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.

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.

Polymorphisms in the CTSH gene may influence the progression of diabetic retinopathy: a candidate-gene study in the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

BACKGROUND: The incidence of type 1 diabetes mellitus (T1DM) is increasing globally, and as a consequence, more patients are affected by microvascular complications such as diabetic retinopathy (DR). The aim of this study was to elucidate possible associations between diabetes-related single-nucleotide polymorphisms (SNP) and the development of DR. METHODS: Three hundred and thirty-nine patients with T1DM from the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987) went through an ophthalmic examination in 1995; 185 of these were reexamined in 2011. The development of DR was assessed by comparison of overall DR level between baseline and follow-up in the worst eye at baseline. Patients were graded on a modified version of the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and 20 SNPs were genotyped in 130 of the 185 patients. RESULTS: We found the CTSH/rs3825932 variant (C > T) was associated with reduced risk of progression to proliferative diabetic retinopathy (PDR) (OR [95 % CI] = 0.20 [0.07-0.56], p = 2.4 × 10(-3), padjust = 0.048) and ERBB3/rs2292239 variant (G > T) associated with increased risk of two-step progression (OR [95 % CI] = 2.76 [1.31-5.80], p = 7.5 × 10(-3), padjust = 0.15). The associations were independent of other known risk factors, such as HbA1c, sex, and diastolic blood pressure. CONCLUSION: In conclusion, CTSH/rs3825932 and ERBB3/rs2292239 SNPs were associated with reduced risk of progression to PDR and two-step progression of DR on the ETDRS scale accordingly. The variant CTSH remained statistically significant after adjusting for multiple testing. Our results suggest an overlap between genetic variants that confer risk of T1DM and progression of DR.

Retinal vascular fractals predict long-term microvascular complications in type 1 diabetes mellitus: the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

AIMS/HYPOTHESIS: Fractal analysis of the retinal vasculature provides a global measure of the complexity and density of retinal vessels summarised as a single variable: the fractal dimension. We investigated fractal dimensions as long-term predictors of microvasculopathy in type 1 diabetes. METHODS: We included 180 patients with type 1 diabetes in a 16 year follow-up study. In baseline retinal photographs (from 1995), all vessels in a zone 0.5-2.0 disc diameters from the disc margin were traced using Singapore Institute Vessel Assessment-Fractal image analysis software. Artefacts were removed by a certified grader, and fractal dimensions were calculated using the box-counting method. At follow-up (in 2011), diabetic neuropathy, nephropathy and proliferative retinopathy were assessed and related to baseline fractal dimensions in multiple regressions adjusted for sex and baseline age, diabetes duration, HbA1c, BP, BMI, vibration perception threshold, albuminuria, retinopathy and vessel diameters. RESULTS: Mean baseline age and diabetes duration were 21.0 and 13.4 years, respectively, and of patients 50.0% were males. The mean fractal dimension was 1.3817. The 16 year incidences of neuropathy, nephropathy and proliferative retinopathy were 10.8%, 8.0% and 27.9%, respectively. Multiple regression analyses showed a lower fractal dimension to significantly predict incident neuropathy (OR 1.17 per 0.01 fractal dimension decrease [95% CI 1.01, 1.36]), nephropathy (OR 1.40 per 0.01 fractal dimension decrease [95% CI 1.10, 1.79]) and proliferative retinopathy (OR 1.22 per 0.01 fractal dimension decrease [95% CI 1.09, 1.37]). CONCLUSIONS/INTERPRETATION: The retinal vascular fractal dimension is a shared biomarker of diabetic microvasculopathy, thus indicating a possible common pathogenic pathway. Retinal fractal analysis therefore is a potential tool for risk stratification in type 1 diabetes.

Hypoglycemia Prevention and User Acceptance of an Insulin Pump System with Predictive Low Glucose Management.

BACKGROUND: The MiniMed 640G sensor-augmented insulin pump system (Medtronic, Inc., Northridge, CA) can automatically suspend insulin delivery in advance of predicted hypoglycemia and restart it upon recovery. The aims of this analysis were to determine the rate at which predicted hypoglycemia was avoided with this strategy, as well as to assess user acceptance of the system and its insulin management features. SUBJECTS AND METHODS: Forty subjects with type 1 diabetes used the system for 4 weeks. We retrospectively evaluated performance of the system, using downloaded pump and sensor data, and evaluated user acceptance via questionnaires. RESULTS: There were 2,322 suspend before low events (2.1 per subject-day). The mean (± SD) duration of pump suspension events was 56.4 ± 9.6 min, and the mean subsequent sensor glucose (SG) nadir was 71.8 ± 5.2 mg/dL. SG values following 1,930 (83.1%) of the predictive suspensions did not reach the preset low limit. Nadir SG values of ≤50 and ≤60 mg/dL were seen in 207 (8.9%) and 356 (15.3%) of the predictive suspensions, respectively. Blood glucose (BG) and SG values before and during the study were comparable (P > 0.05). The mean absolute relative difference between paired SG and BG values was 10.9 ± 13.8%. Subjects felt confident using the system, agreed that it helped protect them from hypoglycemia, and wished to continue using it. CONCLUSIONS: Automatic insulin pump suspension as implemented in the MiniMed 640G system can help patients avoid hypoglycemia, without significantly increasing hyperglycemia.

Comparison between Early Treatment Diabetic Retinopathy Study 7-field retinal photos and non-mydriatic, mydriatic and mydriatic steered widefield scanning laser ophthalmoscopy for assessment of diabetic retinopathy.

AIMS: To compare non-mydriatic, mydriatic and steered mydriatic widefield retinal images with mydriatic 7-field Early Treatment Diabetic Retinopathy Study (ETDRS)-standards in grading diabetic retinopathy (DR). METHODS: We examined 95 patients (190 eyes) with type 1 diabetes. A non-mydriatic, a mydriatic and four steered mydriatic 200° widefield retinal images were captured (Optos 200Tx, Optos plc, Dunfermline, Scotland) and compared to mydriatic 7-field 45° ETDRS images (Topcon 3D OCT-2000, Topcon, Tokyo, Japan). Images were graded for DR according to ETDRS-protocol by a trained and certified grader masked to the results of the corresponding grading. For agreement kappa-statistics were used. RESULTS: Exact level agreement with 7-field images was found in 76.3%, 76.1% and 70.7% for non-mydriatic, mydriatic and steered mydriatic widefield images, respectively. Corresponding values for one-level agreement were 99.0%, 98.9% and 99.5%, respectively. Non-mydriatic matched mydriatic widefield images almost fully with exact and one-level agreement of 96.8% and 100.0%, respectively. Mydriatic steered images resulted in higher grading in 24 eyes. CONCLUSIONS: Widefield images matched 7-field images favorably. Widefield images can be captured without pupil-dilation and only one image is needed. However, because of overlapping eyelashes and distortion some lesion might be missed. Mydriatic steered images in selected cases may solve some of these problems.

The significance of the prepubertal diabetes duration for the development of retinopathy and nephropathy in patients with type 1 diabetes.

OBJECTIVE: A Danish nationwide prospective cohort of children and adolescents with type 1 diabetes was followed for 8 years to study the effect of the prepubertal duration of diabetes on early retinopathy and elevated albumin excretion rate (AER) (>20 microg/min). RESEARCH DESIGN AND METHODS: In 1989, blood glucose control (HbA(1c)) and AER was investigated in approximately 80% of all Danish children and adolescents with type 1 diabetes. A cohort of 339 young patients were restudied in 1995 including physical examination, demographic data, HbA(1c), AER, and fundus photography with central reading. Among the patients, a number of 304 had a prepubertal onset of diabetes defined as an onset age less than 11.7 years in girls and 12.9 years in boys. Microalbuminuria was defined as an AER of 20-150 microg min(-1) and macroalbuminuria as AER >150 microg min(-1) in two out of three timed overnight urine samples. RESULTS: At the follow-up in 1995-1996, no patients were younger than 12 years of age. The prevalence of any level of retinopathy was 17.7% in the age group 12-15 years, 45.4% from 16 to 20 years, and increased to 67.6% in patients more than 20 years of age. Diabetic retinopathy was significantly associated to poor long-term metabolic control (HbA(1c)) (P<.0001) and to diabetes duration both in patients with a prepubertal onset of disease as well as patients with a pubertal (P<.001) onset of disease. However, the pubertal diabetes duration contributed two times more than the prepubertal diabetes duration. Mean postpubertal diabetes duration to any retinopathy was significantly shorter (9.4 years) in patients with prepubertal onset of the disease compared to patients with postpubertal onset (11.8 years) (P=.0004). In total, the prevalence of elevated AER (>20 microg/min) increased from 4% in 1989 to 13% in 1995. None of the patients younger than 15 years of age had elevated AER, while the prevalence of elevated AER was about 14% from 15 years of age and onwards. Elevated AER in 1995 was significantly related to long-term metabolic control (P<.001) and elevated AER in the preceding years (P<.001) but was not correlated to diabetes duration neither before nor after the age of 12 years. CONCLUSION: The prepubertal diabetes duration is significantly associated with the development of diabetic retinopathy. The period, however, contributes less compared to the years after puberty. In concert with other studies, we found no association between raised AER and diabetes duration. This may be explained by the fact that other factors are more significant and dilute the significance of diabetes duration. Nonetheless, it seems prudent to optimise blood glucose control irrespective of age.

Retinal vessel calibers predict long-term microvascular complications in type 1 diabetes: the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

Diabetic neuropathy, nephropathy, and retinopathy cause significant morbidity in patients with type 1 diabetes, even though improvements in treatment modalities delay the appearance and reduce the severity of these complications. To prevent or further delay the onset, it is necessary to better understand common underlying pathogenesis and to discover preclinical biomarkers of these complications. Retinal vessel calibers have been associated with the presence of microvascular complications, but their long-term predictive value has only been sparsely investigated. We examined retinal vessel calibers as 16-year predictors of diabetic nephropathy, neuropathy, and proliferative retinopathy in a young population-based Danish cohort with type 1 diabetes. We used semiautomated computer software to analyze vessel diameters on baseline retinal photos. Calibers of all vessels coursing through a zone 0.5-1 disc diameter from the disc margin were measured and summarized as the central artery and vein equivalents. In multiple regression analyses, we found wider venular diameters and smaller arteriolar diameters were both predictive of the 16-year development of nephropathy, neuropathy, and proliferative retinopathy. Early retinal vessel caliber changes are seemingly early markers of microvascular processes, precede the development of microvascular complications, and are a potential noninvasive predictive test on future risk of diabetic retinopathy, neuropathy, and nephropathy.

Novopen Echo® for the delivery of insulin: a comparison of usability, functionality and preference among pediatric subjects, their parents, and health care professionals.

BACKGROUND: Despite advances in insulin pen design and functionality, the selection of pens available for children with diabetes is limited. This study assessed the usability, functionality and attitudes towards NovoPen Echo®, a new durable insulin pen designed for pediatric patients that combines a simple memory function with half-increment dosing, versus NovoPen® Junior and HumaPen® Luxura™ HD in pediatric subjects, their parents, and health care professionals (HCPs). METHODS: Pens were evaluated in random order during 1:1 interviews in the three target groups (pediatric subjects, parents, and HCPs) in Germany, France, and Canada. Study participants were asked to prepare each pen, perform injections into foam cushions, and provide feedback via a standardized questionnaire. RESULTS: In total, 205 participants were included in the study. On a scale of 1-6 (1=most favorable; 6=least favorable regarding overall appearance, shape, colors, thickness and length), NovoPen Echo received the most favorable rating for design and overall appearance (mean±standard deviation=1.71±0.79) compared with NovoPen Junior (2.02±0.93) and HumaPen Luxura HD (2.36±1.01). Furthermore, 89% of pediatric subjects and 94% of parents rated the memory function of NovoPen Echo as very easy/easy to use. When asked to rate the pens overall, 80% of participants preferred NovoPen Echo to the other pens (p<0.0001). CONCLUSIONS: The results demonstrate a high overall level of satisfaction with NovoPen Echo among pediatric subjects, parents, and HCPs. The novel design aspects of NovoPen Echo, namely the simple memory function, half-increment units and, ease of use and design, may contribute towards promoting treatment adherence, which is essential in the pediatric setting.

[Insulin treatment in children]. / Insulinbehandling af børn.

Improving the diabetes metabolic regulation decreases the risk of microvascular diabetic complications. Insulin treatment in children therefore tends to be intensified to multiple-dose insulin (MDI) or continuous subcutaneous insulin injection (CSII). Further, insulin analogues are increasingly used. The pharmacokinetics of human and analogue insulin are summarised. It is concluded that pharmacokinetic studies on analogue insulin in children are required. Yet, no clear evidence of improved glycaemic control of the intensified treatment regimes has been shown in children. Long-term randomised studies are needed.

Thiamine-responsive megaloblastic anaemia: a cause of syndromic diabetes in childhood.

Thiamine-responsive megaloblastic anaemia (TRMA) is a rare autosomal recessive condition, characterized by megaloblastic anaemia, non-autoimmune diabetes mellitus, and sensorineural hearing loss. We describe three infants with TRMA from two consanguineous Pakistani families, who were not known to be related but originated from the same area in Pakistan. All children were homozygous, and the parents were heterozygous for a c.196G>T mutation in the SLC19A2 gene on chromosome 1q23.3, which encodes a high-affinity thiamine transporter. The result is an abnormal thiamine transportation and vitamin deficiency in the cells. Thiamine in high doses (100-200 mg/d) reversed the anaemia in all our patients. Two patients discontinued insulin treatment successfully after a short period, while the third patient had to continue with insulin. The hearing loss persisted in all three children. The diagnosis of TRMA should be suspected in patients with syndromic diabetes including hearing loss and anaemia, even if the latter is only very mild and, particularly, in the case of consanguinity.

Screening Copenhagen school children at risk of type 2 diabetes mellitus using random capillary blood glucose.

AIM: To screen adolescents at risk of type 2 diabetes mellitus (T2DM) using random capillary blood glucose (RCBG). METHODS: Ninth grade pupils who were overweight and/or had a family history of T2DM were offered to have RCBG measured and were referred for further investigation if the value was > or = 7.8 mmol/L. RESULTS: Two thousand four hundred and eleven pupils were examined, 19% were overweight, 4% being obese. 589 met inclusion criteria and 384 participated. Ethnic minorities and pupils in low socio-economic school-areas (SESA) were significantly more overweight than ethnic Danes and pupils in high SESA. Compared to ethnic Danish pupils, the relative risk of having a positive parent history of T2DM was increased five-fold for ethnic Turkish and Arab pupils and 13-fold for ethnic Pakistani pupils. One pupil had a diagnosed T2DM. Two had elevated RCBG values. One of these had an undiagnosed T2DM. CONCLUSION: Our study shows a high prevalence of overweight adolescents in Copenhagen, especially in school areas with low socio-economic standard and in pupils with Turkish, Pakistani and Arab ethnicity. Only three out of the 10 pupils with the highest risk participated. New strategies to reach and motivate risk groups to follow health recommendations and new methods of screening should be developed.