Farid H. Mahmud

Celiac Disease and Pediatric Type 1 Diabetes: Diagnostic and Treatment Dilemmas

Despite the advent of sensitive and specific serologic testing, routine screening for celiac disease (CD) in diabetic populations may not be universal practice, and many clinicians struggle to find the optimal approach to managing CD in pediatric Type 1 diabetes (T1D) patients. While some clinicians advocate screening for CD in all patients with T1D, others are unsure whether this is warranted. The diagnosis of patients who present with symptomatic CD, including malabsorption and obvious pathology upon biopsy, remains straightforward, with improvements noted on a gluten-free diet. Many patients identified by screening, however, tend to be asymptomatic. Evidence is inconclusive as to whether the benefits of screening and potentially treating asymptomatic individuals outweigh the harms of managing a population already burdened with a serious illness. This review focuses on current knowledge of CD in children and youth with T1D, highlighting important elements of the diseases pathophysiology, epidemiology, clinical presentation, and diagnostic challenges.

Social Determinants of Health on Glycemic Control in Pediatric Type 1 Diabetes

OBJECTIVE To evaluate the relationship between the social determinants of health (SDH) and glycemic control in a large pediatric type 1 diabetes (T1D) population. STUDY DESIGN Deprivation Indices (DI) were used to ascertain population-level measures of socioeconomic status, family structure, and ethnicity in patients with T1D followed at The Hospital for Sick Children August 2010-2011 (n = 854). DI quintile scores were determined for individual patients based on de-identified postal codes, and linked to mean patient A1Cs as a measure of glycemic control. We compared mean A1C between the most and least deprived DI quintiles. Associations were estimated controlling for age and sex, and repeated for insulin pump use. RESULTS The T1D population evaluated in this study was most concentrated in the least and most deprived quintiles of the Material DI. A1C levels were highest in patients with the greatest degree of deprivation (fifth vs first quintile) on the Material DI (9.2% vs 8.3%, P < .0001), Social DI (9.1% vs 8.3%, P < .0001), and Ethnic Concentration Index (8.9% vs 8.4%, P = .03). These relationships between measures of the SDH and A1C were not evident for patients on insulin pumps. On regression analysis, higher A1C was predicted by older age, female sex, not using pump therapy, and being in the most deprived quintile for Material and Social Deprivation, but not Ethnic Concentration. CONCLUSIONS Measures of the SDH comprising Material and Social Deprivation were significantly associated with suboptimal glycemic control in our pediatric T1D cohort. Use of insulin pump therapy also predicted A1C and may have a moderating effect on these relationships.

Type 2 diabetes in children and adolescents

The emergence of Type 2 diabetes (T2D) in children and adolescents parallels the rising rates of childhood obesity. As a condition of impaired insulin sensitivity and relative insulin deficiency resulting in hyperglycemia, T2D has a complex underlying physiology that is reflected by the multiple approaches used to optimize medical care and prevent the myriad of diabetes-related complications. T2D diagnosed in children and adolescents represents a distinct and challenging condition to evaluate and treat. Here, we highlight the epidemiology, pathophysiology, risk factors, clinical presentation and diagnosis, treatment and public health impact of T2D in children and adolescents.

Urinary markers of renal inflammation in adolescents with Type 1 diabetes mellitus and normoalbuminuria

Diabet. Med. 29, 1297–1302 (2012)

Mild neonatal hyperthyrotrophinaemia: 10-year experience suggests the condition is increasingly common but often transient

To examine a large population of infants with mild neonatal hyperthyrotrophinaemia (MNH) and determine prevalence, clinical characteristics and treatment history.

Impaired endothelial function in pediatric patients with Turner Syndrome and healthy controls: a case-control study

BackgroundTurner Syndrome women are at high risk of vascular disease and the assessment of early risk factors in Turner Syndrome girls is an emerging focus of research. Our objective was to evaluate endothelial function (EF), a preclinical measure of atherosclerosis, in Turner Syndrome girls compared with controls.MethodsA cross-sectional case-control study of Turner Syndrome girls and healthy controls. Subjects underwent fasting insulin and glucose with calculation of HOMA-IR, fasting lipid profile, anthropometrics, and EF testing using peripheral arterial tonometry (PAT). Subjects, aged 10-18 years, had karyotype-confirmed Turner Syndrome; growth hormone (GH), thyroxine and estrogen use were not exclusion criteria. Controls were age- and BMI-matched healthy girls. Fifteen Turner Syndrome and 15 controls were recruited.ResultsTurner Syndrome girls had lower height, higher HDL and higher waist:height ratio than controls. PAT-hyperemia ratio (RH-PAT) scores were lower in Turner Syndrome (1.64 ± 0.34 vs. 2.08 ± 0.32, p = 0.002) indicating impaired EF. Among Turner Syndrome, RH-PAT did not vary with estrogen therapy or with karyotype 45,XO compared with other karyotypes. However, endothelial function was better in GH-treated compared with GH-untreated Turner Syndrome (1.80 ± 0.36 vs. 1.4 + 0.22, p = 0.02) although there were no differences in HOMA-IR, adiponectin or IGF-1.ConclusionGirls with Turner Syndrome exhibit impaired endothelial function compared with controls, which may explain higher risk for vascular disease. GH may protect endothelial function in Turner Syndrome.

Altered sleep patterns in adolescents with type 1 diabetes: implications for insulin regimen.

Changes in sleep duration and pattern are well described in adolescence. Only 20% of adolescents meet recommendations for hours of sleep during the week (9–9.25 h) (1), and adolescents frequently overcompensate on weekends with delayed awakening times (2). Limited data exist describing sleep patterns in type 1 diabetic patients. This is directly relevant to determining optimal insulin treatment regimens and achieving target metabolic control. We describe sleeping times in adolescent diabetic patients in relation to age-matched peers with attention to the influence of insulin regimens. Seventy-five adolescent patients with diabetes and 54 healthy individuals aged 12–18 years were assessed. Sleep timings on typical weekends and weekdays were collected as part of a larger, institutional …

Celiac Disease Alone and Associated With Type 1 Diabetes Mellitus

Objectives: The aim of the study was to evaluate complication screening and follow-up patterns in a population with type 1 diabetes mellitus and celiac disease (T1D/CD) in relation to a matched cohort with celiac disease (CD) alone at our center. Methods: We retrospectively reviewed the health charts of 41 children with T1D and biopsy-proven CD and compared anthropometrics and complication of screening within 2 years from CD diagnosis. Follow-up patterns were determined 3 years postdiagnosis. This population was then compared with a population with both symptomatic and asymptomatic CD matched for age and sex. Results: In comparison with T1D/CD, patients with CD alone had a significantly lower height, weight and body mass index (BMI z score 0.01 vs 0.81, P = 0.001) and higher rates of screening for anemia (95% vs 71%, P = 0.003) and bone health (49% vs 29%, P = 0.05). Minimal rates of laboratory abnormalities were observed in either group, irrespective of symptoms at presentation, but CD alone more often presented with anemia than T1D/CD. Repeat serology testing was significantly more frequently performed in the T1D/CD group. Follow-up was equally variable with a median of 3 (range 0–4) visits with a gastroenterologist during the first 3 years postdiagnosis. Conclusions: These results suggest that patients with T1D/CD represent a distinct and possibly milder phenotype from CD alone. Complication screening was variable and negative for the majority of the patients. Guidelines for follow-up may need to be tailored to specific groups to standardize evaluation and complication screening, especially with regard to bone health.

The Urinary Cytokine/Chemokine Signature of Renal Hyperfiltration in Adolescents with Type 1 Diabetes

Objective Urinary cytokine/chemokine levels are elevated in adults with type 1 diabetes (T1D) exhibiting renal hyperfiltration. Whether this observation extends to adolescents with T1D remains unknown. Our first objective was to determine the relationship between hyperfiltration and urinary cytokines/chemokines in normotensive, normoalbuminuric adolescents with T1D using GFRcystatin. Our second aim was to determine the relationship between urine and plasma levels of inflammatory biomarkers, to clarify the origin of these factors. Methods Urine and serum cytokines/chemokines (Luminex platform) and GFRcystatin were measured in normofiltering (n = 111, T1D-N, GFR<135 ml/min/1.73 m2) and hyperfiltering (n = 31, T1D-H, GFR≥135 ml/min/1.73 m2) adolescents with T1D (ages 10–16), and in age and sex matched healthy control subjects (HC, n = 59). Results We noted significant step-wise increases in urinary cytokine/chemokine excretion according to filtration status with highest levels in T1D-H, with parallel trends in serum analyte concentrations. After adjusting for serum glucose at the time of sampling, differences in urinary cytokine excretion were not statistically significant. Only serum IL-2 significantly differed between HC and T1D (p = 0.0076). Conclusions Hyperfiltration is associated with increased urinary cytokine/chemokine excretion in T1D adolescents, and parallel trends in serum cytokine concentration. The GFR-associated trends in cytokine excretion may be driven by the effects of ambient hyperglycemia. The relationship between hyperfiltration, glycemia, and variations in serum and urine cytokine expression and their impact on future renal and systemic vascular complications requires further study.

ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes

Background Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long‐term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin‐converting–enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents. Methods We screened 4407 adolescents with type 1 diabetes between the ages of 10 and 16 years of age and identified 1287 with values in the upper third of the albumin‐to‐creatinine ratios; 443 were randomly assigned in a placebo‐controlled trial of an ACE inhibitor and a statin with the use of a 2‐by‐2 factorial design minimizing differences in baseline characteristics such as age, sex, and duration of diabetes. The primary outcome for both interventions was the change in albumin excretion, assessed according to the albumin‐to‐creatinine ratio calculated from three early‐morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve. Key secondary outcomes included the development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk (carotid intima–media thickness and levels of high‐sensitivity C‐reactive protein and asymmetric dimethylarginine). Results The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low‐density lipoprotein, and non–high‐density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima–media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy. Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups. Conclusions The use of an ACE inhibitor and a statin did not change the albumin‐to‐creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476.)