Sex differences in kidney metabolism may reflect sex-dependent outcomes in human diabetic kidney disease.

Diabetic kidney disease (DKD) is the main cause of chronic kidney disease (CKD) and progresses faster in males than in females. We identify sex-based differences in kidney metabolism and in the blood metabolome of male and female individuals with diabetes. Primary human proximal tubular epithelial cells (PTECs) from healthy males displayed increased mitochondrial respiration, oxidative stress, apoptosis, and greater injury when exposed to high glucose compared with PTECs from healthy females. Male human PTECs showed increased glucose and glutamine fluxes to the TCA cycle, whereas female human PTECs showed increased pyruvate content. The male human PTEC phenotype was enhanced by dihydrotestosterone and mediated by the transcription factor HNF4A and histone demethylase KDM6A. In mice where sex chromosomes either matched or did not match gonadal sex, male gonadal sex contributed to the kidney metabolism differences between males and females. A blood metabolomics analysis in a cohort of adolescents with or without diabetes showed increased TCA cycle metabolites in males. In a second cohort of adults with diabetes, females without DKD had higher serum pyruvate concentrations than did males with or without DKD. Serum pyruvate concentrations positively correlated with the estimated glomerular filtration rate, a measure of kidney function, and negatively correlated with all-cause mortality in this cohort. In a third cohort of adults with CKD, male sex and diabetes were associated with increased plasma TCA cycle metabolites, which correlated with all-cause mortality. These findings suggest that differences in male and female kidney metabolism may contribute to sex-dependent outcomes in DKD.

A pilot and feasibility study of a randomized clinical trial testing a self-compassion intervention aimed to increase physical activity behaviour among people with prediabetes.

BACKGROUND: Seventy-five per cent of individuals with prediabetes will eventually be diagnosed with type 2 diabetes. Physical activity is a cornerstone in reducing type 2 diabetes risk but can be a challenging behaviour to adopt for those living with prediabetes. Individuals with prediabetes experience difficult emotions associated with being at risk for a chronic disease, which can undermine self-regulation. Self-compassion enhances self-regulation because it mitigates difficult emotions and promotes adaptive coping. We performed a pilot randomized controlled trial to determine the feasibility and acceptability of a self-compassion informed intervention to increase physical activity for persons with prediabetes. METHODS: This explanatory mixed methods study tested the feasibility and acceptability of a two-arm, randomized, single-blind, actively controlled, 6-week online intervention. Using a 1:1 allocation ratio, participants (identified as people with prediabetes, low physical activity, and low self-compassion) were randomized to a self-compassion (Mage = 60.22 years) or control condition (Mage = 56.13 years). All participants received behaviour change education (e.g. SMART goals, action-coping planning) and either other health knowledge (control condition: e.g. sleep, benefits of water) or self-compassion training (intervention condition: practising mindfulness, writing a letter to themselves offering the same support that they would offer to a friend). The primary outcome was to determine the feasibility and acceptability of the trial. To be considered feasible, our outcomes needed to meet or surpass our pre-determined criteria (e.g. time for group formation: 14-20 participants per month). Feasibility was assessed by examining the recruitment rates, retention, adherence, fidelity, and capacity. Semi-structured interviews were conducted with participants to determine trial acceptability. As a secondary purpose, we examined the means on key study variables (secondary and exploratory variables; see Table 1) at all planned time points (baseline, intervention-end, 6- and 12-week follow-up) to identify if they are suitable to include in the efficacy trial (see Additional Table 3). RESULTS: Eighteen participants were screened and randomized to one of two conditions. Retention, instructor fidelity, safety, capacity, adherence to most of the study aspects, and acceptability by participants and facilitators all met the criteria for feasibility. Recruitment rate, process time, and adherence to home practice were below our criteria, and we offer ways to address these shortcomings for the efficacy trial. CONCLUSION: The results from this study suggest that it should be feasible to deliver our intervention while highlighting the alterations to components that may be altered when delivering the efficacy trial. We outline our changes which should improve and enhance the feasibility and acceptability of our planned intervention. Funding for this study was from the Canadian Institutes of Health Research (CIHR). TRIAL REGISTRATION: ClinicalTrials.gov, NCT04402710 . Registered on 09 April 2020.

Comparison of Clinical and Social Characteristics of Canadian Youth Living With Type 1 and Type 2 Diabetes.

OBJECTIVES: Our aim in this study was to describe the clinical and social characteristics of 2 Canadian cohorts of adolescents with diabetes. METHODS: Participants from the Improving renal Complications in Adolescents with type 2 diabetes through REsearch (iCARE) study (n=322) and the Early Determinants of Cardio-Renal Disease in Youth With Type 1 Diabetes (n=199) study were compared. RESULTS: Adolescents were 10 to 18 years of age (mean ± standard deviation: 14.8±2.4 years). The T2DM cohort had a shorter duration of diabetes. Both groups had glycated hemoglobin levels above target. The type 2 diabetes (T2D) cohort was comprised of predominantly Indigenous youth. The type 1 diabetes (T1D) cohort was 58.3% European/Caucasian, with a high proportion (41.7%) of visible minority groups (Afro-Caribbean, Asian/Pacific Islander, Hispanic). The prevalence of obesity, hypertension, left ventricular hypertrophy, albuminuria and hyperfiltration was higher in the T2D cohort. The T1D cohort was more socially and economically advantaged in all 4 dimensions of health inequality. CONCLUSIONS: There are significant differences in clinical and social characteristics of adolescents with T2D and T1D in Canada. Both have inadequate glycemic control with evidence of onset and progression of diabetes-related complications.

Differential effects of a school-based obesity prevention program: A cluster randomized trial.

School-based healthy living interventions are widely promoted as strategies for preventing obesity. The peer-led Healthy Buddies™ curriculum has been shown to improve obesity-related outcomes in school-aged children. We examined whether these improvements existed among subgroups of children stratified by sex, income level and urban/rural geography. In a cluster-randomized controlled trial, elementary schools in Manitoba, Canada, were randomly allocated to Healthy Buddies™ (10 schools, 340 students) or standard curriculum (10 schools, 347 students). Healthy Buddies™ participants had 21weekly lessons on healthy eating, physical activity and self-efficacy, delivered by children age 9-12 to children age 6-8. We assessed pre- and post-intervention body mass index (BMI) z-scores, waist circumference, healthy living knowledge, dietary intake and self-efficacy among the younger children. Compared to standard curriculum (n = 154), Healthy Buddies™ participants (n = 157) experienced a greater reduction in waist circumference (-1.7 cm; 95% confidence interval [CI][-2.8, -0.5 cm]) and improved dietary intake (4.6; 95% CI [0.9, 8.3]), healthy living knowledge (5.9; 95% CI [2.3, 9.5]) and self-efficacy (5.3; 95% CI [1.0, 9.5]) scores. In subgroup analyses, effects for waist circumference (-2.0 cm; 95% CI [-3.6, -0.5]), healthy living knowledge (9.1; 95% CI [4.4, 13.8]) and self-efficacy (8.3; 95% CI [3.3, 13.3]) were significant among boys. Dietary intake (10.5; 95% CI [5.5, 15.4]), healthy living knowledge (9.8; 95% CI [4.5, 15.0]) and self-efficacy (6.7; 95% CI [0.7, 12.7]) improved among urban-dwelling but not rural-dwelling children. Healthy Buddies™ was effective for boys and children living in urban settings. Enhanced curricula may be needed to improve program effectiveness for select subgroups of school-aged children.

Minimal effect of walking before dinner on glycemic responses in type 2 diabetes: outcomes from the multi-site E-PAraDiGM study.

AIM: To examine the effect of walking before dinner on 24-h glycemic control in individuals with type 2 diabetes using the standardized multi-site Exercise-Physical Activity and Diabetes Glucose Monitoring (E-PAraDiGM) Protocol. METHODS: Eighty participants were studied under two conditions (exercise vs. non-exercise control) separated by 72 h in a randomized crossover design. Each condition lasted 2 days during which standardized meals were provided. Exercise consisted of 50 min of treadmill walking at 5.0 km/h before the evening meal, while control involved 50 min of sitting. The primary outcome measure was mean glucose during the 24-h period following exercise (or sitting) measured by continuous glucose monitoring. RESULTS: Of the 80 participants who were initially randomized, 73 completed both exercise and control. Sixty-three participants [29 males, 34 females; age = 64 ± 8 years, body mass index = 30.5 ± 6.5 kg/m2 and HbA1c = 51 ± 8 mmol/mol (6.8 ± 0.7%), mean ± SD] complied with the standardized diets and had complete continuous glucose monitoring data. Exercise did not affect mean 24-h glucose compared to control (0.03 mmol/L; 95% CI - 0.17, 0.22, P = 0.778) but individual differences between conditions ranged from - 2.8 to +1.8 mmol/L. Exercise did not affect fasting glucose, postprandial glucose or glucose variability. Glucose concentrations measured by continuous glucose monitoring were reduced during the 50 min of walking in exercise compared to sitting in control (- 1.56 mmol/L; 95% CI - 2.18, - 0.95, p < 0.001). CONCLUSION: Contrary to previous acute exercise studies, 50 min of walking before dinner in the E-PAraDiGM protocol did not affect 24-h glucose profiles. However, highly heterogeneous responses to exercise were observed. TRIAL REGISTRATION: NCT02834689.

Biological and socioeconomic determinants of prediabetes in youth: an analysis using 2007 to 2011 Canadian Health Measures Surveys.

OBJECTIVES: To describe rates of prediabetes among youth in Canada and the associated social and biological characteristics. METHODS: We analyzed the cross-sectional data from the first (2007-2009) and second (2009-2011) cycles of the Canadian Health Measures Survey (CHMS) for youth aged 6-19 years. Prediabetes was defined using the glycated hemoglobin (A1C) guidelines set out by the American Diabetes Association (ADA) and the Canadian Diabetes Association (CDA) of A1C ranges 5.7-6.4% (38.8-46.4 mmol/mol) and 6.0-6.4% (42.1-46.4 mmol/mol), respectively. RESULTS: An elevated A1C was observed in 22.8% of our sample (n = 3449) based on the ADA definition and 5.2% of youth using the CDA definition. Independent predictors in a fully adjusted model for prediabetes were non-White (odds ratio (OR) 2.62: 95% Confidence intervals 2.05-3.35), obese (OR 1.53: 1.19-1.96), less physically active youth (0.97: 0.95-0.99), and parents with high school education or less (1.34: 1.02-1.74). Moreover, significant regional variations were noted with higher rates for all regions except Ontario. CONCLUSION: Prediabetes is relatively common in Canada and associated with common biologic and socioeconomic factors. Importantly, regular physical activity was significantly associated with reduced odds of prediabetes. Targeted screening and continued emphasis on physical activity may help curb the increasing rates of prediabetes.

Exclusive breastfeeding in hospital predicts longer breastfeeding duration in Canada: Implications for health equity.

BACKGROUND: Breastfeeding has many established health benefits for women and children. We examined the association between maternal education, newborn feeding in hospital, and long-term breastfeeding duration. METHODS: We studied 3195 Canadian mother-infant dyads in the CHILD pregnancy cohort. Newborn feeding was documented from hospital records. Caregivers reported sociodemographic factors and infant feeding at 3, 6, 12, 18, and 24 months. RESULTS: Overall, 97% of newborns initiated breastfeeding and 74% were exclusively breastfed in hospital. Exclusively breastfed newborns were ultimately breastfed longer compared with those who received formula supplementation during their hospital stay (median 11.0 vs 7.0 months, P < .001). After controlling for maternal age, ethnicity, birth mode, and gestational age, exclusively breastfed newborns had a 21% reduced risk of breastfeeding cessation (HR = 0.79, 0.71-0.87). This effect was strongest among women without a postsecondary education (HR = 0.65, 0.53-0.79). DISCUSSION: Exclusive breastfeeding in hospital is associated with longer breastfeeding duration, particularly among women of lower socioeconomic status. Initiatives that support exclusive breastfeeding of newborns in hospital could improve long-term breastfeeding rates and help reduce health inequities arising in early life.

Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies.

BACKGROUND: Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. METHODS: We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points. RESULTS: From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference -0.37 kg/m2; 95% confidence interval [CI] -1.10 to 0.36; I2 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I2 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome. INTERPRETATION: Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. Protocol registration: PROSPERO-CRD42015019749.

The association between time spent in vigorous physical activity and dietary patterns in adolescents: a cross-sectional study.

BACKGROUND: Physical activity interventions targeting weight status have yielded mixed results. This variability may be attributed to compensatory changes in dietary patterns after increasing physical activity (PA) levels. Therefore, we sought to determine whether dietary patterns varied with time spent in vigorous-intensity PA in youth. METHODS: Cross-sectional analysis of 330 youth enrolled in a school-based prospective cohort in central Alberta. Physical activity was assessed with waist mounted accelerometers (Actical) worn for 7 days. Main outcomes included consumption of unhealthy foods and the unhealthy food index obtained from a validated web-based 24-hour dietary recall instrument. Secondary outcomes included macronutrient intake, food group (Canada's Food Guide to Healthy Eating) intake, and diet quality. RESULTS: Compared with youth participating in < 7 min/ day of vigorous physical activity, those achieving ≥ 7 min/day displayed no change in healthy or unhealthy food consumption. However, linear regression suggests a modest association between diet quality and vigorous-intensity PA. CONCLUSION: These data demonstrate that in this cohort of Canadian youth, time spent being physically active is associated with healthier dietary patterns and not with increased consumption of unhealthy foods.

The associations between cardiovascular risk factors, physical activity, and arterial stiffness in youth.

BACKGROUND: The primary aim of this population-based study was to determine if arterial stiffness is associated with cardiovascular disease (CVD) risk factor clustering and physical activity in youth 12-14 years old. We hypothesized that arterial stiffness would be positively associated with CVD risk factor clustering and negatively associated with physical activity in a dose-response manner in this cohort of youth. METHODS: This was a cross sectional study of 485 youth recruited from the 1995 Manitoba birth cohort. The primary outcome, arterial stiffness, was assessed noninvasively using conventional pulse wave analysis and velocity. The primary exposure variables included 1) a measure of cardiometabolic risk, defined as a composite of novel and traditional risk factors for cardiovascular disease and type 2 diabetes and 2) self-reported physical activity. RESULTS: Neither cardiometabolic risk factor clustering, nor physical activity were associated with either measure of arterial stiffness in this cohort of youth 12-14 years. Cardiometabolic risk decreased with increasing levels of vigorous physical activity, (P < .05) and increased with increasing body mass index. CONCLUSIONS: Cardiometabolic risk factor clustering and physical activity are not associated with arterial stiffness in youth 12-14 years of age. Increased vigorous physical activity is associated with reduced cardiometabolic risk in youth independent of body mass index.

Physical activity among Canadian children on school days and nonschool days.

BACKGROUND: Schools are frequently cited as a favorable venue to promote physical activity (PA), however little data exist describing times when students are least active. Our objective was to overcome this limitation and describe time periods when students are least active. METHODS: We used a cross-sectional design to assess patterns of PA in 923 grade 5 students [mean age: 10.9 (± 0.4) years] from 30 schools in Alberta, Canada. Students wore time-stamped pedometers for 9 consecutive days, providing 7 full days of data. We compared step counts adjusted for nonwear time between school days and nonschool days as well as during school hours and after school hours. RESULTS: 689 (75%) students provided complete data. The average daily step count was higher on school days (boys 13,476 ± 4123 step/day; girls 11,436 ± 3158 steps/day) than nonschool days (boys 11,009 ± 5542 steps/day; girls 10,256 ± 5206 steps/day). More steps were also taken during school hours than nonschool hours (boys +206 ± 420 steps/hour, P < .001; girls 210 ± 347, P < .001 steps/hour). CONCLUSIONS: PA levels of children are below Canadian recommended levels for optimal growth and health. Health promotion should emphasize PA particularly among girls, outside school hours, and weekends.

Impaired arterial compliance and aerobic endurance in kidney transplant recipients.

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recipients (KTR). Two risk factors for cardiovascular disease that have not been examined in this population are arterial compliance and aerobic capacity. The primary objective was to determine small and large artery compliance and aerobic endurance in KTR. A secondary objective was to explore the relationship between aging and arterial compliance and aerobic endurance in KTR. METHODS: Sixty-two clinically stable KTR were recruited from the University of Alberta Renal Transplant Clinic. Small and large artery compliance was assessed using computerized arterial pulse waveform analysis. Aerobic endurance was determined using the six-minute walk test. Age-matched normative data from healthy individuals was used for comparison. RESULTS: Small arterial compliance was lower in KTR (5.5+/-3 ml/mm Hg x 100) compared to age-matched healthy individuals' predicted values (7.9+/-0.9 ml/mm Hg x 100, P<0.0001). No difference was found for large artery compliance between KTR (16.0+/-6.6 ml/mm Hg x 10) and age-matched healthy predicted values (15.2+/-1.3 ml/mm Hg x 10, P=0.5). Small and large artery compliance were 35% (P=0.026) and 36% (P=0.005) higher in younger (<51 years) versus older (>51 years) KTR, respectively. The six-minute walk distance was 28% lower in KTR (495+/-92 m) compared to healthy age-predicted values (692+/-56 m P<0.0001). CONCLUSIONS: Compromised arterial compliance and poor aerobic endurance may partially explain the high incidence of cardiovascular disease in KTR. Interventions demonstrated to improve these parameters may afford substantial clinical benefit in this population.