Call to action for a life course approach.

Gestational diabetes remains the most common medical disorder in pregnancy, with short-term and long-term consequences for mothers and offspring. New insights into pathophysiology and management suggest that the current gestational diabetes treatment approach should expand from a focus on late gestational diabetes to a personalised, integrated life course approach from preconception to postpartum and beyond. Early pregnancy lifestyle intervention could prevent late gestational diabetes. Early gestational diabetes diagnosis and treatment has been shown to be beneficial, especially when identified before 14 weeks of gestation. Early gestational diabetes screening now requires strategies for integration into routine antenatal care, alongside efforts to reduce variation in gestational diabetes care, across settings that differ between, and within, countries. Following gestational diabetes, an oral glucose tolerance test should be performed 6-12 weeks postpartum to assess the glycaemic state. Subsequent regular screening for both dysglycaemia and cardiometabolic disease is recommended, which can be incorporated alongside other family health activities. Diabetes prevention programmes for women with previous gestational diabetes might be enhanced using shared decision making and precision medicine. At all stages in this life course approach, across both high-resource and low-resource settings, a more systematic process for identifying and overcoming barriers to preventative care and treatment is needed to reduce the current global burden of gestational diabetes.

Pulmonary Resilience: Moderating the Association between Oxygen Exposure and Pulmonary Outcomes in Extremely Preterm Newborns.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy associated with high morbidity and mortality. Although most prevalent following extremely preterm birth, BPD is diagnosed at 36 weeks post-menstrual age, when the disease trajectory is underway, and long-term physiological implications may be irreversible. There is an urgent and unmet need to identify how early exposures can be modified to decrease the risk of developing BPD before disease progression becomes irreversible. Extremely preterm newborns encounter a paradox at birth: oxygen is a life-sustaining component of ex utero life yet is undeniably toxic. Attempts at minimizing supplemental oxygen exposure by targeting lower oxygen saturations appear to decrease BPD but may increase mortality. Given the potential association between lower oxygen saturations and increased mortality, practice guidelines favor targeting higher saturations. This uniformly increases oxygen exposure, prompting a cascade of pathogenic mechanisms implicated in BPD development. In this review, we introduce the concept of pulmonary resilience: a homeostatic process driven by the autonomic nervous system (ANS) as a moderator of physiologic stress that when functional, could inform successful environmental adaptation following extremely preterm birth. We hypothesize that infants with early-life ANS dysfunction require a higher oxygen dose for survival; conversely, oxygen exposure could be safely limited in infants with more robust early-life ANS function, an indicator of pulmonary resilience. Characterizing the pulmonary resilience continuum to guide individualized supplemental oxygen dosing may reduce morbidity and mortality in this growing population of extremely preterm infants at risk for BPD.

Single Cell RNA Sequencing of Human Milk-Derived Cells Reveals Sub-Populations of Mammary Epithelial Cells with Molecular Signatures of Progenitor and Mature States: a Novel, Non-invasive Framework for Investigating Human Lactation Physiology.

Cells in human milk are an untapped source, as potential "liquid breast biopsies", of material for investigating lactation physiology in a non-invasive manner. We used single cell RNA sequencing (scRNA-seq) to identify milk-derived mammary epithelial cells (MECs) and their transcriptional signatures in women with diet-controlled gestational diabetes (GDM) with normal lactation. Methodology is described for coordinating milk collections with single cell capture and library preparation via cryopreservation, in addition to scRNA-seq data processing and analyses of MEC transcriptional signatures. We comprehensively characterized 3740 cells from milk samples from two mothers at two weeks postpartum. Most cells (>90%) were luminal MECs (luMECs) expressing lactalbumin alpha and casein beta and positive for keratin 8 and keratin 18. Few cells were keratin 14+ basal MECs and a small immune cell population was present (<10%). Analysis of differential gene expression among clusters identified six potentially distinct luMEC subpopulation signatures, suggesting the potential for subtle functional differences among luMECs, and included one cluster that was positive for both progenitor markers and mature milk transcripts. No expression of pluripotency markers POU class 5 homeobox 1 (POU5F1, encoding OCT4) SRY-box transcription factor 2 (SOX2) or nanog homeobox (NANOG), was observed. These observations were supported by flow cytometric analysis of MECs from mature milk samples from three women with diet-controlled GDM (2-8 mo postpartum), indicating a negligible basal/stem cell population (epithelial cell adhesion molecule (EPCAM)-/integrin subunit alpha 6 (CD49f)+, 0.07%) and a small progenitor population (EPCAM+/CD49f+, 1.1%). We provide a computational framework for others and future studies, as well as report the first milk-derived cells to be analyzed by scRNA-seq. We discuss the clinical potential and current limitations of using milk-derived cells as material for characterizing human mammary physiology.

Continued Disparities in Postpartum Follow-Up and Screening Among Women With Gestational Diabetes and Hypertensive Disorders of Pregnancy: A Systematic Review.

The postpartum period represents a critical window to initiate targeted interventions to improve cardiometabolic health following pregnancies complicated by gestational diabetes mellitus and/or a hypertensive disorder of pregnancy. The purpose of this systematic review was to examine studies published since 2011 that report rates of postpartum follow-up and risk screening for women who had gestational diabetes and/or a hypertensive disorder of pregnancy and to identify disparities in care. Nine observational studies in which postpartum follow-up visits and/or screening rates were measured among US women following pregnancies complicated by gestational diabetes and/or a hypertensive disorder of pregnancy were reviewed. Rates of postpartum follow-up ranged from 5.7% to 95.4% with disparities linked to black race and Hispanic ethnicity, low level of education, and coexisting morbidities such as mental health disorders. Follow-up rates were increased if the provider was an obstetrician/endocrinologist versus primary care. Payer source was not associated with follow-up rates. The screening rate for diabetes in women who had gestational diabetes did not exceed 58% by 4 months across the studies analyzed, suggesting little improvement in the last 10 years. While women who had a hypertensive disorder appear to have had a postpartum blood pressure measured, it is unclear whether follow-up intervention occurred. Overall, postpartum screening rates for at-risk women remain suboptimal and vary substantially. Further research is warranted including reliable population-level data to inform equitable progress to meeting the evidence-informed guidelines.

Fat redistribution following suction lipectomy: defense of body fat and patterns of restoration.

No randomized studies in humans have examined whether fat returns after removal or where it returns. We undertook a prospective, randomized-controlled trial of suction lipectomy in nonobese women to determine if adipose tissue (AT) is defended and if so, the anatomic pattern of redistribution. Healthy women with disproportionate AT depots (lower abdomen, hips, or thighs) were enrolled. Baseline body composition measurements included dual-energy X-ray absorptiometry (DXA) (a priori primary outcome), abdominal/limb circumferences, subcutaneous skinfold thickness, and magnetic resonance imaging (MRI) (torso/thighs). Participants (n = 32; 36 ± 1 year) were randomized to small-volume liposuction (n = 14, mean BMI: 24 ± 2 kg/m(2)) or control (n=18, mean BMI: 25 ± 2) following baseline. Surgery group participants underwent liposuction within 2-4 weeks. Identical measurements were repeated at 6 weeks, 6 months, and 1 year later. Participants agreed not to make lifestyle changes while enrolled. Between-group differences were adjusted for baseline level of the outcome variable. After 6 weeks, percent body fat (%BF) by DXA was decreased by 2.1% in the lipectomy group and by 0.28% in the control group (adjusted difference (AD): -1.82%; 95% confidence interval (CI): -2.79% to -0.85%; P = 0.0002). This difference was smaller at 6 months, and by 1 year was no longer significant (0.59% (control) vs. -0.41% (lipectomy); AD: -1.00%; CI: -2.65 to 0.64; P = 0.23). AT reaccumulated differently across various sites. After 1 year the thigh region remained reduced (0.77% (control) vs. -1.83% (lipectomy); AD: -2.59%; CI: -3.91 to -1.28; P = 0.0001), but AT reaccumulated in the abdominal region (0.64% (control) vs. 0.42% (lipectomy); AD: -0.22; CI: -2.35 to 1.91; P = 0.84). Following suction lipectomy, BF was restored and redistributed from the thigh to the abdomen.

Chronically increased S6K1 is associated with impaired IRS1 signaling in skeletal muscle of GDM women with impaired glucose tolerance postpartum.

CONTEXT: The rapidly increasing prevalence of gestational diabetes mellitus (GDM) globally places a growing population at risk for developing type 2 diabetes mellitus (T2DM), particularly those with persistent impaired glucose tolerance (IGT) postpartum. OBJECTIVE: We sought to 1) identify dynamic insulin signaling abnormalities in vivo in a prospective, longitudinal study of GDM women compared to weight-matched pregnant controls both antepartum and postpartum; and 2) determine abnormalities that might distinguish GDM women who normalize their glucose tolerance postpartum from those with persistent IGT. DESIGN: Skeletal muscle biopsies were obtained before and after a 75-g glucose load in nine overweight to obese GDM women and 10 weight-matched pregnant controls antepartum and postpartum. Postpartum biopsies were collected in five weight-matched GDM women with IGT (GDM/IGT). RESULTS: GDM women had decreased skeletal muscle insulin-stimulated insulin receptor and insulin receptor substrate 1 (IRS1) tyrosine activation and reduced IRS1, concomitant with increased basal IRS1 serine phosphorylation and basal p70 S6-kinase (S6K1) activation, which resolved postpartum. However, GDM/IGT subjects had a persistent impairment in IRS1 activation and increased S6K1 phosphorylation compared to GDM subjects with normal glucose tolerance. CONCLUSIONS: This study reveals that women with GDM demonstrate impaired IRS1 signaling associated with increased S6K1 activation in skeletal muscle in vivo. This defect is maintained postpartum in GDM/IGT subjects, despite similar body weights and cytokine levels. Given that GDM women with persistent IGT are at a high risk of developing T2DM, understanding how the nutrient-sensitive mammalian target of rapamycin/S6K1 pathway is chronically activated in GDM may lead to important therapies that could prevent the progression to T2DM.

Single-dose rexinoid rapidly and specifically suppresses serum thyrotropin in normal subjects.

CONTEXT: Retinoid X receptor agonists (rexinoids) have demonstrated benefit in patients with certain malignancies but appear to cause central hypothyroidism in some patients with advanced cancer. The influence of rexinoids on thyroid function in healthy subjects is not clear. OBJECTIVE: The objective of this study was to determine the effect of a single dose of bexarotene on levels of TSH, T4, and T3 in healthy subjects. DESIGN: This study was a randomized, double-blind, placebo-controlled, crossover trial. SETTING: This study was conducted at the General Clinical Research Center (University of Colorado Health Sciences Center, Aurora, CO). SUBJECTS: Six healthy adults (>18 yr old) were studied. INTERVENTION: Single-dose rexinoid (bexarotene, 400 mg/m2) or placebo, with TSH measurements at 0, 1, 2, 4, 8, 12, 24, and 48 h, were used. MAIN OUTCOME MEASURE: The main outcome was the serum TSH level at 24 h. RESULTS: Single-dose bexarotene suppressed serum TSH (P < 0.001) over time. Compared with placebo, levels of TSH were significantly lower by 12 h (P = 0.043); the nadir of 0.32 +/- 0.02 mU/liter (P < 0.001) was seen at 24 h. Free T4 index and free T3 index were also significantly lower than placebo over time (48 h) (P = 0.029; P = 0.004, respectively). Serum prolactin, cortisol, and triglycerides were not affected (P > 0.05 for all). There was no significant effect of single-dose bexarotene on rT3 or T3/rT3 ratio at 24 h. CONCLUSION: A single dose of a rexinoid can rapidly and specifically suppress serum TSH levels in healthy subjects. These data provide insight into the mechanisms by which rexinoids cause central hypothyroidism and potential ways this effect can be used for treatment of disorders such as thyroid hormone resistance and TSH-secreting pituitary tumors.

Short-term triglyceride lowering with fenofibrate improves vasodilator function in subjects with hypertriglyceridemia.

OBJECTIVE: The objective of this study was to investigate the effects of lowering plasma triglycerides (TGs) on endothelial function and gain insight into the role played by free fatty acids (FFAs) in hypertriglyceridemia-associated vascular dysfunction. METHODS AND RESULTS: Eleven hypertriglyceridemic subjects without coronary artery disease, diabetes, elevated low-density lipoprotein cholesterol, tobacco use, or hypertension were studied using a randomized, double-blinded, crossover design (fenofibrate and placebo, 14 days). After each regimen, forearm blood flow was assessed by plethysmography in response to arterial acetylcholine, nitroprusside, and verapamil infusion. Hourly plasma TGs, FFA, glucose, and insulin were measured during a 24-hour feeding cycle to characterize the metabolic environment. Changes in plasma FFA after intravenous heparin were used to estimate typical FFA accumulation in the luminal endothelial microenvironment. Fenofibrate lowered plasma TG (P<0.001), total cholesterol (P<0.01), and apolipoprotein B (P<0.01) without altering high-density lipoprotein or low-density lipoprotein cholesterol concentrations. Forearm blood flow in response to acetylcholine (P<0.0001), nitroprusside (P<0.001), and verapamil (P<0.0001) improved after fenofibrate. Fenofibrate lowered 24-hour (P<0.0001) and post-heparin (P<0.001) TG and tended to lower 24-hour (P=0.054) and post-heparin (P=0.028) FFA. CONCLUSIONS: Vascular smooth muscle function significantly improves after lowering plasma TG without changes in confounding lipoproteins or insulin resistance. The data raise additional questions regarding the role of FFA in hypertriglyceridemia-associated vascular dysfunction.