Persistent Albuminuria in Children with Type 2 Diabetes: A Canadian Paediatric Surveillance Program Study.

OBJECTIVE: To determine the prevalence and the clinical features associated with persistent albuminuria in Canadian children aged <18 years with type 2 diabetes. STUDY DESIGN: This national prospective surveillance study involved a network of pediatricians and pediatric endocrinologists. Cases of persistent albuminuria in children with type 2 diabetes were reported during a 24-month period from 2010 to 2012. Persistent albuminuria was defined as an elevated albumin-to-creatinine ratio in a minimum of 2 out of 3 urine samples obtained at least 1 month apart over 3-6 months and confirmed with a first morning sample. Descriptive statistics were used to illustrate demographic and clinical features of the population. The prevalence of persistent albumuria was estimated using data from a previous national surveillence study of type 2 diabetes in children. RESULTS: Fifty cases were reported over the 24-month study period. The estimated prevalence of persistent albuminuria in children with type 2 diabetes in Canada was 5.1%. The median duration of diabetes at the time of diagnosis of albuminuria was 21 days (IQR, 0-241 days). Almost two-thirds (64%) were female, 80% were of Canadian First Nations heritage, and 76% were from Manitoba. Exposure to gestational or pregestational diabetes in utero occurred in 65%, and 48% had a family history of diabetes-related renal disease. Structural anomalies of the kidney were found in 37%. CONCLUSION: Persistent albuminuria occurs in youths with type 2 diabetes in the first year after diagnosis, demonstrates regional variation, and is associated with First Nations heritage and exposure to maternal diabetes during pregnancy.

Children have type 2 diabetes too: an historical perspective.

Prior to 1985, type 2 diabetes was a disease of adults. Simultaneously with the global epidemic of childhood obesity, type 2 diabetes has increased in children. Initially, the presentation of small case series of type 2 diabetes in children was met with skepticism. As the number and size of the case series grew and the first long-term outcomes of end-stage complications in young adults appeared in the literature, the international community took notice with guarded interest. Type 2 diabetes disproportionately affects the children of specific ethnic groups and from disadvantaged socioeconomic environments, especially Indigenous populations. The past decade has seen unprecedented intense global interest in the etiology, treatment, and prevention of type 2 diabetes in children.

Maternal diabetes mellitus and congenital anomalies of the kidney and urinary tract (CAKUT) in the child.

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of chronic kidney disease in children. The relevance of timing of diabetes mellitus (DM) exposure on risk of CAKUT in exposed children is unknown. STUDY DESIGN: Population-based nested case-control study. SETTING & PARTICIPANTS: Infants born between fiscal years 1996/1997 and 2009/2010 in Manitoba, Canada, identified using administrative data housed at the Manitoba Centre for Health Policy. PREDICTORS: Pregestational (including first 20 weeks' gestation) and gestational (>20 weeks) DM and relevant confounders (maternal age; renin-angiotensin-aldosterone system inhibitor use; low socioeconomic status; alcohol, illicit drug, and smoking use during pregnancy; region of residence; and size for gestational age [surrogate of glycemic control]). OUTCOME: CAKUT identified by International Classification of Diseases codes. RESULTS: 945 case patients with CAKUT and 4,725 controls (matched for gestational age, sex, and birth year) were identified. Maternal pregestational DM occurred in 39 (4.1%) of the CAKUT group and 111 (2.3%) controls (P = 0.002), whereas gestational DM occurred in 40 (4.2%) of the CAKUT group and 157 (3.3%) controls (P = 0.2). In the conditional multivariable logistic regression model, pregestational DM was associated with CAKUT (OR, 1.67; 95% CI, 1.14-2.46), whereas gestational DM was not (OR, 1.29; 95% CI, 0.90-1.85). Both large (LGA) and small for gestational age (SGA) also were associated significantly with CAKUT (LGA: OR, 1.34 [95% CI, 1.11-1.63]; SGA: OR, 1.59 [95% CI, 1.26-2.01]). LIMITATIONS: Lack of data for maternal glycemic control and body mass index. CONCLUSIONS: This study suggests that DM in the first 20 weeks of pregnancy is associated with CAKUT in exposed infants. The association between CAKUT and LGA suggests that poor glycemic control increases risk. Screening and intervention studies in women of childbearing age with DM are warranted to determine whether the risk of chronic kidney disease in children can be modified.

Effects of lifestyle intervention on dietary intake, physical activity level, and gestational weight gain in pregnant women with different pre-pregnancy Body Mass Index in a randomized control trial.

BACKGROUND: The objectives of this study were to assess the efficacy of lifestyle intervention on gestational weight gain in pregnant women with normal and above normal body mass index (BMI) in a randomized controlled trial. METHODS: A total of 116 pregnant women (<20 weeks of pregnancy) without diabetes were enrolled and 113 pregnant women completed the program. Participants were randomized into intervention and control groups. Women in the intervention group received weekly trainer-led group exercise sessions, instructed home exercise for 3-5-times/week during 20-36 weeks of gestation, and dietary counseling twice during pregnancy. Participants in the control group did not receive the intervention. All participants completed a physical activity questionnaire and a 3-day food record at enrolment and 2 months after enrolment. RESULTS: The participants in the intervention group with normal pre-pregnancy BMI (≤24.9 kg/M2, n = 30) had lower gestational weight gain (GWG), offspring birth weight and excessive gestational weight gain (EGWG) on pregnancy weight gain compared to the control group (n = 27, p < 0.05). Those weight related-changes were not detected between the intervention (n = 27) and control group (n = 29) in the above normal pre-pregnancy BMI participants. Intervention reduced total calorie, total fat, saturated fat and cholesterol intake were detected in women with normal or above normal pre-pregnancy BMI compared to the control group (p < 0.05 or 0.01). Increased physical activity and reduced carbohydrate intake were detected in women with normal (p < 0.05), but not above normal, pre-pregnancy BMI at 2 months after the onset of the intervention compared to the control group. CONCLUSION: The results of the present study demonstrated that the lifestyle intervention program decreased EGWG, GWG, offspring birth weight in pregnant women with normal, but not above normal, pre-pregnancy BMI, which was associated with increased physical activity and decreased carbohydrate intake. TRIAL REGISTRATION: NCT00486629.

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

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

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

Quality of life in First Nation youth with type 2 diabetes.

To assess quality of life (QOL) in youth with type 2 diabetes, to compare youth and parent-proxy perceptions of youth QOL, to determine if youth QOL is associated with diabetes control, and to determine if demographic and/or medical history is associated with youth QOL and/or diabetes control. The study was quantitative and cross-sectional with a descriptive correlational approach. We administered the Pediatric QOL Inventory 4.0 (PedsQL 4.0) and the Pediatric QOL 3.0 Diabetes Module (PedsQL 3.0) questionnaires to 28 youth with type 2 diabetes aged 7-18 and their parents attending a regional diabetes program in Winnipeg, Manitoba that serves a large geographic region of central Canada. We examined QOL scores for the generic and diabetes specific tools, and for correlation between the child and parent scores. We examined youth QOL scores along with medical and family history variables for their predictive value on diabetes control as measured by the glycosylated hemoglobin A1C value. Youth with type 2 diabetes reported higher scores in all domains of the generic and diabetes-specific tools compared to their parent report, indicating that the youth were more optimistic about their health-related QOL than their parents. The youth and their parents reported lowest QOL scores in the school-functioning, Worry and Communications scales related to diabetes. Living in remote communities, family experience with complications of diabetes, duration of diabetes, high A1C, and oral medications (but not insulin) had a negative impact on specific domains. First Nation youth with type 2 diabetes have a higher QOL than is perceived by their parents. QOL may be affected by specific demographic and clinical factors that may be modifiable to reduce the psychosocial burden of illness. These findings have implications for designing counseling strategies for adolescents with type 2 diabetes and their parents.

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.

Breastfeeding Initiation Associated With Reduced Incidence of Diabetes in Mothers and Offspring.

OBJECTIVE: To examine associations between breastfeeding initiation and subsequent diabetes among First Nations (indigenous people in Canada who are not Métis or Inuit) and non-First Nations mothers and their offspring with and without gestational diabetes mellitus (GDM). METHODS: This retrospective database study included 334,553 deliveries (1987-2011) in Manitoba with up to 24 years of follow-up for diabetes using population-based databases. Information of breastfeeding initiation before hospital discharge was obtained from hospital abstracts recorded by nurses in postpartum wards. Cox proportional hazard models were applied to examine the association between breastfeeding initiation and risk of diabetes in mothers and their offspring. RESULTS: Breastfeeding initiation was recorded in 83% of non-First Nations mothers and 56% of First Nations mothers (P<.001). Breastfeeding initiation was associated with a reduced risk of incident (later developed) diabetes in non-First Nations mothers without GDM (hazard ratio [HR] 0.73 [or -27% of risk], 95% confidence interval [CI] 0.68-0.79), non-First Nations mothers with GDM (HR 0.78 or -22% of risk, CI 0.69-0.89), First Nations mothers without GDM (HR 0.89 or -11% of risk, CI 0.81-0.98), and First Nations mothers with GDM (HR 0.82 or -18% of risk, CI 0.73-0.92) with 24 years of follow-up or less. With 24 years of follow-up or less, breastfeeding initiation was associated with a 17% lower risk of youth-onset type 2 diabetes in offspring (HR 0.83, CI 0.69-0.99, P=.038). The association between breastfeeding initiation and subsequent diabetes in mothers and offspring was independent of family income, rural residence, First Nations status, GDM, parity, gestational hypertension, and age of the mother. CONCLUSION: Breastfeeding initiation is associated with a reduced risk of diabetes among women and their offspring in Manitoba. The results suggest that breastfeeding might be a potentially modifiable factor to reduce the risk of diabetes in both First Nations and non-First Nations women and children.

Exposure to Gestational Diabetes Mellitus: Impact on the Development of Early-Onset Type 2 Diabetes in Canadian First Nations and Non-First Nations Offspring.

OBJECTIVE: Type 2 diabetes is increasing in children worldwide, with Canadian First Nations (FN) children disproportionally affected. The prevalence of gestational diabetes mellitus (GDM) also is increasing. The objective of this study was to evaluate the impact of GDM exposure in utero and FN status on the subsequent risk of type 2 diabetes in offspring in the first 30 years of life. RESEARCH DESIGN AND METHODS: In this population-based historical prospective cohort study, we used administrative databases linked to a clinical database to explore the independent association and interaction between GDM and FN status on the subsequent development of type 2 diabetes in offspring. RESULTS: Among 321,008 births with a median follow-up of 15.1 years, both maternal GDM and FN status were independently associated with subsequent risk of type 2 diabetes in offspring in the first 30 years of life (hazard ratio 3.03 [95% CI 2.44-3.76; P < 0.0001] vs. 4.86 [95% CI 4.08-5.79; P < 0.0001], respectively). No interaction between GDM and FN status on type 2 diabetes risk was observed. FN status had a stronger impact on the development of type 2 diabetes in offspring than GDM. CONCLUSIONS: GDM is an important modifiable risk factor for type 2 diabetes, and its prevention may reduce the prevalence of subsequent type 2 diabetes in offspring. This study adds unique and rigorous evidence to the global public health debate about the impact of GDM on the long-term health of offspring.

The prevalence of the HNF-1alpha G319S mutation in Canadian aboriginal youth with type 2 diabetes.

OBJECTIVE: To investigate the prevalence of the unique HNF-1alpha G319S mutation in a population of aboriginal youth with type 2 diabetes and to describe the relationship between clinical and historical characteristics and the presence or absence of the HNF-1alpha G319S mutation. RESEARCH DESIGN AND METHODS: Participating youth were genotyped for the G319S mutation of the HNF-1alpha gene. Clinical, laboratory, and historical data were collected via chart review (blinded to genotype results). Comparison data were derived from another study involving young nondiabetic pregnant aboriginal women. RESULTS: A total of 51 youth seen sequentially in a type 2 diabetes clinic participated in this study. Of these, 21 (41.2%) had at least one copy of the mutant allele. The allele frequency in the study population was 0.29 (95% CI 0.20-0.38), which was significantly different from the allele frequency of 0.13 in the comparison population (chi(2) = 6.78, P = 0.009). The frequency of the homozygous mutation (S319/S319) was 0.18. Mean BMI was significantly lower (P = 0.002), mean HbA(1c) was significantly higher (P = 0.02), and acanthosis nigricans was significantly less frequent (P = 0.004) in those with the mutation compared with the wild type. Mean insulin levels were lower and insulin sensitivity (assessed by homeostasis model assessment [HOMA]) was greater in the homozygote group compared with the wild-type group (P = 0.002 and P = 0.0007, respectively). A dose-dependent gradient was observed for these characteristics. CONCLUSIONS: These data support the association between the HNF-1alpha G319S mutation and early-onset type 2 diabetes in this population. Those with the mutation lacked clinical characteristics of insulin resistance (e.g., obesity and acanthosis nigricans) and had lower insulin levels, suggesting that an insulin-secretory and/or -production defect plays an important role in the development of diabetes in this group. Further investigation of the pathophysiology of the S319 homo- and heterozygote is needed because it may impact treatment and/or prevention of this disease.

Type 2 diabetes mellitus in children: prenatal and early infancy risk factors among native canadians.

BACKGROUND: Type 2 diabetes mellitus is increasingly being observed among children and youth, including the Native population of Canada. Only one study has investigated prenatal and early infancy risk factors for the disease. METHODS: A case-control study was conducted; 46 patients younger than 18 years were recruited from the only clinical center for the treatment of diabetes serving the province of Manitoba, and 92 age- and sex-matched controls were recruited from a pediatric ambulatory clinic serving a large Native population in Winnipeg, Manitoba. Information on exposure to prenatal and early infancy risk factors was obtained through questionnaires administered by a Native nurse-interviewer. RESULTS: Multiple logistic regression modeling identified preexisting diabetes (odds ratio [OR], 14.4; 95% confidence interval [CI], 2.86-72.5), gestational diabetes (OR, 4.40; 95% CI, 1.38-14.1), and breastfeeding longer than 12 months (OR, 0.24; 95% CI, 0.13-0.99) as significant independent predictors of diabetic status. Other factors, such as low (<2500 g) and high (>4000 g) birth weight and maternal obesity, were also associated with diabetes in our population, but the elevated risks were not statistically significant. CONCLUSION: Breastfeeding reduces the risk of type 2 diabetes among Native Canadian children and should be promoted as a potential intervention to control the disease.

Markers of platelet activation are increased in adolescents with type 2 diabetes.

OBJECTIVE: In adults with diabetes, in vivo platelet activation is a marker for atherosclerosis and cardiovascular disease (CVD). This pilot study investigated whether adolescents with diabetes had evidence of increased in vivo platelet activation. RESEARCH DESIGN AND METHODS: In vivo platelet activation was compared in four groups of age-matched adolescents: type 1 diabetes (T1D, n = 15), type 2 diabetes (T2D; n = 15), control subjects with normal BMI (n = 14), and overweight/obese control subjects (n = 13). Platelet surface activation markers and plasma levels of soluble activation markers were measured and compared among groups. RESULTS: Increased expression of all activation markers was observed in T2D compared with either control group (P < 0.05); levels of soluble markers were also higher in T2D than in T1D (P < 0.05). There were no differences in marker expression between the nondiabetic control groups. CONCLUSIONS: Platelet activation in adolescents with T2D may be a marker for the risk of CVD development in early adulthood.

Earlier onset of complications in youth with type 2 diabetes.

OBJECTIVE: To evaluate the risk of complications in youth with type 2 diabetes. RESEARCH DESIGN AND METHODS: Population-based cohorts of 342 youth (1-18 years of age) with prevalent type 2 diabetes, 1,011 youth with type 1 diabetes, and 1,710 nondiabetic control youth were identified between 1986 and 2007 from a clinical registry and linked to health care records to assess long-term outcomes using ICD-9CM and ICD-10CA codes. RESULTS: Youth with type 2 diabetes had an increased risk of any complication (hazard ratio 1.47 [95% CI 1.02-2.12]). Significant adverse clinical factors included age at diagnosis (1.08 [1.02-2.12]), HbA1c (1.06 [1.01-1.12]), and, surprisingly, renin-angiotensin-aldosterone system (RAAS) inhibitor use (1.75 [1.27-2.41]). HNF-1α G319S polymorphism was protective in the type 2 diabetes cohort (0.58 [0.34-0.99]). Kaplan-Meier statistics revealed an earlier diagnosis of renal and neurologic complications in the type 2 diabetes cohort, manifesting within 5 years of diagnosis. No difference in retinopathy was seen. Cardiovascular and cerebrovascular diseases were rare; however, major complications (dialysis, blindness, or amputation) started to manifest 10 years after diagnosis in the type 2 diabetes cohort. Youth with type 2 diabetes had higher rates of all outcomes than nondiabetic control youth and an overall 6.15-fold increased risk of any vascular disease. CONCLUSIONS: Youth with type 2 diabetes exhibit complications sooner than youth with type 1 diabetes. Younger age at diagnosis is potentially protective, and glycemic control is an important modifiable risk factor. The unexpected adverse association between RAAS inhibitor use and outcome is likely a confounder by indication; however, further evaluation in young people is warranted.

Elements and enablers for interprofessional education clinical placements in diabetes teams.

OBJECTIVE: The purpose of this review is to describe the elements and enablers for interprofessional education (IPE) clinical placements in diabetes teams. METHODS: We describe the development of an IPE clinical placement for health professional students in a diabetes team and share the lessons learned over 6 years, from 2008 to 2013. The 6 collaborative practice competencies of the Canadian Interprofessional Health Collaborative and the requirements for Accreditation of Interprofessional Health Professional Education opportunities guided the development of an IPE clinical placement in a diabetes team. RESULTS: A formal IPE clinical placement in diabetes teams requires attention to the site and diabetes team-specific elements and enablers for IPE. That includes students and preceptors from 2 or more health professions, a formal curriculum on collaborative care, adequate IPE resources and strong institutional support for a culture of collaborative care and integration of students in diabetes teams. CONCLUSIONS: Diabetes teams can provide a valuable IPE opportunity for health professional students, recognizing that there are challenges that must be addressed in organizational structure of clinical placements in diabetes teams. Studies of the effectiveness of IPE in diabetes teams on collaboration competencies in future diabetes healthcare professionals and long-term patient outcomes are needed.

The Improving Renal Complications in Adolescents With Type 2 Diabetes Through the REsearch (iCARE) Cohort Study: rationale and Protocol.

BACKGROUND: Youth-onset type 2 diabetes is associated with a high burden of renal complications, culminating with end stage kidney disease in early adulthood. The establishment of relevant bioclinical determinants of albuminuria and ultimately progression of chronic kidney disease in youth is critically important to facilitate patient risk stratification and aid in the development of treatment targets and tailored prevention strategies. In response to the important gaps in knowledge, we created a prospective cohort study of youth with type 2 diabetes titled the Improving Renal Complications in Adolescents with Type 2 Diabetes through the REsearch (iCARE) Study. METHODS: iCARE is a prospective observational cohort study of individuals with type 2 diabetes diagnosed prior to 18 years of age; the recruitment target was 400 patients. Phase 1 entailed a detailed phenotypic assessment of youth, including anthropometrics, biochemistry, 24-hour ambulatory blood pressure monitoring, overnight urine collections for albumin excretion, renal ultrasound and iohexol-derived glomerular filtration rate. Phase 2 of the study is an evaluation of psychological factors, including hair-derived cortisol; validated questionnaires for perceived stress, distress and resiliency; and a detailed evaluation of systemic and urine inflammatory biomarkers. Annual follow up is planned to assess temporal associations between clinical risk factors and renal outcomes, including progression of albuminuria. CONCLUSION: This study will provide novel insight into the risk factors for albuminuria and progression of chronic kidney disease in youth with type 2 diabetes. New knowledge generated by this study will inform clinical care, and the infrastructure developed will provide a framework for future intervention studies.

Dietary determinants of hepatic steatosis and visceral adiposity in overweight and obese youth at risk of type 2 diabetes.

BACKGROUND: Dietary determinants of hepatic steatosis, an important precursor for nonalcoholic fatty liver disease, are undefined. OBJECTIVE: We explored the roles of sugar and fat intake as determinants of hepatic steatosis and visceral obesity in overweight adolescents at risk of type 2 diabetes. DESIGN: This was a cross-sectional study of dietary patterns and adipose tissue distribution in 74 overweight adolescents (aged: 15.4 ± 1.8 y; body mass index z score: 2.2 ± 0.4). Main outcome measures were hepatic steatosis (≥5.5% fat:water) measured by magnetic resonance spectroscopy and visceral obesity (visceral-to-subcutaneous adipose tissue ratio ≥0.25) measured by magnetic resonance imaging. Main exposure variables were dietary intake and habits assessed by the Harvard Youth Adolescent Food Frequency Questionnaire. RESULTS: Hepatic steatosis and visceral obesity were evident in 43% and 44% of the sample, respectively. Fried food consumption was more common in adolescents with hepatic steatosis than in adolescents without hepatic steatosis (41% compared with 18%; P = 0.04). Total fat intake (ß = 0.51, P = 0.03) and the consumption of >35% of daily energy intake from fat (OR: 11.8; 95% CI: 1.6, 86.6; P = 0.02) were both positively associated with hepatic steatosis. Available carbohydrate (ß = 0.54, P = 0.02) and the frequent consumption of soda were positively associated with visceral obesity (OR: 6.4; 95% CI: 1.2, 34.0; P = 0.03). Daily fiber intake was associated with reduced odds of visceral obesity (OR: 0.82; 95% CI: 0.68, 0.98; P = 0.02) but not hepatic steatosis. CONCLUSION: Hepatic steatosis is associated with a greater intake of fat and fried foods, whereas visceral obesity is associated with increased consumption of sugar and reduced consumption of fiber in overweight and obese adolescents at risk of type 2 diabetes.

Preliminary analysis of immune activation in early onset type 2 diabetes.

INTRODUCTION: First Nations and other Aboriginal children are disproportionately affected by cardiometabolic diseases, including type 2 diabetes (T2D). In T2D, the disruption of insulin signalling can be driven by pro-inflammatory immunity. Pro-inflammatory responses can be fueled by toll-like receptors (TLR) on immune cells such as peripheral blood mononuclear cells (PBMC, a white blood cell population). TLR4 can bind to lipids from bacteria and food sources activating PBMC to produce cytokines tumour necrosis factor (TNF)-α and interleukin (IL)-1ß. These cytokines can interfere with insulin signalling. Here, we seek to understand how TLR4 activation may be involved in early onset T2D. We hypothesized that immune cells from youth with T2D (n = 8) would be more reactive upon TLR4 stimulation relative to cells from age and body mass index (BMI)-matched controls without T2D (n = 8). METHODS: Serum samples were assayed for adipokines (adiponectin and leptin), as well as cytokines. Freshly isolated PBMC were examined for immune reactivity upon culture with TLR4 ligands bacterial lipopolysaccharide (LPS, 2 and 0.2 ng/ml) and the fatty acid palmitate (200 µM). Culture supernatants were evaluated for the amount of TNF-α and IL-1ß produced by PBMC. RESULTS: Youth with T2D displayed lower median serum adiponectin levels compared to controls (395 vs. 904 ng/ml, p < 0.05). PBMC isolated from youth with and without T2D produced similar levels of TNF-α and IL-1ß after exposure to the higher LPS concentration. However, at the low LPS dose the T2D cohort exhibited enhanced IL-1ß synthesis relative to the control cohort. Additionally, exposure to palmitate resulted in greater IL-1ß synthesis in PBMCs isolated from youth with T2D versus controls (p < 0.05). These differences in cytokine production corresponded to greater monocyte activation in the T2D cohort. CONCLUSION: These preliminary results suggest that cellular immune responses are exaggerated in T2D, particularly with respect to IL-1ß activity. These studies aim to improve the understanding of the biology behind early onset T2D and its vascular complications that burden First Nations people.

Developmental origins of type 2 diabetes in aboriginal youth in Canada: it is more than diet and exercise.

Type 2 diabetes mellitus (T2DM) is classically viewed as a disease of adults caused by poor nutrition, physical inactivity, and obesity. However, with increasing awareness of the heterogeneity of T2DM, new risk factors are being identified that add complexity. Some of these new risk factors have been identified in Canadian people with Aboriginal Oji-Cree heritage, a group that demonstrates one of the highest rates of T2DM in the world. This high prevalence may be due to the rapid change, over the past 50 years, away from their traditional way of life on the land. Another environmental change is the increased rate of pregnancies complicated by obesity, gestational diabetes, or T2DM, resulting in more children being exposed to an abnormal intrauterine environment. Furthermore, the Oji-Cree of central Canada possesses the unique HNF-1α G319S polymorphism associated with reduced insulin secretion. We propose that intrauterine exposure to maternal obesity and T2DM, associated with the HNF-1α G319S polymorphism, results in fetal programming that accelerates the progression of early-onset T2DM. This paper describes the evolution of T2DM in children with a focus on the Oji-Cree people over the past 25 years and the unique prenatal and postnatal gene-environment interaction causing early-onset T2DM.