression analyses with adjustment. Results: Baseline VitD sufficiency was 66.3%. Overall, VitD compounds did not show strong associations with any glucose homeostasis measures. 25OHD3 showed direct significant associations with: FPG at <20 and 24−28 weeks (standardized ß coefficient (ß) 0.124, p = 0.030 and 0.111, p = 0.026 respectively), 2 h plasma glucose at 24−28 weeks (ß 0.120, p = 0.018), and insulin sensitivity (1/HOMA-IR, ß 0.127, p = 0.027) at 35−37 weeks; it showed an inverse association with fasting DI (QUCKI*HOMA-ß) at <20 and 24−28 weeks (ß −0.124, p = 0.045 and ß −0.148, p = 0.004 respectively). 25OHD2 showed direct associations with post-challenge insulin sensitivity (Matsuda, ß 0.149, p = 0.048) at 24−28 weeks) and post-challenge DI (Matsuda*Stumvoll phase 1) at 24−28 and 35−37 weeks (ß 0.168, p = 0.030, ß 0.239, p = 0.006). No significant association with C3-epimer was observed at any time period. Conclusions: In these women with average baseline VitD in sufficiency range, VitD compounds did not show clear beneficial associations with glucose homeostasis measures.