DNA methylation signatures of youth-onset type 2 diabetes and exposure to maternal diabetes.

OBJECTIVE: Youth-onset type 2 diabetes (T2D) is physiologically distinct from adult-onset, but it is not clear how the two diseases differ at a molecular level. In utero exposure to maternal type 2 diabetes (T2D) is known to be a specific risk factor for youth-onset T2D. DNA methylation (DNAm) changes associated with T2D but which differ between youth- and adult-onset might delineate the impacts of T2D development at different ages and could also determine the contribution of exposure to in utero diabetes. METHODS: We performed an epigenome-wide analysis of DNAm on whole blood from 218 youth with T2D and 77 normoglycemic controls from the iCARE (improving renal Complications in Adolescents with type 2 diabetes through REsearch) cohort. Associations were tested using multiple linear regression models while adjusting for maternal diabetes, sex, age, BMI, smoking status, second-hand smoking exposure, cell-type proportions and genetic ancestry. RESULTS: We identified 3830 differentially methylated sites associated with youth T2D onset, of which 3794 were moderately (adjusted p-value < 0.05 and effect size estimate > 0.01) associated and 36 were strongly (adjusted p-value < 0.05 and effect size estimate > 0.05) associated. A total of 3725 of these sites were not previously reported in the EWAS Atlas as associated with T2D, adult obesity or youth obesity. Moreover, three CpGs associated with youth-onset T2D in the PFKFB3 gene were also associated with maternal T2D exposure (FDR < 0.05 and effect size > 0.01). This is the first study to link PFKFB3 and T2D in youth. CONCLUSION: Our findings support that T2D in youth has different impacts on DNAm than adult-onset, and suggests that changes in DNAm could provide an important link between in utero exposure to maternal diabetes and the onset of T2D.

Incidence and prevalence of type 2 diabetes in Manitoba children 2009-10 to 2017-18: First Nation versus all other Manitobans.

AIM: To describe the incidence and prevalence of type 2 diabetes in children in Manitoba over a ten-year period. METHODS: Population-based, provincial databases were linked to calculate the incidence and prevalence of type 2 diabetes in children < 18 years of age in Manitoba from 2009-10 to 2017-18. First Nation and all other Manitoban children are described separately. RESULTS: The incidence of type 2 diabetes increased from 16.0/100,000/year in 2009-10 to 31‧1/100,000/year in 2017-18 (p < 0.001). For First Nation children, the incidence increased from 73‧4 to 121‧2/100,000/year (p < 0.001). For all other Manitoban children, the incidence increased from 3‧3 to 10‧7/100,000/year (p < 0.001). The prevalence of type 2 diabetes rose from 66‧4 to 124‧2/100,000/year between 2009 -10 and 2017-18 (<0.001). The prevalence in First Nation children rose from 282‧8 to 517‧9/100,000/year (p < 0.001) and in all other Manitoban children from 18‧4 to 35.0/100,000/year (p < 0.001). CONCLUSIONS: The incidence and prevalence of type 2 diabetes is increasing in Manitoban children. While the greatest increase is seen in all other Manitoban children, type 2 diabetes disproportionally affects First Nation children. Understanding the prevalence and incidence of type 2 diabetes in children is necessary for resource allocation and to inform program planning, aimed at both prevention and management.

24-h ambulatory blood pressure readings and associations with albuminuria in youth with type 2 diabetes: A cross sectional analysis from the iCARE cohort.

AIMS: To evaluate associations between 24-h ambulatory blood pressure monitor (ABPM) data vs. single casual blood pressure (BP) and albuminuria in youth with type 2 diabetes. METHODS: A cross-sectional analysis of youth with type 2 diabetes 10-<18 yrs. from the iCARE cohort. MAIN EXPOSURES: daytime HTN (+/- nocturnal), isolated nocturnal HTN and single casual BP. MAIN OUTCOME: non-orthostatic urine albumin: creatinine ratio (ACR) ≥ 3 mg/mmol and log-transformed urine ACR. Regressions evaluated associations between 1. HTN status based on ABPM and log-transformed urine ACR (continuous) and 2. ABPM-derived BP z-scores and casual BPcentiles and albuminuria status (categorical). RESULTS: Of 281 youth included, 19.6 % had daytime HTN (+/- nocturnal), and 28.5 % isolated nocturnal HTN on 24-h ABPM. In multivariate linear regression, HTN (ABPM) (ß = 0.553; p = 0.001), duration of diabetes (ß = 0.857; p = 0.02), HbA1c (ß = 1.172; p ≤0.0001) and ACEI/ARB use (ß = 3.94; p < 0.0001) were positively associated with log-transformed ACR; (R2 = 0.184). In logistic regression analysis, all ABPM LMS z-scores were positively associated with albuminuria; casual BPcentile was not significant. CONCLUSIONS: Youth with type 2 diabetes have high rates of HTN based on 24-ABPM data. ABPM-derived measures of BP are associated with albuminuria. These data support the routine use of ABPM devices to diagnose hypertension in youth with type 2 diabetes.

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.

Mental health comorbidity is common in children with type 2 diabetes.

OBJECTIVE: To describe the prevalence of mental health comorbidity in children with type 2 diabetes compared to a matched population without diabetes and children with type 1 diabetes. RESEARCH DESIGN AND METHODS: Population-based cohorts of 528 youth (7-18 years of age) with prevalent type 2 diabetes, 1519 matched children without diabetes and 778 youth with type 1 diabetes were identified from a clinical registry and linked to provincial health care records to assess the prevalence of mental health comorbidity using ICD-9CM, ICD-10CA and ATC codes. RESULTS: The majority of children with type 2 diabetes were of First Nations heritage. Compared to their matched peers, children with type 2 diabetes where more likely to have a mood or anxiety disorder before and after diagnosis [RR 2.38 (1.63, 3.48) p < 0.001 and 1.70 (1.39, 2.08) p < 0.001 respectively], to attempt/complete suicide [RR 3.18 (1.30, 7.81) p = 0.012 and 2.18 (1.32, 3.60) p = 0.0002 respectively] and be prescribed an antipsychotic [RR 2.33 (1.23, 4.39) p = 0.009 and 1.76 (1.23, 2.52) p = 0.002 respectively]. Following adjustment for age and sex, children with type 2 diabetes, compared to children with type 1 diabetes where more likely to have a mood or anxiety disorder and be prescribed an antipsychotic after diagnosis [RR 1.43 (1.07, 1.91) p = 0.015; RR 2.41 (1.44, 4.06) p = 0.0009 respectively]. CONCLUSIONS: Children with type 2 diabetes have high rates of comorbid mental illness. Programs to provide care, support, and education must address the mental health comorbidity in the context of the demographic, socioeconomic, and psycho-cultural characteristics of the population.

Hospitalization and comorbidity in children with type 2 diabetes.

OBJECTIVE: To describe hospitalization rates and reasons for hospitalization in children with type 2 diabetes (T2D) and to compare these rates to a matched cohort without diabetes and to children with type 1 diabetes (T1D). METHODS: Population-based cohorts of 528 children (7-18 years of age) with prevalent T2D, 1519 matched control children without diabetes and 778 children with T1D were identified from a clinical registry and linked to health care records to assess hospitalizations and reasons for hospitalizations using ICD-9CM and ICD-10CA codes. RESULTS: Children with T2D are more likely than their matched controls and children with T1D to be admitted to hospital in the year prior to diagnosis {RR 2.83 (1.77, 4.53) p < 0.0001 and 8.05 (4.05, 16.00) p < 0.0001, respectively}, in the first year post diagnosis {RR 3.19 (2.08, 4.89) p < 0.0001 and 3.04 (1.86, 4.98) p < 0.0001, respectively} and in the 5 year post diagnosis period {RR 1.99 (1.56, 2.53) p < 0.0001 and 1.91 (1.48, 2.46) p < 0.0001, respectively}. Mental illness was the most common cause for hospital admission in both children with T2D and their matched controls. CONCLUSIONS: This differs from children with T1D where endocrine causes constitute the most common reason for hospital admission. This analysis provides novel data on hospitalization rates and diagnoses in the increasing population of children with T2D. This information is important to inform health care programming and health policy planning to best meet the needs of this population.

Pregestational Diabetes Exposure In Utero: Validation of a Definition for Use in Administrative Data.

OBJECTIVE: Our aim in this study was to determine the best administrative data case definition for pregestational diabetes exposure. METHODS: We compared the performance of case definitions for pregestational diabetes exposure within the administrative health data housed in the Manitoba Population Health Research Repository at the Manitoba Centre for Health Policy with an identified population of women in whom the diagnosis of pregestational diabetes was known from the clinical database of the Manitoba Diabetes Education Resource for Children and Adolescents (DER-CA) (August 12, 1989 through January 28, 2015). The DER-CA database contains maternal diabetes status during pregnancy and also includes women diagnosed with type 2 diabetes in childhood whose pregnancies were thus all complicated by pregestational diabetes exposure. Linkage of mother-child dyads is possible within the Repository. Diagnosis codes from the International Classification of Diseases---ninth or tenth revision and physician tariff codes were used to identify diabetes in the biologic mothers of children with type 2 diabetes identified from the DER-CA database. The timing of the diagnosis of diabetes in the mother with respect to the gestational age of the pregnancy was determined. RESULTS: The best administrative definition of pregestational diabetes exposure was any incident code for diabetes in the mother before the pregnancy of the index child or within the first 25 weeks of pregnancy (sensitivity: 84.77%; positive predictive value: 92%). CONCLUSION: The definition cited can be used to define pregestational diabetes exposure in studies utilizing administrative data.

Diabetic ketoacidosis at presentation of type 1 diabetes in children in Canada during the COVID-19 pandemic.

Type 1 diabetes is a common chronic illness in childhood. Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes. Early recognition of symptoms of diabetes and immediate initiation of treatment are important factors in preventing DKA at first presentation. We describe the numbers of children presenting with DKA at initial diagnosis across eight Canadian paediatric centres during the COVID-19 pandemic (March 15, 2020 to July 31, 2020) and compare this to the same time period in 2019. Comparing the pre-COVID to the COVID-19 time period, presentation in DKA increased from 36.4% to 55.0% (P<0.0001) and presentation in severe DKA from 37.0% to 48.3% (P=0.044). These findings are concerning and emphasize the importance of awareness of the signs and symptoms of diabetes. In addition, these findings raise concern about access to appropriate and timely care during the COVID-19 pandemic.

Cardiovascular Comorbidity Associated With Albuminuria in Youth-Onset Type 2 Diabetes: Analyses From the iCARE Study.

OBJECTIVES: Little is known about the relationship between albuminuria in youth with type 2 diabetes (T2D) and cardiovascular risk. We aimed to determine whether youth with T2D and albuminuria have evidence of increased cardiovascular risk and/or early cardiovascular dysfunction compared with youth with T2D without albuminuria. METHODS: Youth with T2D were stratified by albuminuria status. Cardiovascular risk factors, including body mass index (BMI), 24-hour blood pressure, lipid profile, smoking and smoking exposure, habitual physical activity and screen time, were compared between groups. Left ventricular structure and function and carotid intima-media thickness (cIMT) were evaluated in participants who underwent cardiac imaging. RESULTS: Two hundred sixty-five youth participated, 83 (31.3%) of whom had albuminuria. Ethnicity, sex, BMI z score, age at diagnosis, duration of diabetes and hepatocyte nuclear factor-1alpha status did not differ between youth stratified by albuminuria. Smoking, exposure to second-hand smoke and low physical activity levels did not differ between groups. Youth with albuminuria were more likely to have hypertension, dyslipidemia and poor glycemic control. Left ventricular structure and carotid cIMT did not differ between groups, but youth with albuminuria had evidence of early left ventricular diastolic dysfunction. CONCLUSIONS: We found evidence of increased cardiovascular disease risk factors and left ventricular diastolic dysfunction in youth with T2D and albuminuria compared with those without albuminuria, despite a relatively short duration of disease. Thus, albuminuria may serve as a marker of early cardiovascular disease risk in youth with T2D.

Transition of Youth With Type 2 Diabetes: Predictors of Health-Care Utilization After Transition to Adult Care From Population-Based Administrative Data.

OBJECTIVES: In this study, we aimed to compare health-care visits pre- and posttransition from pediatric to adult care between youth with type 2 and type 1 diabetes. METHODS: We linked a clinical database with the Manitoba Population Research Data Repository to compare health-care visits 2 years before and after transition, and investigated baseline factors influencing health-care engagement. RESULTS: Youth with type 2 diabetes (n=196) vs type 1 diabetes (n=456) were more likely to be female (61% vs 44%), older at diagnosis (13.6 vs 10.6 years), live in northern regions and to be in the lowest socioeconomic status quartile (53% vs 5.4%). Seventy-six percent of youth with type 2 diabetes attended a follow-up visit within 2 years of transition compared to 97% of youth with type 1 diabetes. Youth with type 2 diabetes had higher rates of hospitalization pretransition (19.6 vs 11.6 admissions/100 patient years) and posttransition (24.7 vs 11.7 admissions/100 patient years) and fewer medical visits (pretransition: 2.4 vs 3.0 visits/person year [p<0.01]; posttransition: 1.6 vs 2.1 visits/person year [p<0.01]). Accounting for sex, geography, age, education, socioeconomic status and diabetes type, achieving 4 visits in 2 years posttransition was predicted by the number of visits pretransition (odds ratio, 1.35; 95% confidence interval, 1.23 to 1.49) and diabetes type (type 2 diabetes: odds ratio, 0.57; 95% confidence interval, 0.34 to 0.98). CONCLUSIONS: Youth with type 2 diabetes attend fewer medical follow-up visits pre- and posttransition to adult care compared to youth with type 1 diabetes. Focused, informed, specific transition planning is needed that addresses the unique characteristics of this population.

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.

Youth perceptions and experiences of type 2 diabetes: Protocol for a collaborative knowledge translation approach and qualitative study.

AIMS: The aim of this study is to generate an in-depth understanding of youth perceptions and experiences of living with type 2 diabetes to inform knowledge translation, research and intervention development. DESIGN: Interpretive descriptive qualitative study. METHODS: Twenty to 25 youth aged 10-18 years with a diagnosis of type 2 diabetes will be purposively recruited through the Diabetes Education Resource for Children and Adolescents in Winnipeg, Manitoba, and through the Improving Renal Complications in Adolescents With Type 2 Diabetes Through the REsearch [iCARE] cohort. Socio-demographic information will be collected. Semi-structured interviews will occur iteratively with inductive thematic analysis. Data will be professionally transcribed and managed using NVivo 1.0 software. The University Ethics Committee approved this study (May 2020). DISCUSSION: There is a critical gap in understanding youth experiences of type 2 diabetes. Research involving youth with type 2 diabetes is predominantly quantitative in nature, largely reflecting risk factors, underlying mechanisms and treatment outcomes associated with diabetes management. In-depth qualitative research on youth experiences can help identify youth priorities, provide insight into critical misalignments between stakeholder perspectives, and drive forward a more consolidated youth-centred research agenda. IMPACT: Understanding and applying knowledge of youth experiences is critical as the prevalence of, and challenges associated with, youth onset type 2 diabetes continues to increase worldwide. This research will generate a robust interpretive description of youth lived experiences and perceptions of type 2 diabetes where such research is lacking, to inform basic and applied research within an interdisciplinary investigative and clinical research team with relevance to other jurisdictions. In response to calls for youth-oriented research in type 2 diabetes, this work will catalyse collaborative knowledge translation using creative and youth-directed initiatives.

Intrauterine exposure to diabetes and risk of cardiovascular disease in adolescence and early adulthood: a population-based birth cohort study.

BACKGROUND: It is unclear whether intrauterine exposure to maternal diabetes is associated with risk factors for cardiovascular disease and related end points in adulthood. We examined this potential association in a population-based birth cohort followed up to age 35 years. METHODS: We performed a cohort study of offspring born between 1979 and 2005 (n = 293 546) and followed until March 2015 in Manitoba, Canada, using registry-based administrative data. The primary exposures were intrauterine exposure to gestational diabetes and type 2 diabetes mellitus. The primary outcome was a composite measure of incident cardiovascular disease events, and the secondary outcome was a composite of risk factors for cardiovascular disease in offspring followed up to age 35 years. RESULTS: The cohort provided 3 628 576 person-years of data (mean age at latest follow-up 20.5 [standard deviation 6.4] years, 49.3% female); 2765 (0.9%) of the offspring experienced a cardiovascular disease end point, and 12 673 (4.3%) experienced a cardiovascular disease risk factor. After propensity score matching, the hazard for cardiovascular disease end points was elevated in offspring exposed to gestational diabetes (adjusted hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.12-1.79) but not type 2 diabetes (adjusted HR 1.40, 95% CI 0.98-2.01). A similar association was observed for cardiovascular disease risk factors (gestational diabetes: adjusted HR 1.92, 95% CI 1.75-2.11; type 2 diabetes: adjusted HR 3.40, 95% CI 3.00-3.85). INTERPRETATION: Intrauterine exposure to maternal diabetes was associated with higher morbidity and risk related to cardiovascular disease among offspring up to 35 years of age.

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.

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.

Association of Gestational Diabetes and Type 2 Diabetes Exposure In Utero With the Development of Type 2 Diabetes in First Nations and Non-First Nations Offspring.

Importance: Type 2 diabetes is increasing worldwide, disproportionately affecting First Nations (FN) people. Identifying early-life determinants of type 2 diabetes is important to address the intergenerational burden of illness. Objective: To investigate the association of in utero exposure to gestational diabetes and type 2 diabetes, stratified by FN status, with the development of type 2 diabetes in offspring. Design, Setting, and Participants: This cohort study was derived from the linkage of a pediatric diabetes clinical database and a population-based research data repository in Manitoba, Canada. Mother-infant dyads with a hospital birth or midwifery report in the data repository between April 1, 1984, and April 1, 2008, were identified. The dates of analysis were August through December 2017. Children identified with type 1 diabetes, monogenic diabetes, or secondary diabetes were excluded. Exposures: Primary exposures included maternal gestational diabetes or type 2 diabetes and FN status. Main Outcomes and Measures: The primary outcome was incident type 2 diabetes in offspring by age 30 years. Results: In this cohort study of 467 850 offspring (mean follow-up, 17.7 years; 51.2% male), FN status and diabetes exposure were associated with incident type 2 diabetes in offspring after adjustment for sex, maternal age, socioeconomic status, birth size, and gestational age. Type 2 diabetes exposure conferred a greater risk to offspring compared with gestational diabetes exposure (3.19 vs 0.80 cases per 1000 person-years, P < .001). Compared with no diabetes exposure, any diabetes exposure accelerated the time to the development of type 2 diabetes in offspring by a factor of 0.74 (95% CI, 0.62-0.90) for gestational diabetes and a factor of 0.50 (95% CI, 0.45-0.57) for type 2 diabetes. First Nations offspring had a higher risk compared with non-FN offspring (0.96 vs 0.14 cases per 1000 person-years, P < .001). First Nations offspring had accelerated type 2 diabetes onset by a factor of 0.52 (95% CI, 0.49-0.55) compared with non-FN offspring. Neither interaction between FN and type 2 diabetes (0.92; 95% CI, 0.80-1.05) nor interaction between FN and gestational diabetes (0.97; 95% CI, 0.77-1.20) was significant (P = .21 and P = .75, respectively). Conclusions and Relevance: Important differences exist in offspring risk based on type of diabetes exposure in utero. These findings have implications for future research and clinical practice guidelines, including early pregnancy screening and follow-up of the offspring.

Prenatal, Obstetric and Perinatal Factors Associated With the Development of Childhood-Onset Type 2 Diabetes.

OBJECTIVE: To explore associations among prenatal, obstetric and perinatal factors and the development of childhood-onset type 2 diabetes. METHODS: This retrospective, case-control study utilized administrative data housed at the Manitoba Centre for Health Policy. De-identified health records were examined from a sample of 270 children (aged 10 to 17 years at time of diagnosis) with type 2 diabetes and 1341 children without type 2 diabetes matched for age, sex and geographic location. Patients and control subjects were linked to their de-identified biological mothers' health records. Prenatal, obstetric and perinatal factors were investigated. Univariate and multivariable conditional regression analyses were conducted to identify key factors associated with the development of type 2 diabetes in children. RESULTS: The mean age at diagnosis was 13.1 years, and 61% of patients were girls. The majority (71.1%) of children with type 2 diabetes resided in rural areas. Exposure to maternal pregestational diabetes increased the odds of childhood-onset type 2 diabetes nearly 6-fold, and exposure to gestational diabetes carried a 4-fold increased risk. Breastfeeding was found to be protective, decreasing the risk of childhood-onset type 2 diabetes (odds ratio = 0.52, 95% confidence interval = 0.36-0.74). Low maternal income was significantly associated with development of childhood-onset type 2 diabetes (odds ratio = 6.67, 95% confidence interval = 3.01-14.79). CONCLUSIONS: Health and social policies and programs are needed to provide financial, educational and clinical resources that target women whose pregnancies are affected by poverty, type 2 diabetes or gestational diabetes. Breastfeeding should be encouraged to aid in the prevention of childhood-onset type 2 diabetes.