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Background: To compare the acute and chronic effects of frequent, short physical activity (PA) bouts spread throughout the day to a time-matched intervention consisting in a single continuous daily bout of PA on glucose control and potential underlying mechanisms in adults at risk of developing type 2 diabetes (T2D). Methods: BURST2D is a single-center, parallel-group, randomized controlled trial, in which sedentary adults with overweight/obesity and pre-diabetes (18-45 y, BMI: 25-40 kg/m2, fasting glucose: 100-125 mg/dL or 2h glucose: 140-199 mg/dL or HbA1c: 5.7-6.4%) will be randomly assigned to one of two 3-month PA interventions: BREAK, nine bouts of 5-min brisk walking performed every hour for nine consecutive hours (45-min/d total), 5 days/wk; ONE, one continuous 45-min bout of brisk walking, 5 days/wk. Primary outcomes will be daily glycemic mean and variability, fasting glucose and HbA1c, postprandial plasma glucose and insulin, glucose kinetics, and content of skeletal muscle proteins related to insulin signaling and glucose uptake. Secondary outcomes will be whole-body insulin sensitivity, 24-h total substrate oxidation, postprandial triglycerides, daily PA and sedentary behavior (SB) patterns, knowledge and attitude towards PA and SB, barriers and facilitators to intervention compliance, self-perceived appetite, mood, and sleep. Outcomes will be assessed at baseline and after one month and/or three months of intervention. Conclusions: This study will establish the acute and chronic effects of breaking up SB, independent of increases in PA, on glucose control and underlying mechanisms in adults with pre-diabetes. Results will advance the science of T2D prevention. Trial registration: This study is registered with the ClinicalTrials.gov, registry number NTC05041491.

In human studies, new model systems are needed for improved mechanistic investigation of developmental predisposition for metabolic disease but also to serve as benchmarks in early life prevention or intervention efforts. In this regard, human infant umbilical cord-derived mesenchymal stem cells (MSCs) are an emerging tool. However, long-term clinical relevance to in vivo markers of metabolic disease is unknown.In a cohort of 124 mother/child dyads, this study tested the hypothesis that triglyceride content (TG) of infant MSCs undergoing adipogenesis in vitro (MSC-TG) is associated with in vivo adiposity (percent fat mass) from birth to early childhood and with fasting glucose and insulin in early childhood.MSC-TG was positively associated with in vivo child adiposity at birth, age 4 to 6 months, and age 4 to 6 years. MSC-TG was associated with fasting glucose, but not insulin, at 4 to 6 years. Importantly, MSC-TG explained an additional 13% variance in child adiposity at 4 to 6 years, after accounting for other established birth predictors (weight and percent fat mass at birth) and other established covariates related to child adiposity (e.g., breastfeeding exposure, physical activity).This work demonstrates the strength of the MSC model for predicting offspring metabolic phenotype into childhood, even when considering the important contribution of other early life risk factors.

Pregnancy conditions like maternal pre-pregnancy obesity and gestational diabetes (GDM) have been linked with the development of placenta, a critical organ required for maternal-fetal interface during gestation, and can lead to adverse health outcomes in both mother and fetus. However, the molecular signatures associated with these conditions are not fully understood. Epigenetic clocks, which are based upon DNA methylation of age-related CpGs, are thought to better reflect biological age compared to chronological age and have been used in different tissues as potential biomarkers. In the present study, we hypothesized that altered placental epigenetic gestational aging is associated with pre-pregnancy obesity and GDM. We explored these relationships by leveraging data from three diverse cohorts in the Environmental influences on Child Health Outcomes (ECHO) program (overall N=830) . First, we investigated associations between maternal pre-pregnancy obesity and GDM and estimated placental epigenetic gestational age acceleration (eGAA) . Next, we examined associations between these two conditions and methylation of each CpG site within the robust placental clock (558 CpGs) . Significant associations were not observed between pre-pregnancy obesity and GDM and eGAA. Interestingly, pre-pregnancy obesity was associated with methylation levels at 28 placental clock CpGs (q Disclosure K.Huff: None. C.Marsit: None. S.Niemiec: None. H.Volk: None. T.M.O'shea: None. R.Fry: None. K.Roell: None. C.Bulka: None. K.E.Boyle: None. C.Breton: None. A.Burt: None. D.Dabelea: None. L.Kahn: None. M.R.Karagas: None. Funding National Institutes of Health (UH3OD023348)