Showing papers in "Pediatric Diabetes in 2019"

Does obesity cause type 2 diabetes mellitus (T2DM)? Or is it the opposite?

Abstract: Obesity is believed to be a promoter of type 2 diabetes mellitus (T2DM). Reports indicate that severe obesity in childhood and adolescence increases the risk of T2DM in youth and young adults. T2DM, which is commonly asymptomatic, frequently is not recognized until random blood glucose is measured. Screening blood glucose levels measured in obese individuals are more effective for identifying undiagnosed persons, than screening the general population and therefore introduces a selection bias for discovery. The following commentary will indicate why these observations do not indicate that obesity is the cause of T2DM. Also, it will be shown that the insulin resistance of T2DM occurs primarily in the muscles of lean individuals predisposed to diabetes before they become obese. This insulin resistance is not secondary to, but instead, is the cause of the excessive fat accumulation associated with T2DM. Moreover, this early muscle insulin resistance is the etiology of the hyperlipidemia and excess fat accumulation characteristic of T2DM.

Gut microbiome dysbiosis and increased intestinal permeability in children with islet autoimmunity and type 1 diabetes: A prospective cohort study.

Abstract: Aims/hypothesis To investigate the longitudinal relationship between the gut microbiome, circulating short chain fatty acids (SCFAs) and intestinal permeability in children with islet autoimmunity or type 1 diabetes and controls. Methods We analyzed the gut bacterial microbiome, plasma SCFAs, small intestinal permeability and dietary intake in 47 children with islet autoimmunity or recent-onset type 1 diabetes and in 41 unrelated or sibling controls over a median (range) of 13 (2-34) months follow-up. Results Children with multiple islet autoantibodies (≥2 IA) or type 1 diabetes had gut microbiome dysbiosis. Anti-inflammatory Prevotella and Butyricimonas genera were less abundant and these changes were not explained by differences in diet. Small intestinal permeability measured by blood lactulose:rhamnose ratio was higher in type 1 diabetes. Children with ≥2 IA who progressed to type 1 diabetes (progressors), compared to those who did not progress, had higher intestinal permeability (mean [SE] difference +5.14 [2.0], 95% confidence interval [CI] 1.21, 9.07, P = .006), lower within-sample (alpha) microbial diversity (31.3 [11.2], 95% CI 9.3, 53.3, P = .005), and lower abundance of SCFA-producing bacteria. Alpha diversity (observed richness) correlated with plasma acetate levels in all groups combined (regression coefficient [SE] 0.57 [0.21], 95% CI 0.15, 0.99 P = .008). Conclusions/interpretation Children with ≥2 IA who progress to diabetes, like those with recent-onset diabetes, have gut microbiome dysbiosis associated with increased intestinal permeability. Interventions that expand gut microbial diversity, in particular SCFA-producing bacteria, may have a role to decrease progression to diabetes in children at-risk.

Diabetic ketoacidosis at diagnosis of type 1 diabetes and glycemic control over time: The SEARCH for diabetes in youth study

Abstract: BACKGROUND The diagnosis of type 1 diabetes (T1D) in youth is often associated with diabetic ketoacidosis (DKA). We aimed to evaluate if the presence of DKA at diagnosis of T1D is associated with less favorable hemoglobin A1c (HbA1c) trajectories over time. METHODS The SEARCH for Diabetes in Youth study of 1396 youth aged <20 years with newly diagnosed T1D were followed for up to 13 (median 8 [interquartile range or IQR 6-9]) years after diagnosis. Of these, 397 (28%) had DKA (bicarbonate level < 15 mmol/L and/or pH < 7.25 (venous) or < 7.30 (arterial or capillary) or mention of DKA in medical records) at diabetes onset. Longitudinal HbA1c levels were measured at each follow-up visit (average number of HbA1c measures 3.4). A linear piecewise mixed effects model was used to analyze the effect of DKA status at diagnosis of T1D on long-term glycemic control, adjusting for age at diagnosis, diabetes duration at baseline, sex, race/ethnicity, household income, health insurance status, time-varying insulin regimen and glucose self-monitoring, study site, and baseline fasting C-peptide level. RESULTS At baseline, HbA1c levels were significantly higher in youth with T1D diagnosed in DKA vs those who were not (9.9% ± 1.5% vs 8.5% ± 1.4%, respectively). After the first year with diabetes, there was a significant difference in the rate of change in HbA1c levels by DKA status: HbA1c was 0.16% higher each year in youth with DKA compared to those without (interaction P-value<0.0001), after adjusting for aforementioned covariates. CONCLUSIONS DKA at T1D diagnosis is associated with worsening glycemic control over time, independent of demographic, socioeconomic, and treatment-related factors and baseline fasting C-peptide.

Reduced burden of diabetes and improved quality of life: Experiences from unrestricted day-and-night hybrid closed-loop use in very young children with type 1 diabetes.

Abstract: Objective To evaluate the experiences of families with very young children aged 1 to 7 years (inclusive) with type 1 diabetes using day-and-night hybrid closed-loop insulin delivery. Methods Parents/caregivers of 20 children aged 1 to 7 years with type 1 diabetes completed a closed-loop experience survey following two 3-week periods of unrestricted day-and-night hybrid closed-loop insulin therapy using Cambridge FlorenceM system at home. Benefits, limitations, and improvements of closed-loop technology were explored. Results Responders reported reduced burden of diabetes management, less time spent managing diabetes, and improved quality of sleep with closed-loop. Ninety percent of the responders felt less worried about their child's glucose control using closed-loop. Size of study devices, battery performance and connectivity issues were identified as areas for improvement. Parents/caregivers wished for more options to input information to the system such as temporary glucose targets. Conclusions Parents/caregivers of very young children reported important quality of life benefits associated with using closed-loop, supporting adoption of this technology in this population.

Closed loop control in adolescents and children during winter sports: Use of the Tandem Control‐IQ AP system

Abstract: Objective Artificial pancreas (AP) systems have been shown to improve glycemic control throughout the day and night in adults, adolescents, and children. However, AP testing remains limited during intense and prolonged exercise in adolescents and children. We present the performance of the Tandem Control-IQ AP system in adolescents and children during a winter ski camp study, where high altitude, low temperature, prolonged intense activity, and stress challenged glycemic control. Methods In a randomized controlled trial, 24 adolescents (ages 13-18 years) and 24 school-aged children (6-12 years) with Type 1 diabetes (T1D) participated in a 48 hours ski camp (∼5 hours skiing/day) at three sites: Wintergreen, VA; Kirkwood, and Breckenridge, CO. Study participants were randomized 1:1 at each site. The control group used remote monitored sensor-augmented pump (RM-SAP), and the experimental group used the t: slim X2 with Control-IQ Technology AP system. All subjects were remotely monitored 24 hours per day by study staff. Results The Control-IQ system improved percent time within range (70-180 mg/dL) over the entire camp duration: 66.4 ± 16.4 vs 53.9 ± 24.8%; P = .01 in both children and adolescents. The AP system was associated with a significantly lower average glucose based on continuous glucose monitor data: 161 ± 29.9 vs 176.8 ± 36.5 mg/dL; P = .023. There were no differences between groups for hypoglycemia exposure or carbohydrate interventions. There were no adverse events. Conclusions The use of the Control-IQ AP improved glycemic control and safely reduced exposure to hyperglycemia relative to RM-SAP in pediatric patients with T1D during prolonged intensive winter sport activities.

Trends in prevalence of cardiovascular risk factors from 2002 to 2012 among youth early in the course of type 1 and type 2 diabetes. The SEARCH for Diabetes in Youth Study.

Abstract: Background Given diabetes is an important risk factor for cardiovascular disease (CVD), we examined temporal trends in CVD risk factors by comparing youth recently diagnosed with type 1 diabetes (T1D) and type 2 diabetes (T2D) from 2002 through 2012. Methods The SEARCH for Diabetes in Youth Study identified youth with diagnosed T1D (n = 3954) and T2D (n = 706) from 2002 to 2012. CVD risk factors were defined using the modified Adult Treatment Panel III criteria for metabolic syndrome: (a) hypertension; (b) high-density lipoprotein cholesterol ≤40 mg/dL; (c) triglycerides ≥110 mg/dL; and (d) waist circumference (WC) >90th percentile. Prevalence of CVD risk factors, stratified by diagnosis year and diabetes type, was reported. Univariate and multivariate logistic models and Poisson regression were fit to estimate the prevalence trends for CVD risk factors individually and in clusters (≥2 risk factors). Results The prevalence of ≥2 CVD risk factors was higher in youth with T2D than with T1D at each incident year, but the prevalence of ≥2 risk factors did not change across diagnosis years among T1D or T2D participants. The number of CVD risk factors did not change significantly in T1D participants, but increased at an annual rate of 1.38% in T2D participants. The prevalence of hypertension decreased in T1D participants, and high WC increased in T2D participants. Conclusion The increase in number of CVD risk factors including large WC among youth with T2D suggests a need for early intervention to address these CVD risk factors. Further study is needed to examine longitudinal associations between diabetes and CVD.

Persistent heterogeneity in diabetes technology reimbursement for children with type 1 diabetes: The SWEET perspective.

Abstract: Background Frequent use of modern diabetes technologies increases the chance for optimal type 1 diabetes (T1D) control. Limited reimbursement influences the access of patients with T1D to these modalities and could worsen their prognosis. We aimed to describe the situation of reimbursement for insulins, glucometers, insulin pumps (CSII) and continuous glucose monitoring (CGM) for children with T1D in European countries participating in the SWEET Project and to compare data from EU countries with data from our previous study in 2009. Methods The study was conducted between March 2017 and August 2017. First, we approached diabetes technology companies with a survey to map the reimbursement of insulins and diabetic devices. The data collected from these companies were then validated by members of the SWEET consortium. Results We collected data from 29 European countries, whereas all types of insulins are mostly fully covered, heterogeneity was observed regarding the reimbursement of strips for glucometers (from 90 strips/month to no limit). CSII is readily available in 20 of 29 countries. Seven countries reported significant quota issues or obstacles for CSII prescription, and two countries had no CSII reimbursement. CGM is at least partially reimbursed in 17 of 29 countries. The comparison with the 2009 study showed an increasing availability of CSII and CGM across the EU. Conclusions Although innovative diabetes technology is available, a large proportion of children with T1D still do not benefit from it due to its limited reimbursement.

Sleep and type 1 diabetes in children and adolescents: Proposed theoretical model and clinical implications

Abstract: Youth with type 1 diabetes mellitus (T1D) experience more sleep disturbances and shorter sleep durations compared to their healthy peers. Researchers have now uncovered the negative mental health and physical health outcomes associated with poor sleep in youth with T1D. The field of T1D sleep research currently operates under the broad notion that sleep behaviors impact treatment adherence, which ultimately lead to worse long-term health outcomes. This model however does not explain how behavior influences T1D management and sleep outcomes on a day-to-day basis, leading to difficulties in providing tailored treatment recommendations. In this review, we present a theoretical framework that describes the recursive cycle between sleep behaviors, T1D outcomes, and symptoms of negative affect/stress over a 24-hour period. This model is guided by the sleep literature, showing a clear relationship between poor sleep and negative affect, and the T1D literature demonstrating a link between poor sleep and disease management for youth with T1D. Further, emerging literature indicates a need for additional parent sleep assessment considering that T1D management and fear of hypoglycemia negatively impact parent sleep behaviors. Recommendations are provided to move the field toward effective intervention studies and new areas of research to evaluate and modify the proposed model.

Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials-GPPAD-02 study design and first results.

Abstract: Primary prevention of type 1 diabetes (T1D) requires intervention in genetically at-risk infants. The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has established a screening program, GPPAD-02, that identifies infants with a genetic high risk of T1D, enrolls these into primary prevention trials, and follows the children for beta-cell autoantibodies and diabetes. Genetic testing is offered either at delivery, together with the regular newborn testing, or at a newborn health care visits before the age of 5 months in regions of Germany (Bavaria, Saxony, Lower Saxony), UK (Oxford), Poland (Warsaw), Belgium (Leuven), and Sweden (Region Skane). Seven clinical centers will screen around 330 000 infants. Using a genetic score based on 46 T1D susceptibility single-nucleotide polymorphisms (SNPs) or three SNPS and a first-degree family history for T1D, infants with a high (>10%) genetic risk for developing multiple beta-cell autoantibodies by the age of 6 years are identified. Screening from October 2017 to December 2018 was performed in 50 669 infants. The prevalence of high genetic risk for T1D in these infants was 1.1%. Infants with high genetic risk for T1D are followed up and offered to participate in a randomized controlled trial aiming to prevent beta-cell autoimmunity and T1D by tolerance induction with oral insulin. The GPPAD-02 study provides a unique path to primary prevention of beta-cell autoimmunity in the general population. The eventual benefit to the community, if successful, will be a reduction in the number of children developing beta-cell autoimmunity and T1D.

Bone turnover markers in children and adolescents with type 1 diabetes-A systematic review.

Abstract: Type 1 diabetes (T1D) is associated with impaired bone health and both osteocalcin (OCN) and procollagen type 1 amino terminal propetide (P1NP) (markers of bone formation) and C-terminal cross-linked telopeptide (CTX) (marker of bone resorption) are decreased in adult patients with T1D. We review the existing literature characterizing these bone turnover markers in children and adolescents with T1D and by meta-analysis examine whether alterations in OCN, P1NP, and CTX are evident and if potential changes correlate to the metabolic control (hemoglobin A1c, HbA1c). Systematic searches at MEDLINE and EMBASE were conducted in January 2018 identifying all studies describing OCN, P1NP, or CTX in children and adolescents with T1D. A total of 26 studies were included, representing data from more than 1000 patients with T1D. Pooled analyses of standard mean difference and summary effects analysis were performed when sufficient data were available. Pooled analysis revealed mean OCN to be significantly lower in children and adolescents with T1D compared to healthy controls (standard mean difference: -1.87, 95% confidence interval, CI: -2.83; -0.91) whereas both P1NP and CTX did not differ from the controls. Only data on OCN was sufficient to make pooled correlation analysis revealing a negative correlation between OCN and HbA1c (-0.31 95% CI: -0.45; -0.16). In conclusion, OCN is decreased in children and adolescents with T1D, whether CTX and P1NP are affected as well is unclear, due to very limited data available. New and large studies including OCN, P1NP, and CTX (preferably as z-scores adjusting for age variability) is needed to further elucidate the status of bone turnover in children and adolescents with T1D.

Five heterogeneous HbA1c trajectories from childhood to adulthood in youth with type 1 diabetes from three different continents: A group-based modeling approach

Abstract: Objectives Only a fraction of youth meet established targets for glycemic control; many experience deteriorating control over time. We compared trajectories of hemoglobin A1c (HbA1c) among youth from three trans-continental type 1 diabetes (T1D) registries and identified clinical variables associated with the odds of following increasing vs stable trajectories. Research design and methods Analyses included longitudinal data from 15 897 individuals age 8 to 18 with T1D for at least 2 years and HbA1c measurements in at least 5 years during the observation period. Cohorts were selected from Australasian Diabetes Data Network (ADDN; Australia), German/Austrian/Luxembourgian Diabetes-Patienten-Verlaufsdokumentation initiative (DPV; Germany/Austria/Luxembourga), and the T1D Exchange Clinic Network (T1DX; US) clinic registries. Group-based trajectory modeling and multivariable logistic regression identified unique HbA1c trajectories and their predictors. Results Five heterogeneous trajectories of glycemic control in each registry were identified: low, intermediate, high stable; intermediate and high increasing. The overall HbA1c level for each trajectory group tended to be lowest in the DPV, higher in the ADDN, and highest in the T1DX. The absolute level of HbA1c and the proportion of individuals within each trajectory varied across registries: 17% to 22% of individuals followed an increasing trajectory. Compared with maintaining a stable trajectory, following an increasing trajectory was significantly associated with ethnic minority status, lower height z-score, higher BMI z-score, insulin injection therapy, and the occurrence of severe hypoglycemia; however, these factors were not consistent across the three registries. Conclusions We report the first multinational registry-based comparison of glycemic control trajectories among youth with T1D from three continents and identify possible targets for intervention in those at risk of an increasing HbA1c trajectory.

Prevalence of type 2 diabetes among adolescents in Brazil: Findings from Study of Cardiovascular Risk in Adolescents (ERICA)

Abstract: Background Type 2 diabetes mellitus (T2DM) in adolescents represents a clinical challenge related to lifestyle and obesity; however, only a few data are available in developing countries. Therefore, our aim was to investigate the prevalence of T2DM and prediabetes among Brazilian adolescents, as well as to describe the cardio-metabolic profile according to the diagnosis. Methods This is a cross-sectional school-based multicenter study including youth aged 12 to 17 years from cities with more than 100 000 inhabitants in Brazil (n = 37 854 students). Fasting glucose, hemoglobin A1c (HbA1c) and other cardio-metabolic risk factors were measured. Prediabetes was defined by glucose levels 100 to 125 mg/dL or HbA1c 5.7% to 6.4%. T2DM was defined by self-report, glucose ≥126 mg/dL or HbA1c ≥ 6.5%. Multinomial logistic regression was used to estimate the odds ratio (OR) of prediabetes or T2DM according to covariates. Results Prevalences of prediabetes and T2DM were 22.0% (95% confidence interval [CI] 20.6%-23.4%) and 3.3% (95% CI 2.9%-3.7%), respectively. This estimates represented 213 830 adolescents living with T2DM and 1.46 million adolescents with prediabetes in Brazil. Prevalences of cardio-metabolic risk factors were higher in adolescents with prediabetes and T2DM. In the multinomial logistic model, obesity (OR 1.59, 95% CI 1.20-2.11), high waist circumference (OR 1.51, 95% CI 1.13-2.01), and skipping breakfast (OR 1.48, 95% CI 1.21-1.81) were associated with an increased OR for T2DM, while studying at rural area (OR 0.56, 95% CI 0.41-0.78) was associated with a decreased OR for T2DM. Conclusions The prevalence of T2DM and prediabetes was high among Brazilian adolescents, which highlights that this disease became a public health challenge not only among adults in Brazil.

Subclinical arterial damage in children and adolescents with type 1 diabetes: A systematic review and meta-analysis.

Abstract: Background and objective Type 1 diabetes is an important risk factor for the development of cardiovascular disease. Pulse wave velocity (PWV) and carotid intima-media thickness (cIMT) measurements are well recognized as independent predictors for future cardiovascular disease. The aim of the present study was to systematically review the literature and conduct a meta-analysis assessing measures of subclinical arterial damage in children and adolescents with type 1 diabetes in comparison to healthy controls. Methods PubMed and Cochrane Library were searched to identify studies comparing cIMT and carotid-femoral PWV levels between children with type 1 diabetes and healthy controls. Meta-analysis was performed to compare the difference of overall mean cIMT and carotid-femoral PWV levels between the two groups. New Castle Ottawa quality assessment scale for case-control studies was used to assess study quality. Results Twenty-three studies were finally included in the meta-analysis (20 studies for cIMT and 4 studies for carotid-femoral PWV). Youth with type 1 diabetes had significantly higher cIMT levels than controls (mean difference [d] = 0.03, 95% confidence interval [CI] = 0.02-0.04), as well as higher carotid-femoral PWV levels (d = 0.26, 95% CI = 0.18-0.34). Heterogeneity was present only in the cIMT analysis (I2 > 90%). Conclusions Youth with type 1 diabetes showed signs of subclinical arterial damage, as suggested by higher levels of cIMT and carotid-femoral PWV compared to healthy controls at childhood and adolescence. Preventive and therapeutic interventions early in course of disease may be further studied to decrease morbidity in this high-risk young patient group. PROSPERO registration number: 2018 CRD42018094354.

Utility of waist circumference-to-height ratio as a screening tool for generalized and central obesity among Iranian children and adolescents: The CASPIAN-V study.

Abstract: Background Waist-to-height ratio (WHtR) is regarded as a simple anthropometric index for evaluating central adiposity because of its independence of age, gender, and ethnicity. Objective The purpose of this study was to determine the optimal WHtR cutoff value in screening obesity and to compare it with other obesity indicators including body mass index (BMI) and waist circumference (WC) in Iranian children and adolescents. Methods This large survey was conducted on 14 274 Iranian children and adolescents as a national school-based surveillance study (CASPIAN) in 2015. The receiver operating characteristic curve analysis was performed to estimate the optimal cut-off points of WHtR for the prediction of general and central obesity. The area under curve (AUC) was used to compare the ability of WHtR cut-off points, BMI and WC percentiles to discriminate students with and without obesity according to age and sex. Results The optimal WHtR cutoff value for predicting general obesity was 0.49 and 0.48 for boys and girls, respectively and for central obesity according to WC ≥ 90th percentile was 0.50 for both genders. AUC values of WHtR for predicting general and central obesity were 87% and 96%, which indicates its strong predictive ability. For central obesity, the AUCs of WHtR were superior to those of WC percentiles. The kappa agreement coefficient was 0.55 between WC ≥ 90th percentile and WHtR ≥ 0.5. Conclusions The WHtR ≥ 0.5 as a simple and useful screening tool is better than WC, for predicting general and central obesity in different age and sex groups of Iranian children and adolescents.

Glycemic control and bone mineral density in children and adolescents with type 1 diabetes.

Abstract: Background/objective Fracture risk is increased in patients with type 1 diabetes. We aimed to evaluate bone mineral density (BMD) and to identify risk factors associated to lower BMD in Danish children and adolescents with type 1 diabetes. Methods In this cross-sectional study BMD Z-score were determined by dual-energy X-ray absorptiometry (DXA) from a cohort of otherwise healthy children and adolescents with type 1 diabetes. Puberty Tanner stage, hemoglobin A1c (HbA1c), disease duration, and age at diabetes onset were investigated for associations to DXA results. Results We included 85 patients, 39 girls, 46 boys, with a median (range) age of 13.2 (6-17) years; disease duration 4.2 (0.4-15.9) years; HbA1c of the last year 61.8 (41-106) mmol/mol. Our patients were taller and heavier than the background population. When adjusted for increased height SD and body mass index SD, no overall difference in BMD Z-score was found. When stratified by sex, boys had significantly increased adjusted mean BMD Z-score, 0.38 (95% confidence interval [CI]: 0.13;0.62), girls; -0.27 (95% CI: -0.53;0.00). For the whole cohort, a negative correlation between mean latest year HbA1c and BMD Z-score was found, adjusted s -0.019 (95%CI: -0.034;-0.004, P = 0.01). Poor glycemic control (HbA1c > 58 mmol/mol [7.5%]) within the latest year was likewise negatively correlated with BMD Z-score, adjusted s -0.35 (95%CI: -0.69;-0.014, P = 0.04). Conclusions Our study suggests that elevated blood glucose has a negative effect on the bones already before adulthood in patients with type 1 diabetes, although no signs of osteoporosis were identified by DXA.

Association of insulin-manipulation and psychiatric disorders: A systematic epidemiological evaluation of adolescents with type 1 diabetes in Austria.

Abstract: BACKGROUND/OBJECTIVE The aim of this study was to systematically assess the association of insulin-manipulation (intentional under- and/or overdosing of insulin), psychiatric comorbidity and diabetes complications. METHODS Two diagnostic interviews (Diabetes-Self-Management-Patient-Interview and Children's-Diagnostic-Interview for Psychiatric Disorders) were conducted with 241 patients (age 10-22) with type 1 diabetes (T1D) from 21 randomly selected Austrian diabetes care centers. Medical data was derived from medical records. RESULTS Psychiatric comorbidity was found in nearly half of the patients with insulin-manipulation (46.3%) compared to a rate of 17.5% in patients, adherent to the prescribed insulin therapy. Depression (18.3% vs 4.9%), specific phobia (21.1% vs 2.9%), social phobia (7.0% vs 0%), and eating disorders (12.7% vs 1.9%) were elevated in patients with insulin-manipulation. Females (37.7%) were more often diagnosed (P = 0.001) with psychiatric disorders than males (18.4%). In females, the percentage of psychiatric comorbidity significantly increased with the level of non-adherence to insulin therapy. Insulin-manipulation had an effect of +0.89% in HbA1c (P = <0.001) compared to patients adherent to insulin therapy, while there was no association of psychiatric comorbidity with metabolic control (HbA1c 8.16% vs 8.12% [65.68 vs 65.25 mmol/mol]). Ketoacidosis, severe hypoglycemia, and frequency of outpatient visits in a diabetes center were highest in patients with insulin-manipulation. CONCLUSIONS This is the first study using a systematic approach to assess the prevalence of psychiatric disorders in patients who do or do not manipulate insulin in terms of intentional under- and/or overdosing. Internalizing psychiatric disorders were associated with insulin-manipulation, especially in female patients and insulin-manipulation was associated with deteriorated metabolic control and diabetes complications.

Translating glycated hemoglobin A1c into time spent in glucose target range: A multicenter study.

Abstract: Background Approximately 90% of children and adolescents with type 1 diabetes in Sweden use continuous glucose monitoring (CGM), either as real-time CGM or intermittently scanned CGM to monitor their glucose levels. Time in target range (TIT) is an easily understandable metric for assessing glycemic control. Objective The aim of this study was to examine the relation between TIT and hemoglobin A1c (HbA1c). Subjects and methods Subjects were recruited from three diabetes care centers in Sweden. Glucose data were collected for 133 children and adolescents with type 1 diabetes through CGM using Diasend. Subjects with registration time over 80% were included in the analysis. HbA1c was collected from SWEDIABKIDS, the Swedish pediatric diabetes quality registry. TIT was defined as 3.9 to 7.8 mmol/L (70-140 mg/dL) and time in range (TIR) as 3.9 to 10 mmol/L (70-180 mg/dL). Results During the period of 60 days, 105 subjects provided complete data for analysis. Mean age was 12.2 (±3.3) years, mean HbA1c was 53.9 (±8.2) mmol/mol or 7.1% (±0.7%). Mean sensor glucose value was 8.6 (±1.3) mmol/L, mean coefficient of variation was 42.2% (±7.2%), mean TIT was 40.9% (±SD 12.2%), and mean TIR was 60.8% (±13.1%). There was a significant nonlinear relation between TIT during 60 days and HbA1c, R2 = 0.69. Conclusion This study suggests a nonlinear relation between time spent in glucose target range and HbA1c. The finding implies that time spent in TIT could be a useful metric in addition to HbA1c to assess glycemic control.

Predicting progression to type 1 diabetes from ages 3 to 6 in islet autoantibody positive TEDDY children.

Abstract: Objective: The capacity to precisely predict progression to type 1 diabetes (T1D) in young children over a short time span is an unmet need. We sought to develop a risk algorithm to predict progression in children with high-risk human leukocyte antigen (HLA) genes followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Methods: Logistic regression and 4-fold cross-validation examined 38 candidate predictors of risk from clinical, immunologic, metabolic, and genetic data. TEDDY subjects with at least one persistent, confirmed autoantibody at age 3 were analyzed with progression to T1D by age 6 serving as the primary endpoint. The logistic regression prediction model was compared to two non-statistical predictors, multiple autoantibody status, and presence of insulinoma-associated-2 autoantibodies (IA-2A). Results: A total of 363 subjects had at least one autoantibody at age 3. Twenty-one percent of subjects developed T1D by age 6. Logistic regression modeling identified 5 significant predictors - IA-2A status, hemoglobin A1c, body mass index Z-score, single-nucleotide polymorphism rs12708716_G, and a combination marker of autoantibody number plus fasting insulin level. The logistic model yielded a receiver operating characteristic area under the curve (AUC) of 0.80, higher than the two other predictors; however, the differences in AUC, sensitivity, and specificity were small across models. Conclusions: This study highlights the application of precision medicine techniques to predict progression to diabetes over a 3-year window in TEDDY subjects. This multifaceted model provides preliminary improvement in prediction over simpler prediction tools. Additional tools are needed to maximize the predictive value of these approaches. (Less)

Diabetic ketoacidosis in children newly diagnosed with type 1 diabetes mellitus: Role of demographic, clinical, and biochemical features along with genetic and immunological markers as risk factors. A 20-year experience in a tertiary Belgian center.

Abstract: BACKGROUND Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes (T1D). Little is known about the association between genetic and immunological markers and the risk for DKA at onset of T1D. The aim of this study was to create a model foreseeing the onset of DKA in newly diagnosed patients. METHODS This retrospective study included 532 T1D children (aged <18 years at diagnosis) recruited in our hospital, from 1995 to 2014. DKA and its severity were defined according to the criteria of ISPAD. Genetic risk categories for developing T1D were defined according to the Belgian Diabetes Registry. Multivariate statistical analyses were applied to investigate risk factors related to DKA at diagnosis. RESULTS Overall 42% of patients presented DKA at diagnosis. This study outlined the major risk of DKA at diagnosis for younger children (<3 years) and for those belonging to ethnic minorities. Children carrying neutral genotypes had a 1.5-fold increased risk of DKA at diagnosis than those with susceptible or protective genotypes, a paradoxical observation not previously reported. Only solitary positive IA-2A increased the risk of DKA at diagnosis. The proposed model could help to predict the probability of DKA in 70% of newly diagnosed cases. CONCLUSIONS This was the first reported implication of IA-2A positivity and neutral genotypes predisposing to DKA at diagnosis regardless of its severity. Earlier diagnosis through genetic and immunological screening of high-risk children could decrease DKA incidence at diabetes onset.

Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort.

Abstract: BACKGROUND: Maturity-onset diabetes of the young (MODY) is caused by autosomal dominant mutations in one of 13 confirmed genes Estimates of MODY prevalence vary widely, as genetic screening is usually restricted based on clinical features, even in population studies We aimed to determine prevalence of MODY variants in a large and unselected pediatric diabetes cohort METHODS: MODY variants were assessed using massively parallel sequencing in the population-based diabetes cohort (n = 1363) of the sole tertiary pediatric diabetes service for Western Australia (population 26 million) All individuals were screened, irrespective of clinical features MODY variants were also assessed in a control cohort (n = 993) RESULTS: DNA and signed consent were available for 821 children Seventeen children had pathogenic/likely pathogenic variants in MODY genes, two diagnosed with type 2 diabetes, four diagnosed with antibody-negative type 1 diabetes (T1DM), three diagnosed with antibody-positive T1DM, and eight previously diagnosed with MODY Prevalence of MODY variants in the sequenced cohort was 21%, compared to 03% of controls CONCLUSIONS: This is the first comprehensive study of MODY variants in an unselected population-based pediatric diabetes cohort The observed prevalence, increasing access to rapid and affordable genetic screening, and significant clinical implications suggest that genetic screening for MODY could be considered for all children with diabetes, irrespective of other clinical features

Associations between circulating inflammatory markers, diabetes type and complications in youth

Abstract: BACKGROUND: Inflammation is implicated in the pathogenesis of diabetes and its complications in adults. Little is known about the relative contribution of inflammation in common types of diabetes in youth: type 1 diabetes (T1D), type 2 diabetes (T2D), and cystic fibrosis-related diabetes (CFRD). This study investigates inflammatory markers by diabetes type and complication status, and assesses indicators of inflammation and complications. METHODS: A cross-sectional study of 134 T1D, 32 T2D, 32 CFRD and 48 subjects without diabetes (including 11 with CF and normal glucose tolerance) was undertaken. Inflammation was assessed by sE-selectin by ELISA, hsCRP by turbidimetry, WCC and ESR. Nephropathy was defined by albuminuria, autonomic neuropathy by heart rate variability, and peripheral neuropathy by vibration and thermal threshold testing and retinopathy by seven-field stereoscopic fundus photography. Descriptive statistics, parametric and non-parametric ANOVA and regression analyses were performed, with significance at P < .05. RESULTS: Of 198 diabetic participants; 49% female, mean (SD) age, median diabetes duration and median HbA1c were 16 (2.5) and 6 (3-9) years, and 8.1 (6.9-9.3)%, respectively. All inflammatory markers were lower in T1D than in other diabetes groups (P < .05) but higher than in non-diabetic controls. T2D (n = 32) and CFRD (n = 32) subjects had comparable elevated levels of inflammation. Body mass index (BMI) was a strong independent explanatory variable of inflammation. In multivariate analysis, hsCRP and ESR were associated with complications in addition to HbA1c, BMI, and diastolic BP. CONCLUSIONS: Circulating inflammatory markers are elevated in adolescents with diabetes, being higher and comparable in T2D and CFRD than in T1D. Inflammation is independently associated with diabetes complications, consistent with inflammation driving vascular pathology in diabetes.

Online education for gluten-free diet teaching: Development and usability testing of an e-learning module for children with concurrent celiac disease and type 1 diabetes.

Abstract: Background and objective Celiac disease (CD), the most common genetically-based food intolerance, affects 3% to 16% of children with type 1 diabetes (T1D). Treatment involves lifelong adherence to a gluten-free diet (GFD). Individualized dietary education is resource-intensive. We, therefore, sought to develop and test the usability of an e-learning module aimed at educating patients and caregivers regarding implementation of the GFD in children with concurrent CD and T1D. Methods An interactive e-learning module was developed based on extensive review of CD, T1D, and educational literature. A mixed-methods usability testing approach was used to refine and evaluate the module, using qualitative semi-structured interviews, observations, and satisfaction and knowledge questionnaires in two iterative cycles. The module was refined based on themes identified from each usability cycle. Results Eighteen patients (8 in cycle 1, 10 in cycle 2) and 15 caregivers (7 in cycle 1, 8 in cycle 2) participated. Patient participants had CD and T1D for a mean (SD) of 6.1 ± 5.1 and 8.3 ± 5.5 years, respectively. Their mean age was 13.5 ± 4.5 years. Thematic analysis of usability interviews showed the module to be appealing and resulted in minor module revisions after each cycle to improve usability. Mean satisfaction scores post-module completion were high (4.67 ± 0.54), indicating participants were "very satisfied" with the education. Knowledge test scores increased significantly from pre- to post-module completion (P = 0.001). Conclusion A multifaceted user-centered usability approach demonstrated that an innovative, interactive e-learning module is effective in knowledge retention and can provide comprehensive and accessible information in the implementation of the GFD teaching in children with CD and T1D.

Implementing clinic-wide depression screening for pediatric diabetes: An initiative to improve healthcare processes.

Abstract: Objective Youth with type 1 diabetes (T1D) endorse high rates of depressive symptoms, which can significantly impair self-management, glycemic control, and quality of life. Current guidelines recommend annual depression screening for all adolescents with T1D, but few models exist to implement screening procedures across clinics in this population. The primary aim of this project was to increase depression screening from 0% to 80% in four clinics, and to describe the structured quality improvement process to reach this goal. Methods All patients aged 12 to 21 years old with T1D at four participating clinics in a Midwestern hospital system were eligible to participate. Using a two-stage process, patients were administered the Patient Health Questionnaire (PHQ-2 plus PHQ-9 if positive) annually. Rates of depression screening by clinic site, rates of positive depression screens, social worker documentation of follow-up care, and associations with diabetes-related health outcomes were analyzed. Results Over 2 years, average depression screening rates increased from 0% to 75% across all clinics, and 89% of patients with a positive screen met with a social worker for a targeted mental health assessment. At initial screening, 7.6% of patients screened positive for at-risk depressive symptoms on the PHQ-2 and from that group, 6.7% additionally screened positive on the PHQ-9. Conclusions Annual depression screenings were feasibly implemented across four clinics and the use of real-time data listening and automated processes facilitated successful implementation. Future directions include further automation, targeted training and billing mechanisms, dissemination to non-metropolitan clinics, and further assessment of depression screening tools for adolescents with T1D.

A person-centered education for adolescents with type 1 diabetes-A randomized controlled trial.

Abstract: Introduction Young people with type 1 diabetes and their parents need to receive person-centered education to be able to manage their diabetes. Guided Self-Determination-Young (GSD-Y) is a person-centered communication and reflection education model that can be used in educational program for young people with type 1 diabetes. Objective To evaluate whether GSD-Y leads to improved glycaemic control, increased self-perceived health and health-related quality of life, fewer diabetes-related family conflicts, and improved self-efficacy in a group-based intervention for adolescents starting continuous subcutaneous insulin infusion (CSII) and their parents. Methods This randomized controlled trial included 71 adolescents starting CSII. Participants were followed for 12 months. The intervention group (n = 37) attended seven group training sessions over a period of 5 months, using the GSD-Y model, the control group received standard care. Variables evaluated were HbA1c, self-perceived health, health-related quality of life, family conflicts, self-efficacy, and usage of continuous glucose monitoring. Results When adjusted for sex and family conflicts, there was a difference in glycaemic control between the groups at 12 months, favoring the intervention group (62 vs 70 mmol/mol, P = .009). When analyses were performed on boys and girls separately and adjusted for family conflicts, the only difference detected was for boys after 12 months (P = .019). The intervention showed no effect on self-perceived health, health-related related quality of life, family conflicts, or self-efficacy. Conclusions An intervention with GSD-Y may have an effect on glycaemic control. The content of the GSD-Y groups may serve as a model for person-centered care in adolescents with type 1 diabetes.

Serum catestatin concentrations are decreased in obese children and adolescents.

Abstract: Background Catestatin is a chromogranin A-derived peptide with a wide spectrum of biological activities, such as inhibiting catecholamine release, decreasing blood pressure, stimulating histamine release, reducing beta-adrenergic stimulation, and regulating oxidative stress. Objectives The aims of our study were to determine serum catestatin concentrations in obese children and adolescents in regard to presence or absence of metabolic syndrome (MS) and to evaluate the possible relations between catestatin levels and other cardiovascular risk factors. Subjects Ninety-two obese subjects with a body mass index z score > 2, aged 10 to 18 years, and 39 healthy, normal weight controls were enrolled in the study. Methods Serum catestatin concentrations were measured using an enzyme-linked immunosorbent assay. Results Significantly lower serum catestatin concentrations were recorded in the group of obese subjects compared with a control group (10.03 ± 5.05 vs 13.13 ± 6.25 ng/mL, P = 0.004). Further analyses revealed significantly lower catestatin concentrations in the subgroup of obese patients with MS (9.02 ± 4.3 vs 10.54 ± 5.36 vs 13.13 ± 6.25, P = 0.008). Serum catestatin concentrations were significantly negatively correlated with diastolic blood pressure (r = -0.253, P = 0.014), homeostatic model assessment of insulin resistance (r = -0.215, P = 0.037) and high sensitivity C-reactive protein (r = -0.208, P = 0.044). Conclusions To the best of our knowledge, this study is the first to report catestatin concentrations in obese children and adolescents and their possible relations with MS and cardiovascular risk factors in a pediatric population. Obese subjects with MS have lower serum catestatin concentrations than obese subjects without MS and controls.

Exploring the role of motivational interviewing in adolescent patient-provider communication about type 1 diabetes

Abstract: OBJECTIVE Adolescents with type 1 diabetes (T1D) frequently experience deterioration in glycemic control. Providers have unique opportunities to address diabetes self-management, yet little is known about the most effective way to communicate with adolescents. This investigation used a motivational interviewing (MI) framework to characterize naturally-occurring adolescent patient-provider communication in medical encounters and examined relations between adolescent patient-provider communication and (a) T1D self-management and (b) glycemic control (hemoglobin A1c [HbA1c]). METHODS Medical encounters between pediatric endocrine providers and 55 adolescents with T1D (49% female; M age = 14.8 years; M baseline HbA1c = 8.6%) were audio recorded and coded using standardized rating instruments. Patients and parents completed measures assessing T1D care behaviors and self-efficacy. Assessments were completed at routine endocrinology visits (baseline) and 1 and 3-month post-baseline; HbA1c was obtained from medical records at baseline and 3-month. RESULTS Hierarchical multiple regressions showed that greater provider use of MI non-adherent behaviors (eg, confronting, persuading) was associated with (a) poorer 3-month HbA1c, P < 0.001; (b) worse 1-month adolescent diabetes adherence P < 0.001, and (c) lower diabetes self-efficacy at 1-month (P < 0.001) follow-up. Lower patient self-efficacy for diabetes self-management mediated the relation between provider use of MI non-adherent language and lower diabetes adherence (P = 0.020). CONCLUSION Providers' use of persuasion and confrontation regarding risks of non-adherence was associated with poorer glycemic control and adherence. Communication training for providers that targets reductions in MI-inconsistent language may have the potential to improve diabetes self-care in this vulnerable population.

Glucose metabolism in children and adolescents: Population‐based reference values and comparisons to children and adolescents enrolled in obesity treatment

Abstract: BACKGROUND Alterations in glucose metabolism that lead to the development of metabolic and cardiovascular disease may begin already in childhood. OBJECTIVE This study aims to generate pediatric age and sex-specific reference values for fasting concentrations of glucose, hemoglobin A1c (HbA1c), insulin, C-peptide, and homeostasis model assessment: insulin resistance (HOMA-IR) in Danish/North-European white children and adolescents from a population-based cohort and to compare values from children and adolescents with overweight/obesity with this reference. METHODS The population- and obesity clinic-based cohorts consisted of 2451 and 1935 children and adolescents between 6 and 18 years of age. Anthropometric measurements and blood samples were obtained and percentile curves were calculated. RESULTS In the population-based cohort, glucose, insulin, and HOMA-IR values increased before the expected onset of puberty (P < .05). Thereafter, all variables decreased in girls (P < .05) and HbA1c decreased in boys (P < .05). Concentrations of all measured markers of glucose metabolism were higher in the obesity clinic-based cohort than the population-based cohort (both sexes P < .001). Specifically, insulin and HOMA-IR continued to increase to 18 years in the clinic-based cohort, particularly among boys. CONCLUSIONS Fasting glucose, insulin, and HOMA-IR change during childhood, making pediatric reference values essential for timely identification of derangements in glucose metabolism. Children and adolescents with obesity exhibit increased concentrations of these biomarkers.

Screening for cystic fibrosis-related diabetes and prediabetes: Evaluating 1,5-anhydroglucitol, fructosamine, glycated albumin, and hemoglobin A1c.

Abstract: OBJECTIVE Dysglycemia is prevalent in cystic fibrosis (CF) but screening with annual oral glucose tolerance tests (OGTT) can be burdensome. We investigated alternate glycemic markers-hemoglobin A1c (HbA1c), 1,5-anhydroglucitol (1,5AG), fructosamine (FA), and glycated albumin (GA)-as screening tests for CF-related diabetes (CFRD) and pre-diabetes (CFPD) in youth with CF as defined by the gold-standard OGTT 2-hour glucose (2hG). METHODS Youth 10 to 18 years with CF had a 1,5AG, FA, GA, HbA1c, and 2-hour OGTT collected. Correlations between all glycemic markers and 2hG were evaluated. Area under the receiver operative characteristic (ROC-AUC) curves were generated. Optimal cut points for predicting CFPD (2hG ≥ 140 mg/dL) and CFRD (2hG ≥ 200 mg/dL) were determined. RESULTS Fifty-eight youth with CF were included (2hG < 140, n = 16; CFPD, n = 33; CFRD, n = 9; 41% male, mean ± SD age 14.2 ± 3.6 years, BMI z-score 0.0 ± 0.8, % predicted forced expiratory volume in 1 second [FEV1] 89.9 ± 15.1, % predicted forced vital capacity [FVC] 103.2 ± 14.6). ROC-AUC's for all alternate markers were low for CFPD (0.52-0.67) and CFRD (0.56-0.61). At a cut point of 5.5%, HbA1c had 78% sensitivity (95% CI: 0.45-0.94) and 41% specificity (95% CI: 0.28-0.55) for identifying CFRD, correlating to a ROC-AUC of 0.61 (95% CI: 0.42-0.8). CONCLUSIONS All alternate markers tested demonstrate poor diagnostic accuracy for identifying CFRD by 2hG.

A structured 1-year education program for children with newly diagnosed type 1 diabetes improves early glycemic control.

Abstract: BACKGROUND The diagnosis of type 1 diabetes (T1D) brings significant medical, psychosocial, and educational challenges for the child, family, and medical team. We developed a structured certified diabetes educator (CDE) led program spanning the year after diagnosis with the goal of supporting families as their understanding of this chronic disease and its management evolves. OBJECTIVE The aim of this study was to determine the effect of this program upon hemoglobin A1c (HbA1c), and how this effect is mitigated by socioeconomic status (SES). METHODS Patients enrolled in the type 1 year 1 (T1Y1) program were assigned a CDE who provided intensive coaching, tailored to family lifestyle, and readiness to assume independence. We identified all patients diagnosed with T1D in the 2 years before (controls) and after (T1Y1 group) the start of the T1Y1 program on January 7, 2014. RESULTS There were 675 patients diagnosed with T1D between July 2012 and June 2016 (284 controls, 391 T1Y1). HbA1c was significantly lower in the T1Y1 group at 6 (6.7% vs. 7.1%, P < 0.001), 12 (7.3% vs. 7.8%, P < 0.001) and 18 (7.6% vs. 7.9%, P = 0.01) months, but not 24 (7.8% vs. 8%, P = 0.14) months after diagnosis. This effect was not observed in patients with lower SES. CONCLUSION Additional structured education and support in the year after diagnosis can improve short-term outcomes in children with T1D, but this effect may not persist after discontinuing intensive coaching. Families of lower SES did not benefit from this approach.

KLF11 variant in a family clinically diagnosed with early childhood‐onset type 1B diabetes

Abstract: KLF11 is the causative gene for maturity-onset diabetes of the young 7 (MODY7). KLF11 regulates insulin gene expression through binding to the GC box in the promoter. To date, only two KLF11 mutations have been identified in three families with early-onset type 2 diabetes. Here, we report a novel KLF11 variant associated with early childhood-onset type 1B diabetes. The proband and his younger sister exhibited hyperglycemia at age 1 year, and their mother developed diabetes at age 4 years. These three individuals required insulin injection from the initial phase of the disease. Being negative for islet cell autoantibodies, they were diagnosed with type 1B diabetes. Mutation screening for 30 diabetes-associated genes identified a heterozygous KLF11 variant (p.His418Gln) in the proband and his sister. The variant was also detected in the affected mother, as well as in the allegedly unaffected maternal grandmother. In silico analyses indicated that this variant involves a highly conserved histidine residue in the first C2 H2 zinc finger domain which ligates a zinc ion. In vitro analyses showed that expression levels and intracellular localization of His418Gln-KLF11 were comparable to those of wildtype (WT)-KLF11. Luciferase assays demonstrated that while WT-KLF11 suppressed the activity of a 6 × GC box-containing reporter, His418Gln-KLF11 lacked the suppressive effect. Notably, His418Gln-KLF11 canceled the suppressive effect of co-transfected WT-KLF11. Such a dominant-negative effect was absent in the previously reported Ala347Ser-KLF11 variant. These results indicate that specific variants of KLF11 (MODY7) with a dominant-negative effect underlie early childhood-onset type 1B diabetes with incomplete penetrance. This study documents a novel monogenic mutation associated with diabetes in children.