Additional insulin dosing for fat and protein in children with type 1 diabetes using multiple daily injections.

OBJECTIVE: High-fat high-protein (HFHP) meals are associated with post-prandial hyperglycemia in type 1 diabetes (T1D), administration of additional insulin for such meals is recommended in order to optimize glucose levels. Optimal timing of additional insulin for HFHP meals in children and young people receiving multiple daily injections (MDI) remains unclear. AIM: To investigate the glycemic impact of additional insulin doses given before or after eating a HFHP meal in children with T1D using MDI. RESEARCH DESIGN AND METHODS: A randomized, controlled three period crossover trial of 27 participants aged 13 years (6.1-17.7) at two Pediatric Diabetes centers was conducted. Additional rapid-acting insulin for the fat-protein content of a standardized HFHP meal was given at three time points + 0 + 1 + 2 h of usual pre - prandial carbohydrate insulin ; calculated using an algorithm extrapolated from current evidence base and clinical recommendations. Post-prandial glucose (PPG) parameters were calculated for 420 minutes using continuous glucose monitoring. The primary outcome was mean PPG excursion. Secondary outcomes included peak glucose, time to peak and hypoglycemia incidence. RESULTS: There was no difference in post-prandial glucose parameters when additional HFHP insulin was administered at + 0 , + 1 , or + 2 h : mean glucose excursion (mmol/L) (SE): 1.9(0.7), 1.2(0.7), 2.5(0.7); p = 0.5); mean peak glucose (mmol/L)(SE): 10.9(0.9), 11.5(0.8), 11.5(0.9); p = 0.9; time to peak glucose (mins)(SE): 82.3(35.4), 113.6(30.9), 95.1(32.1); p = 0.8. Mild hypoglycemia was common (55%) in all groups (p = 0.97). CONCLUSION: We found no benefit in giving additional insulin as a split dose for HFHP meals in children using MDI, mild hypoglycemia was common. Future studies would benefit from refinement of the insulin dose algorithm.

Frequent Monitoring of C-Peptide Levels in Newly Diagnosed Type 1 Subjects Using Dried Blood Spots Collected at Home.

Objective: To evaluate an approach to measure ß-cell function by frequent testing of C-peptide concentrations in dried blood spots (DBSs). Patients: Thirty-two children, aged 7 to 17 years, with a recent diagnosis of type 1 diabetes. Design: Mixed-meal tolerance test (MMTT) within 6 and again at 12 months after diagnosis, with paired venous and DBS C-peptide sampling at 0 and 90 minutes. Weekly DBS C-peptide before and after standardized breakfasts collected at home. Results: DBS and plasma C-peptide levels (n = 115) correlated strongly (r = 0·91; P < 0.001). The Bland-Altman plot indicated good agreement. The median number of home-collected DBS cards per participant was 24 over a median of 6.9 months. Repeated DBS C-peptide levels varied considerably within and between subjects. Adjustment for corresponding home glucose measurements reduced the variance, permitting accurate description of changes over time. The correlation of the C-peptide slope over time (assessed by repeated home DBS) vs area under the curve during the two MMTTs was r = 0.73 (P < 0.001). Mixed models showed that a 1-month increase in diabetes duration was associated with 17-pmol/L decline in fasting DBS C-peptide, whereas increases of 1 mmol/L in glucose, 1 year older age at diagnosis, and 100 pmol/L higher baseline plasma C-peptide were associated with 18, 17, and 61 pmol/L higher fasting DBS C-peptide levels, respectively. In addition, glucose responsiveness decreased with longer diabetes duration. Conclusion: Our approach permitted frequent assessment of C-peptide, making it feasible to monitor ß-cell function at home. Evaluation of changes in the slope of C-peptide through this method may permit short-term evaluation of promising interventions.

Predictors of glycemic control in the first year of diagnosis of childhood onset type 1 diabetes: A systematic review of quantitative evidence.

Early glycemic control is associated with reduced future vascular complications risk in type 1 diabetes (T1D). The aim of this study was to systematically review evidence on the predictors of glycemic control within 12 months of diagnosis of childhood onset T1D. Inclusion criteria for the electronic search were: interventional and observational studies that assessed and quantified an association between the predictor and glycemic control within 12 months of diagnosis of childhood onset T1D. A total of 17 915 articles were identified from 6 databases and 20 studies were finally included in the analysis. Harvest plots and narrative synthesis were used to summarize data from intervention (n = 0), prospective/retrospective cohort (n = 15), and cross-sectional (n = 5) studies. Significant predictors of poorer glycemic control 0 to 3 months after diagnosis were older age and female gender. Non-white ethnicity, diabetes autoantibody positivity, measures of deprivation, and non-private health insurance were potential predictors. Predictors of poorer glycemic control 4 to 12 months after diagnosis were: older age, non-white ethnicity, a single parent family, high hemoglobin A1c (HbA1c) levels at diagnosis, longer T1D duration, and non-intensive insulin therapy. Potential predictors included: family with health issues, clinical factors, and comorbidities at diagnosis. Most significant predictors of poor glycemic control within 12 months of diagnosis of childhood onset T1D are non-modifiable. These factors need to be recognized and addressed through individualized and multidisciplinary diabetes care. Further research is required to confirm the association of potential predictors with early glycemic control.

An alternative sensor-based method for glucose monitoring in children and young people with diabetes.

OBJECTIVE: To determine accuracy, safety and acceptability of the FreeStyle Libre Flash Glucose Monitoring System in the paediatric population. DESIGN, SETTING AND PATIENTS: Eighty-nine study participants, aged 4-17 years, with type 1 diabetes were enrolled across 9 diabetes centres in the UK. A factory calibrated sensor was inserted on the back of the upper arm and used for up to 14 days. Sensor glucose measurements were compared with capillary blood glucose (BG) measurements. Sensor results were masked to participants. RESULTS: Clinical accuracy of sensor results versus BG results was demonstrated, with 83.8% of results in zone A and 99.4% of results in zones A and B of the consensus error grid. Overall mean absolute relative difference (MARD) was 13.9%. Sensor accuracy was unaffected by patient factors such as age, body weight, sex, method of insulin administration or time of use (day vs night). Participants were in the target glucose range (3.9-10.0 mmol/L) ∼50% of the time (mean 12.1 hours/day), with an average of 2.2 hours/day and 9.5 hours/day in hypoglycaemia and hyperglycaemia, respectively. Sensor application, wear/use of the device and comparison to self-monitoring of blood glucose were rated favourably by most participants/caregivers (84.3-100%). Five device related adverse events were reported across a range of participant ages. CONCLUSIONS: Accuracy, safety and user acceptability of the FreeStyle Libre System were demonstrated for the paediatric population. Accuracy of the system was unaffected by subject characteristics, making it suitable for a broad range of children and young people with diabetes. TRIAL REGISTRATION NUMBER: NCT02388815.

Management of children with type 1 diabetes during illness: a national survey.

AIM: Adequate sick-day management at home can reduce the risk of progression to diabetic ketoacidosis and admission to hospital. The aim of this project was to review the management of diabetes during illness. METHOD: The Association of Children's Diabetes Clinicians (ACDC) carried out a questionnaire survey of all paediatric diabetes units. In addition, parents of children with type 1 diabetes completed an online questionnaire. RESULTS: The survey of 127 units had a 73% response rate. Sick-day management guidelines were in place in 93%. All guidelines advised giving extra insulin during illness. In 67%, the extra dose was based on a fraction of total daily dose. 22% used units per kg body weight (U/kg). 21% used locally derived formulae to calculate extra dose of insulin. 3% of units advised only blood ketone monitoring. Although all units had an out-of-hours access policy for the families, 45% received advice from the general paediatric registrar. Only in 15%, the advice was directly from a member of the paediatric diabetes team. 680 parents completed the questionnaire. 86% reported receiving training on managing sick days. The majority (52.2%) receiving an informal session at diagnosis. 40% did not know what to do in the presence of raised blood glucose and high blood ketones. CONCLUSIONS: There was a wide variation in the practice of monitoring and advice given during illness. Both surveys highlight need for national guidance as well and to improve quality of sick-day rule education programmes for parents of children with type 1 diabetes.

Protocol for systematic review of evidence on the determinants and influence of early glycaemic control in childhood-onset type 1 diabetes.

BACKGROUND: Landmark studies in adult-onset type 1 diabetes (T1D) populations indicate that improved glycaemic control through use of intensive insulin therapy is strongly associated with reduced risk for the development of diabetes-related complications and mortality in later years. However, it is unclear whether these associations can be extrapolated to childhood-onset T1D, given the influence of other important biological and psychosocial determinants of glycaemic control, particularly during adolescence. The aims of the review are (1) to investigate the impact of early glycaemic control (within the first 2 years after diagnosis) on subsequent glycaemic trends and risk of complications during the life course of childhood-onset T1D and (2) to identify the predictors of early glycaemic control in children and young people (0-25 years). METHODS: The methods used in this study are systematic identification, review and mapping of quantitative (intervention and observational) and qualitative literature; assessing the effect and predictors of early glycaemic control in T1D (diagnosed ≤18 years) on risk or prevalence of later complications. An iterated search strategy, with no language or period restrictions, was applied to identify studies from six electronic databases. This will be supplemented by hand-searching (reference lists and contacting authors of studies meeting the inclusion criteria). Studies assessing glycaemic control within the first 2 years of diagnosis in children (at baseline) will be quality-assessed against predefined criteria and mapped descriptively to future health outcomes. Extracted data will be analysed and synthesised using narrative and forest plots or harvest plots for quantitative evidence and thematic analyses for qualitative studies. To get a deeper understanding of the predictors of early glycaemic control in reducing complications in childhood and adult life, we will integrate qualitative and quantitative evidence using mixed methods or parallel synthesis approach. DISCUSSION: These linked reviews will be the first to systematically investigate the effects of early glycaemic control and integrate both the quantitative and qualitative evidence on predictors of early glycaemic control in childhood-onset T1D in reducing future diabetes complications. This will help identify and map current research and inform development of effective future interventions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015024546.

Comparison of breath gases, including acetone, with blood glucose and blood ketones in children and adolescents with type 1 diabetes.

Previous studies have suggested that breath gases may be related to simultaneous blood glucose and blood ketone levels in adults with type 2 and type 1 diabetes. The aims of this study were to investigate these relationships in children and young people with type 1 diabetes in order to assess the efficacy of a simple breath test as a non-invasive means of diabetes management. Gases were collected in breath bags and measurements were compared with capillary blood glucose and ketone levels taken at the same time on a single visit to a routine hospital clinic in 113 subjects (59 male, age 7 years 11 months-18 years 3 months) with type 1 diabetes. The patients were well-controlled with relatively low concentrations of the blood ketone measured (ß hydroxybutyrate, 0-0.4 mmol l(-1)). Breath acetone levels were found to increase with blood ß hydroxybutyrate levels and a significant relationship was found between the two (Spearman's rank correlation ρ = 0.364, p < 10(-4)). A weak positive relationship was found between blood glucose and breath acetone (ρ = 0.16, p = 0.1), but led to the conclusion that single breath measurements of acetone do not provide a good measure of blood glucose levels in this cohort. This result suggests a potential to develop breath gas analysis to provide an alternative to blood testing for ketone measurement, for example to assist with the management of type 1 diabetes.

How can cerebral edema during treatment of diabetic ketoacidosis be avoided?

Cerebral edema during diabetic ketoacidosis (DKA) is a rare complication but it can be devastating, with significant mortality and long-term morbidity. Certain risk factors have been teased out with some large case-control studies, but more research needs to be done to make management guidelines safer. This article will discuss how DKA might be prevented from occurring in the first instance, known risk factors for cerebral edema, fluid and insulin management, the importance of careful monitoring during DKA treatment, and the importance of recognizing and acting on the earliest symptoms to prevent long-term harm.

Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man.

Understanding transcriptional regulation of pancreatic development is required to advance current efforts in developing beta cell replacement therapies for patients with diabetes. Current knowledge of key transcriptional regulators has predominantly come from mouse studies, with rare, naturally occurring mutations establishing their relevance in man. This study used a combination of homozygosity analysis and Sanger sequencing in 37 consanguineous patients with permanent neonatal diabetes to search for homozygous mutations in 29 transcription factor genes important for murine pancreatic development. We identified homozygous mutations in 7 different genes in 11 unrelated patients and show that NKX2-2 and MNX1 are etiological genes for neonatal diabetes, thus confirming their key role in development of the human pancreas. The similar phenotype of the patients with recessive mutations and mice with inactivation of a transcription factor gene support there being common steps critical for pancreatic development and validate the use of rodent models for beta cell development.

Oxfordshire Childrens Diabetes - The Primary Schools Intervention Programme.

Poorly controlled diabetes adversely affects a child's education, with concentration difficulties, alterations in mood, behaviour and fatigue associated with high or low blood glucose levels. Between years 2004-6 we started all toddlers and children on intensive insulin regimens (multiple dose injection or pump) making it imperative that they received support during the school day. This required close monitoring of blood glucose levels and counting carbohydrate intake to adjust rapid-acting insulin dose or pump bolus at every meal. We report our experience of formulating a sustainable structure of support in primary schools based on trained volunteers who partake in the daily 'Individualised Care Plan (ICP)'. After overcoming multiple barriers, an acceptable system was negotiated with our Primary Care Trust (PCT) and Local Education Authority (LEA). In 2009, the PCT confirmed 3 years funding for a Paediatric Diabetes specialist nurse (PDSN) for schools. In 2010, the first full school year with agreed protocols was in place. By July 2012, our nurses had trained a total of 342 volunteers who provide care for 132 children. The Oxfordshire Schools Intervention Programme ensures that legal obligations are met. A risk assessment allows the LEA to provide indemnity to their school staff to give injections and do blood tests, after training and competency sign-off by a PDSN. Parents, volunteers and PDSN jointly agree a comprehensive 'ICP' and utilise a hand-held communication record book. Diabetes control improved (age 4-11 years cohort from 2004 onwards: Mean (SD) HbA1c in 2001-4 = 8.38 (1.09)%; in 2005-8 = 7.74 (0.81)%; in 2009-12 = 7.58 (0.69)%; ANOVA p<0.001). This requires 500-1000 hours of DSN time to train/retrain/problem-solve annually (approximately 5-10days per month). The cost-benefits are discussed. We advocate that our programme supports each child's ICP, use of intensive insulin regimes in school-day and reassures parents that schools can deliver this safely.

Inpatient care for children with diabetes: are standards being met?

BACKGROUND: Hospital inpatient care is frequently mentioned by parents as unsatisfactory for children with diabetes. Ward staff are now less familiar with diabetes, as admissions are less common and diabetes management is more intensive. OBJECTIVE: To compare current practice with Department of Health Children's Diabetes Working Group care standards. METHODS: This audit surveyed the organisation of inpatient care for children with diabetes in three regional networks in southern England, and was funded by the Healthcare Quality Improvement Partnership. RESULTS: All 27 services completed the questionnaire. Protocols for diabetic ketoacidosis, surgery, new diagnosis and hypoglycaemia were generally available on wards (70% had all four protocols) but less available in emergency departments (EDs) (52%). Trained children's nurses worked on every shift in children's wards (100%) but not necessarily in EDs (33%). Diabetes link nurses were identified on 74% of wards and 61% of high-dependency units (HDUs), and diabetes specialist nurses have inpatient liaison in their job description (89%) and working role (93%). Standards achieved less often were access to dietetic advice on wards (37%), education sessions for ED and ward staff, and informing diabetes team (only 26% within 2 h of admission during the day, and only 11% would contact the diabetes consultant overnight for a child admitted to a paediatric intensive care unit/HDU). Half of centres reported insulin errors. CONCLUSIONS: This first audit of children's diabetes inpatient care organisation demonstrates that some standards can be achieved, but others, such as having children's nurses on every shift in EDs, lack of dietetic advice to ward staff, and liaison with the diabetes team quickly out of hours, are more challenging. Further planned audit outcomes are to produce patient and parent literature for children admitted to hospital and to refine the standards further.

The fifth UK paediatric diabetes services survey: meeting guidelines and recommendations?

AIM: To assess the provision of UK paediatric and adolescent diabetes services and examine changes in service delivery since 2002. METHOD: Questionnaires were sent to the lead paediatric consultant from all paediatric and adolescent diabetes services (n=205). Questions were based on National Institute for Health and Clinical Excellence and Scottish Intercollegiate Guidelines recommendations for diabetes care in childhood. Results were analysed using parametric and non-parametric tests. RESULTS: 129 Services (63%) returned questionnaires involving 220 clinics. Staffing has improved and 98% of consultants have a special interest in diabetes (89%, 2002). In 88% of services, the diabetes specialist nurse worked solely in paediatric diabetes (53%, 2002). Only 21% of clinics have a psychological professional integrated within the diabetes team (20%, 2002). Over 94% of services offered support with intensive insulin regimens causing problems at school for 36% of services. Almost all services offer annual microvascular screening (98-100%) but transitional care was variable; only 76% of services have specific local protocols for transition and 21% organise transfer by letter only. CONCLUSION: Paediatric and adolescent diabetes services are rising to the challenge of providing high-quality care despite rising prevalence and increasingly complex insulin regimes. Services have improved in a number of key areas but serious deficiencies remain.

Maternal but not paternal association of ambulatory blood pressure with albumin excretion in young offspring with type 1 diabetes.

OBJECTIVE: Familial predisposition to hypertension has been associated with the development of diabetic nephropathy in adults, but there are limited data in adolescents. Our aim was to assess whether parental ambulatory blood pressure (ABP) was associated with ABP and albumin excretion in young offspring with type 1 diabetes. RESEARCH DESIGN AND METHODS: Twenty-four-hour ABP monitoring was performed in 509 young offspring (mean +/- SD age 15.8 +/- 2.3 years) with type 1 diabetes, 311 fathers, and 444 mothers. Systolic (SBP) and diastolic blood pressure (DBP) measurements during 24 h, daytime, and nighttime were calculated. Three early morning urinary albumin-to-creatinine ratios (ACRs), A1C, and anthropometric parameters were available for the offspring. RESULTS: All paternal ABP parameters, except for nighttime SBP, were independently related to the offspring's ABP (24-h SBP beta = 0.18, 24-h DBP beta = 0.22, daytime SBP beta = 0.25, daytime DBP beta = 0.23, and nighttime DBP beta = 0.18; all P < 0.01). Maternal 24-h DBP (beta = 0.19, P = 0.004), daytime DBP (beta = 0.09, P = 0.04), and nighttime SBP (beta = 0.24 P = 0.001) were related to the corresponding ABP parameter in the offspring. Significant associations were found between the offspring's logACR and maternal ABP. The association with 24-h DBP (beta = 0.16, P = 0.02), daytime DBP (beta = 0.16 P = 0.02), and nighttime DBP (beta = 0.15 P = 0.03) persisted even after adjustment for the offspring's ABP. Mothers of offspring with microalbuminuria had higher ABP than mothers of offspring without microalbuminuria (all P < 0.05). CONCLUSIONS: In this cohort, parental ABP significantly influenced offspring blood pressure, therefore confirming familial influences on this trait. In addition, maternal ABP, particularly DBP, was closely related to ACR in the offspring, suggesting a dominant effect of maternal genes or an effect of the intrauterine environment on microalbuminuria risk.

Prevalence of abnormal lipid profiles and the relationship with the development of microalbuminuria in adolescents with type 1 diabetes.

OBJECTIVE: To explore the prevalence of lipid abnormalities and their relationship with albumin excretion and microalbuminuria in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: The study population comprised 895 young subjects with type 1 diabetes (490 males); median age at the baseline assessment was 14.5 years (range 10-21.1), and median diabetes duration was 4.8 years (0.2-17). A total of 2,194 nonfasting blood samples were collected longitudinally for determination of total cholesterol, LDL cholesterol, HDL cholesterol, TG, and non-HDL cholesterol. Additional annually collected data on anthropometric parameters, A1C, and albumin-to-creatinine ratio (ACR) were available. RESULTS: Total cholesterol, LDL cholesterol, HDL cholesterol, and non-HDL cholesterol were higher in females than in males (all P < 0.001). A significant proportion of subjects presented sustained lipid abnormalities during follow-up: total cholesterol >5.2 mmol/l (18.6%), non-HDL cholesterol >3.4 mmol/l (25.9%), TG >1.7 mmol/l (20.1%), and LDL cholesterol >3.4 mmol/l (9.6%). Age and duration were significantly related to all lipid parameters (P < 0.001); A1C was independently related to all parameters (P < 0.001) except HDL cholesterol, whereas BMI SD scores were related to all parameters (P < 0.05) except total cholesterol. Total cholesterol and non-HDL cholesterol were independently related to longitudinal changes in ACR (B coefficient +/- SE): 0.03 +/- 0.01/1 mmol/l, P = 0.009, and 0.32 +/- 0.014/1 mmol/l, P = 0.02, respectively. Overall mean total cholesterol and non-HDL cholesterol were higher in microalbuminuria positive (n = 115) than in normoalbuminuric subjects (n = 780): total cholesterol 4.7 +/- 1.2 vs. 4.5 +/- 0.8 mmol/l (P = 0.04) and non-HDL cholesterol 3.2 +/- 1.2 vs. 2.9 +/- 0.8 mmol/l (P = 0.03). CONCLUSIONS: In this longitudinal study of adolescents with type 1 diabetes, sustained lipid abnormalities were related to age, duration, BMI, and A1C. Furthermore, ACR was related to both total cholesterol and non-HDL cholesterol, indicating a potential role in the pathogenesis of diabetic nephropathy.