Egan, Aoife M.

Hyperglycemia in prediabetes is accompanied by increased amino acid (AA) concentrations and impaired suppression of glucagon secretion by glucose. It is unknown whether an abnormal response to AA contributes or hepatic steatosis exacerbates α-cell dysfunction. Therefore, lean participants and participants with obesity (with and without hepatic steatosis) were studied on two occasions in random order using a graded glucose infusion. Saline or an AA mixture was infused. The glucagon secretion rate (GSR) was derived from peripheral glucagon concentrations, and the change in glucose required to reduce GSR by 50% (G50) was calculated for each participant. AAs were measured during the experiment. On both occasions, experimental conditions produced a progressive rise in insulin secretion and an inverse exponential suppression of glucagon. G50 did not differ between groups in response to glucose alone. AA infusion did not change G50 in lean participants. G50 increased during AA infusion in participants with obesity with and without hepatic steatosis, leading us to report these participants as a single group. The relative change in AA concentrations across study days was generally similar between groups. We conclude that despite a normal response to glucose, obesity increases α-cell responses to AA in humans. Article Highlights The aim of this study was to understand the pathogenesis of α-cell dysfunction in prediabetes. The primary hypothesis was that α-cell responsivity to glucose (reduction of the glucagon secretion rate by 50%) is impaired by amino acid (AA) infusion. A secondary hypothesis was that this abnormal response is exacerbated by hepatic steatosis. AA infusion impaired α-cell suppression in response to rising glucose in participants with obesity, but not in lean participants, despite a normal response to glucose alone. This abnormal response was unaffected by the presence or absence of hepatic steatosis. It seems likely that an abnormal α-cell response to AAs precedes an abnormal response to glucose alone.

ABSTRACT Early-life nutrition profoundly influences long-term metabolic health, and breast milk not only provides nutrients but also conveys maternal signals shaping infant metabolic development. While postpartum exercise by lactating women benefits maternal health, its impact on milk-borne signaling remains largely undefined. Small extracellular vesicles (sEVs) in breast milk are key mediators of maternal–infant communication because of their selectively packaged bioactive cargo and resistance to infant digestive enzymes and acids, enabling delivery of their cargo to peripheral tissues. Here, we show that a single session of moderate-intensity postpartum aerobic exercise robustly increases human breast milk sEV concentration, which persists for multiple post-exercise milk collections. Exercise enriches breast milk with sEVs containing regulatory metabolic cargo (proteins, miRNAs, and metabolites), which translates into enhanced mitochondrial capacity in neonatal-stage cells. These findings implicate sEVs as an exercise-responsive signaling compartment in breast milk capable of connecting postpartum maternal physical activity to beneficial infant metabolic programming. Highlights Acute moderate-intensity exercise increases human breast milk sEV concentration The exercise-mediated sEV increase lasts for multiple subsequent milk expressions Exercise coordinates a multi-omic enrichment of sEVs in breast milk Exercised breast milk sEVs enhance mitochondrial respiration in UC-MSCs

Background: Pregnancy in teenagers and emerging adults is associated with an increased risk of adverse outcomes. Similarly, pregnancies complicated by pregestational and gestational diabetes mellitus (GDM) carry a higher risk of complications. However, limited data exist on the intersection of these two high-risk conditions. Our objective was to establish the prevalence of teenage and emerging adult pregnancies complicated by diabetes in a population-based cohort and compare outcomes to pregnancies uncomplicated by diabetes, noting a background prevalence of GDM of 8.1% and pregestational diabetes of 1.2% across all age groups in the United States. Methods: This is a retrospective cohort study conducted in Olmsted County, Minnesota, USA. It includes female residents aged ≤21 years with a pregnancy ICD-10 code between January 1, 2013, and December 31, 2022. The main outcome measures assessed include maternal characteristics and maternal and fetal pregnancy outcomes. Results: A total of 1491 pregnancies in 1379 individuals were identified and included. In total, 68 (4.6%) pregnancies were complicated by diabetes: 51 (3.4%) with GDM and 17 (1.1%) with pregestational diabetes. In this study, pregnancies with diabetes had higher rates of adverse outcomes including cesarean delivery (GDM 29.4% vs. pregestational 60.0% vs. no diabetes 17.0%, P < 0.001), preeclampsia (GDM 15.7% vs. pregestational 40.0% vs. no diabetes 7.3%, P < 0.001), large-for-gestational-age neonates (GDM 13.7% vs. pre-existing 50.0% vs. no diabetes 5.8%, P < 0.001), and neonatal hypoglycemia (GDM 42.6% vs. pregestational 60.0% vs. no diabetes 13.3%, P < 0.001). Conclusions: The prevalence of pregestational diabetes in our teenage and emerging adult population is similar to that of the general pregnancy population; however, the prevalence of GDM is significantly lower. Overall, diabetes in teenage pregnancy is associated with an elevated risk of adverse maternal and neonatal outcomes. Future research should evaluate interventions aimed at reducing adverse pregnancy outcomes in this vulnerable population.

In this study, we propose two new mathematical models able to quantify glucagon secretion during a graded glucose infusion, in the presence and absence of amino acids. The models provide an index of α-cell responsivity, G 50 , i.e., the glucose increase required to suppress glucose secretion rate (GSR) by 50%. Results show that the presence of amino acids reduced α-cell responsivity to glucose.

OBJECTIVE To assess whether initiating metformin at 25 weeks' gestation influences exclusive breastfeeding at 12 weeks postpartum in gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS We performed a prespecified secondary analysis of the Effectiveness of Metformin in Addition to Usual Care in the Reduction of Gestational Diabetes Effects (EMERGE) trial, a multicenter, double-blind, placebo-controlled randomized study. A total of 535 pregnant women (510 with newly diagnosed GDM) were allocated 1:1 to metformin (titrated to 2.5 g/day) or placebo alongside usual care. Infant feeding was prospectively documented at birth and at 4 and 12 weeks postpartum. The primary outcome was exclusive breastfeeding at 12 weeks (intention to treat). Multivariable logistic regression adjusted for race, education, smoking, booking BMI, health care access markers, and diagnostic oral glucose tolerance test (OGTT) glucose levels. RESULTS Twelve-week feeding data were available for 476 pregnancies (236 in the metformin group and 240 in the placebo group). Exclusive breastfeeding at 12 weeks was 27% with metformin and 26% with placebo (absolute difference +1.3%; 95% CI –6.3 to 8.7; P = 0.75). The adjusted odds ratio (OR) for metformin versus placebo was 1.24 (95% CI 0.79–1.96; P = 0.36). Feeding patterns shifted from breastfeeding to formula temporally in both groups (P &lt; 0.001), with no treatment-by-time interaction (P = 0.61). Non-Caucasian ethnicity independently predicted exclusive breastfeeding (adjusted OR 2.37; 95% CI 1.27–4.42). CONCLUSIONS Starting metformin treatment at 25 weeks in the GDM group was not associated with differences in exclusive breastfeeding at 12 weeks postpartum. Where metformin was discontinued at delivery, the results support compatibility of antenatal metformin with breastfeeding objectives. Breastfeeding outcomes were more linked to sociodemographic factors than metabolic ones, highlighting the need for culturally appropriate postpartum support.

Abstract Background Pregnancies complicated by gestational diabetes mellitus (GDM) are associated with increased risks of adverse perinatal outcomes, and with long-term metabolic and cardiovascular consequences for both mother and child. The original EMERGE randomized controlled trial (RCT) evaluated the effectiveness of early metformin in addition to usual care in women with GDM on glycaemic control and perinatal outcomes. The EMERGE Mothers and Kids study is a longitudinal follow-up of the EMERGE trial participants, designed to investigate the long-term metabolic, cardiovascular, and neurodevelopmental outcomes in mothers and their offspring. Methods This is a prospective, observational cohort study of participants and their children from the EMERGE trial (NCT06327191). A single follow-up visit will be conducted up to 6 years after the index pregnancy. Maternal assessments include anthropometric data, glucose tolerance, and metabolic parameters. Child assessments include growth metrics, adiposity measured via skinfold thickness, and neurodevelopmental status assessed through validated questionnaires. Additional data on quality of life, mental health, breastfeeding, and health economics will also be collected. Discussion This study aims to provide insights into the long-term safety and efficacy of metformin use during pregnancy and its potential impact on the long term maternal and child health outcomes, contributing to evidence-based management of GDM. Trial registration: ClinicalTrials.gov; Identifier: NCT06327191

Background: Increasing maternal body mass index (BMI) represents a risk factor for Gestational Diabetes Mellitus (GDM) and adverse obstetrical and perinatal outcomes. Objective: To stratify clinical outcomes for pregnancies affected by GDM according to maternal BMI. Methods: Retrospective cohort study including individuals ≥18 years of age who were diagnosed with GDM from 2018 to 2022. Universal GDM screening was employed with a 50 g oral glucose challenge test ± a 100 g oral glucose tolerance test. Maternal demographics, preexisting medical conditions, and selected obstetric and neonatal morbidities were evaluated. Results: A total of 2193 pregnancies in 2110 women affected by GDM were identified. This included 506 (23.0%) with normal baseline maternal BMI, 596 (27.2%) with overweight, and 1091 (49.7%) with obese BMI. Adverse maternal outcomes were more frequent in the obese compared to overweight or normal BMI categories (cesarean delivery: normal 26.9% vs. overweight 28.5% vs. obese 40.9%; p < 0.001; hypertensive disorders of pregnancy: normal 8.7% vs. overweight 12.1% vs. obese 16.8%; p < 0.001). Postpartum glucose intolerance was higher in women with obesity (normal 7.3% vs. overweight 5.9% vs. obese 14.9%; p < 0.001). Infants born to mothers with obesity had higher birthweights (normal 3.3 kg vs. overweight 3.4 kg vs. obese 3.5 kg; p < 0.001), were more likely to have neonatal hypoglycemia (normal 29.4% vs. overweight 24.3% vs. obese 41.9%; p < 0.001) and require intensive care unit admission (normal 8.1% vs. overweight 5.9% vs. obese 11.9%; p < 0.001). Conclusions: Patients with GDM and baseline BMI in the obese range experienced the highest rate of adverse outcomes, while those with overweight BMI had similar outcomes to individuals who had normal BMI at baseline.