Brandy Wicklow

Metabolic Consequences of Hepatic Steatosis in Overweight and Obese Adolescents

OBJECTIVE To test the hypothesis that hepatic steatosis is associated with risk factors for type 2 diabetes in overweight and obese youth, mediated by cardiorespiratory fitness. RESEARCH DESIGN AND METHODS This was a cross-sectional study comparing insulin sensitivity between 30 overweight and obese adolescents with hepatic steatosis, 68 overweight and obese adolescents without hepatic steatosis, and 11 healthy weight adolescents without hepatic steatosis. Cardiorespiratory fitness was determined by a graded maximal exercise test on a cycle ergometer. Secondary outcomes included presence of metabolic syndrome and glucose response to a 75-g oral glucose challenge. RESULTS The presence of hepatic steatosis was associated with 55% lower insulin sensitivity (P = 0.02) and a twofold greater prevalence of metabolic syndrome (P = 0.001). Differences in insulin sensitivity (3.5 vs. 4.5 mU ⋅ kg−1 ⋅ min−1, P = 0.03), prevalence of metabolic syndrome (48 vs. 20%, P = 0.03), and glucose area under the curve (816 vs. 710, P = 0.04) remained between groups after matching for age, sex, and visceral fat. The association between hepatic steatosis and insulin sensitivity (β = −0.24, t = −2.29, P < 0.025), metabolic syndrome (β = −0.54, t = −5.8, P < 0.001), and glucose area under the curve (β = 0.33, t = 3.3, P < 0.001) was independent of visceral and whole-body adiposity. Cardiorespiratory fitness was not associated with hepatic steatosis, insulin sensitivity, or presence of metabolic syndrome. CONCLUSIONS Hepatic steatosis is associated with type 2 diabetes risk factors independent of cardiorespiratory fitness, whole-body adiposity, and visceral fat mass.

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 (β = 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 (β = 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.

Cardiorespiratory fitness and adiposity in metabolically healthy overweight and obese youth.

OBJECTIVE: Controversy exists surrounding the contribution of fitness and adiposity as determinants of the Metabolically Healthy Overweight (MHO) phenotype in youth. This study investigated the independent contribution of cardiorespiratory fitness and adiposity to the MHO phenotype among overweight and obese youth. METHODS: This cross-sectional study included 108 overweight and obese youth classified as MHO (no cardiometabolic risk factors) or non-MHO (≥1 cardiometabolic risk factor), based on age- and gender-specific cut-points for fasting glucose, triglycerides, high-density lipoprotein cholesterol, systolic and diastolic blood pressure, and hepatic steatosis. RESULTS: Twenty-five percent of overweight and obese youth were classified as MHO. This phenotype was associated with lower BMI z-score (BMI z-score: 1.8 ± 0.3 vs 2.1 ± 0.4, P = .02) and waist circumference (99.7 ± 13.2 vs 106.1 ± 13.7 cm, P = .04) compared with non-MHO youth. When matched for fitness level and stratified by BMI z-score (1.6 ± 0.3 vs 2.4 ± 0.2), the prevalence of MHO was fourfold higher in the low BMI z-score group (27% vs 7%; P = .03). Multiple logistic regression analyses revealed that the best predictor of MHO was the absence of hepatic steatosis even after adjusting for waist circumference (odds ratio 0.57, 95% confidence interval 0.40–0.80) or BMI z-score (odds ratio 0.59, 95% confidence interval 0.43–0.80). CONCLUSIONS: The MHO phenotype was present in 25% of overweight and obese youth and is strongly associated with lower levels of adiposity, and the absence of hepatic steatosis, but not with cardiorespiratory fitness.

Hepatic Steatosis and Low Cardiorespiratory Fitness in Youth With Type 2 Diabetes

The purpose of this study was to examine the association between cardiorespiratory fitness, ectopic triglyceride accumulation, and insulin sensitivity among youth with and without type 2 diabetes. Subjects included 137 youth ages 13–18 years including 27 with type 2 diabetes, 97 overweight normoglycemic controls, and 13 healthy weight normoglycemic controls. The primary outcome measure was cardiorespiratory fitness defined as peak oxygen uptake indexed to fat free mass. Secondary outcomes included liver and muscle triglyceride content determined by 1H‐magnetic resonance spectroscopy and insulin sensitivity determined by frequently sampled intravenous glucose tolerance test. Despite similar measures of adiposity, peak oxygen uptake was 11% lower (38.9 ± 7.9 vs. 43.9 ± 6.1 ml/kgFFM/min, P = 0.002) and hepatic triglyceride content was nearly threefold higher (14.4 vs. 5.7%, P = 0.001) in youth with type 2 diabetes relative to overweight controls. In all 137 youth, cardiorespiratory fitness was negatively associated with hepatic triglyceride content (r = −0.22, P = 0.02) and positively associated with insulin sensitivity (r = 0.29, P = 0.002) independent of total body and visceral fat mass. Hepatic triglyceride content was also negatively associated with insulin sensitivity (r = −0.35, P < 0.001), independent of adiposity, sex, age, and peak oxygen uptake. This study demonstrated that low cardiorespiratory fitness and elevated hepatic triglyceride content are features of type 2 diabetes in youth. Furthermore, cardiorespiratory fitness and hepatic triglyceride are associated with insulin sensitivity in youth. Taken together, these data suggest that cardiorespiratory fitness and hepatic steatosis are potential clinical biomarkers for type 2 diabetes among youth.

Feasibility of a type 1 diabetes primary prevention trial using 2000 IU vitamin D3 in infants from the general population with increased HLA-associated risk.

Abstract:  Recent epidemiologic, immunologic, and NOD mouse studies suggest that intervention in the vitamin D system may be a successful method to prevent type 1 diabetes. Newborns at increased HLA‐associated risk are randomized to receive either 400 or 2000 IU vitamin D3 by 1 month of age. We show that recruitment of babies from the general population for identification of HLA‐associated risk status followed by enrollment to a randomized controlled prevention trial is feasible in Canada.

Vigorous intensity exercise for glycemic control in patients with type 1 diabetes.

Regular physical activity has substantial health benefits in persons with type 1 diabetes, including reduced risk of complications and cardiovascular mortality as well as improved self-rated quality of life. Despite these benefits, individuals with type 1 diabetes are often less active than their peers without diabetes. When factors such as time constraints, work pressure and environmental conditions are often cited as barriers to physical activity in the general population, 2 additional major factors may also explain the low rates of physical activity in young people with type 1 diabetes: (1) fear of hypoglycemia both during and after (particularly overnight) exercise and (2) a lack of empiric evidence for the efficacy of physical activity for achieving optimal glycemic control. A number of acute exercise trials recently showed that the inclusion of vigorous intensity physical activity in conventional moderate intensity (i.e. walking and light cycling) exercise sessions may overcome these barriers. No studies have tested the efficacy of high-intensity physical activity on glycemic control (A1C) or post-exercise hypoglycemia in a randomized controlled trial. This article summarizes the literature related to the role of physical activity for the management of blood glucose levels in individuals with type 1 diabetes and provides a rationale for the need of a randomized controlled trial examining the effects of vigorous-intensity physical activity on blood glucose control.

Lifestyle Therapy for the Treatment of Youth with Type 2 Diabetes

Type 2 diabetes (T2D) in youth is a relatively novel condition facing paediatric health care providers. Few experimental trials exist to guide clinical management in this population. Supporting and prescribing modifiable lifestyle behaviours is cornerstone in the management of T2D in adults. Clinical trials in obese adolescents suggest that intensive lifestyle interventions that include both dietary changes and increased physical activity elicit clinically meaningful reductions in weight and improve cardiovascular risk profiles. Observational studies in youth with T2D suggest that better diet quality and increased physical activity are associated with better metabolic control; however, the limited experimental data available does not support these observations. Trials evaluating lifestyle monotherapy for the treatment of hyperglycaemia in youth with T2D do not exist, and the only study evaluating combined lifestyle and pharmacologic therapy did not show additional benefit over pharmacologic treatment with metformin alone. Physiological and psychosocial differences between youth and adults with T2D likely contribute to the differences in the effectiveness of lifestyle therapy for improving glycaemic control. The current review describes these topics in detail and provides recommendations for paediatric health care providers for the promotion of lifestyle therapy for the management of hyperglycaemia and cardiovascular risk factors for youth with T2DM.

Biopsy-proven acute tubular necrosis in a child attributed to vancomycin intoxication

Acute renal failure in children treated with vancomycin typically presents with interstitial nephritis. There is debate as to the extent of direct tubular toxicity attributable to vancomycin, especially in the absence of aminoglycoside treatment. We report a case of acute tubular necrosis (ATN) associated with vancomycin toxicity in an 8-year-old boy where there is no likely alternate explanation for toxic or ischemic injury. Treatment with hemodialysis resulted in the elimination of vancomycin from the circulation and subsequent improvement in renal function.

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)-1β. 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-1β 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-1β after exposure to the higher LPS concentration. However, at the low LPS dose the T2D cohort exhibited enhanced IL-1β synthesis relative to the control cohort. Additionally, exposure to palmitate resulted in greater IL-1β 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-1β activity. These studies aim to improve the understanding of the biology behind early onset T2D and its vascular complications that burden First Nations people.

Severe subacute GM2 gangliosidosis caused by an apparently silent HEXA mutation (V324V) that results in aberrant splicing and reduced HEXA mRNA

We have characterized the molecular basis of β‐hexosaminidase A (HEX A) deficiency in a patient ascertained through an ophthalmologic examination that revealed cherry red spots on his retina. The absence of neurological deficit in this child until 3