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BackgroundLess than one-third of women gain an appropriate amount of weight during pregnancy, which can influence the long-term health of both the mother and the child. Economically disadvantaged women are the most vulnerable to maternal obesity, excessive weight gain during pregnancy, and poor birth outcomes. Effective and scalable health care strategies to promote healthy weight gain during pregnancy specifically tailored for these women are lacking. ObjectiveThis paper presents the design and protocol of a biphasic, community-based eHealth trial, SmartMoms in WIC, to increase the adherence to healthy gestational weight gain (GWG) recommendations in low-income mothers receiving women, infant, and children (WIC) benefits. MethodsPhase 1 of the trial included using feedback from WIC mothers and staff and participants from 2 community peer advisory groups to adapt an existing eHealth gestational weight management intervention to meet the needs of women receiving WIC benefits. The health curriculum, the format of delivery, and incentive strategies were adapted to be culturally relevant and at an appropriate level of health literacy. Phase 2 included a pragmatic randomized controlled trial across the 9 health care regions in Louisiana with the goal of enrolling 432 women. The SmartMoms in WIC intervention is an intensive 24-week behavioral intervention, which includes nutrition education and exercise strategies, and provides the technology to assist with weight management, delivered through a professionally produced website application. ResultsPhase 1 of this trial was completed in July 2019, and recruitment for phase 2 began immediately thereafter. All data are anticipated to be collected by Spring 2023. ConclusionsThe SmartMoms in WIC curriculum was methodically developed using feedback from community-based peer advisory groups to create a culturally relevant, mobile behavioral intervention for mothers receiving WIC benefits. The randomized clinical trial is underway to test the effectiveness of a sustainable eHealth program on the incidence rates of appropriate GWG. SmartMoms in WIC may be able to offer an innovative, cost-effective, and scalable solution for GWG management in women served by WIC. Trial RegistrationClinicalTrials.gov NCT04028843; https://clinicaltrials.gov/ct2/show/NCT04028843 International Registered Report Identifier (IRRID)DERR1-10.2196/18211

BackgroundTwo-thirds of pregnant women exceed gestational weight gain (GWG) recommendations. Because excess GWG is associated with adverse outcomes for mother and child, development of scalable and cost-effective approaches to deliver intensive lifestyle programs during pregnancy is urgent. ObjectiveThe aim of this study was to decrease the proportion of women who exceed the Institute of Medicine (IOM) 2009 GWG guidelines. MethodsIn a parallel-arm randomized controlled trial, 54 pregnant women (age 18-40 years) who were overweight (n=25) or obese (n=29) were enrolled to test whether an intensive lifestyle intervention (called SmartMoms) decreased the proportion of women with excess GWG, defined as exceeding the 2009 IOM guidelines, compared to no intervention (usual care group). The SmartMoms intervention was delivered through mobile phone (remote group) or in a traditional in-person, clinic-based setting (in-person group), and included a personalized dietary intake prescription, self-monitoring weight against a personalized weight graph, activity tracking with a pedometer, receipt of health information, and continuous personalized feedback from counselors. ResultsA significantly smaller proportion of women exceeded the IOM 2009 GWG guidelines in the SmartMoms intervention groups (in-person: 56%, 10/18; remote: 58%, 11/19) compared to usual care (85%, 11/13; P=.02). The remote intervention was a lower cost to participants (mean US $97, SD $6 vs mean US $347, SD $40 per participant; P

OBJECTIVE: To determine whether the relationship between average glucose (AG) levels and hemoglobin A1c (HbA1c) differs across racial/ethnic groups. RESEARCH DESIGN AND METHODS: We performed a prospective substudy of GRADE, a comparative effectiveness randomized trial conducted in 36 centers in the U.S. A total of 1,454 of the 5,047 participants in the GRADE cohort, including 534 non-Hispanic White (NHW), 389 non-Hispanic Black (NHB), and 327 Hispanic White patients and 204 patients of other racial/ethnic backgrounds, were included in the substudy. Continuous glucose monitoring (CGM) performed for 10 days was used to calculate AG10. Immediately after CGM, HbA1c and glycated albumin were measured. Fasting plasma glucose (FPG) and glucose area under the curve (AUC) were derived from a 75-g oral glucose tolerance test. RESULTS: The relationship between AG10 and HbA1c was significantly different for NHB compared with NHW patients and those of other racial/ethnic groups. HbA1c levels were 0.2–0.6 percentage points higher in NHB than in NHW patients for AG10 levels from 100 to 250 mg/dL. For an HbA1c of 7%, AG10 was 11 mg/dL higher for NHW than for NHB patients. Similar findings were observed across races for relationships of FPG and AUC with HbA1c and for glucose measurements with glycated albumin levels. Differences in the relationship between AG10 and HbA1c across racial groups remained after adjustments for any demographic or other differences between racial/ethnic subgroups. CONCLUSIONS: The relationship between several measures of glucose with HbA1c and glycated albumin consistently differed across races. These findings should be considered in setting treatment goals and diagnostic levels. [ABSTRACT FROM AUTHOR]

Objective: Hypoglycemia is a major concern in type 2 diabetes (T2DM), but little is known about its likelihood compared across common therapies. We compared the likelihood of hypoglycemia among metformin-treated patients with T2DM randomized to the addition of one of 4 common therapies. Research design & methods: Randomized, controlled trial of 5,047 participants with T2DM of <10 years' duration, hemoglobin A1c (HbA1c) 6.8–8.5% (50.8–69.4 mmol/mol). Randomization to addition of glargine U100, glimepiride, liraglutide, or sitagliptin over 5.0 ± 1.3 (mean ± SD) years. HbA1c was measured quarterly; if a level >7.5% (>58.5 mmol/mol) was confirmed, rescue glargine and/or aspart insulin was added. We conducted a per-protocol analysis of 4,830, who attended at least one post-baseline visit and took at least one dose of assigned study medication. We assessed severe hypoglycemia events reported throughout the entire study. At quarterly visits, all participants were asked about hypoglycemic symptoms within the last 30 days, and those in the glargine and glimepiride groups were asked for any measured glucose <70 mg/dL (3.9 mmol/L) within this time period. Results: While participants were taking their assigned medications, severe hypoglycemia occurred in 10 (0.8%), 16 (1.3%), 6 (0.5%), and 4 (0.3%), (p<0.05) and hypoglycemic symptoms in 659 (54.2%), 833 (68.3%), 375 (32.4%), and 361 (29.1%) of participants following randomization to glargine, glimepiride, liraglutide, and sitagliptin, respectively (p<0.001). Conclusions: In metformin-treated patients with T2DM who add a second medication, hypoglycemia is most likely with addition of glimepiride, less with glargine, and least likely with liraglutide and sitagliptin. Trial registration: ClinicalTrials.gov Identifier: NCT01794143. [ABSTRACT FROM AUTHOR]

Summary: Anti‐obesity medications (AOMs) have emerged as one element of comprehensive obesity clinical care intended to improve long‐term health outcomes for children and adolescents. The number of pediatric AOM clinical trials has burgeoned in recent years as new pharmacotherapeutics have been developed. Factors related to growth and development in children and adolescents can present unique challenges in terms of designing and conducting clinical trials investigating the safety and efficacy of AOMs. These barriers can delay the AOM development and evaluation process, increase the cost of performing trials, create challenges in the interpretation of results, influence the generalizability of the findings and present ethical dilemmas. In an effort to address these issues and provide guidance to streamline the process of designing and conducting pediatric AOM clinical trials, relevant key stakeholders convened a series of roundtable meetings to discuss, debate and achieve harmonization on design features. Stakeholder participants included a multidisciplinary group of international pediatric obesity experts, patient (parent) representatives and representatives from academic medicine, key regulatory agencies and industry. Topics of discussion included primary efficacy end‐points, secondary end‐points, eligibility criteria, trial run‐in and follow‐up phases, use of active comparators and guidelines for down‐titration and/or stopping rules for excessive weight reduction. Consensus recommendations were agreed upon. Regarding end‐points, emphasis was placed on moving away from BMI z‐score as a primary outcome, incorporating multiple alternative BMI‐related outcomes and measuring adiposity/body fat as a prominent secondary end‐point. Trial eligibility criteria were carefully considered to maximize generalizability while maintaining safety. The limited value of trial run‐in phases was discussed. It was also underscored that designing trials with extended follow‐up periods after AOM withdrawal should be avoided owing to ethical issues (including possible psychological harm) related to weight regain without providing the opportunity to access other treatments. The panel emphasized the value of the randomized, placebo‐controlled trial but recommended the thoughtful consideration of the use of active comparators in addition to, or instead of, placebo to achieve clinical equipoise when appropriate. Finally, the panel recommended that clinical trial protocols should include clear guidance regarding AOM down‐titration to avoid excessive weight reduction when applicable. [ABSTRACT FROM AUTHOR]

Objectives Insulin resistance is associated with elevations in plasma branched-chain amino acids (BCAAs). BCAAs compete with aromatic amino acids including tryptophan for uptake into β cells. To explore relationships between BCAAs and tryptophan metabolism, adiposity, and glucose tolerance, we compared urine metabolites in overweight/obese youth with type 2 diabetes (T2D) with those in nondiabetic overweight/obese and lean youth. Methods Metabolites were measured in 24-hour and first-morning urine samples of 56 nondiabetic adolescents with overweight/obesity, 42 adolescents with T2D, and 43 lean controls, aged 12 to 21 years. Group differences were assessed by Kruskal Wallis or ANOVA. Results Groups were comparable for age, pubertal status, and ethnicity. Youth with T2D were predominantly female and had highest percent body fat. BCAAs, branched-chain ketoacids (BCKAs), tryptophan, and kynurenine were higher in urine of subjects with T2D. There were no differences between lean controls and nondiabetic youth with overweight/obesity. T2D was associated with diversion of tryptophan from the serotonin to the kynurenine pathway, with higher urinary kynurenine/serotonin ratio and lower serotonin/tryptophan and 5-HIAA/kynurenine ratios. Urinary BCAAs, BCKAs, tryptophan, and ratios reflecting diversion to the kynurenine pathway correlated positively with metrics of body fat and hemoglobin A1c. Increases in these metabolites in the obese T2D group were more pronounced and statistically significant only in adolescent girls. Conclusion Increases in urinary BCAAs and BCKAs in adolescent females with T2D are accompanied by diversion of tryptophan metabolism from the serotonin to the kynurenine pathway. These adaptations associate with higher risks of T2D in obese adolescent females than adolescent males. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (5,047 participants, mean follow-up 5.0 years), differences in glycemic control were demonstrated over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia. RESEARCH DESIGN AND METHODS: The composite outcome was time to first occurrence of any of the following: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent nonsevere hypoglycemia. Secondary analyses included examination of individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated with the Kaplan-Meier estimator. Cox proportional hazards models were used to assess pairwise group differences in risk of an outcome. RESULTS: Risk of reaching the composite outcome (events per 100 participants per treatment year [PTYs]) was lowest with liraglutide (19 per 100 PTYs) followed by sitagliptin (26 per 100 PTYs), glargine (29 per 100 PTYs), and glimepiride (40 per 100 PTYs); all pairwise comparisons were statistically significant. The order was the same for risk of weight gain and hypoglycemia, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across prespecified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction. CONCLUSIONS: Among participants treated with common second-line drug classes for type 2 diabetes, the liraglutide group had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy. [ABSTRACT FROM AUTHOR]

Background: Nonalcoholic fatty liver disease (NAFLD) is a leading cause of end‐stage liver disease. NAFLD diagnosis and follow‐up relies on a combination of clinical data, liver imaging, and/or liver biopsy. However, intersite imaging differences impede diagnostic consistency and reduce the repeatability of the multisite clinical trials necessary to develop effective treatments. Purpose/Hypothesis: The goal of this pilot study was to harmonize commercially available 3 T magnetic resonance imaging (MRI) measurements of liver fat and stiffness in human participants across academic sites and MRI vendors. Study Type: Cohort. Subjects: Four community‐dwelling adults with obesity. Field strength/Sequence: 1.5 and 3 T, multiecho 3D imaging, PRESS, and GRE. Assessment: Harmonized proton density fat fraction (PDFF) and magnetic resonance spectroscopy (MRS) protocols were used to quantify the FF of synthetic phantoms and human participants with obesity using standard acquisition parameters at four sites that had four different 3 T MRI instruments. In addition, a harmonized magnetic resonance elastography (MRE) protocol was used to quantify liver stiffness among participants at two different sites at 1.5 and 3 T field strengths. Data were sent to a single data coordinating site for postprocessing. Statistical Tests: Linear regression in MATLAB, ICC analyses using SAS 9.4, one‐sided 95% confidence intervals for the ICC. Results: PDFF and MRS FF measurements were highly repeatable among sites in both humans and phantoms. MRE measurements of liver stiffness in three individuals at two sites using one 1.5 T and one 3 T instrument showed repeatability that was high although lower than that of MRS and PDFF. Conclusions: We demonstrated harmonization of PDFF, MRS, and MRE‐based quantification of liver fat and stiffness through synthetic phantoms, traveling participants, and standardization of postprocessing analysis. Multisite MRI harmonization could contribute to multisite clinical trials assessing the efficacy of interventions and therapy for NAFLD. Level of Evidence: 2 Technical Efficacy Stage: 2 [ABSTRACT FROM AUTHOR]

Context: Exercise can decrease central adiposity, but the effect of exercise dose and the relationship between central adiposity and exercise-induced compensation is unclear. Objective: Test the effect of exercise dose on central adiposity change and the association between central adiposity and exercise-induced weight compensation. Methods: In this ancillary analysis of a 6-month randomized controlled trial, 170 participants with overweight or obesity (mean ± SD body mass index: 31.5 ± 4.7 kg/m²) were randomized to a control group or exercise groups that reflected exercise recommendations for health (8 kcal/kg/week [KKW]) or weight loss and weight maintenance (20 KKW). Waist circumference was measured, and dual-energy X-ray absorptiometry assessed central adiposity. Predicted weight change was estimated and weight compensation (weight change – predicted weight change) was calculated. Results: Between-group change in waist circumference (control: .0 cm [95% CI, −1.0 to 1.0], 8 KKW: −.7 cm [95% CI, −1.7 to .4], 20 KKW: −1.3 cm [95% CI, −2.4 to −.2]) and visceral adipose tissue (VAT; control: −.02 kg [95% CI, −.07 to .04], 8 KKW: −.01 kg [95% CI, −.07 to .04], 20 KKW: −.04 kg [95% CI, −.10 to .02]) was similar (P ≥ .23). Most exercisers (82.6%) compensated (weight loss less than expected). Exercisers who compensated exhibited a 2.5-cm (95% CI, .8 to 4.2) and .23-kg (95% CI, .14 to .31) increase in waist circumference and VAT, respectively, vs those who did not (P < .01). Desire to eat predicted VAT change during exercise (β = .21; P = .03). Conclusion: In the presence of significant weight compensation, exercise at doses recommended for health and weight loss and weight maintenance leads to negligible changes in central adiposity. [ABSTRACT FROM AUTHOR]

There is evidence suggesting that infection with SARS-CoV-2 can lead to several long-term sequelae including diabetes. This mini-review examines the rapidly evolving and conflicting literature on new-onset diabetes after COVID-19, which we term NODAC. We searched PubMed, MEDLINE, and medRxiv from inception until December 1, 2022, using Medical Subject Headings (MeSH) terms and free text words including "COVID-19," "SARS-CoV-2," "diabetes," "hyperglycemia," "insulin resistance," and "pancreatic ß-cell." We also supplemented searches by examining reference lists from retrieved articles. Current evidence suggests that COVID-19 increases the risk of developing diabetes, but the attributable risk is uncertain because of limitations of study designs and the evolving nature of the pandemic, including new variants, widespread population exposure to the virus, diagnostic options for COVID-19, and vaccination status. The etiology of diabetes after COVID-19 is likely multifactorial and includes factors associated with host characteristics (eg, age), social determinants of health (eg, deprivation index), and pandemic-related effects both at the personal (eg, psychosocial stress) and the societal-community level (eg, containment measures). COVID-19 may have direct and indirect effects on pancreatic ß-cell function and insulin sensitivity related to the acute infection and its treatment (eg, glucocorticoids); autoimmunity; persistent viral residency in multiple organs including adipose tissue; endothelial dysfunction; and hyperinflammatory state. While our understanding of NODAC continues to evolve, consideration should be given for diabetes to be classified as a post-COVID syndrome, in addition to traditional classifications of diabetes (eg, type 1 or type 2), so that the pathophysiology, natural history, and optimal management can be studied. [ABSTRACT FROM AUTHOR]

Objective: To conduct a preliminary assessment of the relationships between cardiorespiratory fitness, adiposity, and cardiometabolic health using gold standard measures in diverse youth ranging from overweight to severe obesity. Methods: Twenty of 30 participants (mean [SD]; age 13.2 [1.8] y, 55% female, 45% African American) met the criteria for VO2peak during a graded cycle ergometer test to volitional fatigue. The body composition was measured by dual-energy X-ray absorptiometry (percentage of body fat, fat mass index, and fat-free mass) and magnetic resonance imaging (abdominal visceral and subcutaneous [SAT] adipose tissue). The VO2peak was expressed relative to fat-free mass. Fasting lipid levels, glycemic biomarkers, and vital signs were examined individually and used in a composite cardiometabolic risk score. Accelerometer-measured physical activity and sedentary time were included as covariates. Results: VO2peak was negatively associated with abdominal SAT (r = −.49, P <.05), but not visceral adipose tissue or markers of cardiometabolic health. The association between SAT and VO2peak was partly explained by habitual sedentary time. Conclusions: We demonstrated a significant negative association between cardiorespiratory fitness and SAT in a diverse group of high-risk youth. The inclusion of rigorous, laboratory-based measures and youth with severe obesity extends the previous work in pediatric populations. [ABSTRACT FROM AUTHOR]

Observation studies suggest differences in myelination in relation to differences in early life nutrition. This two-center randomized controlled trial investigates the effect of a 12-month nutritional intervention on longitudinal changes in myelination, cognition, and behavior. Eighty-one full-term, neurotypical infants were randomized into an investigational (N = 42) or a control group (N = 39), receiving higher versus lower levels of a blend of nutrients. Non-randomized breastfed infants (N = 108) served as a reference group. Main outcomes were myelination (MRI), neurodevelopment (Bayley-III), social-emotional development (ASQ:SE-2), infant and toddler behavior (IBQ-R and TBAQ), and infant sleep (BISQ) during the first 2 years of life. The full analysis set comprised N = 67 infants from the randomized groups, with 81 myelin-sensitive MRI sequences. Significantly higher myelination was observed in the investigational compared to the control group at 6, 12, 18, and 24 months of life, as well as significantly higher gray matter volume at 24 months, a reduced number of night awakenings at 6 months, increased day sleep at 12 months, and reduced social fearfulness at 24 months. The results suggest that brain development may be modifiable with brain- and age-relevant nutritional approaches in healthy infants and young children, which may be foundational for later learning outcomes. [ABSTRACT FROM AUTHOR]

Introduction: People with a low or high haemoglobin glycation index (HGI) have lower or higher HbA1c than other people with the same FPG. This study compared the prevalence of prediabetes based on FPG, 2hOGTT and HbA1c in people with low, moderate or high HGI. Methods: Prediabetes was diagnosed based on ADA cutpoints in 10,488 NHANES participants without self‐reported diabetes. HGI was calculated as the difference between a participant's observed HbA1c and a predicted HbA1c where predicted HbA1c = 0.024 FPG + 3.1. Participants were divided into low (HGI < −0.15%), moderate (HGI −0.15% to +0.15%) and high (HGI > +0.15%) HGI subgroups. Results: The prevalence of prediabetes was 42.4% based on FPG, 27.2% based on HbA1c and 17.2% based on 2hOGTT. FPG and HbA1c thus overdiagnosed prediabetes by 25.2% and 10.0%, respectively, compared to the OGTT gold standard. Prevalence was (1) similar in low, moderate and high HGI participants based on 2hOGTT, (2) highest in low HGI participants based on FPG, and (3) highest in high HGI participants based on HbA1c. Among participants with mismatched FPG and HbA1c, OGTT was normal in (1) 79.5% of participants with normal FPG but prediabetic HbA1c (mean HGI = +0.53%), and (2) 75.2% of participants with normal HbA1c but prediabetic FPG (mean HGI = −0.30%). Conclusions: FPG overdiagnosed prediabetes in people with low HGI. HbA1c overdiagnosed prediabetes in people with high HGI. Clinical use of HGI could improve prediabetes diagnosis and help health care providers avoid inappropriate or delayed treatment of people with extremes of HGI. [ABSTRACT FROM AUTHOR]

Background: Active workstations offer the potential for augmenting energy expenditure (EE) in sedentary occupations. However, comparisons of EE during pedal and treadmill desk usage at self-selected intensities are lacking. Methods: A sample of 16 adult participants (8 men and 8 women; 33.9 [7.1] y, 22.5 [2.7] kg/m2) employed in sedentary occupations had their EE measured using indirect calorimetry during 4 conditions: (1) seated rest, (2) seated typing in a traditional office chair, (3) self-paced pedaling on a pedal desk while typing, and (4) self-paced walking on a treadmill desk while typing. Results: For men and women, self-paced pedal and treadmill desk typing significantly increased EE above seated typing (pedal desk: +1.20 to 1.28 kcal/min and treadmill desk: +1.43 to 1.93 kcal/min, P <.001). In men, treadmill desk typing (3.46 [0.19] kcal/min) elicited a significantly higher mean EE than pedal desk typing (2.73 [0.21] kcal/min, P <.001). No significant difference in EE was observed between treadmill desk typing (2.68 [0.19] kcal/min) and pedal desk typing among women (2.52 [0.21] kcal/min). Conclusions: Self-paced treadmill desk usage elicited significantly higher EE than self-paced pedal desk usage in men but not in women. Both pedal and treadmill desk usage at self-selected intensities elicited approximate 2-fold increases in EE above what would typically be expected during traditional seated office work. [ABSTRACT FROM AUTHOR]

Context Blood pressure and plasma catecholamines normally decline during sleep and rapidly increase in early morning. This is blunted in adults with type 2 diabetes (T2D). Objective We hypothesize that increased sympatho-adrenal activity during sleep differentiates youth with T2D from nondiabetic obese youth and lean youth. Methods Fasting spot morning and 24-hour urines were collected in obese adolescents with and without T2D, and normal-weight controls. Fractionated free urine catecholamines (epinephrine, norepinephrine, and dopamine) were measured, and the ratio of fasting spot morning to 24-hour catecholamines was calculated. Results Urinary 24-hour catecholamine levels were comparable across the 3 groups. Fasting morning epinephrine and the ratio of fasting morning/24-hour epinephrine were higher in youth with T2D (P = 0.004 and P = 0.035, respectively). In males, the ratio of fasting morning/24-hour epinephrine was also higher in youth with T2D (P = 0.005). In females, fasting morning norepinephrine and the ratio of fasting morning/24-hour dopamine were lower in obese youth with and without T2D (P = 0.013 and P = 0.005, respectively) compared with lean youth. Systolic blood pressure was higher in diabetic participants than other groups; males trended higher than females. Conclusion Circadian rhythm in catecholamines is disrupted in youth-onset T2D, with a blunted overnight fall in urinary epinephrine in males. Conversely, fasting morning norepinephrine and dopamine levels were lower in obese females with or without T2D. Higher nocturnal catecholamines in males with T2D might associate with, or predispose to, hypertension and cardiovascular complications. Lower catecholamine excretion in females with obesity might serve an adaptive, protective role. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the pharmacokinetic, pharmacodynamic and safety profile of the glucagon‐like peptide‐1 receptor agonist, lixisenatide, for the treatment of type 2 diabetes (T2D) in pediatric individuals. Materials and Methods: In this Phase 1, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, ascending repeated dose study (NCT02803918), participants aged ≥10 and < 18 years were randomized 3:1 to receive once‐daily lixisenatide in 2‐week increments of 5, 10, and 20 μg (n = 18) or placebo (n = 5) for 6 weeks. Results: Mean lixisenatide concentrations generally increased with increasing doses irrespective of anti‐drug antibody (ADA) status; however, mean lixisenatide concentrations and inter‐subject variability were higher for participants with positive ADA status. Improvements in fasting plasma glucose, post‐prandial glucose, AUC0–4.5, HbA1c, and body weight were observed with lixisenatide. Overall, the safety profile was consistent with the known profile in adults, with no unexpected side effects and no treatment‐emergent adverse events resulting in death or discontinuation. The most common events in the lixisenatide group were vomiting (11.1%) and nausea (11.1%). No symptomatic hypoglycemia was reported in either group. No clinically significant hematologic, biochemical or vital sign abnormalities were observed. Conclusions: Mean lixisenatide concentrations generally increased with increasing dose, irrespective of ADA status. Lixisenatide was associated with improved glycemic control and a trend in body weight reduction compared with placebo. The safety and tolerability profile of repeated lixisenatide doses of up to 20 μg per day in children and adolescents with T2D was reflective of the established safety profile of lixisenatide in adults. [ABSTRACT FROM AUTHOR]

Recent advancements in immunology and islet biology have unveiled remarkable prospects for the postponement of Type 1 diabetes (T1D) through the strategic modulation of the immune system. In this Perspective, we discuss the pharmaceutical strides achieved, traversing from pre-clinical validation to the execution of impactful clinical trials. We begin with the initial investigations involving cyclosporine and glucocorticoids in rodent models, such as the non-obese diabetic (NOD) mouse, which guided early clinical trials. We then discuss the pre-clinical studies using suitable mouse models that eventually led to contemporary clinical trials targeting immune cell functionality and cytokine signaling pathways. Collectively, these discoveries promote the exciting paradigm of immune system modulation to mitigate autoimmunity, which continues to broaden. Notably, the use of baricitinib, a potent JAK1/2 inhibitor, and teplizumab, an anti-CD3 monoclonal antibody, represent discrete methodologies converging upon a singular outcome: the preservation of islet beta-cell functionality. The latter interventional strategies build on the original idea that tempering specific facets of the immune system will generate therapeutic benefit. Enthusiasm from these discoveries stems from efficacy with reduced side effects when compared with past approaches. The success of therapeutic intervention(s) in pre-clinical studies, combined with knowledge about stages of progression to clinical T1D, have ultimately encouraged the design of more successful clinical trials targeting highly specific populations at risk. Collectively, these findings instill a profound sense of optimism, suggesting that the prevention and even reversal of T1D may soon be within reach. [Display omitted] [ABSTRACT FROM AUTHOR]

The limitations of self-report measures of dietary intake are well-known. Novel, technology-based measures of dietary intake may provide a more accurate, less burdensome alternative to existing tools. The first objective of this study was to compare participant burden for two technology-based measures of dietary intake among school-age children: the Automated-Self-Administered 24-hour Dietary Assessment Tool-2018 (ASA24-2018) and the Remote Food Photography Method (RFPM). The second objective was to compare reported energy intake for each method to the Estimated Energy Requirement for each child, as a benchmark for actual intake. Forty parent–child dyads participated in two, 3-d dietary assessments: a parent proxy-reported version of the ASA24 and the RFPM. A parent survey was subsequently administered to compare satisfaction, ease of use and burden with each method. A linear mixed model examined differences in total daily energy intake between assessments, and between each assessment method and the Estimated Energy Requirement (EER). Reported energy intake was 379 kcal higher with the ASA24 than the RFPM (P = 0·0002). Reported energy intake with the ASA24 was 231 kcal higher than the EER (P = 0·008). Reported energy intake with the RFPM did not differ significantly from the EER (difference in predicted means = −148 kcal, P = 0·09). Median satisfaction and ease of use scores were five out of six for both methods. A higher proportion of parents reported that the ASA24 was more time-consuming than the RFPM (74·4 % v. 25·6 %, P = 0·002). Utilisation of both methods is warranted given their high satisfaction among parents. [ABSTRACT FROM AUTHOR]

Background: Energy expenditure (EE) estimates for a broad age range of youth performing a variety of activities are needed. Methods: 106 participants (6–18 years) completed 6 free-living activities (seated rest, movie watching, coloring, stair climbing, basketball dribbling, jumping jacks) and up to 9 treadmill walking bouts (13.4 to 120.7 m/min; 13.4 m/min increments). Breath-by-breath oxygen uptake (VO2) was measured using the COSMED K4b2 and EE was quantified as youth metabolic equivalents (METy1:VO2/ measured resting VO2, METy2:VO2/estimated resting VO2). Age trends were evaluated with ANOVA. Results: Seated movie watching produced the lowest mean METy1 (6- to 9-year-olds: 0.94 ± 0.13) and METy2 values (13- to 15-year-olds: 1.10 ± 0.19), and jumping jacks produced the highest mean METy1 (13- to 15-year-olds: 6.89 ± 1.47) and METy2 values (16- to 18-year-olds: 8.61 ± 2.03). Significant age-related variability in METy1 and METy2 were noted for 8 and 2 of the 15 evaluated activities, respectively. Conclusions: Descriptive EE data presented herein will augment the Youth Compendium of Physical Activities. [ABSTRACT FROM AUTHOR]

Aims: A high haemoglobin glycation index (HGI) is associated with greater risk for hypoglycaemia and chronic vascular disease. Standardizing how the HGI is calculated would normalize results between research studies and hospital laboratories and facilitate the clinical use of HGI for assessing risk. Methods: The HGI is the difference between an observed HbA1c and a predicted HbA1c obtained by inserting fasting plasma glucose (FPG) into a regression equation describing the linear relationship between FPG and HbA1c in a reference population. We used data from the 2005–2016 U.S. National Health and Nutrition Examination Survey (NHANES) to identify a reference population of 18,675 diabetes treatment–naïve adults without self‐reported diabetes. The reference population regression equation (predicted HbA1c = 0.024 FPG + 3.1) was then used to calculate the HGI and divide participants into low (<−0.150), moderate (−0.150 to <0.150) and high (≥0.150) HGI subgroups. Diabetes status was classified by OGTTs. Results: As previously reported in multiple studies, a high HGI was associated with black race independent of diabetes status, and with older age, higher BMI and higher CRP in normal and prediabetic but not diabetic participants. The mean HGI was 0.6% higher in self‐reported diabetic adults. The HGI was not associated with plasma insulin, HOMA‐IR or 2 h OGTT in participants classified as normal, prediabetic or diabetic. Conclusions: The regression equation derived from this demographically diverse diabetes treatment–naïve adult NHANES reference population is suitable for standardizing how the HGI is calculated for both clinical use and in research to mechanistically explain population variation in the HGI and why a high HGI is associated with greater risk for chronic vascular disease. [ABSTRACT FROM AUTHOR]

Cranberries are high in polyphenols, and epidemiological studies have shown that a high-polyphenol diet may reduce risk factors for diabetes and CVD. The present study aimed to determine if short-term cranberry beverage consumption would improve insulin sensitivity and other cardiovascular risk factors. Thirty-five individuals with obesity and with elevated fasting glucose or impaired glucose tolerance participated in a randomised, double-blind, placebo-controlled, parallel-designed pilot trial. Participants consumed 450 ml of low-energy cranberry beverage or placebo daily for 8 weeks. Changes in insulin sensitivity and cardiovascular risk factors including vascular reactivity, blood pressure, RMR, glucose tolerance, lipid profiles and oxidative stress biomarkers were evaluated. Change in insulin sensitivity via hyperinsulinaemic–euglycaemic clamp was not different between the two groups. Levels of 8-isoprostane (biomarker of lipid peroxidation) decreased in the cranberry group but increased in the placebo group (–2·18 v. +20·81 pg/ml; P = 0·02). When stratified by baseline C-reactive protein (CRP) levels, participants with high CRP levels (>4 mg/l) benefited more from cranberry consumption. In this group, significant differences in the mean change from baseline between the cranberry (n 10) and the placebo groups (n 7) in levels of TAG (–13·75 v. +10·32 %; P = 0·04), nitrate (+3·26 v. −6·28 µmol/l; P = 0·02) and 8-isoprostane (+0·32 v. +30·8 pg/ml; P = 0·05) were observed. These findings indicate that 8 weeks of daily cranberry beverage consumption may not impact insulin sensitivity but may be helpful in lowering TAG and changing certain oxidative stress biomarkers in individuals with obesity and a proinflammatory state. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to determine whether different measures of habitual physical activity (PA) at baseline predict weight change, weight compensation, and changes in energy intake (EI) during a 24-week supervised aerobic exercise intervention.Methods: Data from 108 participants (78 women; 48.7 [SD: 11.6] years; BMI 31.4 [SD: 4.6] kg/m2 ), randomly assigned to either the moderate-dose exercise group (8 kcal/kg of body weight per week) or the high-dose exercise group (20 kcal/kg of body weight per week) of the Examination of Mechanisms of Exercise-induced Weight Compensation (E-MECHANIC) trial, were analyzed. Moderate-to-vigorous PA (MVPA), steps per day, and PA energy expenditure (PAEE) were measured with SenseWear armbands (BodyMedia, Pittsburgh, Pennsylvania), and total activity energy expenditure and EI were estimated with doubly labeled water, all over 2 weeks, before and toward the end of the intervention. Multiple linear regression models, adjusted for sex, exercise group, and baseline value of the outcome, were used.Results: Baseline habitual MVPA levels predicted weight change (β = -0.275; P = 0.020), weight compensation (β = -0.238; P = 0.043), and change in EI (β = -0.318; P = 0.001). Associations between baseline PAEE and outcomes were comparable, whereas steps per day and, importantly, total activity energy expenditure (via doubly labeled water) did not significantly predict change in weight-related outcomes.Conclusions: While acknowledging substantial variability in the data, on average, lower baseline habitual MVPA and PAEE levels were associated with less weight loss from exercise, higher compensation, and increased EI. [ABSTRACT FROM AUTHOR]

Aims: To assess the pharmacokinetic (PK) and pharmacodynamic characteristics of VI‐0521, a fixed‐dose combination of immediate‐release phentermine (PHEN) and extended‐release topiramate (TPM) in adolescents aged 12 to 17 years with obesity, and to report weight loss and adverse events using this drug combination. Materials and methods: This was a multicentre, randomized, double‐blind, parallel‐design, placebo‐controlled study in adolescents with obesity. A total of 42 adolescents were randomly assigned in a 1:1:1 ratio to placebo, or to a mid‐dose (PHEN/TPM 7.5 mg/46 mg), or a top‐dose (PHEN/TPM 15 mg/92 mg) of VI‐0521. A total of 26 adolescents were included in the PK analysis (14 from the mid‐dose group and 12 from the top‐dose group). Results: On day 56, arithmetic means of terminal elimination half‐life, apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) were consistent across dose levels for both PHEN and TPM. Arithmetic means of CL/F and Vc/F for PHEN and TPM administered as a combination in adolescents with obesity were within 10% to 30% of those previously assessed in adults with obesity enrolled in phase II and III studies. A higher proportion of adolescents in both the mid‐ and top‐dose groups (13.3% and 50.0%, respectively) compared with placebo (0.0%) reached ≥5% weight loss at day 56. The least squares (LS) mean change in systolic blood pressure from baseline to day 56 was −5.2 mmHg for the placebo group, −2.5 mmHg for the mid‐dose group, and − 5.5 mmHg for the top‐dose group. The LS mean change in diastolic blood pressure from baseline to day 56 was −2.4 mmHg for the placebo group, +3.8 mmHg for the mid‐dose group, and + 2.0 mmHg for the top‐dose group. Participants in the top‐dose group had increases in heart rate from baseline of 4.1 bpm, while participants in the mid‐dose group experienced a mean decrease in heart rate of 4.5 bpm at day 56. Both PHEN/TPM dose combinations were safe and well tolerated. Conclusions: Treatment of adolescents with obesity using a fixed‐dose combination of PHEN/TPM for 8 weeks resulted in exposure to PHEN and TPM that was comparable to that observed in adults, statistically significant weight loss, and a tolerable safety profile. These data indicate that both mid‐ and top‐dose levels are appropriate for longer‐term safety and efficacy studies in adolescents. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to compare the proinsulin to C-peptide (PI:C) ratio in those with recent-onset type 1 diabetes versus those with no diabetes and to explore the effect of age on PI:C ratio. Methods: Nineteen participants (n=9 with type 1 diabetes and n=10 with no diabetes) between 10 and 19 years of age were enrolled in a single-visit crosssectional study and underwent blood collection after 10 hours fasting to measure proinsulin and C-peptide levels as well as other glycemic parameters. Results: The median PI:C ratio was significantly different between type 1 diabetes and nondiabetes groups (6.24% vs. 1.46%, P<0.01). A significant negative correlation was seen between PI:C ratio and patient age after adjustment for duration of diabetes (r2=0.61, P=0.02) in the type 1 diabetes group. Conclusion: Even in this narrow age window, a higher degree of ß-cell dysfunction indicated by a higher PI:C ratio was seen in younger children. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to characterize changes in body composition during pregnancy in women with obesity.Methods: Fifty-four healthy women with obesity (class 1, 30-34.9 kg/m2 : n = 25; class 2, 35-39.9 kg/m2 : n = 21; class 3, ≥ 40.0 kg/m2 : n = 8) expecting a singleton pregnancy were studied. Body composition was measured in early pregnancy (13-16 weeks), midpregnancy (24-27 weeks), and late pregnancy (35-37 weeks) using air displacement plethysmography, stable isotopes, and skinfold thickness measurements. Fasting glucose, insulin, and leptin were measured.Results: The gain in fat-free mass was lower in the second trimester compared with the third (2.7 ± 0.2 to 5.3 ± 0.2 kg; P < 0.001), whereas fat mass accumulation declined over time (0.6 ± 0.3 to -0.7 ± 0.4 kg; P = 0.005). Women with class 1 and 2 obesity gained 1.1 ± 0.7 kg of fat mass during pregnancy, while women with class 3 obesity lost 4.1 ± 0.6 kg (both P < 0.001). The difference in fat accumulation between obesity classes was observed only in the second trimester (P = 0.02). Gestational weight gain was associated positively with changes in plasma concentrations of insulin, leptin, and insulin resistance (all P < 0.01).Conclusions: Gestational weight gain in pregnancy differs by obesity class and trimester. Women with class 3 obesity gain less body weight and fat mass. Fat mass gain is most likely preventable in the second trimester. [ABSTRACT FROM AUTHOR]

Based on self-report in the GRADE diabetes study, cumulative incidence of retinopathy was low over 5 years (3.7 %; 184 of 4098 participants) and did not differ among the 4 treatment groups (glargine 4.0 %, glimepiride 3.2 %, liraglutide 3.7 %, sitagliptin 3.8 %). There were no differences in retinopathy with specific therapies in GRADE. Clinicaltrials.gov identifier: NCT01794143 [Display omitted] • Retinopathy is linked to T2DM duration, glycemic control, and other risk factors. • Retinopathy over a 5-year period in people with T2DM < 10 years is reported. • Low prevalence and incidence of diabetes-related retinopathy no matter the treatment [ABSTRACT FROM AUTHOR]