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.

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.

Poor Sleep, Increased Stress and Metabolic Comorbidity in Adolescents and Youth With Type 2 Diabetes.

OBJECTIVES: The impacts of stress and disrupted sleep on type 2 diabetes management and related comorbidities in adolescents and youth remain unknown. In this study, we examine sleep in adolescents and youth living with type 2 diabetes and matched controls and its association with stress, glycemic management, albuminuria and hypertension. METHODS: A cross-sectional analysis was conducted to assess the relationship between sleep quality (Pittsburgh Sleep Quality Index [PSQI]) and stress (Perceived Stress Scale-14 [PSS-14] and Kessler Psychological Distress Scale [K6]) with metabolic control within a cohort of male and female adolescents and youth (10 to 23 years old) with type 2 diabetes and weight- and ethnicity-matched controls. RESULTS: One hundred eighty-one adolescents and youth with type 2 diabetes (15.0±2.44 years of age, body mass index z score [BMIz] 1.85±0.60, 62.5% female) and 52 controls (16±2.9 years, BMIz 1.99±0.58, 61.5% female) were included in the investigation. Participants slept for an average of 8.38 hours per night, and 49% of individuals with type 2 diabetes and 46% of controls rated their sleep quality as "poor." No sex differences were seen for sleep scores (p=0.13), but females reported higher stress (p=0.001) and distress (p=0.03). No differences in glycated hemoglobin (p=0.11), BMIz (p=0.28), hypertension (p=0.24) or albuminuria (p=0.79) were seen in individuals reporting good vs poor sleep. Regression analysis showed that poor sleep was associated with higher glycated hemoglobin (p=0.029). CONCLUSIONS: Many adolescents and youth reported poor sleep, which was associated with stress, distress and worse glycemic management. Differences were observed between sexes. The long-term effects of poor sleep and psychological distress warrant further study.

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.

Emergency management of adrenal insufficiency in children: advocating for treatment options in outpatient and field settings.

Adrenal insufficiency (AI) remains a significant cause of morbidity and mortality in children with 1 in 200 episodes of adrenal crisis resulting in death. The goal of this working group of the Pediatric Endocrine Society Drug and Therapeutics Committee was to raise awareness on the importance of early recognition of AI, to advocate for the availability of hydrocortisone sodium succinate (HSS) on emergency medical service (EMS) ambulances or allow EMS personnel to administer patient's HSS home supply to avoid delay in administration of life-saving stress dosing, and to provide guidance on the emergency management of children in adrenal crisis. Currently, hydrocortisone, or an equivalent synthetic glucocorticoid, is not available on most ambulances for emergency stress dose administration by EMS personnel to a child in adrenal crisis. At the same time, many States have regulations preventing the use of patient's home HSS supply to be used to treat acute adrenal crisis. In children with known AI, parents and care providers must be made familiar with the administration of maintenance and stress dose glucocorticoid therapy to prevent adrenal crises. Patients with known AI and their families should be provided an Adrenal Insufficiency Action Plan, including stress hydrocortisone dose (both oral and intramuscular/intravenous) to be provided immediately to EMS providers and triage personnel in urgent care and emergency departments. Advocacy efforts to increase the availability of stress dose HSS during EMS transport care and add HSS to weight-based dosing tapes are highly encouraged.

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.

Maternal obesity, diabetes during pregnancy and epigenetic mechanisms that influence the developmental origins of cardiometabolic disease in the offspring.

Since 1980, global obesity has doubled, and the incidence of cardiometabolic diseases such as type 2 diabetes and heart disease is also increasing. While genetic susceptibility and adult lifestyle are implicated in these trends, evidence from clinical cohorts, epidemiological studies and animal model experiments support a role for early-life environmental exposures in determining the long-term health of an individual, which has led to the formulation of the Developmental Origins of Health and Disease (DOHaD) theory. In fact, maternal obesity and diabetes during pregnancy, which are on the rise, are strongly associated with altered fetal growth and development as well as with lifelong perturbations in metabolic tissues. A mounting body of evidence implicates epigenetic mechanisms (e.g. DNA methylation and histone modifications) in the regulation of these effects and their transmission to future generations. This review critically discusses the current evidence (in animal model systems and humans) that implicates maternal obesity and diabetes during pregnancy in perturbing the epigenome of the next generation, and the consequential impact on growth, organ development and ultimately cardiometabolic disease progression. Additionally, this review will address some of the limitations of the DOHaD approach and areas that require further study. For example, future research requires verification of the mechanistic impact of the epigenetic marks and their persistence over the life course. Ultimately, this knowledge is needed to establish optimal screening, prevention and therapeutic approaches for children at risk of cardiometabolic disease development.

The Metabolic Phenotype of Youth Onset Type 2 Diabetes: The Role of Pregestational Diabetes Exposure and the Hepatic Nuclear Factor 1Alpha G319S Polymorphism.

INTRODUCTION: The influence of exposure to diabetes in utero and the HNF-1α G319S polymorphism on the metabolic phenotype of youth with T2DM at diagnosis is unknown. The objective of this study is to describe the metabolic phenotype at diagnosis of youth with T2DM: a) by exposure to gestational or pregestational diabetes and b) by HNF-1α G319S genotype. METHODS: A cross-sectional retrospective chart review of youth with T2DM diagnosed between 2006 and 2011 seen at a single centre was performed. The primary variables of interest and selected clinical and biochemical characteristics at birth and at diagnosis of diabetes were extracted. Descriptive statistics and regression analyses were undertaken. RESULTS: One hundred eighty-four youth were included. Youth exposed to pregestational diabetes were younger at diagnosis (-1.26 years, p<0.001), had a shorter gestation (-1.73 weeks, p<0.001) and a lower waist z-score (-2.77, p<0.001) compared to those not exposed to diabetes in utero. Youth homozygous for the HNF-1α G319S polymorphism were younger (-1.77 years p<0.001), had a lower BMI z-score (-0.32, p=0.04), waist z-score (-1.91, p=0.04), HbA1c (-1.73%; 18.9 mmol/mol, p<0.01), triglycerides (-90.3 mg/dl; -1.02 mmol/L, p=0.04) and higher HDL-c (8.88 mg/dl; 0.23 mmol/L, p=0.001) compared to wild-type youth at diagnosis. Homozygote youth were less likely to have hypertension or acanthosis nigricans at diagnosis (OR 0.27, p=0.03; OR 0.32, p=0.04 respectively). CONCLUSION: Differences in the metabolic phenotype of subgroups of youth with T2DM suggest differences in the pathophysiology of diabetes. An understanding of specific phenotypes is necessary to plan and inform both prevention and intervention strategies.

Is the change in body mass index among children newly diagnosed with type 1 diabetes mellitus associated with obesity at transition from pediatric to adult care?

BACKGROUND: Insulin therapy is lifesaving treatment for individuals with type 1 diabetes (T1D). Its initiation maybe associated with significant weight gain because of change from a catabolic to an anabolic state. Excessive weight-gain increases the risk of obesity and is associated with chronic disease. OBJECTIVE: To examine if change in body mass index (BMI) among children in the 6 months after diagnosis with type 1 diabetes mellitus is associated with long-term obesity. METHODS: This was a population-based retrospective study of 377 children (aged 2-18 yr) with type 1 diabetes. Measured heights and weights were used to calculate BMI z-scores based on Centers for Disease Control and Prevention (CDC) cut-points. Generalized Linear Models using BMI group, and age group at diagnosis; postdiagnosis weight change; and sex were applied to assess associations between postdiagnosis weight change and BMI z-score at transition to adult care. RESULTS: Mean BMI z-score increased from 0.28 at diagnosis, to 0.53 at 6 months and 0.66 at transition to adult care. Change in BMI z-scores differed by initial BMI group and magnitude of postdiagnosis weight change. Younger children (<11 yr) had higher (p = 0.004) BMI z-scores at diagnosis but not at last visit (p = 0.1) than older (≥11 yr) children at diagnosis. BMI z-score at diagnosis, postdiagnosis weight change, female sex, and longer duration with TID were associated with higher BMI z-score at time of transition. CONCLUSIONS: BMI z-score at diagnosis was the strongest predictor of BMI z-score at time of transition to adult care, however; its effect was mediated by magnitude of weight change 6 months after diagnosis, sex, and age group at diagnosis.

Not as skinny as we used to think: Body mass index in children and adolescents at diagnosis of type 1 diabetes mellitus.

This retrospective analysis of clinical data for children (2-18 years old) with incident T1D found surprisingly low (9%) prevalence of underweight, and high (15% overweight; 8% obesity) respectively at diagnosis. These results suggests a need to rethink the classic clinical teaching surrounding skinnier presentation at diagnosis, and importantly, the corresponding expectation of weight gain after insulin therapy initiation.

Exploring the role of the HNF-1αG319S polymorphism in ß cell failure and youth-onset type 2 diabetes: Lessons from MODY and Hnf-1α-deficient animal models.

The prevalence of youth-onset type 2 diabetes (T2D) is rapidly increasing worldwide, disproportionately affecting Indigenous youth with Oji-Cree heritage from central Canada. Candidate gene screening has uncovered a novel and private polymorphism in the Oji-Cree population in the hepatocyte nuclear factor-1 alpha (HNF-1α) gene, where a highly conserved glycine residue at position 319 is changed to a serine (termed HNF-1αG319S or simply G319S). Oji-Cree youth who carry one or two copies of the "S-allele" present at diagnosis with less obesity, reduced indicators of insulin resistance, and lower plasma insulin levels at diagnosis, suggestive of a primary defect in the insulin-secreting ß cells. Few studies on the impact of the HNF-1αG319S variant on ß cell function have been performed to date; however, much can be learned from other clinical phenotypes of HNF-1α-deficiency, including HNF-1α mutations that cause maturity-onset diabetes of the young 3 (MODY3). In addition, evaluation of Hnf-1α-deficient murine models reveals that HNF-1α plays a central role in the regulation of insulin secretion by regulating the expression of key genes involved in ß cell glucose-sensing, mitochondrial function, and the maintenance of the ß cell phenotype in differentiated ß cells. The overall goal of this minireview is to explore the impact of HNF-1α-deficiency on the ß cell to better inform future research into the mechanisms of ß cell dysfunction in Oji-Cree youth with T2D.

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

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

Maternal health issues and cardio-metabolic outcomes in the offspring: a focus on Indigenous populations.

Non-communicable diseases (NCDs) including diabetes, obesity and cardiovascular disease are the leading causes of death worldwide. Indigenous populations are disproportionally affected. In an effort to halt the increasing disease burden, the mechanisms underlying the increasing rate of NCDs are an important area of study. Recent evidence has focused on the perinatal period as an influential period impacting the future cardio-metabolic health of the offspring. This concept has been defined as metabolic foetal programming and supports the importance of the developmental origins of health and disease in research and clinical practice, specifically in prevention efforts to protect future generations from NCDs. An understanding of the underlying mechanisms involved is not clear as of yet. However, an understanding of these mechanisms is imperative in order to plan effective intervention strategies. As much of the discussion below is gleaned from large epidemiological studies and animal studies, further research with prospective cohorts is necessary.