Effect of fenofibrate on residual beta cell function in adults and adolescents with newly diagnosed type 1 diabetes: a randomised clinical trial.

AIMS/HYPOTHESIS: Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, shows some promise in alleviating beta cell stress and preserving beta cell function in preclinical studies of type 1 diabetes. The aim of this phase 2, placebo-controlled, double-blinded, randomised clinical trial was to investigate the efficacy and safety of fenofibrate in adults and adolescents with newly diagnosed type 1 diabetes. METHODS: We enrolled 58 individuals (aged 16 to 40 years old) with newly diagnosed type 1 diabetes and randomised them to daily oral treatment with fenofibrate 160 mg or placebo for 52 weeks (in a block design with a block size of 4, assigned in a 1:1 ratio). Our primary outcome was change in beta cell function after 52 weeks of treatment, assessed by AUC for C-peptide levels following a 2 h mixed-meal tolerance test. Secondary outcomes included glycaemic control (assessed by HbA1c and continuous glucose monitoring), daily insulin use, and proinsulin/C-peptide (PI/C) ratio as a marker of beta cell stress. We assessed outcome measures before and after 4, 12, 26 and 52 weeks of treatment. Blinding was maintained for participants, their healthcare providers and all staff involved in handling outcome samples and assessment. RESULTS: The statistical analyses for the primary outcome included 56 participants (n=27 in the fenofibrate group, after two withdrawals, and n=29 in the placebo group). We found no significant differences between the groups in either 2 h C-peptide levels (mean difference of 0.08 nmol/l [95% CI -0.05, 0.23]), insulin use or glycaemic control after 52 weeks of treatment. On the contrary, the fenofibrate group showed a higher PI/C ratio at week 52 compared with placebo (mean difference of 0.024 [95% CI 0.000, 0.048], p<0.05). Blood lipidome analysis revealed that fenofibrate repressed pathways involved in sphingolipid metabolism and signalling at week 52 compared with placebo. The 52 week intervention evoked few adverse events and no serious adverse events. Follow-up in vitro experiments in human pancreatic islets demonstrated a stress-inducing effect of fenofibrate. CONCLUSIONS/INTERPRETATION: Contrary to the beneficial effects of fenofibrate found in preclinical studies, this longitudinal, randomised, placebo-controlled trial does not support the use of fenofibrate for preserving beta cell function in individuals with newly diagnosed type 1 diabetes. TRIAL REGISTRATION: EudraCT number: 2019-004434-41 FUNDING: This study was funded by the Sehested Hansens Foundation.

The INNODIA Type 1 Diabetes Natural History Study: a European cohort of newly diagnosed children, adolescents and adults.

AIMS/HYPOTHESIS: Type 1 diabetes is an heterogenous condition. Characterising factors explaining differences in an individual's clinical course and treatment response will have important clinical and research implications. Our aim was to explore type 1 diabetes heterogeneity, as assessed by clinical characteristics, autoantibodies, beta cell function and glycaemic outcomes, during the first 12 months from diagnosis, and how it relates to age at diagnosis. METHODS: Data were collected from the large INNODIA cohort of individuals (aged 1.0-45.0 years) newly diagnosed with type 1 diabetes, followed 3 monthly, to assess clinical characteristics, C-peptide, HbA1c and diabetes-associated antibodies, and their changes, during the first 12 months from diagnosis, across three age groups: <10 years; 10-17 years; and ≥18 years. RESULTS: The study population included 649 individuals (57.3% male; age 12.1±8.3 years), 96.9% of whom were positive for one or more diabetes-related antibodies. Baseline (IQR) fasting C-peptide was 242.0 (139.0-382.0) pmol/l (AUC 749.3 [466.2-1106.1] pmol/l × min), with levels increasing with age (p<0.001). Over time, C-peptide remained lower in participants aged <10 years but it declined in all age groups. In parallel, glucose levels progressively increased. Lower baseline fasting C-peptide, BMI SD score and presence of diabetic ketoacidosis at diagnosis were associated with lower stimulated C-peptide over time. HbA1c decreased during the first 3 months (p<0.001), whereas insulin requirement increased from 3 months post diagnosis (p<0.001). CONCLUSIONS/INTERPRETATION: In this large cohort with newly diagnosed type 1 diabetes, we identified age-related differences in clinical and biochemical variables. Of note, C-peptide was lower in younger children but there were no main age differences in its rate of decline.

Lipid levels in a cohort of healthy Danish schoolchildren ages 5 to 17 years.

It is internationally recognized to use clinical decision limits (CDL) when interpreting the lipid levels in both adults and children, even though the evidence for children is scarce. The purpose of this study is to describe how lipid levels progress in healthy Danish children ages 5 to 17 years. This study is based on the Childhood Health, Activity, and Motor Performance School Study Denmark (CHAMPS-study DK) consisting of 1456 observations of schoolchildren aged 5 to 17 years. Participants have been tested for blood levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and remnant cholesterol levels are calculated. Finally, sex-specific percentile reference curves are presented. Percentile reference curves stratified by sex were generated for all cholesterols and showed that the total cholesterol level peaks at 4.32 mmol/l in 10-year-old boys and 4.46 mmol/l in nine-year-old girls. HDL levels in boys peak at 1.72 mmol/l in nine-year-old boys. HDL levels in girls and LDL levels in both sexes are nearly constant. Triglycerides kept rising to the age of 17 years in both sexes and remnant cholesterol decreased from age 5 to 17 years in both sexes. BMI z-score adjustment revealed no significant association with total cholesterol in both sexes but a significant association between HDL, LDL, triglycerides, and remnant cholesterol. This study is the first to generate percentile reference curves for blood levels of total cholesterol, LDL, HDL, triglycerides, and remnant cholesterol in a cohort of healthy Danish children aged 5 to 17 years.

Differences in insulin sensitivity in the partial remission phase of childhood type 1 diabetes; a longitudinal cohort study.

AIMS: Studies suggest that type 1 diabetes (T1D) contributes to impaired insulin sensitivity (IS). Most children with T1D experience partial remission but the knowledge regarding the magnitude and implications of impaired IS in this phase is limited. Therefore, we investigate the impact of IS on the partial remission phase. METHODS: In a longitudinal study of children and adolescents, participants were seen at three clinical visits during the first 14.5 months after diagnosis of T1D. Partial remission was defined as IDAA1c (HbA1c (%) + 4*daily insulin dose) ≤ 9. Beta-cell function was considered significant by a stimulated c-peptide > 300 pmol/L. Participants were characterized by (i) remission or non-remission and (ii) stimulated c-peptide levels above or below 300 pmol/L. IS, body mass index (BMI), total body fat, sex, age, pubertal status and ketoacidosis at onset were compared. RESULTS: Seventy-eight children and adolescents aged 3.3-17.7 years were included. At 14.5 months post-diagnosis, 54.5% of the participants with stimulated c-peptide > 300 pmol/L were not in partial remission. Participants not in remission had significant lower IS 2.5 (p = 0.032), and 14.5 (p = 0.022) months after diagnosis compared to participants in partial remission with similar c-peptide levels. IS did not fluctuate during the remission phase. CONCLUSIONS: A number of children and adolescents have impaired IS in the remission phase of paediatric T1D and are not in remission 14.5 months after diagnosis despite stimulated c-peptide > 300 pmol/L.

The metabolic syndrome is frequent in children and adolescents with type 1 diabetes compared to healthy controls.

OBJECTIVE: There is a rise in overweight and obesity among children and adolescents with type 1 diabetes (T1D) in parallel with the rise in the metabolic syndrome (MetS) among children and adolescents. The aim of the study was to describe the prevalence and characteristics of MetS in children and adolescents with T1D compared to their healthy counterparts. RESEARCH DESIGN AND METHODS: The study includes two Danish cohorts; (i) the Copenhagen cross sectional cohort 2016 of 277 children and adolescents with T1D that attend the pediatric outpatient clinic at a large hospital in greater Copenhagen and (ii) the CHAMPS-study DK which is a population-based cohort study of Danish children and adolescents (control cohort). Participants were categorized to have MetS if at least two of the following criteria were met: (i) systolic and/or diastolic blood pressure ≥ 90th percentile, (ii) waist circumference ≥90th percentile, and (iii) triglyceride ≥90th percentile and/or HDL ≤10th percentile. RESULTS: The prevalence of children with Mets in the T1D cohort was higher than in the control cohort (p = 0.002). Moreover, participants with T1D had MetS at a lower level of BMI (p < 0.001) and waist circumference (p < 0.001) than participants with MetS from the control cohort (z-scores = 0.90 and 1.51). Participants with MetS were younger than the other T1D participants (median 12.8 [9.9,14.8] vs. median 14.6 [11.2,16.9] years, p = 0.006). CONCLUSIONS: Children and adolescents with T1D have an increased risk of MetS compared to healthy controls and clinicians and caretakers should consider early prevention and health promotion strategies.

Reference serum percentile values of adiponectin, leptin, and adiponectin/leptin ratio in healthy Danish children and adolescents.

The adipokines adiponectin and leptin play key roles in human metabolic regulation and have gained great attention as biomarkers for various metabolic pathologies. Though, pediatric reference values are few and needed. This study aims to establish age- and sex-specific adipokine reference percentiles based on healthy Danish school children. Further, it elucidates sex-specific differences in associations between z-scores of examined adipokines and metabolic variables. Serum adiponectin and serum leptin from 853 observations of healthy Danish schoolchildren aged 8-17 years (median 10.0) were quantified by immunoassays. Age- and sex-specific adipokine reference percentiles were calculated cross-sectionally using the LMS method, and adipokine z-scores were calculated from the fitted model. Multiple linear regression models were used to examine sex-specific differences in associations between adipokine z-scores and various metabolic variables. Girls had a higher median value of adiponectin (11.31 vs. 10.65 µg/mL, p < .001) and leptin (2.30 vs. 1.00 ng/mL, p < .001) and a lower median value of adiponectin/leptin ratio (4.64 vs. 10.76, p < .001) compared to boys. Sex-specific differences were found in associations between adiponectin z-score and HDL (p = .010), between leptin z-score and waist circumference z-score (p = .027) and LDL (p = .048), and between adiponectin/leptin ratio z-scores and waist circumference z-score (p = .044) and LDL (p = .040). Reference percentiles of adiponectin, leptin, and adiponectin/leptin ratio are presented in this paper. To our knowledge, this study is the first to demonstrate sex-specific differences in associations between adipokine z-scores and waist circumference z-score and lipids, respectively in healthy children and adolescents.

Unaffected bone mineral density in Danish children and adolescents with type 1 diabetes.

AIMS: Adults with type 1 diabetes mellitus (T1D) have decreased bone mineral density (BMD). Our study aimed at determining BMD and the association to metabolic control in children and adolescents with T1D. METHODS: 244 patients (113 girls) with a median age of 14.3 years and T1D duration of 1-16 years were included. A dual-energy X-ray absorptiometry scan assessed BMD Z-scores excluding the head (total body less head, TBLH). TBLH-BMD were then investigated for associations to diabetes relevant variables such as HbA1c, insulin treatment, anthropometry and physical activity. RESULTS: In all participants the TBLH-BMD Z-score (0.22 ± 0.96) was significantly higher than the references. Separated by sex, TBLH-BMD Z-score in boys (0.11 ± 0.84) was no different from healthy peers whereas TBLH-BMD Z-score was significantly higher in girls (0.36 ± 1.09). The higher TBLH-BMD Z-score in girls were explained by higher BMI Z-scores. Participants with assumed final height (based on age) had an average TBLH-BMD Z-score of 0.78 ± 1.06, significantly higher than references independent of gender, HbA1c, height- and weight Z-scores. Multiple regression analyses showed that TBLH BMD Z-score associated negatively to HbA1c (P = 0.003), pump treatment (P = 0.019) and screen-time (P = 0.005) and positively to weight Z-score (P < 0.001). Physical activity, sex and puberty did not significantly associate to TBLH-BMD Z-score. CONCLUSION: Unlike adults with T1D, BMD is not decreased in children and adolescents with T1D and even elevated after attained final height. As HbA1c negatively associates to BMD, decreased BMD may progress over time. Whether changes in microarchitecture or bone metabolism precede changes in BMD needs further investigation.

High prevalence of disordered eating behavior in Danish children and adolescents with type 1 diabetes.

OBJECTIVE: A higher prevalence of disordered eating behavior (DEB) has been demonstrated in children and adolescents with type 1 diabetes (T1D) compared to healthy aged-matched peers. DEB is associated with higher HbA1c levels and increased risk of developing complications to T1D. The aim of this study was to determine the prevalence of DEB in a Danish cohort of children and adolescents with T1D aged 11 to 19 years and to characterize them regarding metabolic control and relevant clinical data. RESEARCH DESIGN AND METHODS: In a cross-sectional study, we determined the prevalence of DEB using the revised Diabetes Eating Problem Survey (DEPS-R) questionnaire. HbA1c and relevant clinical data were obtained at the time they filled in the questionnaire. RESULTS: Hundred and ninety-two children and adolescents (46% girls) aged 11 to 19 years with T1D were included from the pediatric diabetes outpatient clinic. A total of 40 participants (21%) had DEB. The prevalence was higher among girls compared with boys (34.1% vs 8.9%) and those who had DEB were older (16.7 vs 15.0 years, P < .001), had longer duration of T1D (7.5 vs 4.9 years, P < .001), higher BMI Z-scores (1.2 vs 0.3, P < .001), higher HbA1c (72.8 (8.8%) vs 62.0 (7.8%) mmol/mol, P < .001), higher total cholesterol (4.6 mmol/L vs 4.2 mmol/L, P = .0048), and LDL (2.7 vs 2.3, P = .001) compared with those with no signs of DEB. CONCLUSION: As in other countries, the prevalence of DEB is high in Danish adolescents with T1D. Early detection of DEB is essential to prevent short- and long-term complications to T1D.

Episodes of severe hypoglycemia is associated with a progressive increase in hemoglobin A1c in children and adolescents with type 1 diabetes.

OBJECTIVE: To investigate the trajectory in glycemic control following episodes of severe hypoglycemia (SH) among children and adolescents with type 1 diabetes (T1D). METHODS: A Danish national population-based study comprising data from 2008-17. SH was defined according to the 2014 ISPAD guidelines. A mixed model was applied with HbA1c as outcome and SH episodes and time since first episode as explanatory variables. Data were adjusted for age, gender and diabetes duration. RESULTS: A total of 4244 children (51.6% boys) with 18 793 annual outpatient visits were included. Mean (SD) age at diabetes onset was 9.0 (4.1) years. Median diabetes duration at inclusion in the study was 1.2 (Q1 = 0.9, Q3 = 3.0) years, and median diabetes duration at last visit was 5.0 (Q1 = 2.7, Q3 = 8.1) years. A total of 506 children experienced at least one episode of SH during the nine-year follow-up; 294 children experienced one episode, 115 two episodes and 97 three or more episodes of SH. HbA1c increased with episodes of SH and in the years following the first episode. The glycemic trajectory peaked 2 to 3 years after an SH episode. The accumulated deterioration in glycemic control was in the range of 5% in patients with two or more episodes equivalent to an increase in HbA1c of 4 mmol/mol (HbA1c ~0.4%). CONCLUSION: SH was followed by a progressive and lasting increase in HbA1c among Danish children and adolescents with T1D. Thus, in addition to the known risk of new episodes of hypoglycemia and cognitive impairment, SH contributes to long-term diabetes complications.

Decreased markers of bone turnover in children and adolescents with type 1 diabetes.

BACKGROUND AND AIM: Adults with type 1 diabetes (T1D) have increased risk of bone fractures and decreased bone mineral density (BMD). Alterations in bone turnover have been suggested as the link between T1D and the impaired bone health. Furthermore, bone turnover has been suggested to have beneficial effects on glucose metabolism. This study aimed at describing bone turnover markers (BTM), and the relationship with glycemic control, in children and adolescents with T1D. METHODS: A total of 173 (47% girls) children and adolescents aged 7.7 to 17.5 years with T1D for more than 1 year were included. Participants were evaluated by BMD together with measurements of selected BTM; two formation markers: osteocalcin (OCN) and procollagen type-1 amino-terminal propeptide (P1NP) and one resorption marker, C-terminal cross-linked telopeptide of type-1 collagen (CTX). BTM were converted into Z-scores utilizing new national references. RESULTS: Mean OCN Z-score (-0.68 ± 1.31), P1NP Z-score (-0.33 ± 1.03) and CTX Z-score (-0.43 ± 1.10) were all significantly lower than the reference population (P < .001). No associations were seen between BTM and T1D duration. BMD Z-score was comparable to the reference population and associated with none of individual BTMs. CTX Z-score was negatively associated with HbA1c (P = .007) independent of both exogenous and residual endogenous insulin. CONCLUSIONS: Markers of bone formation and resorption were decreased in children and adolescents with T1D. CTX Z-score associated negatively with HbA1c adjusted for insulin treatment and endogenous insulin production indicating a potential association between CTX and insulin sensitivity. The long-term consequences of decreased BTM on BMD need further attention.

Screening for retinopathy in children with type 1 diabetes in Denmark.

BACKGROUND/OBJECTIVE: Children with type 1 diabetes (T1D) are screened regularly for retinopathy with fundus photography to prevent visual impairment. According to Danish national guidelines, screening should take place at age 12, 15, and 18 years after minimum 3 years of diabetes. As glycemic control has improved, prevalence of retinopathy is expected to be decreased. The aim of this study is to investigate the prevalence, degree, and progression of retinopathy in children with T1D and to explore if screening at 12 years is currently indicated in Denmark. METHODS: Data on all Danish children with onset of T1D from 2003 to 2013 (n = 2943) were collected from the "DanDiabKids" registry. For children with registered screenings (n = 2382), prevalence of retinopathy at 12, 15, and 18 years was determined. In children with retinopathy, subsequent screenings were studied to reveal if retinopathy was persistent or temporary. RESULTS: Prevalence of retinopathy at 12, 15, and 18 years was 0.9%, 2.3%, and 3.1%, respectively. Minimal background retinopathy was seen in over 90% and 100% at 12 years. In available re-screenings, retinopathy resolved spontaneously in 87.5% of all cases and 100% of cases at 12 years. CONCLUSIONS: The prevalence of retinopathy in Danish children with T1D was low. At 12 years, prevalence was 0.9% and exclusively minimal background retinopathy with 100% remission in re-screenings. Thus, screening at this age does not seem to have significant clinical relevance. We propose more individualized screening selection before the age of 15.

Bone turnover markers during the remission phase in children and adolescents with type 1 diabetes.

BACKGROUND AND AIM: In rodents, osteocalcin (OCN) stimulates insulin production and insulin sensitivity, both important factors during partial remission in humans with type 1 diabetes (T1D). However, decreased OCN has been reported in both adult and pediatric T1D. This study aims at investigating bone turnover and partial remission in children and adolescents with recent onset T1D. SUBJECTS AND METHODS: Ninety-nine individuals (33% girls) were recruited within 3 months of T1D onset and examined three times, 6 months apart. Outcome variables were bone formation markers OCN and procollagen type 1 amino-terminal propeptide (P1NP) and the bone resorption marker C-terminal crosslinked telopeptide of type 1 collagen (CTX). Dependent variables included IDAA1c (surrogate marker of partial remission), total body bone mineral density (BMD) and stimulated C-peptide as representative of endogenous insulin production. RESULTS: OCN- and P1NP Z-scores were significantly decreased throughout the study, whereas CTX Z-scores were increased. None of the bone turnover markers changed significantly between visits. Total body BMD Z-score did not change during the study but was significantly higher than the reference population at visit 2 (P = .035). There were no differences in the bone turnover markers for those in partial remission as defined by either C-peptide or IDAA1c at any visit. The individual change in CTX Z-score was negatively associated with the increase of IDAA1c (P = .030) independent of C-peptide decline (P = .034). CONCLUSION: Bone turnover markers indicate increased bone resorption and decreased bone formation during the first year of T1D. The negative association between bone resorption and IDAA1c might represent compensatory mechanisms affecting insulin sensitivity.

Systemic TNFα correlates with residual ß-cell function in children and adolescents newly diagnosed with type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is caused by immune-mediated destruction of the ß-cells. After initiation of insulin therapy many patients experience a period of improved residual ß-cell function leading to partial disease remission. Cytokines are important immune-modulatory molecules and contribute to ß-cell damage in T1D. The patterns of systemic circulating cytokines during T1D remission are not clear but may constitute biomarkers of disease status and progression. In this study, we investigated if the plasma levels of various pro- and anti-inflammatory cytokines around time of diagnosis were predictors of remission and residual ß-cell function in children with T1D followed for one year after disease onset. METHODS: In a cohort of 63 newly diagnosed children (33% females) with T1D with a mean age of 11.3 years (3.3-17.7), ten cytokines were measured of which eight were detectable in plasma samples by Mesoscale Discovery multiplex technology at study start and after 6 and 12 months. Linear regression models were used to evaluate association of cytokines with stimulated C-peptide. RESULTS: Systemic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2 and IL-6 inversely correlated with stimulated C-peptide levels over the entire study (P < 0.05). The concentrations of TNFα and IL-10 at study start predicted stimulated C-peptide level at 6 months (P = 0.011 and P = 0.043, respectively, adjusted for sex, age, HbA1c and stage of puberty). CONCLUSIONS: In recent-onset T1D, systemic cytokine levels, and in particular that of TNFα, correlate with residual ß-cell function and may serve as prognostic biomarkers of disease remission and progression to optimize treatment strategies. TRIAL REGISTRATION: The study was performed according to the criteria of the Helsinki II Declaration and was approved by the Danish Capital Region Ethics Committee on Biomedical Research Ethics (journal number H-3-2014-052). The parents of all participants gave written consent.

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

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.

Parental Smoking and Risk of Childhood-onset Type 1 Diabetes.

BACKGROUND: A few prospective studies suggest an association between maternal smoking during pregnancy and lower risk of type 1 diabetes. However, the role of unmeasured confounding and misclassification remains unclear. METHODS: We comprehensively evaluated whether maternal smoking in pregnancy predicts lower risk of childhood-onset type 1 diabetes in two Scandinavian pregnancy cohorts (185,076 children; 689 cases) and a Norwegian register-based cohort (434,627 children; 692 cases). We measured cord blood cotinine as an objective marker of nicotine exposure during late pregnancy in 154 cases and 476 controls. We also examined paternal smoking during pregnancy, in addition to environmental tobacco smoke exposure the first 6 months of life, to clarify the role of characteristics of smokers in general. RESULTS: In the pregnancy cohorts, maternal smoking beyond gestational week 12 was inversely associated with type 1 diabetes, pooled adjusted hazard ratio (aHR) 0.66 (95% CI = 0.51, 0.85). Similarly, in the Norwegian register-based cohort, children of mothers who still smoked at the end of pregnancy had lower risk of type 1 diabetes, aHR 0.65 (95% CI = 0.47, 0.89). Cord blood cotinine ≥30 nmol/L was also associated with reduced risk of type 1 diabetes, adjusted odds ratio 0.42 (95% CI = 0.17, 1.0). We observed no associations of paternal smoking during pregnancy, or environmental tobacco smoke exposure, with childhood-onset type 1 diabetes. CONCLUSION: Maternal sustained smoking during pregnancy is associated with lower risk of type 1 diabetes in children. This sheds new light on the potential intrauterine environmental origins of the disease.

Childhood body mass index in relation to subsequent risk of type 1 diabetes-A Danish cohort study.

The incidence of type 1 diabetes (T1D) is increasing, and obesity may be a contributing factor by increasing the risk and accelerating the onset. We investigated the relation between childhood body mass index z-scores (BMIz) and the later risk of T1D, including association with age at onset of T1D. The study included 238 cases and 10 147 controls selected from the Copenhagen School Health Record Register (CSHRR). Cases of T1D were identified in the Danish Registry of Childhood and Adolescent Diabetes and 2 regional studies and linked to CSHRR. Using conditional logistic regression models, the association of childhood prediagnostic BMIz at 7 and 13 years of age and changes between these ages with subsequent risk (odds ratio, OR) of T1D was estimated. A greater BMIz at 7 and 13 years of age was associated with increased risk of T1D with OR of 1.23 (confidence interval, CI 1.09-1.37; P = .0001) and 1.20 (CI 1.04-1.40; P = .016), respectively. The risk was increased by upward changes in z-scores from birth to 7 years (OR=1.21, P = .003) and from 7 to 13 years of age (OR=1.95, P = .023), but in the latter age interval also by a decline in BMIz (OR = 1.91, P = .034). There were no associations between BMIz at 7 and 13 years of age and the age of onset (P = .34 and P = .42, respectively). Increased BMIz is associated with a moderate increase in risk of T1D, but with no relation to age at onset within the analyzed age range. Increased BMIz over time is unlikely to explain the rising incidence of T1D.

Impaired fasting glucose and the metabolic profile in Danish children and adolescents with normal weight, overweight, or obesity.

OBJECTIVE: Whether the definitions of impaired fasting glucose (IFG) from the American Diabetes Association (ADA) and the World Health Organization (WHO) differentially impact estimates of the metabolic profile and IFG-related comorbidities in Danish children and adolescents is unknown. METHODS: Two thousand one hundred and fifty four (979 boys) children and adolescents with overweight or obesity (median age 12 years) and 1824 (728 boys) children with normal weight (median age 12 years) from The Danish Childhood Obesity Biobank were studied. Anthropometrics, blood pressure, puberty, and fasting concentrations of glucose, insulin, glycosylated hemoglobin (HbA1c), and lipids were measured. RESULTS: About 14.1% of participants with overweight or obesity exhibited IFG according to the ADA and 3.5% according to the WHO definition. Among individuals with normal weight, the corresponding prevalences were 4.3% and 0.3%. IFG was associated with a higher systolic blood pressure, higher concentrations of HbA1c, insulin, C-peptide (P < .0001) and triglycerides (P = .03), and lower HOMA2-IS and HOMA2-B (P < .0001) independent of sex, age, puberty, waist-to-height ratio, and degree of obesity. Furthermore, IFG was associated with a higher risk for hypertension (OR = 1.66 [95%CI: 1.21; 2.28], P = .002) and dyslipidemia (OR = 1.90 [95%CI: 1.38; 2.56], P < .0001) compared with the group without IFG independent of age, sex, and puberty. CONCLUSIONS: The prevalence of IFG, when applying the ADA criterion compared with the WHO criterion, was 4 times higher in individuals with overweight and obesity and 14 times higher in individuals with normal weight in this study sample of children and adolescents. IFG was associated with a higher risk of hypertension and dyslipidemia compared with their normoglycemic peers regardless of the definition applied.

The effect of impaired glucose metabolism on weight loss in multidisciplinary childhood obesity treatment.

OBJECTIVE: To investigate whether children and adolescents exhibiting an impaired glucose metabolism are more obese at treatment entry and less likely to reduce their degree of obesity during treatment. METHODS: The present study is a longitudinal observational study, including children and adolescents from the Children's Obesity Clinic, Holbaek, Denmark. Anthropometrics, pubertal development, socioeconomic status (SES), and fasting concentrations of plasma glucose, serum insulin, serum C-peptide, and whole blood glycosylated hemoglobin (HbA1c) were collected at treatment entry and at follow-up. Proxies of Homeostasis Model Assessment 2-insulin sensitivity (HOMA2-IS) and Homeostasis Model Assessment 2-ß-cell function (HOMA2-B) were calculated with the Homeostasis Model Assessment 2 program. RESULTS: In total, 569 (333 boys) patients, median 11.5 years of age (range 6-22 years), and median body mass index (BMI) z-score 2.94 (range 1.34-5.54) were included. The mean BMI z-score reduction was 0.31 (±0.46) after 13 months (range 6-18) of treatment. At treatment entry, patients with impaired estimates of glucose metabolism were more obese than normoglycemic patients. Baseline concentration of C-peptide was associated with a lower weight loss during treatment in girls (P = .02). Reduction in the insulin concentrations was associated with reduction in BMI z-score in both sexes (P < .0001, P = .0005). During treatment, values of glucose, HbA1c, HOMA2-IS, and HOMA2-B did not change or impact the treatment outcome, regardless of age, sex, SES, or degree of obesity at treatment entry. CONCLUSION: The capability to reduce weight during multidisciplinary treatment in children and adolescents with overweight/obesity is not influenced by an impaired glucose metabolism at study entry or during the course of treatment.

Levels of soluble TREM-1 in children with newly diagnosed type 1 diabetes and their siblings without type 1 diabetes: a Danish case-control study.

BACKGROUND: Type 1 diabetes (T1D) is an organ-specific autoimmune disease with an increase in incidence worldwide including Denmark. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a potent amplifier of pro-inflammatory responses and has been linked to autoimmunity, severe psychiatric disorders, sepsis, and cancer. HYPOTHESIS: Our primary hypothesis was that levels of soluble TREM-1 (sTREM-1) differed between newly diagnosed children with T1D and their siblings without T1D. METHODS: Since 1996, the Danish Childhood Diabetes Register has collected data on all patients who have developed T1D before the age of 18 years. Four hundred and eighty-one patients and 478 siblings with measurements of sTREM-1-blood samples were taken within 3 months after onset-were available for statistical analyses. Sample period was from 1997 through 2005. A robust log-normal regression model was used, which takes into account that measurements are left censored and accounts for correlation within siblings from the same family. RESULTS: In the multiple regression model (case status, gender, age, HLA-risk, season, and period of sampling), levels of sTREM-1 were found to be significantly higher in patients (relative change [95%CI], 1.5 [1.1; 2.2],P = 0.02), but after adjustment for multiple testing our result was no longer statistically significant (P adjust = 0.1). We observed a statistical significant temporal increase in levels of sTREM-1. CONCLUSION: Our results need to be replicated by independent studies, but our study suggests that the TREM-1 pathway may have a role in T1D pathogenesis.

Type 2 diabetes mellitus in Danish children and adolescents in 2014.

BACKGROUND/OBJECTIVE: The global increase in childhood obesity has in some countries been followed by an increase in type 2 diabetes mellitus (T2DM); however, the prevalence of T2DM among Danish children and adolescents is currently unknown. The aims of this cross-sectional study were to determine the prevalence of T2DM in children and adolescents in Denmark together with status on treatment, metabolic control, and late diabetic complications. METHODS: Individuals were identified in the Danish Registry for Diabetes in Children and Adolescents (DanDiabKids), and clinical information regarding these was obtained from the respective pediatric departments. RESULTS: In total, seven young individuals (three boys) with T2DM were identified, according to the American Diabetes Association (ADA)/International Society of Pediatric and Adolecent Diabetes (ISPAD) guidelines, leading to a prevalence of T2DM at 0.6/100 000 inhabitants in Denmark. Only three of the patients had hyperglycemic symptoms at diagnosis. One boy was overweight and six were obese (two boys). Currently, no patients fulfill the treatment target of glycosylated hemoglobin (HbA1c) <7.0% (53 mmol/mol) according to the guidelines for treatment of diabetes. CONCLUSIONS: In 2014, there is no increasing prevalence of T2DM in children and adolescents in Denmark. Nevertheless, the current treatment regimen is not satisfying, as none of the patients truly fulfill the treatment target.