Youth-onset Type 2 Diabetes: An Overview of Pathophysiology, Prognosis, Prevention and Management.

PURPOSE OF REVIEW: This review explores the emerging evidence regarding pathogenesis, future trajectories, treatment options, and phenotypes of youth-onset type 2 diabetes (T2D). RECENT FINDINGS: Youth-onset T2D is increasing in incidence and prevalence worldwide, disproportionately affecting First Nations communities, socioeconomically disadvantaged youth, and people of colour. Youth-onset T2D differs in pathogenesis to later-onset T2D and progresses more rapidly. It is associated with more complications, and these occur earlier. While there are limited licensed treatment options available, the available medications also appear to have a poorer response in youth with T2D. Multiple interacting factors likely contribute to this rising prevalence, as well as the increased severity of the condition, including structural inequities, increasing obesity and sedentary lifestyles, and intergenerational transmission from in-utero exposure to maternal hyperglycemia and obesity. Youth-onset T2D is also associated with stigma and poorer mental health, and these impact clinical management. There is an urgent need to develop effective interventions to prevent youth-onset T2D and enhance engagement of affected youth. It is also critical to better understand the differing phenotypes of youth-onset T2D, to effectively target treatments, and to address intergenerational transmission in high-risk populations.

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.

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.

ISPAD Clinical Practice Consensus Guidelines 2022: Type 2 diabetes in children and adolescents.

Since the 2018 ISPAD guidelines on this topic, follow-up of large cohorts from around the globe have continued informing the current incidence and prevalence of co-morbidities and complications in young adults with youth-onset type 2 diabetes (T2D). This chapter focuses on the risk factors, diagnosis and presentation of youth-onset T2D, the initial and subsequent management of youth-onset T2D, and management of co-morbidities and complications. We include key updates from the observational phase of the multi-center Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial, the SEARCH for Diabetes in Youth (SEARCH) study and new data from the Restoring Insulin Secretion (RISE) study, a head-to-head comparison of youth onset vs adult-onset T2D. We also include an expanded section on risk factors associated with T2D, algorithms and tables for treatment, management, and assessment of co-morbidities and complications, and sections on recently approved pharmacologic therapies for the treatment of youth-onset T2D, social determinants of health, and settings of care given COVID-19 pandemic.

Urinary podocyte-derived microparticles in youth with type 1 and type 2 diabetes.

AIMS/HYPOTHESIS: The release of podocyte-derived microparticles into the urine may reflect early kidney injury in diabetes. We measured the urinary excretion of podocyte-derived microparticles in youth with type 1 and type 2 diabetes, and related the values to blood pressure, renal function and blood glucose levels. METHODS: Cross-sectional, exploratory analysis of urine samples and clinical data from youth with type 1 (n = 53) and type 2 (n = 50) diabetes was carried out. Urinary podocyte-derived microparticle numbers, measured by flow cytometry, were assessed in relation to measures of blood glucose levels and renal function. RESULTS: Podocyte-derived microparticle excretion (MPE) normalised to urinary creatinine (MP/UCr) was higher in type 1 vs type 2 diabetes (median [IQR] MP/UCr: 7.88 [8.97] vs 1.84 [8.62]; p < 0.0001), despite the type 2 diabetes group having higher blood pressure (systolic blood pressure, median [range]: 124 [110-154] vs 114 [94-143] mmHg) and higher proportions of microalbuminuria (44.0% vs 13.2%), but shorter time since diabetes diagnosis (median [range]: 1.2 [0.0-7.0] vs 6.4 [2.0-13.9] years), than the type 1 diabetes cohort. MPE in youth with type 1 diabetes was associated with blood glucose (p = 0.01) and eGFR (p = 0.03) but not HbA1c, systolic or diastolic blood pressure or urine albumin/creatinine ratio. After adjustment for age at baseline, duration of diabetes, sex and BMI, the association with eGFR remained significant (p = 0.04). No associations were found between MPE and these clinical variables in youth with type 2 diabetes. CONCLUSIONS/INTERPRETATION: Significant associations between podocyte MPE, blood glucose levels and eGFR were observed in youth with type 1 diabetes but not in those with type 2 diabetes, notwithstanding increased renal pathology in the type 2 diabetes cohort. These findings suggest that podocyte injury differs in the two diabetes cohorts. Graphical abstract.

Experiences of First Nations adolescents living with type 2 diabetes: a focus group study.

BACKGROUND: Despite prevention efforts, type 2 diabetes mellitus continues to increase in incidence among First Nations children and is associated with early and aggressive complications. We aimed to determine the experiences of adolescents living with type 2 diabetes and the barriers to living well with type 2 diabetes that adolescents perceived. METHODS: We recruited adolescents with type 2 diabetes mellitus from the pediatric diabetes clinic in Winnipeg, Manitoba, to participate in a day-long facilitated focus group discussion. Group discussions were recorded and transcribed verbatim. We used interpretive description methodology to inform the thematic analysis of the transcripts. RESULTS: Eight adolescents with a mean age of 15 years participated. Five adolescents identified as female; most were Indigenous (7/8). The mean duration since diagnosis of diabetes was 2.5 years. Adolescents reported struggling with acceptance of their diagnosis, with the stigma and shame associated with the diagnosis and with daily self-management tasks. Three themes were developed from the focus group discussions: bearing witness, the "weight" of diabetes and support (lack of support). INTERPRETATION: Adolescents with diagnoses of type 2 diabetes experience associated stigma and shame, which are substantial barriers to self-care. A broader understanding of their lived experience, including the socioecological and emotional context, could help to improve health care provision and intervention strategies for this population.

Impact of a screen, triage and treat program for identifying chronic disease risk in Indigenous children.

BACKGROUND: The First Nations Community Based Screening to Improve Kidney Health and Prevent Dialysis project was a point-of-care screening program in rural and remote First Nations communities in Manitoba that aimed to identify and treat hypertension, diabetes and chronic kidney disease. The program identified chronic disease in 20% of children screened. We aimed to characterize clinical screening practices before and after intervention in children aged 10-17 years old and compare outcomes with those who did not receive the intervention. METHODS: This observational, prospective cohort study started with community engagement and followed the principles of ownership, control, access and possession (OCAP). We linked participant data to administrative data at the Manitoba Centre for Health Policy to assess rates of primary care and nephrology visits, disease-modifying medication prescriptions and laboratory testing (i.e., glycosylated hemoglobin [HbA1c], estimated glomerural filtration rate [eGFR] and urine albumin- or protein-to-creatinine ratio). We analyzed the differences in proportions in the 18 months before and after the intervention. We also conducted a 1:2 propensity score matching analysis to compare outcomes of children who were screened with those who were not. RESULTS: We included 324 of 353 children from the screening program (43.8% male; median age 12.3 yr) in this study. After the intervention, laboratory testing increased by 5.8% (95% confidence interval [CI] 1.1% to 10.1%) for HbA1c, by 9.9% (95% CI 4.2% to 15.5%) for eGFR and by 6.2% (95% CI 2.3% to 10.0%) for the urine albumin- or protein-to-creatinine ratio. We observed significant improvements in laboratory testing in screened patients in the group who were part of the program, compared with matched controls. INTERPRETATION: Chronic disease surveillance and care increased significantly in children after the implementation of a point-of-care screening program in rural and remote First Nation communities. Interventions such as active surveillance programs have the potential to improve the chronic disease care being provided to First Nations children.

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.

An evaluation of renin-angiotensin system markers in youth with type 2 diabetes and associations with renal outcomes.

AIMS/HYPOTHESIS: Youth with type 2 diabetes (T2D) have high rates of obesity, hypertension and suboptimal glycemic control. We hypothesized that renin-angiotensin system (RAS) activation is present in youth with T2D and associated with poor glycemic control and renal outcomes. METHODS: Cross-sectional analysis of 183 youth with T2D and 100 controls from the Improving renal Complications in Adolescents with T2D through REsearch cohort. Diabetes youth stratified by urine albumin:creatinine ratio (ACR) < or ≥2 mg/mmol. RAS levels measured with enzyme-linked immunosorbent assay (ELISA) and enzyme activities by synthetic substrates. In T2D, levels log transformed and Tobit linear regressions evaluated for associations with hemoglobin A1c (HbA1c), mean arterial pressure (MAP), estimated glomerular filtration rate (eGFR), ACR. RESULTS: Youth were 14 to 15 years, with diabetes duration 1.7 to 1.8 years; 21.3% albuminuria. Serum: differences in plasma renin activity (<0.0001), and angiotensin converting enzyme (ACE) activity (P = .003) in T2D vs controls. Urine: higher ACE activity and ACE2 protein/activity (all P < .0001) in T2D, higher levels in T2D with albuminuria. Multivariable regressions: higher serum ACE activity (ß = 0.03, SE 0.01;P < .01), urine ACE activity (ß = 0.44, SE 0.18;P < .01), ACE2 (ß = 0.51, SE 0.19;P < .01) positively associated with HbA1c; urine angiotensinogen (AGT) negatively associated (ß = -0.28 [SE 0.06;P < .01]). Higher serum aldosterone (ß = 0.11 [SE 0.04;P < .01]) and urine AGT (ß = 0.32 [SE 0.07;P < .01]) significantly associated with ACR and urine ACE2 (ß = 0.21 [SE 0.13;P < .03]). No associations between RAS markers and eGFR/MAP. CONCLUSIONS/INTERPRETATION: RAS activation present in youth with T2D and associated with higher HbA1c. Higher serum aldosterone and urine AGT associated with albuminuria. The prognostic significance of the combined effect of glycemia and RAS activation on renal outcomes requires additional investigation.

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.

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.

Gender dysphoria assessment and action for youth: Review of health care services and experiences of trans youth in Manitoba.

OBJECTIVES: To describe the paediatric transgender population accessing health care through the Manitoba Gender Dysphoria Assessment and Action for Youth (GDAAY) program, and report youth's experiences accessing health care in Manitoba. METHODS: Demographic, medical, surgical and mental health information was extracted from the medical records of youth referred to the GDAAY program (n=174). A 77-item online survey was conducted with a subset of those youth (n=25) to identify common health care experiences and perceptions of trans youth in Manitoba. RESULTS: Chart review of 122 natal females and 52 natal males, ranging in age from 4.7 to 17.8 years (mean 13.9 years), found 66 patients (46.8%) with a pre-existing or current mental health diagnosis, of which anxiety and depression were the most common (n=43, 30.5%). Qualitative self-reports revealed all patients had negative interactions with health care providers at some point, many having experienced lack of engagement with the medical system due to reported lack of knowledge by the provider on trans-related health services. CONCLUSION: Transgender youth in Manitoba seeking GDAAY services have high rates of anxiety and depression. These youth face adversity in health care settings and are distressed over long wait times for mental health services. Recommendations to improve care include increasing general health care providers' education on gender affirmative care, providing gender sensitivity training for health care providers, gathering preferred names and pronouns during triage, increasing visibility of support for LGBT+ persons in clinics, increasing resource allocation to this field and creating policies so all health care settings are safe places for trans youth.

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.

Increasing incidence of optic nerve hypoplasia/septo-optic dysplasia spectrum: Geographic clustering in Northern Canada.

INTRODUCTION: Owing to the shared embryonic origin, defects in development of optic nerves are often seen in conjunction with defects affecting the surrounding brain and pituitary gland. Optic nerve hypoplasia (ONH) and septo-optic dysplasia (SOD) represent a clinical spectrum associated with visual, pituitary and severe central nervous system structural abnormalities (SODplus). Based on changing clinical patterns, our primary objective was to examine trends in annual incidence of ONH/SOD and geographical clustering in Manitoba. METHODS: This was a retrospective 1996 to 2015 chart review with extraction of anthropometric measures, radiologic findings, parental characteristics, endocrinopathies and neurologic symptoms from all involved in care. Postal codes were used to assign map co-ordinates and identify relevant census-based deprivation indices. RESULTS: Ninety-three children were identified in our catchment area; Poisson regression confirmed a striking 1.11-fold annual increase (95% confidence interval 1.07 to 1.16) or ~800% over two decades. The annual incidence (averaged 2010 to 2014 chart data) reached 53.3 per 100,000, affecting 1 in 1875 live births. Most (~55%) had SODplus. Common presenting features were hypoglycemia, nystagmus, seizures and developmental delay; 40% had hormone deficiencies; 80% had reduced visual acuity, typically bilateral. Many were premature with young, primiparous mothers. Unhealthy maternal lifestyles and severe material deprivation were noted. There was disproportionate clustering in individuals from Northern Manitoba at three times the average provincial rate. CONCLUSION: We noted a dramatic rise in the annual incidence of ONH/SOD, which was strongly associated with poverty and northern communities. The pattern was consistent with environmental or nutritional etiologies. Many children were severely affected with increased morbidity and health care burdens.

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.

Impact of Vitamin D Supplementation on Gross Motor Development of Healthy Term Infants: A Randomized Dose-Response Trial.

UNLABELLED: In addition to benefits for bone health, vitamin D is implicated in muscle function in children and adults. AIMS: To determine if vitamin D dosage positively correlated with gross motor development at 3 and 6 months of age. We hypothesized that higher doses would be associated with higher scores for gross motor skills. METHODS: A consecutive sample of 55 healthy, term, and breastfed infants from Montreal, Canada were recruited from a randomized trial of vitamin D supplementation between 2009 and 2012. Infants were randomized to 400 International Units (IU) (n = 19), 800 IU (n = 18) or 1,200 IU (n = 18) vitamin D3/day. Motor performance at 3 and 6 months was quantified by the Alberta Infant Motor Scale (AIMS). Plasma vitamin D3 metabolites were measured by tandem mass spectrometry. RESULTS: AIMS scores did not differ at 3 months. However, total AIMS scores and sitting subscores were significantly higher at 6 months in infants receiving 400 IU/day compared to 800 IU/day and 1,200 IU/day groups (p < .05). There were weak negative correlations with length and C-3 epimer of 25(OH)D. CONCLUSIONS: In contrast to our hypothesis, gross motor achievements were significantly higher in infants receiving 400 IU/day vitamin D. Our findings also support longer infants being slightly delayed.

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.

Proposed trial: safety and efficacy of resveratrol for the treatment of non-alcoholic fatty liver disease (NAFLD) and associated insulin resistance in adolescents who are overweight or obese adolescents - rationale and protocol.

Non-alcoholic fatty liver (NAFL) disease (NAFLD) affects 30% of overweight adolescents and increases the risk of type 2 diabetes mellitus (T2D). Resveratrol is a naturally occurring compound with potential to reverse NAFL and its associated insulin resistance in adults. The use of resveratrol to reduce risk for T2D through its effect on NAFL has not been examined to date in youth. This paper provides a literature review and protocol for a 30 day proof of principle trial of resveratrol in a population of adolescents at risk for T2D. This randomized double-blind controlled trial is designed with the primary objective of evaluating a twice daily supplementation of 75 mg of resveratrol for safety and tolerability in overweight and obese adolescent subjects (13 to <18 years of age) with NAFL. Secondary objectives are to determine the effect size of the intervention on hepatic steatosis and whole body insulin sensitivity. Adolescents in the intervention arm (n = 10) will receive oral supplementation of resveratrol 75 mg twice daily (with breakfast and dinner) for a total daily dose of 150 mg for the duration of 30 days. The comparison group (n = 10) will receive a placebo twice daily for 30 days. Both cases and controls will receive a standardized lifestyle intervention program. Subjects in both groups will be followed for an additional 30 days post intervention for total study duration of approximately 60 days. Primary outcome measures include a primary side effect profile determined by participant interview, a side effect profile determined by serum biochemistry and vital signs. Secondary outcome measures include an oral glucose tolerance test, liver and cardiac fat content measured by magnetic resonance spectroscopy, anthropometric measures of overweight/obesity, inflammatory markers, and cardiac function and morphology measured with ultrasonography. Additional outcome measures include serum concentrations of resveratrol, compliance to protocol, physical activity, and nutritional assessment. This study will determine the safety and tolerability of resveratrol in an overweight adolescent population and inform the design of a larger randomized controlled trial.