Integrative analysis reveals novel associations between DNA methylation and the serum metabolome of adolescents with type 2 diabetes: A cross-sectional study.

Objective: Rates of type 2 diabetes (T2D) among adolescents are on the rise. Epigenetic changes could be associated with the metabolic alterations in adolescents with T2D. Methods: We performed a cross sectional integrated analysis of DNA methylation data from peripheral blood mononuclear cells with serum metabolomic data from First Nation adolescents with T2D and controls participating in the Improving Renal Complications in Adolescents with type 2 diabetes through Research (iCARE) cohort study, to explore the molecular changes in adolescents with T2D. Results: Our analysis showed that 43 serum metabolites and 36 differentially methylated regions (DMR) were associated with T2D. Several DMRs were located near the transcriptional start site of genes with established roles in metabolic disease and associated with altered serum metabolites (e.g. glucose, leucine, and gamma-glutamylisoleucine). These included the free fatty acid receptor-1 (FFAR1), upstream transcription factor-2 (USF2), and tumor necrosis factor-related protein-9 (C1QTNF9), among others. Conclusions: We identified DMRs and metabolites that merit further investigation to determine their significance in controlling gene expression and metabolism which could define T2D risk in adolescents.

Extracellular Vesicles as Predictors of Individual Response to Exercise Training in Youth Living with Obesity.

BACKGROUND: Exercise is associated with health benefits, including the prevention and management of obesity. However, heterogeneity in the adaptive response to exercise training exists. Our objective was to evaluate if changes in extracellular vesicles (EVs) after acute aerobic exercise were associated with the responder phenotype following 6-weeks of resistance training (RT). METHODS: This is a secondary analysis of plasma samples from the EXIT trial (clinical trial#02204670). Eleven sedentary youth with obesity (15.7 ± 0.5 yrs, BMI ≥95th percentile) underwent acute exercise (60% HRR, 45 min). Blood was collected at baseline [AT0 min], during [AT15-45 min], and 75 min post-recovery [AT120], and EVs purified using size exclusion chromatography from extracted plasma. Afterward, youth participated in 6-weeks RT and were categorized into responders or non-responders based on changes in insulin sensitivity. RESULTS: We assessed EV biophysical profile (size, zeta potential, protein yield, and EV subtype protein expression) in a single-blind fashion. Overall, there was a general increase in EV production in both groups. Average EV size was larger in responders (~147 nm) vs. non-responders (~124 nm; p < 0.05). EV size was positively associated with absolute change in Matsuda index (insulin sensitivity) following RT (r = 0.44, p = 0.08). EV size distribution revealed responders predominantly expressed EVs sized 150-300 nm, whereas non-responders expressed EVs sized 50-150 nm (p < 0.05). At baseline, responders had ~25% lower TSG101, ~85% higher MMP2 levels. EV protein yield was higher in responders than non-responders at AT15 (p < 0.05). CONCLUSIONS: Our data suggest that youth with obesity that respond to RT produce larger EVs that are TSG101+ and CD63+, with increased EV protein yield during acute exercise.

Maternal body mass index, offspring body mass index, and blood pressure at 18 years: a causal mediation analysis.

OBJECTIVE: Understanding the natural history of hypertension is key to identifying prevention strategies. Previous work suggests that in utero exposures and offspring anthropometrics may play a role. This study examined the relationship between maternal pre-pregnancy body mass index (BMI) and the mediating role of childhood and adolescent BMI on offspring blood pressure at 18 years. METHODS: We performed multivariable regression and causal mediation analyses within 3217 mother - offspring pairs from the Avon Longitudinal Study of Parents and Children prospective birth cohort. The main exposure was maternal pre-pregnancy BMI, and the outcome was offspring blood pressure at 18 years of age categorized as normal or elevated. Latent trajectory analysis was used to quantify the mediator, offspring BMI trajectories, derived from multiple measurements throughout childhood and adolescence. Mediation analyses were repeated using current offspring BMI at 18 years as a continuous variable. RESULTS: Multivariable logistic regression revealed that for every 1 unit increase in maternal BMI, the risk of elevated blood pressure at 18 years of age increased by 5% (aOR: 1.05, 95% CI: 1.03-1.07; p < 0.001). The strength of this association was reduced after adjusting for offspring BMI trajectory (aOR: 1.03, 95% CI: 1.00-1.05; p = 0.017) and eliminated after adjusting for offspring BMI at 18 years (aOR: 1.00; 95% CI: 0.98-1.03; p = 0.70). Causal mediation analysis confirmed offspring BMI at 18 years as a mediator, where BMI trajectory accounted for 46% of the total effect of maternal BMI on elevated offspring blood pressure and current BMI account for nearly the entire effect. CONCLUSIONS: Maternal pre-pregnancy BMI is associated with an increased risk of elevated blood pressure in offspring at 18 years of age although it appears to be entirely mediated by offspring BMI.

Physical activity and cardiometabolic health in adolescents with type 2 diabetes: a cross-sectional study.

INTRODUCTION: Youth living with type 2 diabetes display increased risk of cardiovascular disease (CVD). It is unclear if regular physical activity (PA) modifies this risk. RESEARCH DESIGN AND METHODS: We compared CVD risk factors in a cross-sectional study of 164 youth with type 2 diabetes stratified according to weekly vigorous-intensity PA. Outcomes were hemoglobin A1c (HbA1c), ambulatory blood pressure (BP; ambulatory 24-hour readings), plasma lipoproteins, and albuminuria. The main exposure, vigorous-intensity PA, was quantified with the Adolescent Physical Activity Recall Questionnaire. RESULTS: Youth were 15±3 years, and 78% lived rurally and 68% were female, with a mean body mass index (BMI) Z-score of 2.4±1.1 and a mean HbA1c of 9.6% ±2.6%. Youth who participated in regular vigorous-intensity PA (40%; n=67) achieved nearly twice the dose of PA than peers who did not (62 vs 34 metabolic equivalent score-hour/week, p=0.001). After adjusting for duration of diabetes, BMI Z-score, sex, and smoking, youth who engaged in vigorous-intensity PA displayed lower HbA1c (9.1% vs 9.9%, p=0.052), diastolic BP (70 mm Hg vs 73 mm Hg, p=0.002), diastolic load (20% vs 26%, p=0.023), and mean arterial pressure (87.3 mm Hg vs 90.3 mm Hg, p<0.01), compared with youth who did not. Compared with youth who did not participate in regular vigorous-intensity PA, those who did also displayed lower odds of albuminuria after adjusting for duration of diabetes, sex, smoking, rural residence, and BMI Z-score (adjusted OR: 0.40, 95% CI 0.19 to 0.84). CONCLUSIONS: Among youth with type 2 diabetes, participation in vigorous-intensity PA is associated with lower CVD risk.

Interindividual variation in cardiometabolic health outcomes following 6 months of endurance training in youth at risk of type 2 diabetes mellitus.

This study determined the interindividual variation in the cardiometabolic response to 6 months of moderate or vigorous intensity exercise training (ET) among youth at risk for type 2 diabetes mellitus. Youth were randomized to moderate intensity ET (45-55% heart rate reserve; n = 31), vigorous intensity ET (70-85% heart rate reserve; n = 37), or control (n = 36). Only those attending ≥70% of ET sessions were included. Cardiometabolic measures included insulin sensitivity, hepatic triglyceride content, visceral adipose area, and cardiorespiratory fitness. The contribution of ET to interindividual variation was determined using the standard deviation of individual responses (SDIR) and considered meaningful if the SDIR surpassed the smallest worthwhile difference (SWD), calculated as 0.2 × the standard deviation of the control group baseline values. ET meaningfully contributed to the interindividual variation among changes in peak oxygen uptake following moderate (SDIR: 2.04) and vigorous (SDIR: 3.43) ET (SWD: 1.17 mL·kg fat free mass-1·min-1), body fat percentage and hepatic triglyceride content following moderate-intensity ET (SDIR: 1.64, SWD: 1.05%; SDIR: 10.08, SWD: 1.06%, respectively), and visceral fat mass following vigorous ET (SDIR: 11.06, SWD: 7.13 cm2). Variation in the changes in insulin sensitivity were not influenced by ET. The contribution of ET to interindividual variation appears to be influenced by the desired outcome and prescribed intensity. Trial registration at ClinicalTrials.gov (identifier no.: NCT00755547). Novelty: The contribution of exercise to interindividual variation following training depends on the outcome and exercise intensity. Increasing exercise intensity does not systematically reduce non-response among youth at risk for type 2 diabetes.

Filling gaps in type 1 diabetes and exercise research: a scoping review and priority-setting project.

Our team examined the characteristics of patient engagement (PE) practices in exercise-based randomized trials in type 1 diabetes (T1D), and facilitated T1D stakeholders in determining the top 10 list of priorities for exercise research. Two methodological approaches were employed: a scoping review and a modified James Lind Alliance priority-setting partnership. Published (Medline, Embase, CINAHL and Central databases) and grey literature (www.clinicaltrials.gov) were searched to identify randomized controlled trials of exercise interventions lasting minimum 4 weeks and available in English. We extracted information on PE and patient-reported outcomes (PROs) to identify if patient perspectives had been implemented. Based on results, we set out to determine exercise research priorities as a first step towards a patient-engaged research agenda. An online survey was distributed across Canada to collect research questions from patients, caregivers and healthcare providers. We qualitatively analyzed submitted questions and compiled a long list that a 12-person stakeholder steering committee used to identify the top 10 priority research questions. Of 9962 identified sources, 19 published trials and 4 trial registrations fulfilled inclusion criteria. No evidence of PE existed in any included study. Most commonly measured PROs were frequency of hypoglycemia (n=7) and quality of life (n=4). The priority-setting survey yielded 194 submitted research questions. Steering committee rankings identified 10 priorities focused on lifestyle factors and exercise modifications to maintain short-term glycemic control. Recent exercise-based randomized trials in T1D have not included PE and PROs. Patient priorities for exercise research have yet to be addressed with adequately designed clinical trials.

Cardiac structure and function in youth with type 2 diabetes in the iCARE cohort study: Cross-sectional associations with prenatal exposure to diabetes and metabolomic profiles.

OBJECTIVE: This study aimed to determine the degree of left ventricular (LV) dysfunction and its determinants in adolescents with type 2 diabetes (T2D). We hypothesized that adolescents with T2D would display impaired LV diastolic function and that these cardiovascular complications would be exacerbated in youth exposed to maternal diabetes in utero. METHODS: Left ventricular structure and function, carotid artery intima media thickness and strain, and serum metabolomic profiles were compared between adolescents with T2D (n = 121) and controls (n = 34). Sub-group analyses examined the role of exposure to maternal diabetes as a determinant of LV or carotid artery structure and function among adolescents with T2D. RESULTS: Adolescents with T2D were 15.1 ± 2.5 years old, (65% female, 99% Indigenous), had lived with diabetes for 2.7 ± 2.2 years, had suboptimal glycemic control (HbA1c = 9.4 ± 2.6%) and 58% (n = 69) were exposed to diabetes in utero. Compared to controls, adolescents with T2D displayed lower LV diastolic filling (early diastole/atrial filling rate ratio [E/A] = 1.9 ± 0.6 vs 2.2 ± 0.6, P = 0.012), lower LV relaxation and carotid strain (0.12 ± 0.05 vs 0.17 ± 0.05, P = .03) and elevated levels of leucine, isoleucine and valine. Among adolescents with T2D, exposure to diabetes in utero was not associated with differences in LV diastolic filling, LV relaxation, carotid strain or branched chain amino acids. CONCLUSIONS: Adolescents with T2D display LV diastolic dysfunction, carotid artery stiffness, and elevated levels of select branch chain amino acids; differences were not associated with exposure to maternal diabetes in utero.

Aerobic Fitness and Adherence to Guideline-Recommended Minimum Physical Activity Among Ambulatory Patients With Type 2 Diabetes Mellitus.

OBJECTIVE: Lifestyle intervention remains the cornerstone of management of type 2 diabetes mellitus (T2DM). However, adherence to physical activity (PA) recommendations and the impact of that adherence on cardiorespiratory fitness in this population have been poorly described. We sought to investigate adherence to PA recommendations and its association with cardiorespiratory fitness in a population of patients with T2DM. RESEARCH DESIGN AND METHODS: A cross-sectional analysis of baseline data from a randomized clinical trial (NCT00424762) was performed. A total of 150 individuals with medically treated T2DM and atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD were recruited from outpatient clinics at a single academic medical center. All individuals underwent a graded maximal exercise treadmill test to exhaustion with breath-by-breath gas exchange analysis to determine VO2peak. PA was estimated using a structured 7-Day Physical Activity Recall interview. RESULTS: Participants had a mean ± SD age of 54.9 ± 9.0 years; 41% were women, 40% were black, and 21% were Hispanic. The mean HbA1c was 7.7 ± 1.8% and the mean BMI, 34.5 ± 7.2 kg/m2. A total of 72% had hypertension, 73% had hyperlipidemia, and 35% had prevalent ASCVD. The mean ± SD reported daily PA was 34.3 ± 4 kcal/kg, only 7% above a sedentary state; 47% of the cohort failed to achieve the minimum recommended PA. Mean ± SD VO2peak was 27.4 ± 6.5 mL/kg fat-free mass/min (18.8 ± 5.0 mL/kg/min). CONCLUSIONS: On average, patients with T2DM who have or are at risk for ASCVD report low levels of PA and have low measured cardiopulmonary fitness. This underscores the importance of continued efforts to close this therapeutic gap.

A Holistic Approach to Risk for Early Kidney Injury in Indigenous Youth With Type 2 Diabetes: A Proof of Concept Paper From the iCARE Cohort.

BACKGROUND: Indigenous youth with type 2 diabetes (T2D) are disproportionately affected by early onset albuminuria and are at high risk of kidney failure in early adulthood. Traditional biological approaches have failed to fully explain the renal morbidity seen in this population. The improving renal Complications in Adolescents with type 2 diabetes through REsearch cohort (iCARE) study was therefore designed in collaboration with patients, to more holistically evaluate risk factors for renal morbidity. We hypothesize that both biological factors and mental health influence renal outcomes, mediated via inflammatory pathways. OBJECTIVE: The objective of this study was to evaluate the iCARE analytic framework which evaluates relationships between biological factors, mental health, inflammation, and albuminuria utilizing a structural equation modeling (SEM) approach. METHODS: The first 187 youth with T2D (10-25 years) from the Manitoba iCARE cohort are presented here to evaluate our theoretical and analytic framework. An SEM was chosen to evaluate the statistical significance of proposed associations. The primary outcome was a nonorthostatic urine albumin:creatinine ratio ≥2 mg/mmol. Main exposures (ie, latent factors) included psychological health (distress, perceived stress, positive mental health and resilience), hypertension (24 hour monitored), and inflammatory markers (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], fibrinogen). Hemoglobin A1c (HbA1c) and duration of diabetes were covariates. RESULTS: Within the initial cohort (median age = 15 years, duration of diabetes = 2.3 years, 66.8% female), 30.5% (n = 57) had nonorthostatic albuminuria (ALB), and the majority of ALB was persistent (confirmed in 2/3 samples over a 6-month period; n = 47). Youth with ALB had higher HbA1c (10.9% vs 8.9%; P < .001), more hypertension (94.2% vs 78·2%; P = .02), longer duration of diabetes (3.4 vs 2.4 years; P = .01), higher distress (9.2 vs 7.3; P = .02), and stress scores (28.7 vs 26.4; P = .03), and elevated inflammatory markers (CRP: 4.9 vs 3.1 mg/L; P = .01, fibrinogen: 3.7 vs 3.3 µmol/L; P = .02). Factors directly associated with ALB in the SEM were hypertension (0.28; P = .001), inflammation (0.41; P < .001), and HbA1c (0.50; P < .001). Psychological health was independently associated with inflammation (-0.20; P < .001) but not directly associated with ALB. CONCLUSIONS: Albuminuria is highly prevalent in Indigenous youth with T2D. This preliminary analysis supports a theoretical framework linking glycemic control, hypertension, and inflammation, potentially mediated by psychological factors with albuminuria. These data support the need for more holistic models of evaluation and care for youth with T2D and multifactorial interventions to prevent complications.

CONTEXTE: L'albuminurie à déclenchement précoce affecte de façon disproportionnelle les jeunes autochtones atteints de diabète de type 2 (T2D). Ces derniers présentent également un risque plus élevé d'insuffisance rénale au début de l'âge adulte. Les approches biologiques traditionnelles n'ont pas été en mesure d'expliquer entièrement la morbidité rénale observée dans cette population. Ainsi, l'étude de cohorte iCARE (improving renal Complications in Adolescents with type 2 diabetes through REsearch) a été conçue en collaboration avec les patients pour évaluer de façon plus globale les facteurs de risque de morbidité rénale. Nous posons l'hypothèse que les résultats rénaux sont influencés à la fois par la santé mentale du patient et des facteurs biologiques, avec médiation par les voies inflammatoires. OBJECTIF: Évaluer le cadre d'analyse iCARE qui examine les liens entre les facteurs biologiques, la santé mentale, l'inflammation et l'albuminurie à l'aide d'une approche de modélisation par équation structurelle (SEM). MÉTHODOLOGIE: Les 187 premiers jeunes autochtones atteints de T2D (âgés de 10 à 25 ans) de la cohorte manitobaine iCARE sont présentés ici pour évaluer notre cadre théorique et analytique. Une SEM a été choisie pour évaluer la pertinence statistique des associations suggérées. Le résultat principal était un rapport urinaire albumine/créatinine non orthostatique d'au moins 2 mg/mmol. Les principaux risques (c.-à-d. les facteurs latents) comprenaient la santé mentale (détresse, stress perçu, bien-être mental et résilience), l'hypertension (suivie sur 24 heures) et les taux de marqueurs inflammatoires (CRP, ESR, fibrinogène). L'hémoglobine A1c (HbA1c) et la période depuis l'apparition du diabète constituaient les covariables. RÉSULTATS: Les sujets retenus (66,8 % de sujets féminins) avaient 15 ans d'âge médian et étaient diabétiques depuis 2,3 ans. Dans cette cohorte, 30,5 % (n = 57) présentaient une albuminurie non orthostatique (confirmée dans 2/3 des échantillons sur une période de six mois) qui s'est avérée persistante dans la majorité des cas (n = 47). Les jeunes souffrant d'albuminurie présentaient des taux plus élevés d'HbA1c (10,9 c. 8,9 %; P < ,001), davantage d'hypertension (94,2 c. 78,2 %; P = ,02), étaient diabétiques depuis plus longtemps (3,4 c. 2,4 ans; P = ,01), vivaient davantage de détresse (9,2 c. 7,3; P = ,02), et présentaient des scores pour le stress (28,7 c. 26,4; P = ,03) et des taux de marqueurs inflammatoires plus élevés (CRP : 4,9 c. 3,1 mg/L; P = ,01, fibrinogène : 3,7 c. 3,3 µmol/L; P = ,02). Avec la SEM, les facteurs directement associés à l'albuminurie étaient l'hypertension (0,28; P = ,001), l'inflammation (0,41; P < ,001) et l'HbA1c (0,50; P < ,001). La santé psychologique a été associée à l'inflammation de manière indépendante (−0,20; P < ,001), mais n'a pas été directement associée à l'albuminurie. CONCLUSION: L'albuminurie est très répandue chez les jeunes autochtones atteints de T2D. Cette analyze préliminaire vient étayer un cadre théorique qui établit un lien entre l'albuminurie et le contrôle de la glycémie, l'hypertension et l'inflammation; lien potentiellement médié par des facteurs psychologiques. Ces données appuient la nécessité d'avoir des modèles plus holistiques d'évaluation et de prise en charge des jeunes atteints de T2D, et des interventions multifactorielles visant à prévenir les complications.

Gaps in Knowledge and the Need for Patient-Partners in Research Related to Physical Activity and Type 1 Diabetes: A Narrative Review.

Regular physical activity (PA) is a cornerstone in the management of complications associated with type 1 diabetes (T1D). Most national guidelines advocate for regular PA for persons living with T1D, however the evidence to support these recommendations has not be reviewed recently. Additionally, in an era of patient-centered care and patient oriented research, the role of patient partners in the area of PA and T1D interventions has never been explored. The purpose of this narrative review is to overcome these two gaps in the literature. Here we review selected epidemiological evidence and identify gaps in research that would add important information to guide practitioners and future guidelines. We also provide an overview of patient-oriented research projects co-developed with persons living with T1D. Significant gaps in the field include: (1) a lack of adequately powered prospective cohort studies using serial measures of PA and hard chronic disease end-points; (2) no multi-centered, highly powered, randomized controlled trials of PA, and long-term health outcomes; (3) little data on the role of new technologies to support PA-related behavior change, and (4) no trials that involved patients in the design and execution of PA-based clinical trials. This review provides a template for scientists and patient partners to develop future research priorities and agendas in the field.

Infant Feeding and Weight Gain: Separating Breast Milk From Breastfeeding and Formula From Food.

OBJECTIVES: Studies addressing breastfeeding and obesity rarely document the method of breast milk feeding, type of supplementation, or feeding in hospital. We investigated these practices in the CHILD birth cohort. METHODS: Feeding was reported by mothers and documented from hospital records. Weight and BMI z scores (BMIzs) were measured at 12 months. Analyses controlled for maternal BMI and other confounders. RESULTS: Among 2553 mother-infant dyads, 97% initiated breastfeeding, and the median breastfeeding duration was 11.0 months. Most infants (74%) received solids before 6 months. Among "exclusively breastfed" infants, 55% received some expressed breast milk, and 27% briefly received formula in hospital. Compared with exclusive direct breastfeeding at 3 months, all other feeding styles were associated with higher BMIzs: adjusted ß: +.12 (95% confidence interval [CI]: .01 to .23) for some expressed milk, +.28 (95% CI: .16 to .39) for partial breastfeeding, and +.45 (95% CI: .30 to .59) for exclusive formula feeding. Brief formula supplementation in hospital did not alter these associations so long as exclusive breastfeeding was established and sustained for at least 3 months. Formula supplementation by 6 months was associated with higher BMIzs (adjusted ß: +.25; 95% CI: .13 to .38), whereas supplementation with solid foods was not. Results were similar for weight gain velocity. CONCLUSIONS: Breastfeeding is inversely associated with weight gain velocity and BMI. These associations are dose dependent, partially diminished when breast milk is fed from a bottle, and substantially weakened by formula supplementation after the neonatal period.

Exercise in Pregnancy and Children's Cardiometabolic Risk Factors: a Systematic Review and Meta-Analysis.

BACKGROUND: Maternal metabolic health during the prenatal period is an established determinant of cardiometabolic disease risk. Many studies have focused on poor offspring outcomes after exposure to poor maternal health, while few have systematically appraised the evidence surrounding the role of maternal exercise in decreasing this risk. The aim of this study is to characterize and quantify the specific impact of prenatal exercise on children's cardiometabolic health markers, at birth and in childhood. METHODS: A systematic review of Scopus, MEDLINE, EMBASE, CENTRAL, CINAHL, and SPORTDiscus up to December 2017 was conducted. Randomized controlled trials (RCTs) and prospective cohort studies of prenatal aerobic exercise and/or resistance training reporting eligible offspring outcomes were included. Four reviewers independently identified eligible citations and extracted study-level data. The primary outcome was birth weight; secondary outcomes, specified a priori, included large-for-gestational age status, fat and lean mass, dyslipidemia, dysglycemia, and blood pressure. We included 73 of the 9804 citations initially identified. Data from RCTs was pooled using random effects models. Statistical heterogeneity was quantified using the I2 test. Analyses were done between June and December 2017 and the search was updated in December 2017. RESULTS: Fifteen observational studies (n = 290,951 children) and 39 RCTs (n = 6875 children) were included. Observational studies were highly heterogeneous and had discrepant conclusions, but globally showed no clinically relevant effect of exercise on offspring outcomes. Meta-analyzed RCTs indicated that prenatal exercise did not significantly impact birth weight (mean difference [MD] - 22.1 g, 95% confidence interval [CI] - 51.5 to 7.3 g, n = 6766) or large-for-gestational age status (risk ratio 0.85, 95% CI 0.51 to 1.44, n = 937) compared to no exercise. Sub-group analyses showed that prenatal exercise reduced birth weight according to timing (starting after 20 weeks of gestation, MD - 84.3 g, 95% CI - 142.2, - 26.4 g, n = 1124), type of exercise (aerobic only, MD - 58.7 g, 95% CI - 109.7, - 7.8 g; n = 2058), pre-pregnancy activity status (previously inactive, MD - 34.8 g, 95% CI - 69.0, - 0.5 g; n = 2829), and exercise intensity (light to moderate intensity only, MD - 45.5 g, 95% CI - 82.4, - 8.6 g; n = 2651). Fat mass percentage at birth was not altered by prenatal exercise (0.19%, 95% CI - 0.27, 0.65%; n = 130); however, only two studies reported this outcome. Other outcomes were too scarcely reported to be meta-analyzed. CONCLUSIONS: Prenatal exercise does not causally impact birth weight, fat mass, or large-for-gestational-age status in a clinically relevant way. Longer follow up of offspring exposed to prenatal exercise is needed along with measures of relevant metabolic variables (e.g., fat and lean mass). PROTOCOL REGISTRATION: Protocol registration number: CRD42015029163 .

Exercise-induced irisin release as a determinant of the metabolic response to exercise training in obese youth: the EXIT trial.

The mechanisms underlying the metabolic improvements following aerobic exercise training remain poorly understood. The primary aim of this study was to determine if an adipomyokine, irisin, responded to acute exercise was associated with the metabolic adaptations to chronic aerobic exercise in obese youth. The acute response to exercise was assessed in 11 obese youth following 45-min acute bouts of aerobic (AE) and resistance exercise (RE). The irisin area under the curve (pre-exercise, 15, 30, and 45 min) during these AE sessions were the main exposure variables. The primary outcome measure was the change in insulin sensitivity using the Matsuda index, following 6 weeks of RE training, delivered for 45 min, three times per week at 60-65% 1RM. Participants were also categorized as either responders (above) or nonresponders (below) based on the percentage change in the Matsuda index following the 6-week intervention. Irisin increased significantly during the acute bout of AE from 29.23 ± 6.96 to 39.30 ± 7.05 ng/mL; P = 0.028, but not significantly during the RE session (P = 0.182). Absolute and relative change in irisin during the acute bout of AE was associated with absolute and relative change in Matsuda index (r = 0.68; P = 0.022 and r = 0.63; P = 0.037) following the 6-week RE intervention. No such association was observed with the irisin response to acute RE (all P > 0.05). Responders to the 6-week RE intervention displayed a fourfold greater irisin response to acute AE (90.0 ± 28.0% vs. 22.8 ± 18.7%; P = 0.024) compared to nonresponders. Irisin increases significantly following an acute bout of AE, but not RE, and this response is associated with a greater improvement in insulin sensitivity in response to chronic resistance training.

Association Between Handgrip Muscle Strength and Cardiometabolic z-Score in Children 6 to 19 Years of Age: Results from the Canadian Health Measures Survey.

BACKGROUND: It is unclear if muscle strength, another index of fitness, which confers the protection from cardiometabolic risk in adults, is associated with similar protection in children and youth. The purpose of this study was to investigate the association between handgrip strength and cardiometabolic health in a large Canadian sample of children and youth. METHODS: We performed a cross-sectional analysis of the Canadian sample of children and youth aged 6 to 19 years (n = 1376) studied in the Canadian Health Measures Survey (cycles 1 and 2) between 2007 and 2011. The primary exposure variable, handgrip strength, was measured using a handgrip dynamometer. The primary outcome measure was a composite measure of cardiometabolic risk calculated as the sum of z-scores of the following variables: triglycerides, low high-density lipoprotein cholesterol, systolic and diastolic blood pressures, and hemoglobin A1c. All of the analyses were adjusted for confounders. RESULTS: The sample was on average 12.8 ± 3.5 years and displayed a body mass index (BMI) z-score of 0.5 ± 1.2. In unadjusted analyses, handgrip strength was negatively associated with cardiometabolic z-score (estimate = -0.013; P < 0.001). When results were adjusted for age, BMI z-score, and cardiorespiratory fitness, the association was no longer significant; however, an interaction between handgrip strength, sex, and cardiometabolic z-score was observed (estimate = -0.042; P < 0.001). When analyses were stratified by sex, handgrip strength was negatively associated with cardiometabolic z-score (estimate = -0.038; P < 0.001) in girls, but not in boys (estimate = 0.008; P = 0.150). CONCLUSION: In a large sample of Canadian children and adolescents, handgrip strength was associated with cardiometabolic health in girls, but not in boys.

Pancreatic lipid content is not associated with beta cell dysfunction in youth-onset type 2 diabetes.

OBJECTIVE: To determine whether pancreatic lipid content is associated with type 2 diabetes and beta cell function in Indigenous and Caucasian adolescents. METHODS: This was a cross-sectional study comparing (1)H-magnetic resonance spectroscopy-derived pancreatic triglyceride content in adolescents 13 to 18 years of age with type 2 diabetes (n=20) and body mass index-matched normoglycemic controls (n=34). Beta cell function was measured by the acute insulin response and disposition index derived from intravenous glucose tolerance tests. RESULTS: Pancreatic lipid content was not significantly different in youth with type 2 diabetes and their normoglycemic body mass index-matched peers (2.41 [95% CI: 0.63, 5.60] vs. 1.22 [0.08, 5.93]; p=0.27). Pancreatic triglyceride levels were not associated with measures of beta cell function in the cohort. In subgroup analyses, pancreatic lipid content was ∼4-fold higher in youth with type 2 diabetes who were carriers of the G319S mutation in the HNF-1alpha gene (7.45 [2.85, 26.8] vs. 2.20 [0.350, 3.30] % Fat to Water Ratio F/W; p=0.032). CONCLUSIONS: Pancreatic lipid content is not elevated in Indigenous or Caucasian youth with type 2 diabetes compared to normoglycemic youth, nor is it associated with beta cell function. The presence of the G319S mutation in the HNF-1alpha gene in Indigenous youth with type 2 diabetes is associated with higher pancreatic lipid content. Further research is needed to understand the mechanisms that explain beta cell failure in overweight youth with type 2 diabetes.

Fitness is a determinant of the metabolic response to endurance training in adolescents at risk of type 2 diabetes mellitus.

OBJECTIVE: The purpose of this prospective cohort study was to determine whether changes in cardiorespiratory fitness are associated with the metabolic response to endurance training in adolescents at risk of type 2 diabetes mellitus (T2DM). METHODS: Seventy-three overweight and obese adolescents completed a 6-month endurance exercise intervention. Total fat mass, trunk fat mass, visceral adipose tissue, and liver fat were assessed with dual energy X-ray absorptiometry and magnetic resonance imaging spectroscopy. RESULTS: The change in cardiorespiratory fitness with training was independently associated with reductions in BMI z-score (ß = -0.09; P = 0.006), total fat mass (ß = -1.40; P = 0.007), trunk fat mass (ß = -0.70; P = 0.01), and liver fat (ß = -1.80; P = 0.053). Adolescents within the highest tertile of change in fitness were 4.67 (95% CI: 1.15-13.73; P = 0.03), 11.90 (95% CI: 2.37-59.77; P = 0.002), and 6.21 (95% CI: 1.14-33.99; P = 0.035) times more likely to experience decreases in body weight, BMI, and liver fat compared with adolescents in the lowest tertile. CONCLUSIONS: The changes in adiposity and hepatic triglyceride content in response to endurance training are significantly related to the increase in cardiorespiratory fitness in adolescents at risk of T2DM.

The Improving Renal Complications in Adolescents With Type 2 Diabetes Through the REsearch (iCARE) Cohort Study: rationale and Protocol.

BACKGROUND: Youth-onset type 2 diabetes is associated with a high burden of renal complications, culminating with end stage kidney disease in early adulthood. The establishment of relevant bioclinical determinants of albuminuria and ultimately progression of chronic kidney disease in youth is critically important to facilitate patient risk stratification and aid in the development of treatment targets and tailored prevention strategies. In response to the important gaps in knowledge, we created a prospective cohort study of youth with type 2 diabetes titled the Improving Renal Complications in Adolescents with Type 2 Diabetes through the REsearch (iCARE) Study. METHODS: iCARE is a prospective observational cohort study of individuals with type 2 diabetes diagnosed prior to 18 years of age; the recruitment target was 400 patients. Phase 1 entailed a detailed phenotypic assessment of youth, including anthropometrics, biochemistry, 24-hour ambulatory blood pressure monitoring, overnight urine collections for albumin excretion, renal ultrasound and iohexol-derived glomerular filtration rate. Phase 2 of the study is an evaluation of psychological factors, including hair-derived cortisol; validated questionnaires for perceived stress, distress and resiliency; and a detailed evaluation of systemic and urine inflammatory biomarkers. Annual follow up is planned to assess temporal associations between clinical risk factors and renal outcomes, including progression of albuminuria. CONCLUSION: This study will provide novel insight into the risk factors for albuminuria and progression of chronic kidney disease in youth with type 2 diabetes. New knowledge generated by this study will inform clinical care, and the infrastructure developed will provide a framework for future intervention studies.

My voice: a grounded theory analysis of the lived experience of type 2 diabetes in adolescence.

OBJECTIVES: The aims of this study were to (1) describe the lived experiences of youth with type 2 diabetes from the perspectives of youth, their primary caregivers and healthcare professionals; (2) explore the barriers and facilitators to adopting lifestyle approaches for diabetes self-management; and (3) generate a relevant grounded theory. METHODS: This qualitative study was based on a grounded theory framework and consisted of interviews and focus groups with youth with type 2 diabetes (n=8), their primary caregivers (n=6) and healthcare professionals (n=8). Youth and their primary caregivers were purposely selected to represent extremes of successful self-management through lifestyle therapy. Focus groups were held with healthcare professionals (allied health [n=5]; pediatric endocrinologists [n=3]) in an effort to triangulate responses with youth and their primary caregivers. RESULTS: Youth with type 2 diabetes, their primary caregivers and their healthcare professionals described supportive relationships as being important determinants of adopting healthful-living self-management behaviours. All 3 groups also recognized that social determinants of health (i.e. food insecurity, poverty) were significant barriers to adopting healthful living behaviours for families with youth who have type 2 diabetes. Healthcare professionals recognized that the barriers to self-management were different for youth with type 2 diabetes than for youth with type 1 diabetes and felt that families would benefit from a clinic dedicated to meet their unique needs. CONCLUSIONS: Supportive relationships and social determinants of health are perceived as being significant determinants of the adoption of healthful behaviours by youth with type 2 diabetes and should be considered in clinical management and future therapeutic trials.

Is cardiorespiratory fitness a determinant of cardiomyopathy in the setting of type 2 diabetes?

OBJECTIVE: The aim of this study was to determine whether high fitness attenuates the defects in left ventricular (LV) structure, function and triglyceride (TG) content in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Patients (n = 74) with T2DM and ≥1 additional cardiac risk factor were recruited to participate in this cross-sectional study. Outcome measures of interest were LV structure and function by magnetic resonance imaging (MRI) and myocardial TG content by (1)H-magnetic resonance spectroscopy (MRS). The primary exposure variable was cardiorespiratory fitness defined by peak oxygen consumption scaled to fat-free mass (FFM; VO2peak-FFM). RESULTS: Mean age was 53.5 years; 42.9% were women and mean glycosylated haemoglobin (HbA1c) was 8.0% with the mean duration of T2DM 8.2 years. VO2peak-FFM was crudely associated with both LV end systolic (r = 0.35, p = 0.002) and diastolic volumes (r = 0.32, p = 0.004), but not with ejection fraction (r = -0.15, p = 0.206), myocardial TG (r = -0.04, p = 0.734) or early diastolic peak filling rate (PFR; r = -0.01, p = 0.887). In multiple linear regression analyses, among measures of LV structure/function, VO2peak-FFM was independently associated only with LV end-diastolic volume (EDV) (ß = 1.037, p = 0.038). CONCLUSION: In individuals with T2DM at increased cardiovascular (CV) risk, cardiorespiratory fitness is not associated with LV morphology, function or myocardial TG content.