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.

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.

High screen time is associated with asthma in overweight Manitoba youth.

OBJECTIVE: Low physical activity and high sedentary behavior are associated with adverse health outcomes, including asthma. The purposes were to (1) determine if low physical activity and/or high screen time increase the risk of asthma and airway hyperresponsiveness (AHR) in youth and (2) determine if weight status modifies these associations. METHODS: This is a prospective cohort study of healthy weight and overweight Canadian youth. In 2003-2005, 723 youth (8.6 ± 0.5 years; 34.0% asthma, 55.9% boys) were recruited from the 1995 Manitoba Prospective Cohort Study. In 2008-2010, 489 returned for follow-up measures (30.9% asthma, 56.6% boys). The primary exposure variables were parent-reported physical activity and screen time at 8-10 years of age. The primary outcome measures were pediatric allergist-defined asthma and AHR defined as the provocative concentration of methacholine required to induce a 20% fall in forced expiratory volume in 1 second (FEV(1)). RESULTS: Low physical activity (≤2 times weekly) was not associated with asthma or AHR. However, high screen time (≥1 hour/day) was associated with a greater odds of asthma at baseline (odds ratio (OR) = 2.01, 95% confidence interval (CI) = 1.20-3.37, p < .01) and follow-up (OR = 2.11, 95% CI = 1.14-3.89, p < .02) versus low screen time. This association was more pronounced among overweight youth (baseline: OR = 3.95, 95% CI = 1.70-9.12, p < .0001; follow-up: OR = 3.22, 95% CI = 1.17-8.86, p < .02). Screen time was not associated with AHR at baseline or follow-up. CONCLUSIONS: High screen time increases the risk of asthma, particularly among overweight youth. Screen time, in addition to physical activity, should be included in clinical assessments of youth with asthma.

"Asthma isn't an excuse, it's just a condition": youths' perceptions of physical activity and screen time.

OBJECTIVE: During puberty, physical activity patterns begin to decline, while sedentary time increases. These changes may be confounded by asthma. The purpose of this study was to gain insight into youths' perceptions of screen time and physical activity by asthma status. METHODS: Four interviews and seven focus groups with boys only or girls only were conducted with 15- to 16-year-old youth enrolled in either of two asthma-focused cohorts in Manitoba, Canada. Using a semi-structured interview guide, youth were asked about their perceptions of physical activity and screen time such as texting, watching television, electronic games, and Internet chatting and about their perceptions of the influence that asthma has on these behaviors. Data were analyzed using thematic coding. RESULTS: Two themes were common to youth with asthma and without asthma: (1) sports are an integral part of youths' lives and (2) screen time is important to youth. Two themes were identified among youth with asthma only: (1) physical activity used to be more difficult and (2) being active and living with asthma. Youth with asthma described physical activity as neither a hindrance to activity nor an excuse for inactivity, although asthma may still present some challenges. They also acknowledged their reliance on screen time for communication and for entertainment. CONCLUSIONS: Youth with asthma believe that physical activity has become increasingly easier as they become older and that being active with asthma, despite its challenges, is a key part of their lives.

Success with lifestyle monotherapy in youth with new-onset type 2 diabetes.

BACKGROUND: Evidence is lacking to support the efficacy of lifestyle modification as first-line therapy in the clinical management of type 2 diabetes mellitus (T2DM) in adolescents. METHODS: A retrospective chart review of youth diagnosed with T2DM between 1999 and 2008 was conducted. The authors describe the percentage of youth presenting with glycosylated hemoglobin (HbA1c) of <9% who achieved/maintained target glycemic control (HbA1c ≤7.0%) with lifestyle monotherapy during the year following diagnosis. RESULTS: Among the 275 youth with T2DM, 38% (n=104) presented with an HbA1c <9% and were prescribed lifestyle monotherapy at diagnosis. Of the 80 youth who had sufficient follow-up data over 12 months, 54% successfully maintained target glycemic control solely with lifestyle management. The mean HbA1c score at diagnosis was lower in youth who where successful on lifestlye monotherapy compared with those who were not successful. CONCLUSIONS: A significant proportion of youth newly diagnosed with T2DM presenting with an HbA1c <9% effectively achieved/maintained target glycemic control with lifestyle recommendations alone for 12 months. BACKGROUND: Evidence is lacking to support the efficacy of lifestyle modification as first-line therapy in the clinical management of type 2 diabetes mellitus (T2DM) in adolescents. METHODS: A retrospective chart review of youth diagnosed with T2DM between 1999 and 2008 was conducted. The authors describe the percentage of youth presenting with glycosylated hemoglobin (HbA1c) of <9% who achieved/maintained target glycemic control (HbA1c ≤7.0%) with lifestyle monotherapy during the year following diagnosis. RESULTS: Among the 275 youth with T2DM, 38% (n=104) presented with an HbA1c <9% and were prescribed lifestyle monotherapy at diagnosis. Of the 80 youth who had sufficient follow-up data over 12 months, 54% successfully maintained target glycemic control solely with lifestyle management. The mean HbA1c score at diagnosis was lower in youth who where successful on lifestlye monotherapy compared with those who were not successful. CONCLUSIONS: A significant proportion of youth newly diagnosed with T2DM presenting with an HbA1c <9% effectively achieved/maintained target glycemic control with lifestyle recommendations alone for 12 months.

HISTORIQUE: On ne possède pas assez de preuves pour appuyer l'efficacité des modifications au mode de vie comme thérapie de première ligne afin de prendre en charge le diabète de type 2 (DT2) sur le plan clinique chez les adolescents. MÉTHODOLOGIE: Les chercheurs ont procédé à une analyse rétrospective des dossiers d'adolescents ayant un DT2 qui ont été diagnostiqués entre 1999 et 2008. Ils ont décrit le pourcentage d'adolescents dont l'hémoglobine glycosylée (HbA1c) était inférieure à 9 % et qui ont obtenu ou maintenu le contrôle ciblé de leur glycémie (HbA1c ≤7,0 %) grâce à une monothérapie liée au mode de vie au cours de l'année suivant le diagnostic. RÉSULTATS: Chez les 275 adolescents ayant un DT2, 38 % (n=104) avaient une HbA1c inférieure à 9 % et se sont fait proposer une monothérapie liée au mode de vie au moment du diagnostic. Chez les 80 adolescents qui disposaient de données de suivi suffisantes sur 12 mois, 54 % ont réussi à maintenir le contrôle de leur glycémie ciblée par la seule prise en charge de leur mode de vie. L'indice moyen d'HbA1c des jeunes qui parvenaient aux objectifs ciblés grâce à la monothérapie liée au mode de vie était plus faible que celui des jeunes qui n'y parvenaient pas. CONCLUSIONS: Une forte proportion d'adolescents qui venaient de se faire diagnostiquer un DT2 et dont l'HbA1c était inférieur à 9 % ont réussi à obtenir ou à maintenir le contrôle ciblé de leur glycémie seulement en respectant pendant 12 mois les recommandations liées au mode de vie.

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.

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.

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.

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.

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.

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.

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.

Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study.

BACKGROUND: The risk of heart failure in type 2 diabetes mellitus is greater than can be accounted for by hypertension and coronary artery disease. Rodent studies indicate that in obesity and type 2 diabetes mellitus, lipid overstorage in cardiac myocytes produces lipotoxic intermediates that cause apoptosis, which leads to heart failure. In humans with diabetes mellitus, cardiac steatosis previously has been demonstrated in explanted hearts of patients with end-stage nonischemic cardiomyopathy. Whether cardiac steatosis precedes the onset of cardiomyopathy in individuals with impaired glucose tolerance or in patients with type 2 diabetes mellitus is unknown. METHODS AND RESULTS: To represent the progressive stages in the natural history of type 2 diabetes mellitus, we stratified 134 individuals (age 45+/-12 years) into 1 of 4 groups: (1) lean normoglycemic (lean), (2) overweight and obese normoglycemic (obese), (3) impaired glucose tolerance, and (4) type 2 diabetes mellitus. Localized (1)H magnetic resonance spectroscopy and cardiac magnetic resonance imaging were used to quantify myocardial triglyceride content and left ventricular function, respectively. Compared with lean subjects, myocardial triglyceride content was 2.3-fold higher in those with impaired glucose tolerance and 2.1-fold higher in those with type 2 diabetes mellitus (P<0.05). Left ventricular ejection fraction was normal and comparable across all groups. CONCLUSIONS: In humans, impaired glucose tolerance is accompanied by cardiac steatosis, which precedes the onset of type 2 diabetes mellitus and left ventricular systolic dysfunction. Thus, lipid overstorage in human cardiac myocytes is an early manifestation in the pathogenesis of type 2 diabetes mellitus and is evident in the absence of heart failure.

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 .

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.

The relationship between weight gain and blood pressure in children and adolescents.

BACKGROUND: The aim of this study was to determine the relationship between the trajectories of weight gain and systolic blood pressure (SBP) in youth. METHODS: Annual surveys of anthropometry, fitness, SBP, and its determinants (cardiac output, systemic vascular resistance, and arterial compliance) were conducted in youth (aged 5 to 19 years) in a school-based setting between 2004 and 2006. Children were stratified according to change in body mass index (BMI) over time. RESULTS: Within the entire cohort (n = 2089), mean SBP (121 +/- 16 SD v 112 +/- 15 SD mm Hg; P < .01) and the prevalence of high blood pressure (48% v 18%, P < .01) were significantly higher and fitness levels were lower (P < .01) in obese children, relative to healthy-weight peers. After 2 years of follow-up, despite similar SBP and BMI at baseline, the average change in SBP was approximately 4.5-fold greater in children with the largest increase in BMI, relative to children who experienced minimal weight gain. This group also experienced a significantly greater increase in stroke volume (P < .05), while the change in heart rate, arterial compliance, and systemic vascular resistance was comparable with that of children who experienced minimal weight gain. Multiple linear regression analysis revealed that SBP increased 0.77 mm Hg for every kilogram of weight gain over a period of 2 years (P < .01). CONCLUSIONS: Overweight and disproportionate weight gain in children are associated with elevated SBP. These data support the need for interventions to prevent excessive weight gain and obesity in children and adolescents.

Effect of pioglitazone therapy on myocardial and hepatic steatosis in insulin-treated patients with type 2 diabetes.

High levels of myocardial and hepatic triglyceride are common in obesity and type 2 diabetes. Monotherapy with thiazolidinedione agents reduces hepatic steatosis by up to 50% in patients with type 2 diabetes. It is not known if treatment with a thiazolidinedione added to insulin has a similar beneficial antisteatotic effect. The aim of our study was to determine whether the addition of pioglitazone to insulin treatment in patients with type 2 diabetes has antisteatotic action in the heart and the liver. Thirty-two patients were randomized to 6 months of treatment with insulin or insulin plus pioglitazone. In addition to blood tests, we evaluated myocardial and hepatic triglyceride content, as well as subcutaneous and visceral fat mass at the L2 level, by magnetic resonance spectroscopy and imaging, respectively. Despite weight and subcutaneous fat mass gain, hemoglobin A1c was significantly reduced by both treatments. Myocardial and hepatic triglyceride contents were reduced by the treatment with pioglitazone plus insulin (p = .02 and .03, respectively) but not by the treatment with insulin. Systolic and diastolic blood pressure and heart function remained unchanged in both groups. The addition of pioglitazone to insulin therapy reduced myocardial and hepatic steatosis, consistent with the reported ability of the thiazolidinedione agents to redistribute fat from nonadipose to subcutaneous adipose depots.

Adiposity of the heart, revisited.

Obesity is a major risk factor for heart disease. In the face of obesity's growing prevalence, it is important for physicians to be aware of emerging research of novel mechanisms through which adiposity adversely affects the heart. Conventional wisdom suggests that either hemodynamic (that is, increased cardiac output and hypertension) or metabolic (that is, dyslipidemic) derangements associated with obesity may predispose individuals to coronary artery disease and heart failure. The purpose of this review is to highlight a novel mechanism for heart disease in obesity whereby excessive lipid accumulation within the myocardium is directly cardiotoxic and causes left ventricular remodeling and dilated cardiomyopathy. Studies in animal models of obesity reveal that intracellular accumulation of triglyceride renders organs dysfunctional, which leads to several well-recognized clinical syndromes related to obesity (including type 2 diabetes). In these rodent models, excessive lipid accumulation in the myocardium causes left ventricular hypertrophy and nonischemic, dilated cardiomyopathy. Novel magnetic resonance spectroscopy techniques are now available to quantify intracellular lipid content in the myocardium and various other human tissues, which has made it possible to translate these studies into a clinical setting. By using this technology, we have recently begun to study the role of myocardial steatosis in the development of obesity-specific cardiomyopathy in humans. Recent studies in healthy individuals and patients with heart failure reveal that myocardial lipid content increases with the degree of adiposity and may contribute to the adverse structural and functional cardiac adaptations seen in obese persons. These studies parallel the observations in obese animals and provide evidence that myocardial lipid content may be a biomarker and putative therapeutic target for cardiac disease in obese patients.

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.