Constadina Panagiotopoulos

Cutting Edge: Increased IL-17–Secreting T Cells in Children with New-Onset Type 1 Diabetes

CD4+FOXP3+ regulatory T cells are essential for immune tolerance, and murine studies suggest that their dysfunction can lead to type 1 diabetes (T1D). Human studies assessing regulatory T cell dysfunction in T1D have relied on analysis of FOXP3-expressing cells. Recently, distinct subsets of CD4+FOXP3+ T cells with differing function were identified. Notably, CD45RA−CD25intFOXP3low T cells lack suppressive function and secrete the proinflammatory cytokine IL-17. Therefore, we evaluated whether the relative fractions of CD4+FOXP3+ subsets are altered in new-onset T1D subjects. We report that children with new-onset T1D have an increased proportion of CD45RA−CD25intFOXP3low cells that are not suppressive and secrete significantly more IL-17 than other FOXP3+ subsets. Moreover, these T1D subjects had a higher proportion of both CD4+ and CD8+ T cells that secrete IL-17. The bias toward IL-17–secreting T cells in T1D suggests a role for this proinflammatory cytokine in the pathogenesis of disease.

Type 2 Diabetes, Medication-Induced Diabetes, and Monogenic Diabetes in Canadian Children: A Prospective National Surveillance Study

OBJECTIVE To determine in Canadian children aged <18 years the 1) incidence of type 2 diabetes, medication-induced diabetes, and monogenic diabetes; 2) clinical features of type 2 diabetes; and 3) coexisting morbidity associated with type 2 diabetes at diagnosis. RESEARCH DESIGN AND METHODS This Canadian prospective national surveillance study involved a network of pediatricians, pediatric endocrinologists, family physicians, and adult endocrinologists. Incidence rates were calculated using Canadian Census population data. Descriptive statistics were used to illustrate demographic and clinical features. RESULTS From a population of 7.3 million children, 345 cases of non–type 1 diabetes were reported. The observed minimum incidence rates of type 2, medication-induced, and monogenic diabetes were 1.54, 0.4, and 0.2 cases per 100,000 children aged <18 years per year, respectively. On average, children with type 2 diabetes were aged 13.7 years and 8% (19 of 227) presented before 10 years. Ethnic minorities were overrepresented, but 25% (57 of 227) of children with type 2 diabetes were Caucasian. Of children with type 2 diabetes, 95% (206 of 216) were obese and 37% (43 of 115) had at least one comorbidity at diagnosis. CONCLUSIONS This is the first prospective national surveillance study in Canada to report the incidence of type 2 diabetes in children and also the first in the world to report the incidence of medication-induced and monogenic diabetes. Rates of type 2 diabetes were higher than expected with important regional variation. These results support recommendations that screening for comorbidity should occur at diagnosis of type 2 diabetes.

Childhood Obesity and Cardiovascular Dysfunction

Obesity-related cardiovascular disease in children is becoming more prevalent in conjunction with the rise in childhood obesity. Children with obesity are predisposed to an increased risk of cardiovascular morbidity and mortality in adulthood. Importantly, research in children with obesity over the last decade has demonstrated that children may exhibit early signs of cardiovascular dysfunction as a result of their excess adiposity, often independent of other obesity-related comorbidities such as dyslipidemia and insulin resistance. The clinical evidence is accumulating to suggest that the cardiovascular damage, once observed only in adults, is also occurring in obese children. The objective of this review is to provide a synopsis of the current research on cardiovascular abnormalities in children with obesity and highlight the importance and need for early detection and prevention programs to mitigate this potentially serious health problem.

Recognition of HLA Class I–Restricted β-Cell Epitopes in Type 1 Diabetes

Type 1 diabetes results from the autoimmune destruction of insulin-producing pancreatic β-cells by cytotoxic T-lymphocytes (CTLs). In humans, few β-cell epitopes have been reported, thereby limiting the study of β-cell–specific CTLs in type 1 diabetes. To identify additional epitopes, HLA class I peptide affinity algorithms were used to identify a panel of peptides derived from the β-cell proteins islet amyloid polypeptide (IAPP), islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP), insulin, insulinoma-associated antigen 2 (IA-2), and phogrin that were predicted to bind HLA-A*0201. Peripheral blood mononuclear cells from 24 HLA-A*0201 recent-onset type 1 diabetic patients and 11 nondiabetic control subjects were evaluated for γ-interferon secretion in response to peptide stimulation in enzyme-linked immunospot assays. We identified peptides IAPP9-17, IGRP215-223, IGRP152-160, islet IA-2(172-180), and IA-2(482-490) as novel HLA-A*0201–restricted T-cell epitopes in type 1 diabetic patients. Interestingly, we observed a strong inverse correlation between the binding affinity of β-cell peptides to HLA-A*0201 and CTL responses against those peptides in recent-onset type 1 diabetic patients. In addition, we found that self-reactive CTLs with specificity for an insulin peptide are frequently present in healthy individuals. These data suggest that many β-cell epitopes are recognized by CTLs in recent-onset type 1 diabetic patients. These epitopes may be important in the pathogenesis of type 1 diabetes.

Identification of Novel HLA-A*0201–Restricted Epitopes in Recent-Onset Type 1 Diabetic Subjects and Antibody-Positive Relatives

Cytotoxic T-lymphocytes (CTLs) are considered to be essential for β-cell destruction in type 1 diabetes. However, few islet-associated peptides have been demonstrated to activate autoreactive CTLs from type 1 diabetic subjects. In an effort to identify novel epitopes, we used matrix-assisted algorithms to predict peptides of glial fibrillary acidic protein (GFAP), prepro-islet amyloid polypeptide (ppIAPP), and islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP) that likely bind to HLA-A*0201 with a strong affinity and contain a COOH-terminal proteasomal cleavage site. Seven peptides stabilized HLA-A*0201 expression in binding assays and were used to stimulate peripheral blood mononuclear cells and were evaluated for granzyme B secretion. We found that 5 of 13 type 1 diabetic subjects and 4 of 6 antibody-positive relatives exhibited greater numbers of granzyme B–secreting cells in response to at least one putative epitope compared with healthy control subjects. The most prevalent responses in antibody-positive and type 1 diabetic subjects were to ppIAPP(9-17). Other peptides recognized by type 1 diabetic or antibody-positive subjects included GFAP(143-151), IGRP(152-160), and GFAP(214-222). These data implicate peptides of ppIAPP, GFAP, and IGRP as CTL epitopes for a heterogenous CD8+ T-cell response in type 1 subjects and antibody-positive relatives.

Increased Prevalence of Obesity and Glucose Intolerance in Youth Treated with Second—Generation Antipsychotic Medications

Objective: To compare the rates of obesity, impaired fasting glucose (IFG), and type 2 diabetes between second-generation antipsychotic (SGA)-treated and -naive youth. Methods: A retrospective chart review was conducted for all child and adolescent psychiatry emergency admissions over 2.5 years. Data collected included age, sex, psychiatric diagnosis, medications, height, weight, fasting glucose, and lipid profile. Body mass index (BMI) was standardized for age and sex and converted to a z score. Overweight was defined as a BMI between the 85th and 95th percentile and obese as a BMI at the 95th percentile or greater for age and sex. The 2007 American Diabetes Association criteria for IFG and type 2 diabetes were used. Results: Among the 432 admissions, 167 (39%) had both height and weight measured, and 145 (34%) had fasting glucose measured. The mean zBMI was higher in the SGA-treated (n = 68), compared with the SGA-naive group (n = 99) (mean difference 0.81; 95% CI 0.46 to 1.16). In the SGA-treated group, 31% were obese and 26% were overweight, compared with 15% and 8%, respectively, in the SGA-naive group (P < 0.01). In the SGA-treated group (n = 65), 21.5% had IFG or type 2 diabetes, compared with 7.5% in the SGA-naive group (n = 80) (P = 0.01). Conclusions: Youth treated with SGAs have significantly higher rates of obesity and glucose intolerance than SGA-naive youth. These data emphasize the need for consistent metabolic monitoring of youth with psychiatric disorders who are prescribed SGAs.

A population-based study of antipsychotic prescription trends in children and adolescents in British Columbia, from 1996 to 2011.

Objectives: To establish prevalence rates of antipsychotic (AP) prescriptions for children 18 years of age or younger in British Columbia (BC) from 1996 to 2011 by age, sex, AP type, and primary diagnosis; and to identify the predominant AP prescribers for children by specialty training. Methods: BC Ministry of Health administrative data were used to describe AP prescriptions for youth aged 18 years or younger. Comparisons were made using population prevalence based on sex; age group; AP; International Classification of Diseases, Ninth Revision, diagnosis; and prescriber specialty. Results: From 1996 to 2011, overall AP (both first and second generation) prescription prevalence rate increased 3.8-fold (1.66 to 6.37 per 1000 population); second-generation AP (SGA) prescriptions increased 18.1-fold (0.33 to 5.98 per 1000 population). The highest increase in all AP prescriptions occurred in males aged 13 to 18 years (3.3 to 14.4 per 1000 population; 4.4-fold), followed by similar increases in males aged 6 to 12 years (2.3 to 8.6 per 1000 population; 3.7-fold) and in females aged 13 to 18 years (2.8 to 10.7 per 1000 population; 3.8-fold). Overall, the 3 most common diagnoses associated with all AP prescriptions were depressive disorders (12.8%), hyperkinetic syndrome of childhood (11.7%), and neurotic disorders (11.1%); however, variation was observed by prescriber specialty training. Among all new AP prescriptions in 2010/11, 38.6%, 34.3%, and 15.6% were provided by psychiatrists, family physicians, and pediatricians, respectively. Conclusions: There has been an exponential rise in SGA prescriptions in BC secondary to extensive off-label use, not only by psychiatrists but also by family physicians and pediatricians. Knowledge translation initiatives promoting evidence-based prescribing and monitoring practices related to SGA treatment need to target all 3 prescriber groups and be tailored for age subgroups.

A Naturalistic Study of Predictors and Risks of Atypical Antipsychotic Use in an Attention-Deficit/Hyperactivity Disorder Clinic

OBJECTIVE This was an exploratory study to examine the use of atypical antipsychotics in an attention-deficit/hyperactivity disorder (ADHD) clinic. METHOD A total of 194 patients was examined to compare those receiving atypical or second-generation antipsychotics (atypicals) from those who were not. A sample of 27 children on atypicals received laboratory investigation for indicators of possible metabolic effects. RESULTS In all, 19.1% of the patients in the clinic were receiving atypicals with a mean duration of 313 days; 36 of 37 patients on atypicals had received risperidone, with a mean dose of 0.62 mg. Children receiving atypicals were statistically more likely to have a severe co-morbid disorder, a lower Childrens Global Assessment Scale score, a greater total score on the teacher Strengths and Difficulties Questionnaire, and greater difficulty with parent-rated symptoms of being touchy, worried, rages, and explosive outbursts. There were no differences found in measures of functioning, adaptive skills, quality of life, or ADHD symptoms. In the subset of children studied for potential metabolic effects, 68.0% had a waist circumference > or =90(th) percentile that was independent of weight gain, 18.5% had impaired fasting glucose, 12.5% had elevated blood pressure, 11.1% had elevated triglycerides, and 16.7% met full criteria for metabolic syndrome. CONCLUSION Clinical implementation of the efficacy studies of risperidone for disruptive behavior disorders has led to a significant change in practice. Almost 1 in 5 patients are now receiving atypical neuroleptics, typically to treat severe co-morbid disorders and symptoms other than ADHD per se. Despite these children receiving low doses, concomitant stimulants, and low body mass index z-scores, a significant proportion of children demonstrated either one or more components or the full criteria for metabolic syndrome.

Waist Circumference Is a Sensitive Screening Tool for Assessment of Metabolic Syndrome Risk in Children Treated with Second-Generation Antipsychotics

Objective: To compare the prevalence of metabolic syndrome (MetS) and its components in second-generation antipsychotic (SGA)-treated and SGA-naive children; and to explore the utility of clinical markers, such as waist circumference (WC) and body mass index (BMI), as screening tools for MetS. Methods: Subjects were prospectively recruited from the Psychiatry Emergency Unit at British Columbia Childrens Hospital. As part of a quality-assurance project, a metabolic monitoring protocol was implemented, including collection of anthropomorphic and laboratory data. Results: From January 2008 to February 2010, there were 117 SGA-treated and 217 SGA-naive children recruited. The overall prevalence of MetS was 19.0% (16/84; median treatment duration = 14 months) in SGA-treated and 0.8% (1/127) in SGA-naive children (OR 29.7; 95% CI 3.85 to 228.40, P < 0.001), with an increased prevalence of all components except high-density lipoprotein cholesterol (HDL-C), respectively: elevated WC (40.7% and 10.1%; P < 0.001); hypertriglyceridemia (33.7% and 18.8%; P = 0.01); impaired fasting glucose (12.5% and 0.7%; P = 0.005); and elevated blood pressure (41.2% and 16.5%; P < 0.001). SGA treatment was the strongest predictor of MetS (OR 19.2; 95% CI 2.30 to 160.44, P = 0.006) followed by male sex (OR 5.7; 95% CI 1.08 to 30.62, P = 0.04). Presence of abdominal obesity was more sensitive (92.9%) than BMI (68.8%), while fasting glucose of 5.6 mmol/L or more and HDL-C of 1.03mmol/L or less were most specific (94.1%) in correctly identifying MetS. Conclusions: SGA treatment confers a significantly increased risk for MetS over the long term. WC measurement is a simple and sensitive screening tool for determining MetS risk in SGA-treated children. These data highlight the dangers of SGA treatment and the importance of standardized metabolic monitoring using sex- and age-adjusted tables in this population.

The impact of Action Schools! BC on the health of Aboriginal children and youth living in rural and remote communities in British Columbia

Objectives: The aim of the study was to determine the short-term impact of a 7-month whole-school physical activity and healthy eating intervention (Action Schools! BC) over the 2007–2008 school year for children and youth in 3 remote First Nations villages in northwestern British Columbia. Study design: A pre-experimental pre/post design was conducted with 148 children and youth (77 males, 71 females; age 12.5±2.2 yrs). Methods: We evaluated changes in obesity (body mass index [wt/ht2] and waist circumference z-scores: zBMI and zWC), aerobic fitness (20-m shuttle run), physical activity (PA; physical activity questionnaire and accelerometry), healthy eating (dietary recall) and cardiovascular risk (CV risk). Results: zBMI remained unchanged while zWC increased from 0.46±1.07 to 0.57±1.04 (p<0.05). No change was detected in PA or CV risk but aerobic fitness increased by 22% (25.4±15.8 to 30.9±20.0 laps; p<0.01). There was an increase in the variety of vegetables consumed (1.10±1.18 to 1.45±1.24; p<0.05) but otherwise no dietary changes were detected. Conclusions: While no changes were seen in PA or overall CV risk, zWC increased, zBMI remained stable and aerobic fitness improved during a 7-month intervention. 1Published ‘ahead-of-print’ 2 December 2011 (at www.ijch.fi) in accordance with previous publishers routines.