Statin Therapy in Children

Landmark studies such as the Bogalusa Heart study, Pathobiological Determinants of Atherosclerosis in Youth study, and Muscatine and Young Finns studies established that the atherosclerotic process begins in childhood. Early precursors of atherosclerosis may increase risk of cardiovascular morbidity in adulthood. Follow-up studies of children with familial homozygous hypercholesterolemia showed that initiation of statin therapy slowed the progression of carotid intima-media thickness and reduced cardiovascular disease risk. Despite the growing evidence on the efficacy of statins and a rising prevalence of dyslipidemia, there are concerns regarding long-term safety and efficacy. Moreover, data on statin use in children with secondary dyslipidemia are sparse. This chapter provides a comprehensive review of the current state of literature on the indications, contraindications, efficacy and safety data on the use of statins in pediatric dyslipidemia

Role of Vitamin D in Insulin Secretion and Insulin Sensitivity for Glucose Homeostasis

Vitamin D functions are not limited to skeletal health benefits and may extend to preservation of insulin secretion and insulin sensitivity. This review summarizes the literature related to potential vitamin D influences on glucose homeostasis and insulin sensitivity. Cross-sectional data provide some evidence that circulating 25-hydroxyvitamin D (25(OH)D) is inversely associated with insulin resistance, although direct measurements of insulin sensitivity are required for confirmation. Reported associations with insulin secretion, however, are contradictory. Available prospective studies support a protective influence of high 25(OH)D concentrations on type 2 diabetes mellitus risk. There is a general lack of consistency in vitamin D intervention outcomes on insulin secretion and sensitivity, likely due to differences in subject populations, length of interventions, and forms of vitamin D supplementation. Vitamin D receptor gene polymorphisms and vitamin D interactions with the insulin like growth factor system may further influence glucose homeostasis. The ambiguity of optimal vitamin D dosing regimens and optimal therapeutic concentrations of serum 25(OH)D limit available intervention studies. Future studies, including cross-sectional and prospective, should be performed in populations at high risk for both vitamin D deficiency and type 2 diabetes mellitus. Well-designed, placebo-controlled, randomized intervention studies are required to establish a true protective influence of vitamin D on glucose homeostasis

Dietary iron intake in the first 4 months of infancy and the development of type 1 diabetes: a pilot study

<p>Abstract</p> <p>Aims</p> <p>To investigate the impact of iron intake on the development of type 1 diabetes (T1DM).</p> <p>Methods</p> <p>Case-control study with self-administered questionnaire among families of children with T1DM who were less than 10 years old at the time of the survey and developed diabetes between age 1 and 6 years. Data on the types of infant feeding in the first 4 months of life was collected from parents of children with T1DM (n = 128) and controls (n = 67) <10 years old. Because some cases had sibling controls, we used conditional logistic regression models to analyze the data in two ways. First we performed a case-control analysis of all 128 cases and 67 controls. Next, we performed a case-control analysis restricted to cases (n = 59) that had a sibling without diabetes (n = 59). Total iron intake was modeled as one standard deviation (SD) increase in iron intake. The SD for iron intake was 540 mg in the total sample and 539 mg in the restricted sample as defined above.</p> <p>Results</p> <p>The median (min, max) total iron intake in the first 4 months of life was 1159 (50, 2399) mg in T1DM cases and 466 (50, 1224) mg among controls (<it>P </it>< 0.001). For each one standard deviation increase in iron intake, the odds ratio (95% confidence interval) for type 1 diabetes was 2.01 (1.183, 3.41) among all participants (128 cases and 67 controls) while it was 2.26 (1.27, 4.03) in a restricted sample of T1 D cases with a control sibling (59 cases and 59 controls) in models adjusted for birth weight, age at the time of the survey, and birth order.</p> <p>Conclusion</p> <p>In this pilot study, high iron intake in the first 4 months of infancy is associated with T1DM. Whether iron intake is causal or a marker of another risk factor warrants further investigation.</p

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Glycemic control and lipid outcomes in children and adolescents with type 2 diabetes.

BACKGROUND:The incidence of type 2 diabetes (T2DM) in children has increased dramatically. However, limited published information is known about the glycemic control and lipid outcomes in pediatric T2DM outside of clinical trials. OBJECTIVES:To determine the glycemic control and lipid measure outcomes at one and three- year follow-up in children with T2DM. METHODS:A retrospective electronic medical record review of children with T2DM at the Children's Hospital of Alabama over a 12-year period. RESULTS:There were 301 patients with a diagnosis of T2DM who had a 1-year follow-up visit, of which 184 also had a 3-year follow-up. Most patients (78%) received either insulin with metformin or insulin alone at diagnosis. At one year, 37% of the cohort achieved 'optimal glycemic control' (HbA1C ≤6.5%) and 58% of patients achieved durable glycemic control (HbA1C ≤8%). Optimal glycemic control was seen in 48 patients at 3 years. The patients treated with insulin (alone or in combination with metformin) tended to have higher HbA1C at diagnosis, but had improved lipid and glycemic outcomes at follow-up. The group treated with insulin along with metformin had significant improvements in non-HDL, HDL and TC/HDL ratios. The effects of insulin treatment on glycemic control at 3 years were not statistically significant. CONCLUSION:With the current modality of treatment, only a minority of patients achieve optimal glycemic control at 1 and 3 years of follow-up. Studies are warranted to further elucidate the optimal therapies in the management of pediatric T2DM

Racial Disparities on Glycemic Control and Lipid Profiles in Children with Type 1 Diabetes

Objective We assessed the racial (Black–White) differences in glycemic control, prevalence of abnormal lipid profiles and factors influencing temporal trends in children with type 1 diabetes (T1DM). Methods This retrospective study was done in children with T1DM. The outcome measure was based on glycemic control and all lipid determinations which were stratified according to the published guidelines. Results The study included 181 children; 76.2% Whites and 23.8% Blacks. The mean glycated hemoglobin (A1C) was higher in Blacks than in Whites (p < 0.0001). Blacks had elevated total cholesterol (TC) (p = 0.0013), lower TC/HDL ratio (p < 0.0001) and higher concentration of HDL (<0.0001) when compared to Whites. The longitudinal analyses over a 5 year period showed changes in A1C significantly associated with changes in the lipid profiles. The lipid profiles in Blacks were more altered by the trend in A1C with changes in the TC (p = 0.0079), non-HDL (p < 0.0001) and HDL (p < 0.0001). Conclusions Black children with T1DM have poorer glycemic control. However they retained excellent levels of HDL when compared to Whites

Higher Serum Insulin Concentrations Positively Influence the Bone Mineral Density in African American Adolescents

Background: Puberty is a developmental stage of increased insulin resistance that also is a critical period for bone mass accrual. Historically, African Americans (AA) have lesser risk for osteoporotic fractures compared to European Americans (EA). AA also have higher incidence of insulin resistance. The possibility that bone health and insulin secretion or concentrations are linked has not been investigated. Aims: We aimed to examine the associations of bone mineral density (BMD) and bone mineral apparent density (BMAD) with insulin sensitivity and secretion in healthy adolescent girls and healthy female adults and to evaluate ethnic differences in these associations. Study Design: Observational cohort design. Place and Duration of the Study: University of Alabama at Birmingham, between January 2010 and September 2011. Methodology: Healthy, female, non-smoking adolescents and young adults (14-55 years) were enrolled in this observational cohort study. Results: Adolescents had significantly higher fasting insulin (P=0.0002), insulin area under the curve [AUC] (P= 0.0004) and lower insulin sensitivity (P=0.0005) compared to adults. Among adolescents, AA race was significantly associated with BMD (β=0.086, P=0.01) and BMAD (β=0.0075, P=0.002); however, adjusting for insulin AUC explained this difference. Insulin AUC (β=0.0006, P=0.029) and fasting insulin (β=0.0005, P=0.01) were positively associated with BMAD only in AA adolescents. Insulin AUC and fasting insulin were not significant predictors of BMD for adults. Conclusion: The higher insulin concentration among AA adolescents is associated with increased BMD and higher BMAD