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Introduction: Gremlin-1 is a peptide that functions as an antagonist to bone morphogenic proteins and is overexpressed in obesity and type 2 diabetes mellitus. Gremlin-1 has not yet been investigated in pregnancy, pregnancy-related insulin resistance or gestational diabetes mellitus (GDM)., Patients and Methods: Gremlin-1 levels were measured throughout the pregnancy of 58 women at high risk for GDM at the Medical University of Vienna. Furthermore, an oral glucose tolerance test, fasting insulin, fasting glucose, sex hormones, blood lipids, liver and renal parameters, and markers of bone development were evaluated at two points during pregnancy (< 20 weeks of gestation (GW), GW 24-28) and 12-14 weeks postpartum., Results: Gremlin-1 levels decreased from < 20 GW (mean = 9.2 pg/ml, SD = 8.4 pg/ml) to GW 24-28 (mean = 6.7 pg/ml, SD = 5.7 pg/ml, p = 0.033) and increased again postpartum, albeit not significantly (mean = 10.7 pg/ml, SD = 13.1 pg/ml, p = 0.339). During pregnancy, Gremlin-1 levels correlated negatively with osteocalcin and procollagen type I aminoterminal propeptide (P1NP), markers of bone health. Concerning glucose metabolism, Gremlin-1 levels were inversely related to the Insulinogenic Index at GW < 20. However, Gremlin-1 levels were not significantly different between women with normal glucose tolerance and GDM during pregnancy. Postpartum, Gremlin-1 was associated with the fatty liver index, osteocalcin levels, diastolic blood pressure and weight., Conclusion: Gremlin-1 levels decreased significantly during pregnancy. The biomarker is not related to GDM status, but correlates negatively with the Insulinogenic Index, an index related to beta cell function. Trial Registry Number ACTRN12616000924459., (© 2023. The Author(s).)

Background: Whether treatment of gestational diabetes before 20 weeks' gestation improves maternal and infant health is unclear., Methods: We randomly assigned, in a 1:1 ratio, women between 4 weeks' and 19 weeks 6 days' gestation who had a risk factor for hyperglycemia and a diagnosis of gestational diabetes (World Health Organization 2013 criteria) to receive immediate treatment for gestational diabetes or deferred or no treatment, depending on the results of a repeat oral glucose-tolerance test [OGTT] at 24 to 28 weeks' gestation (control). The trial included three primary outcomes: a composite of adverse neonatal outcomes (birth at <37 weeks' gestation, birth trauma, birth weight of ≥4500 g, respiratory distress, phototherapy, stillbirth or neonatal death, or shoulder dystocia), pregnancy-related hypertension (preeclampsia, eclampsia, or gestational hypertension), and neonatal lean body mass., Results: A total of 802 women underwent randomization; 406 were assigned to the immediate-treatment group and 396 to the control group; follow-up data were available for 793 women (98.9%). An initial OGTT was performed at a mean (±SD) gestation of 15.6±2.5 weeks. An adverse neonatal outcome event occurred in 94 of 378 women (24.9%) in the immediate-treatment group and in 113 of 370 women (30.5%) in the control group (adjusted risk difference, -5.6 percentage points; 95% confidence interval [CI], -10.1 to -1.2). Pregnancy-related hypertension occurred in 40 of 378 women (10.6%) in the immediate-treatment group and in 37 of 372 women (9.9%) in the control group (adjusted risk difference, 0.7 percentage points; 95% CI, -1.6 to 2.9). The mean neonatal lean body mass was 2.86 kg in the immediate-treatment group and 2.91 kg in the control group (adjusted mean difference, -0.04 kg; 95% CI, -0.09 to 0.02). No between-group differences were observed with respect to serious adverse events associated with screening and treatment., Conclusions: Immediate treatment of gestational diabetes before 20 weeks' gestation led to a modestly lower incidence of a composite of adverse neonatal outcomes than no immediate treatment; no material differences were observed for pregnancy-related hypertension or neonatal lean body mass. (Funded by the National Health and Medical Research Council and others; TOBOGM Australian New Zealand Clinical Trials Registry number, ACTRN12616000924459.)., (Copyright © 2023 Massachusetts Medical Society.)

Competing Interests: Lecture fees and/or consulting services: Hummel – Astra Zeneca, Boehringer-Ingelheim, Dexcom, Lilly, MSD, Novo Nordisk, Sanofi; Füchtenbusch – Abbott, Astra Zeneca, Berlin Chemie, Boehringer, Glaxo Smith Kline, Lilly, Novo Nordisk, Sanofi; Bührer – Chiesi, Nestlé; Battefeld – Berlin Chemie, Lilly, Novo Nordisk; Groten – Novo Nordisk, JenaPharm; Haak – Abbott, AstraZeneca, MSD, Roche; Kainer – GE Canon; Kautzky-Willer – Novo Nordisk, Lilly, Boehringer Ingelheim, AstraZeneca, Sanofi, Amgen, Novartis; Meissner – Lilly, Novo Nordisk; Nagel-Reupner – Amgen, Boehringer, Novo Nordisk, MSD, Lilly; Schäfer-Graf – Novo Nordik, Sanofi, Berlin-Chemie; Siegmund – Abbott, Astra, Berlin Chemie, Boehringer, Lilly, Medronic, MSD, Novo Nordisk, Roche, Sanofi

Metabolic diseases dramatically affect the life of men and women from infancy up to old age in different and manifold ways and are a major challenge for the healthcare system. The treating physicians are confronted with the different needs of women and men in the clinical routine. Gender-specific differences affect pathophysiology, screening, diagnostic and treatment strategies of diseases as well as the development of complications and mortality rates. Impairments in glucose and lipid metabolism, regulation of energy balance and body fat distribution and therefore the associated cardiovascular diseases, are greatly influenced by steroidal and sex hormones. Furthermore, education, income and psychosocial factors play an important role in the development of obesity and diabetes differently in men and women. Males appear to be at greater risk of diabetes at a younger age and at a lower body mass index (BMI) compared to women but women feature a dramatic increase in the risk of diabetes-associated cardiovascular diseases after the menopause. The estimated future years of life lost owing to diabetes is somewhat higher in women than men, with a higher increase in vascular complications in women but a higher increase of cancer deaths in men. In women prediabetes or diabetes are more distinctly associated with a higher number of vascular risk factors, such as inflammatory parameters, unfavourable changes in coagulation and higher blood pressure. Women with prediabetes and diabetes have a much higher relative risk for vascular diseases. Women are more often morbidly obese and less physically active but may have an even greater benefit in health and life expectation from increased physical activity than men. In weight loss studies men often showed a higher weight loss than women; however, diabetes prevention is similarly effective in men and women with prediabetes with a risk reduction of nearly 40%. Nevertheless, a long-term reduction in all cause and cardiovascular mortality was so far only observed in women. Men predominantly feature increased fasting blood glucose levels, women often show impaired glucose tolerance. A history of gestational diabetes or polycystic ovary syndrome (PCOS) as well as increased androgen levels and decreased estrogen levels in women and the presence of erectile dysfunction or decreased testosterone levels in men are important sex-specific risk factors for the development of diabetes. Many studies showed that women with diabetes reach their target values for HbA 1c , blood pressure and low-density lipoprotein (LDL)-cholesterol less often than their male counterparts, although the reasons are unclear. Furthermore, sex differences in the effects, pharmacokinetics and side effects of pharmacological treatment should be taken more into consideration., (© 2023. The Author(s).)

In 1989 the St. Vincent Declaration aimed to achieve comparable pregnancy outcomes in women with diabetes and those with normal glucose tolerance. However, currently women with pre-gestational diabetes still feature a higher risk of perinatal morbidity and even increased mortality. This fact is mostly ascribed to a persistently low rate of pregnancy planning and pre-pregnancy care with optimization of metabolic control prior to conception. All women should be experienced in the management of their therapy and on stable glycemic control prior to conception. In addition, thyroid dysfunction, hypertension as well as the presence of diabetic complications should be excluded or treated adequately before pregnancy in order to decrease the risk for a progression of complications during pregnancy as well as maternal and fetal morbidity. Near normoglycaemia and HbA 1c in the normal range are targets for treatment, preferably without the induction of frequent resp. severe hypoglycaemic reactions. Especially in women with type 1 diabetes mellitus the risk of hypoglycemia is high in early pregnancy, but it decreases with the progression of pregnancy due to hormonal changes causing an increase of insulin resistance. In addition, obesity increases worldwide and contributes to higher numbers of women at childbearing age with type 2 diabetes mellitus and adverse pregnancy outcomes. Intensified insulin therapy with multiple daily insulin injections and pump treatment are equally effective in reaching good metabolic control during pregnancy. Insulin is the primary treatment option. Continuous glucose monitoring often adds to achieve targets. Oral glucose lowering drugs (Metformin) may be considered in obese women with type 2 diabetes mellitus to increase insulin sensitivity but need to be prescribed cautiously due to crossing the placenta and lack of long-time follow up data of the offspring (shared decision making). Due to increased risk for preeclampsia in women with diabetes screening needs to be performed. Regular obstetric care as well as an interdisciplinary treatment approach are necessary to improve metabolic control and ensure the healthy development of the offspring., (© 2023. The Author(s).)

Gestational diabetes (GDM) is defined as any degree of glucose intolerance with onset during pregnancy and is associated with increased feto-maternal morbidity as well as long-term complications in mothers and the offspring. Women detected to have diabetes early in pregnancy receive the diagnosis of overt, non-gestational, diabetes (glucose: fasting ≥ 126 mg/dl, spontaneous ≥ 200 mg/dl or HbA 1c  ≥ 6.5% before 20 weeks of gestation). GDM is diagnosed by an oral glucose tolerance test (oGTT) or increased fasting glucose (≥ 92 mg/dl). Screening for undiagnosed type 2 diabetes at the first prenatal visit is recommended in women at increased risk (history of GDM/pre-diabetes; malformation, stillbirth, successive abortions or birth weight > 4500 g previously; obesity, metabolic syndrome, age > 35 years, vascular disease; clinical symptoms of diabetes (e.g. glucosuria) or ethnic origin with increased risk for GDM/T2DM (Arab, South- and Southeast Asian, Latin American)) using standard diagnostic criteria. Performance of the oGTT (120 min; 75 g glucose) may already be indicated in the first trimester in high-risk women but is mandatory between gestational week 24-28 in all pregnant women with previous non-pathological glucose metabolism. Following WHO recommendations, which are based on the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, GDM is defined, if fasting venous plasma glucose is ≥ 92 mg/dl or 1 h ≥ 180 mg/dl or 2 h ≥ 153 mg/dl after glucose loading (international consensus criteria). In case of one pathological value a strict metabolic control is mandatory. After bariatric surgery we do not recommend to perform an oGTT due to risk of postprandial hypoglycemia. All women with GDM should receive nutritional counseling, be instructed in blood glucose self-monitoring and motivated to increase physical activity to moderate intensity levels-if not contraindicated (Evidence level A). If blood glucose levels cannot be maintained in the therapeutic range (fasting < 95 mg/dl and 1 h after meals < 140 mg/dl, Evidence level B) insulin therapy should be initiated as first choice (Evidence level A). Maternal and fetal monitoring is required in order to minimize maternal and fetal/neonatal morbidity and perinatal mortality. Regular obstetric examinations including ultrasound examinations are recommended (Evidence level A). Neonatal care of GDM offspring at high risk for hypoglycaemia includes blood glucose measurements after birth and if necessary appropriate intervention. Monitoring the development of the children and recommendation of healthy lifestyle are important issues to be tackled for the whole family. After delivery all women with GDM have to be reevaluated as to their glucose tolerance by a 75 g oGTT (WHO criteria) 4-12 weeks postpartum. Assessment of glucose parameters (fasting glucose, random glucose, HbA 1c or optimally oGTT) are recommended every 2-3 years in case of normal glucose tolerance. All women have to be instructed about their increased risk of type 2 diabetes and cardiovascular disease at follow-up. Possible preventive meassures, in particular lifestyle changes as weight management and maintenance/increase of physical activity should be discussed (evidence level A)., (© 2023. The Author(s).)

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.

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 β coefficient (β) 0.124, p = 0.030 and 0.111, p = 0.026 respectively), 2 h plasma glucose at 24−28 weeks (β 0.120, p = 0.018), and insulin sensitivity (1/HOMA-IR, β 0.127, p = 0.027) at 35−37 weeks; it showed an inverse association with fasting DI (QUCKI*HOMA-β) at <20 and 24−28 weeks (β −0.124, p = 0.045 and β −0.148, p = 0.004 respectively). 25OHD2 showed direct associations with post-challenge insulin sensitivity (Matsuda, β 0.149, p = 0.048) at 24−28 weeks) and post-challenge DI (Matsuda*Stumvoll phase 1) at 24−28 and 35−37 weeks (β 0.168, p = 0.030, β 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.

Glypican-4 (GPC-4) is an adipokine that enhances insulin receptor signaling. Plasma concentrations were found to be elevated in patients with prediabetes but reduced in type 2 diabetes mellitus. No study on Glypican-4 in pregnancy and pregnancy-related insulin resistance has been published yet. GPC-4 levels were investigated in 59 overweight women throughout their pregnancy at the Medical University of Vienna. GPC-4 levels, fasting insulin, fasting glucose, estradiol, liver and renal parameters, and markers of bone development were assessed before the < 21st week of gestation (GW), and at GW 35-37. GPC-4 levels increased from < 21 GW (mean = 2.38 pg/ml, SD = 0.68 pg/ml) to GW 35-37 (mean = 2.96 pg/ml, SD = 0.77 pg/ml, p < 0.001). At the same time, GPC-4 levels correlated negatively with estimated glomerular filtration rate (eGFR), serum protein and serum albumin levels and were positively related to creatinine and uric acid levels at GW 35-37. Concerning glucose metabolism, GPC-4 levels were inversely related to ISSI-2, fasting insulin and HOMA-IR, however, not significantly different between women with normal glucose tolerance (NGT) and GDM (p = 0.239). In conclusion, GPC-4 levels rose significantly during pregnancy, correlated negatively with fasting insulin and HOMA-IR but might not be related to gestational diabetes mellitus status., (© 2021. The Author(s).)

Insulin clearance is an integral component of insulin metabolism. Yet, little is known about separate contribution of hepatic and extrahepatic insulin clearance in type 2 diabetes and in high-risk populations, such as women who experienced gestational diabetes mellitus (pGDM). A model-based method was recently proposed to assess both contributions from 3-hour insulin-modified intravenous glucose tolerance test (IM-IVGTT); the aim of this study was to assess the reliability of short (1 hour) IM-IVGTT in the application of such model-based method and to evaluate the role of the two contributions in determining insulin clearance in pGDM. A total of 115 pGDM women and 41 who remained healthy during pregnancy (CNT) were analyzed early postpartum and underwent a 3-hour IMIVGTT. Peripheral insulin clearance (CL P ), hepatic fractional extraction (FE L ) and extrahepatic distribution volume (V P ) were estimated by performing a best-fit procedure on insulin IMIVGTT data considering firstly the overall 3-hour duration and then limiting data to 1 hour. Results showed no significant difference in parameter values between the 3-hour and the 1-hour IM-IVGTT. Comparison between pGDM and CNT (1-hour) showed no significant difference in CL p (0.23 [0.29] vs. 0.27 [0.43] L·min -1 ; p=0.64), FE L (50.2 [15.1] vs. 50.9 [11.7] %; p=0.63) and V P (2.01 [2.99] vs. 2.70 [4.00] L; p=0.92). In conclusion, short IM-IVGTT provides a reliable assessment of hepatic and extrahepatic insulin clearance through such model-based method. Its application to the study of pGDM women showed no alteration in hepatic and extrahepatic contributions with respect to women who had a healthy pregnancy.Clinical Relevance- This study proves the reliability of short (1 hour) IM-IVGTT to assess hepatic and extrahepatic insulin clearance in women who experienced gestational diabetes.

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/m 2 , 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.

Successful pregnancies rely on adaptations within the mother 1 , including marked changes within the immune system 2 . It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy 3 . However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK 4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T reg ) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T reg cells through RANK in a manner that depends on AIRE + medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T reg cells during pregnancy, and expand the functional role of maternal T reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis.

Introduction: It is of current interest to assess eligibility of hemoglobin A1c (HbA1c) as a screening tool for earlier identification of women with risk for more severe hyperglycemia in pregnancy but data regarding accuracy are controversial. We aimed to evaluate if HbA1c mirrors pathophysiological precursors of glucose intolerance in early pregnancy that characterize women who develop gestational diabetes mellitus (GDM)., Research Design and Methods: 220 pregnant women underwent an HbA1c measurement as well as an oral glucose tolerance test (OGTT) with multiple measurements of glucose, insulin and C-peptide for evaluation of insulin sensitivity and beta-cell function at 16th gestational week (IQR: 14-18). Clinical follow-ups were performed until end of pregnancy., Results: Increased maternal HbA1c ≥5.7% (39 mmol/mol) corresponding to pre-diabetes outside of pregnancy was associated with altered glucose dynamics during the OGTT. Pregnancies with early HbA1c ≥5.7% showed higher fasting (90.4±13.2 vs 79.7±7.2 mg/dL, p<0.001), mean (145.6±31.4 vs 116.2±21.4 mg/dL, p<0.001) as well as maximum glucose concentrations and tended to a delay in reaching the maximum glucose level compared with those with normal-range HbA1c (186.5±42.6 vs 147.8±30.1 mg/dL, p<0.001). Women with increased HbA1c showed impaired beta-cell function and differences in disposition index independent of body mass index status. We observed a high specificity for the HbA1c cut-off of 5.7% for GDM manifestation (0.96, 95% CI 0.91 to 0.98) or need of glucose-lowering medication (0.95, 95% CI 0.90 to 0.98) although overall predictive accuracy was moderate to fair. Further, elevated HbA1c was associated with higher risk for delivering large-for-gestational-age infants, also after adjustment for GDM status (OR 4.4, 95% CI 1.2 to 15.0, p=0.018)., Conclusions: HbA1c measured before recommended routine screening period reflects early pathophysiological derangements in beta-cell function and glucose disposal that are characteristic of GDM development and may be useful in early risk stratification., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recent studies have shown higher levels of CTRP-1 (C1QTNF-related protein) in patients with type 2 diabetes compared to controls. We aimed at investigating CTRP-1 in gestational diabetes mellitus (GDM). CTRP-1 levels were investigated in 167 women (93 with normal glucose tolerance (NGT), 74 GDM) of a high-risk population for GDM. GDM was further divided into GDM subtypes depending on a predominant insulin sensitivity issue (GDM-IR) or secretion deficit (GDM-IS). Glucose tolerance was assessed with indices [Matsuda index, Stumvoll first phase index, insulin-secretion-sensitivity-index 2 (ISSI-2), area-under-the-curve (AUC) insulin, AUC glucose] derived from an oral glucose tolerance test (oGTT) performed at < 21 and 24-28 weeks of gestation. In pregnancy, CTRP-1 levels of GDM (76.86 ± 37.81 ng/ml) and NGT (82.2 ± 35.34 ng/ml; p = 0.104) were similar. However, GDM-IR women (65.18 ± 42.18 ng/ml) had significantly lower CTRP-1 levels compared to GDM-IS (85.10 ± 28.14 ng/ml; p = 0.009) and NGT (p = 0.006). CTRP-1 levels correlated negatively with weight, AUC insulin, Stumvoll first phase index, bioavailable estradiol and positively with HbA1c, Matsuda Index and ISSI-2. A multiple regression analysis revealed bioavailable estradiol (β = - 0.280, p = 0.008) and HbA1c (β = 0.238; p = 0.018) as the main variables associated with CTRP-1 in GDM. Postpartum, waist and hip measurements were predictive of CRTP-1 levels instead. CTRP-1 levels were higher postpartum than during pregnancy (91.92 ± 47.27 vs.82.44 ± 38.99 ng/ml; p = 0.013). CTRP-1 is related to insulin resistance in pregnancy and might be a metabolic biomarker for insulin resistance in GDM. CTRP-1 levels were significantly lower during pregnancy than postpartum, probably due to rising insulin resistance during pregnancy.

Purpose of Review: This narrative review makes the case for greater efforts to reduce cardiovascular disease (CVD) risk in women with diabetes., Recent Findings: In a recent meta-analysis including five CVOTs of diabetes medications with 46,606 subjects, women (vs men) with type 2 diabetes had a higher relative risk for stroke (RR 1.28; 95% CI 1.09, 1.50) and heart failure (1.30; 1.21, 1.40). Prior studies found higher "within-gender" RR for CVD mortality in women with diabetes although men have an absolute higher risk. Women with prior gestational diabetes mellitus (GDM) have a 2-fold higher CVD risk than the background population. Worse CVD and CVD risk factor management in women, as well as lower female therapy adherence, contribute further to these disparities. The mechanism behind this excess risk includes biological, hormonal, socioeconomic, clinical, and behavioral factors that still require further investigation. The need for more intensive CVD reduction in women now includes more attention to screening for both incident diabetes and CVD risk factors among high-risk women.

Aims: To investigate the performance of early pregnancy HbA 1c for predicting gestational diabetes mellitus (GDM) and adverse pregnancy outcomes in obese women., Methods: Post hoc analysis using data from the Vitamin D And Lifestyle Intervention for GDM prevention trials conducted across 9 European countries (2012-2014). Pregnant women (BMI ≥ 29 kg/m 2 ) underwent a baseline HbA 1c and oral glucose tolerance tests at < 20 weeks, 24-28 weeks, and 35-37 weeks. Women with GDM were referred for treatment., Results: Among the 869 women tested, the prevalence of GDM was 25.9% before 20 weeks, with a further 8.6% at 24-28 weeks. The areas under the curves for HbA 1c at the two time points were 0.55 (0.50-0.59) and 0.54 (0.47-0.61), respectively. An early HbA 1c  ≥ 5.7% (39 mmol/mol) (N = 111) showed low sensitivity (18.2%) with 89.1% specificity for GDM before 20 weeks, at 24-28 weeks (sensitivity of 8.0% and specificity of 88.6% after excluding early GDM), and throughout gestation (sensitivity of 15.9% and specificity of 89.4%). The ≥ 5.7% (39 mmol/mol) threshold was significantly associated with concurrent GDM before 20 weeks (adjusted OR (aOR) 2.77(1.39-5.51)) and throughout gestation (aOR 1.72 (1.02-2.89)), but not adverse pregnancy outcomes., Conclusions: Early pregnancy HbA 1c is of limited use for predicting either GDM or adverse outcomes in overweight/obese European women., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Background and Aims: Insulin clearance is a relevant process in glucose homeostasis. In this observational study, we aimed to assess insulin clearance (Cl INS ) in women with former gestational diabetes (fGDM) both early after delivery and after a follow-up., Methods and Results: We analysed 59 fGDM women, and 16 women not developing GDM (CNT). All women underwent an oral glucose tolerance test (OGTT) yearly, and an insulin-modified intravenous glucose tolerance test (IVGTT) at baseline and at follow-up end (until 7 years). Both IVGTT and OGTT Cl INS was assessed as insulin secretion to plasma insulin ratio. We also defined IVGTT first (0-10 min) and second phase (10-180 min) Cl INS . We found that 14 fGDM women progressed to type 2 diabetes (PROG), whereas 45 women remained diabetes-free (NONPROG). At baseline, IVGTT Cl INS showed alterations in PROG, especially in second phase (0.88 ± 0.10 l·min -1 in PROG, 0.60 ± 0.06 in NONPROG, 0.54 ± 0.07 in CNT, p ≤ 0.03). Differences in Cl INS were not found from OGTT. Cox regression analysis showed second phase Cl INS as significant type 2 diabetes predictor (hazard ratio = 1.90, 95% confidence interval 1.09-3.30, p = 0.02)., Conclusion: This study showed that insulin clearance derived from an insulin-modified IVGTT is notably altered in women with history of GDM progressing towards type 2 diabetes., Competing Interests: Declaration of Competing Interest Authors have nothing to disclose., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: This study aimed to design a simple surrogate marker (i.e., predictor) of the minimal model glucose effectiveness (S G ), namely calculated S G (CS G ), from a short insulin-modified intravenous glucose tolerance test (IM-IVGTT), and then to apply it to study women with previous gestational diabetes mellitus (pGDM)., Methods: CS G was designed using the stepwise model selection approach on a population of subjects ( n =181) ranging from normal tolerance to type 2 diabetes mellitus (T2DM). CS G was then tested on a population of women with pGDM ( n =57). Each subject underwent a 3-hour IM-IVGTT; women with pGDM were observed early postpartum and after a follow-up period of up to 7 years and classified as progressors (PROG) or non-progressors (NONPROG) to T2DM. The minimal model analysis provided a reference S G ., Results: CS G was described as CS G =1.06×10⁻²+5.71×10⁻²×K G /G peak , K G being the mean slope (absolute value) of loge glucose in 10-25- and 25-50-minute intervals, and G peak being the maximum of the glucose curve. Good agreement between CS G and S G in the general population and in the pGDM group, both at baseline and follow-up (even in PROG and NONPROG subgroups), was shown by the Bland-Altman plots (<5% observations outside limits of agreement), and by the test for equivalence (equivalence margin not higher than one standard deviation). At baseline, the PROG subgroup showed significantly lower S G and CS G values compared to the NONPROG subgroup ( P <0.03)., Conclusion: CS G is a valid S G predictor. In the pGDM group, glucose effectiveness appeared to be impaired in women progressing to T2DM., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2020 Korean Diabetes Association.)

Background & Aims: As vitamin D deficiency is associated with an increased risk of gestational diabetes mellitus (GDM), we aimed to test vitamin D supplementation as a strategy to reduce GDM risk (evaluated after fasting plasma glucose (FPG), insulin resistance and weight gain) in pregnant overweight/obese women., Methods: The DALI vitamin D multicenter study enrolled women with prepregnancy body mass index (BMI) ≥ 29 kg/m 2 , ≤19 + 6 weeks of gestation and without GDM. Participants were randomized to receive 1600 IU/day vitamin D3 or placebo (each with or without lifestyle intervention) on top of (multi)vitamins supplements. Women were assessed for vitamin D status (sufficiency defined as serum 25-hydroxyvitamin D (25(OH)D) ≥ 50 nmol/l), FPG, insulin resistance and weight at baseline, 24-28 and 35-37 weeks. Linear or logistic regression analyses were performed to assess intervention effects., Results: Average baseline serum 25(OH)D was ≥50 nmol/l across all study sites. In the vitamin D intervention arm (n = 79), 97% of participants achieved target serum vitamin 25(OH)D (≥50 nmol/l) at 24-28 weeks and 98% at 35-37 weeks vs 74% and 78% respectively in the placebo arm (n = 75, p < 0.001). A small but significantly lower FPG (-0.14 mmol/l; CI95 -0.28, -0.00) was observed at 35-37 weeks with the vitamin D intervention without any additional difference in metabolic status, perinatal outcomes or adverse event rates., Conclusion: In the DALI vitamin D trial, supplementation with 1600 IU vitamin D3/day achieved vitamin D sufficiency in virtually all pregnant women and a small effect in FPG at 35-37 weeks. The potential of vitamin D supplementation for GDM prevention in vitamin D sufficient populations appears to be limited., Trial Registration Number: ISRCTN70595832., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

We have read with great interest the accepted manuscript of the meta-analysis performed by Huang, et al. titled "A functional polymorphism rs10830963 in melatonin receptor 1B associated with the risk of gestational diabetes mellitus" published online in the 2019 December 6 issue of Bioscience Reports (https://doi.org/10.1042/BSR20190744). We do agree with the authors' final conclusion that such a meta-analysis should eventually confirm that the MTNR1B rs10830963 G allele is significantly associated with increased risk of gestational diabetes mellitus (GDM) development in pregnant populations with Asian and European ancestry. However we have surprisingly found that our genetic association study (PLoS One (2017), https://doi.org/10.1371/journal.pone.0169781) was included in this meta-analysis, but with mistakenly calculated odds ratios (OR). Therefore we would suggest to use the correct OR values based on our original publication that were already indicating a high genetic effect size for the MTNR1B rs10830963 risk variant on GDM development., (© 2020 The Author(s).)

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/m 2 ., 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.

Women with a previous history of gestational diabetes mellitus (GDM) have increased risk of developing GDM in future pregnancies (i.e. recurrent GDM) and also Type 2 Diabetes (T2D). Insulin clearance represents one of the processes regulating glucose tolerance but has been scarcely investigated for its possible impairment in high-risk subjects. The aim of this study was to identify possible determinants of insulin clearance in women with a previous history of GDM. A detailed model-based analysis of a regular 3-hour, insulin-modified intravenous glucose tolerance test (IM-IVGTT) has been performed in women with a previous history of GDM (pGDM, n = 115) and in women who had a healthy pregnancy (CNT, n = 41) to assess total, first-phase and second-phase insulin clearance (Cl INS-TOT , Cl INS-FP and Cl INS-SP ) and other metabolic parameters (insulin sensitivity S I , glucose effectiveness S G , beta-cell function and disposition index DI). CL INS-SP was found increased in pGDM with respect to CNT and was found significantly inversely linearly correlated with S G (r = -0.20, p = 0.03, slope: -16.2, 95% CI -30.9 to -1.4, intercept: 1.1, 95% CI 0.7-1.4) and also with DI (r = -0.22, p = 0.02, slope: -10.0, 95% CI -18.5 to -1.6, intercept: 0.9, 95% CI 0.7-1.3). Disposition index, accounting for the combined contribution of insulin sensitivity and beta-cell function, and glucose effectiveness were identified as possible determinants of insulin clearance in women with a previous history of GDM. This may be of relevance for more accurate estimation and prevention of the risk for recurrent GDM and T2D.

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/m 2 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.

In 1989 the St. Vincent Declaration aimed to achieve comparable pregnancy outcomes in diabetic and non-diabetic women. However, currently women with pre-gestational diabetes still feature a higher risk of perinatal morbidity and even increased mortality. This fact is mostly ascribed to a persistently low rate of pregnancy planning and pre-pregnancy care with optimization of metabolic control prior to conception. All women should be experienced in the management of their therapy and on stable glycemic control prior to the conception. In addition, thyroid dysfunction, hypertension as well as the presence of diabetic complications should be excluded before pregnancy or treated adequately in order to decrease the risk for a progression of complications during pregnancy as well as maternal and fetal morbidity. Especially in women with type 1 diabetes mellitus in early pregnancy the risk of hypoglycemia is highest and decreases with the progression of pregnancy due to hormonal changes causing steady increase of insulin resistance. In addition, obesity increases worldwide and contributes to increasing numbers of women at childbearing age with type 2 diabetes mellitus and further deterioration of pregnancy outcomes in diabetic women. Maternal glycemic control should aim to achieve normoglycemia and normal HbA 1c levels, possibly without hypoglycemia, but is associated with the development of diabetic embryopathy and fetopathy if dysglycemia occurs. Intensified insulin therapy with multiple daily insulin injections and pump treatment are effective in reaching good metabolic control during pregnancy. Oral glucose lowering drugs (Metformin) may be considered in obese women with type 2 diabetes mellitus to increase insulin sensitivity but should be also prescribed cautiously due to crossing the placenta and lack of long-time follow up data of the offspring.

Gestational diabetes mellitus (GDM) is defined as a glucose tolerance disorder with onset during pregnancy and is associated with increased feto-maternal morbidity as well as long-term complications in mother and child. Women who fulfil the criteria of a manifest diabetes in early pregnancy (fasting plasma glucose >126 mg/dl, spontaneous glucose level >200 mg/dl or HbA1c > 6.5% before 20 weeks of gestation) should be classified as having manifest diabetes in pregnancy and treated as such. Screening for undiagnosed type 2 diabetes at the first prenatal visit (evidence level B) is particularly recommended in women at increased risk (history of GDM or prediabetes, malformation, stillbirth, successive abortions or birth weight >4500 g in previous pregnancies, obesity, metabolic syndrome, age >35 years, vascular disease, clinical symptoms of diabetes, e. g. glucosuria, or ethnic groups with increased risk for GDM/T2DM, e.g. Arabian countries, south and southeast Asia and Latin America). A GDM is diagnosed by an oral glucose tolerance test (OGTT) or a fasting glucose concentration ≥92 mg/dl. Performance of the OGTT (120 min, 75 g glucose) may already be indicated in the first trimester in high risk women but is mandatory between 24-28 gestational weeks in all pregnant women with previous non-pathological glucose metabolism (evidence level B). Based on the results of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study and following the recent WHO recommendations, GDM is present if the fasting plasma glucose level exceeds 92 mg/dl, the 1 h level exceeds 180 mg/dl or the 2 h level exceeds 153 mg/dl after glucose loading (OGTT international consensus criteria). A single increased value is sufficient for the diagnosis and a strict metabolic control is mandatory. After bariatric surgery an OGTT is not recommended due to the risk of postprandial hypoglycemia. All women with GDM should receive nutritional counselling, be instructed in self-monitoring of blood glucose and to increase physical activity to moderate intensity levels, if not contraindicated. If blood glucose levels cannot be maintained in the therapeutic range (fasting <95 mg/dl and 1 h postprandial <140 mg/dl) insulin therapy should be initiated as first choice. Maternal and fetal monitoring is required in order to minimize maternal and fetal/neonatal morbidity and perinatal mortality. After delivery all women with GDM have to be re-evaluated by a 75 g OGTT (WHO criteria) 4-12 weeks postpartum to reclassify the glucose tolerance and every 2 years in cases of normal glucose tolerance (evidence level B). All women have to be informed about their (sevenfold increased relative) risk of developing type 2 diabetes (T2DM) at follow-up and possible preventive measures, in particular weight management, healthy diet and maintenance/increase of physical activity. Monitoring of the development of children and recommendations for a healthy lifestyle are necessary for the whole family. Regular obstetric examinations including ultrasound examinations are recommended. Within the framework of neonatal care, neonates of GDM mothers should undergo blood glucose measurements and if necessary appropriate measures should be initiated.

The rs10830963 variant of the Melatonin Receptor 1B ( MTNR1B ) gene is associated with the development of gestational diabetes mellitus (GDM). We hypothesized that carrying the rs10830963/ G risk allele had effect on antenatal insulin therapy (AIT) initiation in GDM in a body mass index (BMI)-dependent manner. Design : In this post hoc analysis the MTNR1B rs10830963 genotype and the clinical data of 211 Caucasian GDM patients were assessed. As a first step, a pre-pregnancy BMI threshold was determined where the effect of MTNR1B rs10830963/ G allele carrying on AIT initiation was the most significant using logistic regression. Maternal age adjusted real-life odds ratios (OR) values were calculated. The chi-square test was also used to calculate the p value and 10.000 bootstrap simulations were performed in each case to re-assess the statistical power and the OR. Carrying the MTNR1B rs10830963/ G allele increased the odds of AIT initiation (OR = 5.2, p = 0.02 [χ² test], statistical power = 0.53) in GDM patients with pre-pregnancy BMI ≥ 29 kg/m². The statistical power reached 0.77, when the pre-pregnancy BMI cutoff of 27 kg/m² was used and the genetic effect on AIT initiation was still significant, but only using the logistic regression model. Carrying the MTNR1B rs10830963/ G risk allele-in interaction with pre-pregnancy BMI-is likely be considered as a candidate pharmacogenetic marker of antenatal insulin therapy initiation and should be further assessed in precision medicine trials in GDM.

Excess gestational weight gain (GWG) is associated with the development of gestational diabetes mellitus (GDM). Lifestyle trials have not achieved much GWG limitation, and have largely failed to prevent GDM. We compared the effect of substantial GWG limitation on maternal GDM risk. Pregnant women with a body mass index (BMI) ≥29 kg/m² <20 weeks gestation without GDM ( n = 436) were randomized, in a multicenter trial, to usual care (UC), healthy eating (HE), physical activity (PA), or HE and PA lifestyle interventions. GWG over the median was associated with higher homeostasis model assessment insulin resistance (HOMA-IR) and insulin secretion (Stumvoll phases 1 and 2), a higher fasting plasma glucose (FPG) at 24⁻28 weeks (4.66 ± 0.43 vs. 4.61 ± 0.40 mmol/L, p < 0.01), and a higher rate of caesarean section (38% vs. 27% p < 0.05). The GWG over the median at 35⁻37 weeks was associated with a higher rate of macrosomia (25% vs. 16%, p < 0.05). A post hoc comparison among women from the five sites with a GWG difference >3 kg showed no significance difference in glycaemia or insulin resistance between HE and PA, and UC. We conclude that preventing even substantial increases in GWG after the first trimester has little effect on maternal glycaemia. We recommend randomized controlled trials of effective lifestyle interventions, starting in or before the first trimester.

Objective: Risk factors are widely used to identify women at risk for gestational diabetes mellitus (GDM) without clear distinction by pregnancy period or oral glucose tolerance test (OGTT) time points. We aimed to assess the clinical risk factors for Hyperglycemia in pregnancy (HiP) differentiating by these two aspects., Design and Methods: Nine hundred seventy-one overweight/obese pregnant women, enrolled in the DALI study for preventing GDM. OGTTs were performed at ≤19 + 6, 24-28 and 35-37 weeks (IADPSG/WHO2013 criteria). Women with GDM or overt diabetes at one time point did not proceed to further OGTTs. Potential independent variables included baseline maternal and current pregnancy characteristics., Statistical Analysis: Multivariate logistic regression., Results: Clinical characteristics independently associated with GDM/overt diabetes were at ≤19 + 6 weeks, previous abnormal glucose tolerance (odds ratio (OR): 3.11; 95% CI: 1.41-6.85), previous GDM (OR: 2.22; 95% CI: 1.20-4.11), neck circumference (NC) (OR: 1.58; 95% CI: 1.06-2.36 for the upper tertile), resting heart rate (RHR, OR: 1.99; 95% CI: 1.31-3.00 for the upper tertile) and recruitment site; at 24-28 weeks, previous stillbirth (OR: 2.92; 95% CI: 1.18-7.22), RHR (OR: 3.32; 95% CI: 1.70-6.49 for the upper tertile) and recruitment site; at 35-37 weeks, maternal height (OR: 0.41; 95% CI: 0.20-0.87 for upper tertile). Clinical characteristics independently associated with GDM/overt diabetes differed by OGTT time point (e.g. at ≤19 + 6 weeks, NC was associated with abnormal fasting but not postchallenge glucose)., Conclusion: In this population, most clinical characteristics associated with GDM/overt diabetes were non-modifiable and differed by pregnancy period and OGTT time point. The identified risk factors can help define the target population for future intervention trials., (© 2018 European Society of Endocrinology.)

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.

Background: Accuracy of the FreeStyle Libre™ Flash Glucose Monitoring System has not been evaluated in pregnant women with diabetes. The aim of this study was to determine accuracy (compared to self-monitoring of blood glucose [SMBG]), clinical safety, and acceptability of the FreeStyle Libre System when used at home by this population., Materials and Methods: Seventy-four participants, with type 1 (T1D, n = 24), type 2 (T2D, n = 11), or gestational (n = 39) diabetes, were enrolled across 13 sites (9 in United Kingdom, 4 in Austria). Average gestation was 26.6 ± 6.8 weeks (mean ± standard deviation), age was 30.5 ± 5.1 years, diabetes duration was 13.1 ± 7.3 years for T1D and 3.2 ± 2.5 years for T2D, and 49/74 (66.2%) used insulin to manage their diabetes. Sensors were worn for up to 14 days. Sensor glucose values (masked) were compared with capillary SMBG values (made at least 4 times/day)., Results: Clinical accuracy of sensor results versus SMBG results was demonstrated, with 88.1% and 99.8% of results within Zone A and Zones A and B of the Consensus Error Grid, respectively. Overall mean absolute relative difference was 11.8%. Sensor accuracy was unaffected by the type of diabetes, the stage of pregnancy, whether insulin was used, age or body mass index. User questionnaires indicated high levels of satisfaction with sensor wear, system use, and comparison to SMBG. There were no unanticipated device-related adverse events., Conclusions: Good agreement was demonstrated between the FreeStyle Libre System and SMBG. Accuracy of the system was unaffected by patient characteristics, indicating that the system is safe and accurate to use by pregnant women with diabetes.

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/m 2 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/m 2 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/m 2 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.

Objective: In the long term, diabetes mellitus is potentially associated with the occurrence of microvascular damage. This study sought to assess whether a history of prior gestational diabetes mellitus is associated with long-term effects on the women's microcirculation., Methods: Within the scope of a long-term follow-up of the 'Viennese Post-Gestational Diabetes Project', women with prior gestational diabetes mellitus as well as women with previous pregnancy but with no history of gestational diabetes mellitus (controls) were enrolled in this cross-sectional study. Microvascular function was assessed by post-occlusive reactive hyperaemia using laser Doppler fluxmetry. Baseline perfusion, biological zero, peak perfusion, time to peak and recovery time were recorded and compared between both groups., Results: Microvascular function was assessed in 55 women with prior gestational diabetes mellitus (46.1 ± 4.6 years) and 32 women with previous pregnancy but without prior gestational diabetes mellitus (42.9 ± 5.3 years). The mean period of time between delivery and the assessment of microvascular function was 16.2 ± 5.2 years in women with prior gestational diabetes mellitus group and 14.2 ± 4.8 years in controls. Regarding microvascular function, baseline perfusion, biological zero, peak perfusion, time to peak and recovery time did not differ between women with prior gestational diabetes mellitus and controls (all p > 0.05)., Conclusion: In the long term, microvascular function appears not to be impaired in women with prior gestational diabetes mellitus.

Context: Lifestyle approaches for preventing gestational diabetes mellitus (GDM) have produced mixed results., Objective: The aim of the present study was to compare the effectiveness of 3 lifestyle interventions [healthy eating (HE), physical activity (PA), and both HE and PA (HE+PA)] with usual care (UC) in reducing GDM risk., Design: The present study was a multicenter randomized controlled trial conducted from 2012 to 2014 [the DALI (vitamin D and lifestyle intervention for GDM prevention) lifestyle study]., Setting: The study occurred at antenatal clinics across 11 centers in 9 European countries., Patients: Consecutive pregnant women at <20 weeks of gestation with a body mass index (BMI) of ≥29 kg/m2 and without GDM using the International Association of Diabetes and Pregnancy Study Group criteria (n = 436). For the intervention, women were randomized, stratified by site, to UC, HE, PA, or HE+PA. The women received 5 face-to-face and ≤4 telephone coaching sessions using the principles of motivational interviewing. A gestational weight gain (GWG) <5 kg was targeted. The coaches received standardized training and an intervention toolkit tailored to their culture and language., Main Outcome Measures: The endpoints were the GWG at 35 to 37 weeks and the fasting glucose and insulin sensitivity [homeostasis model assessment insulin resistance (HOMA-IR)] at 24 to 28 weeks., Results: We randomized 108 women to HE+PA, 113 to HE, 110 to PA, and 105 to UC. In the HE+PA group, but not HE or PA alone, women achieved substantially less GWG than did the controls (UC) by 35 to 37 weeks (-2.02; 95% confidence interval, -3.58 to -0.46 kg). Despite this reduction, no improvements were seen in fasting or postload glucose levels, insulin concentrations, or HOMA-IR. The birthweights and large and small for gestational age rates were similar., Conclusions: The combined HE+PA intervention was able to limit GWG but did not reduce fasting glycemia. Thus, lifestyle changes alone are unlikely to prevent GDM among women with a BMI of ≥29 kg/m2., (Copyright © 2017 by the Endocrine Society)

Context: Genetic variation in human maternal DNA contributes to the susceptibility for development of gestational diabetes mellitus (GDM)., Objective: We assessed 77 maternal single nucleotide gene polymorphisms (SNPs) for associations with GDM or plasma glucose levels at OGTT in pregnancy., Methods: 960 pregnant women (after dropouts 820: case/control: m99'WHO: 303/517, IADPSG: 287/533) were enrolled in two countries into this case-control study. After genomic DNA isolation the 820 samples were collected in a GDM biobank and assessed using KASP (LGC Genomics) genotyping assay. Logistic regression risk models were used to calculate ORs according to IADPSG/m'99WHO criteria based on standard OGTT values., Results: The most important risk alleles associated with GDM were rs10830963/G of MTNR1B (OR = 1.84/1.64 [IADPSG/m'99WHO], p = 0.0007/0.006), rs7754840/C (OR = 1.51/NS, p = 0.016) of CDKAL1 and rs1799884/T (OR = 1.4/1.56, p = 0.04/0.006) of GCK. The rs13266634/T (SLC30A8, OR = 0.74/0.71, p = 0.05/0.02) and rs7578326/G (LOC646736/IRS1, OR = 0.62/0.60, p = 0.001/0.006) variants were associated with lower risk to develop GDM. Carrying a minor allele of rs10830963 (MTNR1B); rs7903146 (TCF7L2); rs1799884 (GCK) SNPs were associated with increased plasma glucose levels at routine OGTT., Conclusions: We confirmed the robust association of MTNR1B rs10830963/G variant with GDM binary and glycemic traits in this Caucasian case-control study. As novel associations we report the minor, G allele of the rs7578326 SNP in the LOC646736/IRS1 region as a significant and the rs13266634/T SNP (SLC30A8) as a suggestive protective variant against GDM development. Genetic susceptibility appears to be more preponderant in individuals who meet both the modified 99'WHO and the IADPSG GDM diagnostic criteria., Competing Interests: The authors have declared that no competing interests exist.

Gestational diabetes (GDM) is defined as any degree of glucose intolerance with onset during pregnancy and is associated with increased feto-maternal morbidity as well as long-term complications in mothers and offspring. Women detected to have diabetes early in pregnancy receive the diagnosis of overt, non-gestational, diabetes (glucose: fasting > 126 mg/dl, spontaneous > 200 mg/dl or HbA1c > 6.5 % before 20 weeks of gestation). GDM is diagnosed by an oral glucose tolerance test (OGTT) or fasting glucose concentrations (> 92 mg/dl). Screening for undiagnosed type 2 diabetes at the first prenatal visit (Evidence level B) is recommended in women at increased risk using standard diagnostic criteria (high risk: history of GDM or pre-diabetes (impaired fasting glucose or impaired glucose tolerance); malformation, stillbirth, successive abortions or birth weight > 4,500 g in previous pregnancies; obesity, metabolic syndrome, age > 45 years, vascular disease; clinical symptoms of diabetes (e. g. glucosuria)). Performance of the OGTT (120 min; 75 g glucose) may already be indicated in the first trimester in some women but is mandatory between 24 and 28 gestational weeks in all pregnant women with previous non-pathological glucose metabolism (Evidence level B). Based on the results of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study GDM is defined, if fasting venous plasma glucose exceeds 92 mg/dl or 1 h 180 mg/dl or 2 h 153 mg/dl after glucose loading (OGTT; international consensus criteria). In case of one pathological value a strict metabolic control is mandatory. This diagnostic approach was recently also recommended by the WHO. All women should receive nutritional counseling and be instructed in blood glucose self-monitoring and to increase physical activity to moderate intensity levels- if not contraindicated. If blood glucose levels cannot be maintained in the normal range (fasting < 95 mg/dl and 1 h after meals < 140 mg/dl) insulin therapy should be initiated as first choice. Maternal and fetal monitoring is required in order to minimize maternal and fetal/neonatal morbidity and perinatal mortality. After delivery all women with GDM have to be reevaluated as to their glucose tolerance by a 75 g OGTT (WHO criteria) 6-12 weeks postpartum and every 2 years in case of normal glucose tolerance (Evidence level B). All women have to be instructed about their (sevenfold increased relative) risk of type 2 diabetes at follow-up and possibilities for diabetes prevention, in particular weight management and maintenance/increase of physical activity. Monitoring of the development of the offspring and recommendation of healthy lifestyle of the children and family is recommended.

Twenty-six years ago the St. Vincent Declaration aimed for an achievement of a comparable pregnancy outcome in diabetic and non-diabetic women. However, current surveys clearly show that women with pre-gestational diabetes still feature a much higher risk of perinatal morbidity and even increased mortality. This fact is mostly ascribed to a persistently low rate of pregnancy planning and pre-pregnancy care with optimization of metabolic control prior to conception. In addition, obesity increases worldwide, contributing to a growing number of women with type 2 diabetes at a childbearing age, and a further deterioration in outcome in diabetic women. Development of diabetic embryopathy and fetopathy are known to be related to maternal glycemic control (target: normoglycemia and normal HbA1c, if possible without hypoglycemia). The risk for hypoglycemia is at its greatest in early pregnancy and decreases with the progression of pregnancy due to the hormonal changes leading to a marked increase of insulin resistance. Intensified insulin therapy with multiple daily insulin injections and pump treatment are equally effective in reaching good metabolic control during pregnancy. All women should be experienced in the management of their therapy and on stable glycemic control prior to the conception. In addition, thyroid dysfunction, hypertension as well as the presence of diabetic complications should be excluded before pregnancy or treated adequately in order to decrease the risk for a progression of complications during pregnancy as well as for maternal and fetal morbidity.

Currently available models of insulin dynamics are mostly based on the classical compartmental structure and, thus, their physiological utility is limited. In this work, we describe the development of a physiologically based model and its application to data from 154 patients who underwent an insulin-modified intravenous glucose tolerance test (IM-IVGTT). To determine the time profile of endogenous insulin delivery without using C-peptide data and to evaluate the transcapillary transport of insulin, the hepatosplanchnic, renal, and peripheral beds were incorporated into the circulatory model as separate subsystems. Physiologically reasonable population mean estimates were obtained for all estimated model parameters, including plasma volume, interstitial volume of the peripheral circulation (mainly skeletal muscle), uptake clearance into the interstitial space, hepatic and renal clearance, as well as total insulin delivery into plasma. The results indicate that, at a population level, the proposed physiologically based model provides a useful description of insulin disposition, which allows for the assessment of muscle insulin uptake., (Copyright © 2016 the American Physiological Society.)

Introduction: We explored beliefs, perceived barriers, and preferences regarding lifestyle changes among overweight European pregnant women to help inform the development of future lifestyle interventions in the prevention of gestational diabetes mellitus., Methods: An explorative mixed methods, two-staged study was conducted to gather information from pregnant European women (BMI ≥ 25 kg/m2). In three European countries 21 interviews were conducted, followed by 71 questionnaires in six other European countries. Content analysis and descriptive and chi-square statistics were applied (p < 0.05)., Results: Women preferred to obtain detailed information about their personal risk. The health of their baby was a major motivating factor. Perceived barriers for physical activity included pregnancy-specific issues such as tiredness and experiencing physical complaints. Insufficient time was a barrier more frequently reported by women with children. Abstaining from snacking was identified as a challenge for the majority of women, especially for those without children. Women preferred to obtain support from their partner, as well as health professionals and valued flexible lifestyle programs., Conclusions: Healthcare professionals need to inform overweight pregnant women about their personal risk, discuss lifestyle modification, and assist in weight management. Lifestyle programs should be tailored to the individual, taking into account barriers experienced by overweight first-time mothers and multipara women.

We assessed the hematopoietic stem and progenitor cell (HSPC) population in the cord blood of neonates born to mothers with gestational diabetes mellitus (GDM) in a hypothesis generating pilot study, due to that, neonatal polycythemia may be the consequence of GDM pregnancy. Forty-five pregnant women with GDM (last trimester mean HbA1C = 33.9 mmol/mol) and 42 (nondiabetic) control pregnant women were enrolled after their routine 75 g oral glucose tolerance test (OGTT) between the 24th and 28th gestational week (with expected differences in their mean routine clinical characteristics: plasma glucose at OGTT: 0' = 5.07 vs. 4.62 mM, 120' = 8.9 vs. 5.76 mM, age = 35.07 vs. 31.66 years, prepregnancy body mass index = 27.9 vs. 23.9 kg/m(2), GDM vs. control, respectively) on a voluntary basis after signing the informed consent. EDTA-treated cord blood samples were analyzed by flow cytometry and the software Kaluza1.2 using CD45 and CD34-specific fluorescent antibodies to identify the HSPC population (CD34(+) cells within the CD45(dim) blast gate). The proportion of CD34(+)CD45(dim) HSPCs among the nucleated cells was significantly (P < 0.05, statistical power = 60.8%) higher in the cord blood samples of neonates born to mothers with GDM (median 0.38%) compared to neonates born to nondiabetic mothers (median 0.32%) and according to treatment types (P < 0.05) median: control 0.32%, GDM-diet only 0.37%, GDM-on insulin 0.45%; control versus GDM on insulin (P < 0.05). The increased proportion of circulating CD34(+)CD45(dim) cells in the cord blood may possibly be related to altered fetal stem cell mobilization in GDM pregnancy, yet these results should be interpreted only as preliminary due to the small sample sizes.

This paper aims to introduce penalized estimation techniques in clinical investigations of diabetes, as well as to assess their possible advantages and limitations. Data from a previous study was used to carry out the simulations to assess: a) which procedure results in the lowest prediction error of the final model in the setting of a large number of predictor variables with high multicollinearity (of importance if insulin sensitivity should be predicted) and b) which procedure achieves the most accurate estimate of regression coefficients in the setting of fewer predictors with small unidirectional effects and moderate correlation between explanatory variables (of importance if the specific relation between an independent variable and insulin sensitivity should be examined). Moreover a special focus is on the correct direction of estimated parameter effects, a non-negligible source of error and misinterpretation of study results. The simulations were performed for varying sample size to evaluate the performance of LASSO, Ridge as well as different algorithms for Elastic Net. These methods were also compared with automatic variable selection procedures (i.e. optimizing AIC or BIC).We were not able to identify one method achieving superior performance in all situations. However, the improved accuracy of estimated effects underlines the importance of using penalized regression techniques in our example (e.g. if a researcher aims to compare relations of several correlated parameters with insulin sensitivity). However, the decision which procedure should be used depends on the specific context of a study (accuracy versus complexity) and moreover should involve clinical prior knowledge.

Rising rates of diabetes in pregnancy have led to an escalation in research in this area. As in any area of clinical research, definitions of outcomes vary from study to study, making it difficult to compare research findings and draw conclusions. Our aim was to compile and create a repository of definitions, which could then be used universally. A systematic review of the literature was performed on published and ongoing randomized controlled trials in the area of diabetes in pregnancy between 01 Jan 2000 and 01 Jun 2012. Other sources included the World Health Organization and Academic Society Statements. The advice of experts was sought when appropriate definitions were lacking. Among the published randomized controlled trials on diabetes and pregnancy, 171 abstracts were retrieved, 64 full texts were reviewed and 53 were included. Among the ongoing randomized controlled trials published in ClinicalTrials.gov, 90 protocols were retrieved and 25 were finally included. The definitions from these were assembled and the final maternal definitions and foetal definitions were agreed upon by consensus. It is our hope that the definitions we have provided (i) will be widely used in the reporting of future studies in the area of diabetes in pregnancy, that they will (ii) facilitate future systematic reviews and formal meta analyses and (iii) ultimately improve outcomes for mothers and babies., (Copyright © 2015 John Wiley & Sons, Ltd.)

Objective: Ways to prevent gestational diabetes mellitus (GDM) remain unproven. We compared the impact of three lifestyle interventions (healthy eating [HE], physical activity [PA], and both HE and PA [HE+PA]) on GDM risk in a pilot multicenter randomized trial., Research Design and Methods: Pregnant women at risk for GDM (BMI ≥29 kg/m2) from nine European countries were invited to undertake a 75-g oral glucose tolerance test before 20 weeks' gestation. Those without GDM were randomized to HE, PA, or HE+PA. Women received five face-to-face and four optional telephone coaching sessions, based on the principles of motivational interviewing. A gestational weight gain (GWG) <5 kg was targeted. Coaches received standardized training and an intervention toolkit. Primary outcome measures were GWG, fasting glucose, and insulin sensitivity (HOMA) at 35-37 weeks., Results: Among the 150 trial participants, 32% developed GDM by 35-37 weeks and 20% achieved GWG <5 kg. HE women had less GWG (-2.6 kg [95% CI -4.9, -0.2]; P = 0.03) and lower fasting glucose (-0.3 mmol/L [-0.4, -0.1]; P = 0.01) than those in the PA group at 24-28 weeks. HOMA was comparable. No significant differences between HE+PA and the other groups were observed., Conclusions: An antenatal HE intervention is associated with less GWG and lower fasting glucose compared with PA alone. These findings require a larger trial for confirmation but support the use of early HE interventions in obese pregnant women., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims/hypothesis: Betatrophin has recently been introduced as a novel hormone and promotor of beta cell proliferation and improved glucose tolerance in mouse models of insulin resistance. In obese and diabetic humans altered levels were reported and a role in pathophysiology of metabolic diseases was therefore hypothesized. However its release and regulation in women with gestational diabetes mellitus (GDM), as well as its associations with markers of obesity, glucose and lipid metabolism during pregnancy still remain unclear., Methods: Circulating betatrophin was quantified in 21 women with GDM and 19 pregnant body mass index-matched women with normal glucose tolerance (NGT) as well as 10 healthy age-matched non-pregnant women by enzyme-linked immunosorbent assay. Additionally we performed radioimmunassay (RIA) to confirm the results., Results: Betatrophin concentrations measured by ELISA were significantly higher in GDM than in NGT (29.3±4.4 ng/ml vs. 18.1±8.7 ng/ml, p<0.001) which was confirmed by RIA. Betatrophin did not correlate with BMI or insulin resistance but showed a weak association with leptin levels in pregnancy and negative relationship with fasting C-peptide levels in all women. Moreover it correlated significantly with lipid parameters including triglycerides and total cholesterol in pregnancy, as well as estrogen, progesteron and birth weight., Conclusions/interpretation: Circulating betatrophin concentrations are dramatically increased in pregnancy and are significantly higher in GDM versus pregnant NGT. In the light of the previously reported role in lipid metabolism, betatrophin may represent a novel endocrine regulator of lipid alterations in pregnancy. However additional studies are needed to elucidate whether hormonal factors, such as estrogen, control the production of betatrophin and if targeting betatrophin could hold promise in the fight against metabolic disease.

Early reexamination of carbohydrate metabolism via an oral glucose tolerance test (OGTT) is recommended after pregnancy with gestational diabetes (GDM). In this report, we aimed to assess the dominant patterns of dynamic OGTT measurements and subsequently explain them by meanings of the underlying pathophysiological processes. Principal components analysis (PCA), a statistical procedure that aims to reduce the dimensionality of multiple interrelated measures to a set of linearly uncorrelated variables (the principal components) was performed on OGTT data of glucose, insulin and C-peptide in addition to age and body mass index (BMI) of 151 women (n = 110 females after GDM and n = 41 controls) at 3-6 mo after delivery. These components were explained by frequently sampled intravenous glucose tolerance test (FSIGT) parameters. Moreover, their relation with the later development of overt diabetes was studied. Three principal components (PC) were identified, which explained 71.5% of the variation of the original 17 variables. PC1 (explained 47.1%) was closely related to postprandial OGTT levels and FSIGT-derived insulin sensitivity (r = 0.68), indicating that it mirrors insulin sensitivity in the skeletal muscle. PC2 (explained 17.3%) and PC3 (explained 7.1%) were shown to be associated with β-cell failure and fasting (i.e., hepatic) insulin resistance, respectively. All three components were related with diabetes progression (occurred in n = 25 females after GDM) and showed significant changes in long-term trajectories. A high amount of the postpartum OGTT data is explained by principal components, representing pathophysiological mechanisms on the pathway of impaired carbohydrate metabolism. Our results improve our understanding of the underlying biological processes to provide an accurate postgestational risk stratification., (Copyright © 2015 the American Physiological Society.)

Context: Appropriate risk stratification is essential in gestational diabetes (GDM) diagnosis to optimize therapeutic strategies during pregnancy. However, there are sparse data related to the newly recommended International Association of Diabetes and Pregnancy Study Groups criteria and their use in early pregnancy., Objective: This study sought to evaluate clinical and pathophysiological characteristics less up to gestational week (GW) 21 in women with early and late GDM onset., Design and Setting: This was a prospective study conducted at the Medical University of Vienna., Patients and Interventions: Pregnant women (n = 211) underwent an oral glucose tolerance test at 16 GW (interquartile range, 14-18 wk) with multiple measurements of glucose, insulin, and C-peptide for evaluation of insulin sensitivity and ß-cell function in addition to detailed obstetrical risk assessment. Clinical followups were performed until end of pregnancy., Main Outcome Measure: We performed a metabolic characterization of early-onset GDM., Results: Of 81 women, 49 (23%) showed early (GDMEarly ≤ 21 GW) and 32 (15%) later manifestation (GDMLate ≥ 24 GW) whereas 130 (62%) remained normal-glucose-tolerant (NGT). In contrast with GDMLate, GDMEarly were affected by decreased insulin sensitivity (GDMEarly vs NGT, P < .001; GDMEarlyvs GDMLate, P < .001; GDMLate vs NGT, P = .410). However, both early and late manifested subjects showed impairments in ß-cell function. GDMEarly showed highest levels of preconceptional and actual body mass index (BMI), which was related to fasting glucose (r = 0.42, P < .001) and particularly insulin sensitivity (r = -0.51, P < .001). Differences in glucose disposal between the subgroups remained constant in multivariable analysis including the strongest risk factors for GDM, ie, age, history of GDM, and BMI in our population., Conclusions: Early manifestation of GDM is affected by insulin resistance that is partly explained by higher degree in obesity. However, ß-cell dysfunction was also detectable in GDMLate, indicating defective compensatory mechanisms emerging already in early pregnancy.

Background: Tissue-specific dipeptidyl-peptidase 4 (DPP4) dysregulation has been described in adults with diabetes mellitus. The DPP4 -incretin system has not been studied in foetal life. In this study, DPP4 activity and glucagon-like peptide-1 (GLP-1) levels were assessed in cord blood of neonates born to women with gestational diabetes mellitus (GDM) and nondiabetic controls., Material and Methods: This study has been conducted in two Hungarian and one Austrian centres., Patients: A total of 568 pregnant women were enrolled in the study after their OGTT between the 24th and 28th gestational week. Cord blood samplings with DPP4 activity and GLP-1 level measurements were possible in 270 (DPP4: 159 control, 111 GDM) and 112 (GLP-1: 72 control, 40 GDM) cases. OGTT (24-28th gestational week) and cord blood sampling at delivery were performed. Cord serum DPP4 activity was determined in a continuous monitoring microplate-based kinetic assay, and cord plasma GLP-1 was measured using a fluorescence ELISA method., Results: Cord serum DPP4 activity was lower in GDM [mean (95% CI): 28.07 U/L (26.32-29.82 U/L)] than in controls [31.61 U/L (29.93-33.29 U/L), MWU P = 0.0015]. Cord plasma active GLP-1 levels were close to the lower detection limit and were not altered in GDM (control: mean = 3.43 pM, 95% CI: 3.04-3.82 pM, GDM: mean = 3.61 pM, 95% CI: 2.96-4.28 pM - MWU test P = 0.6)., Conclusions: Decreased cord serum DPP4 activity in gestational diabetes mellitus might be the result of an adaptive foetal response or an early dysregulation in the entero-insular axis with consequences beyond the incretin system. Cord plasma GLP-1 levels may reflect the missing oral intake with a limited glucose sensing of L cells via the circulation in foetal life., (© 2014 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: History of gestational diabetes mellitus (GDM) identifies a very young population of females predisposed for type 2 diabetes and cardiovascular disease. Endothelial dysfunction might represent a shared precursor of both disorders. Hence, this study aimed to characterize endothelial biomarkers in relation to impaired insulin sensitivity and progression to overt diabetes early after index pregnancy., Methods: 108 women with previous GDM and 40 controls were included three to six months after delivery and underwent specific metabolic assessments including a frequently sampled intravenous glucose tolerance test and an oral glucose tolerance test. Diabetes progression was assessed in females with pGDM over 10 years of follow-up. Circulating sICAM-1 (intracellular-adhesion-molecule-1), sVCAM-1 (vascular-cell-adhesion-molecule-1) and sE-selectin, representing biomarkers of endothelial dysfunction were assessed at baseline and annually over five years., Results: Endothelial biomarkers were significantly associated with insulin sensitivity (sICAM-1: r = -0.23, p = 0.009; sVCAM-1: r = -0.22, p = 0.011; sE-selectin: r = -0.21, p = 0.018) as well as with GDM status and parameters of subtle inflammation. Analysis of long-term trajectories revealed constantly elevated sICAM-1 (p = 0.033) and sE-selectin (p = 0.007) in 25 subjects with diabetes progression. Accordingly, sE-selectin levels at the early post partum visit predicted a later development of the disease (HR =1.02 95%CI 1.01 to 1.04, p = 0.013), however, this was attenuated after adjustment for BMI., Conclusions: Elevated circulating markers of endothelial dysfunction in young females with GDM history might reflect an early stage on the pathway to the manifestation of future cardiometabolic disorders. Timely identification of women at high risk and optimization of follow-up management might provide an opportunity to prevent disease progression.