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Closed-loop insulin delivery systems have the potential to address suboptimal glucose control in children and adolescents with type 1 diabetes. We compared safety and efficacy of the Cambridge hybrid closed-loop algorithm with usual care over 6 months in this population.In a multicentre, multinational, parallel randomised controlled trial, participants aged 6-18 years using insulin pump therapy were recruited at seven UK and five US paediatric diabetes centres. Key inclusion criteria were diagnosis of type 1 diabetes for at least 12 months, insulin pump therapy for at least 3 months, and screening HbAOf 147 people initially screened, 133 participants (mean age 13·0 years [SD 2·8]; 57% female, 43% male) were randomly assigned to either the closed-loop group (n=65) or the control group (n=68). Mean baseline HbAThe Cambridge hybrid closed-loop algorithm had an acceptable safety profile, and improved glycaemic control in children and adolescents with type 1 diabetes. To ensure optimal efficacy of the closed-loop system, usage needs to be consistently high, as demonstrated with CamAPS FX.National Institute of Diabetes and Digestive and Kidney Diseases.

Summary Objective Progress through puberty involves a complex hormonal cascade, but the individual contributions of hormones, particularly IGF‐1, are unknown. We reanalysed Chard growth study data to explore the tempo of puberty based on changes in both height and hormone levels, using a novel method of growth curve analysis. Design and Subjects Schoolboys (n = 54) and girls (n = 70) from Chard, Somerset, England, recruited in 1981 at age 8/9 and followed to age 16. Measurements Every 6 months, height and Tanner stages (genitalia, breast, pubic hair) were recorded, and in a subsample (24 boys, 27 girls), blood samples were taken. Serum IGF‐1, testosterone (boys) and oestradiol (girls) were measured by radioimmunoassay. Individual growth curves for each outcome were analysed using variants of the super‐imposition by translation and rotation (SITAR) method, which estimates a mean curve and subject‐specific random effects corresponding to size, and age and magnitude of peak velocity. Results The SITAR models fitted the data well, explaining 99%, 65%, 86% and 47% of variance for height, IGF‐1, testosterone and oestradiol, respectively, and 69–88% for the Tanner stages. During puberty, the variables all increased steeply in value in individuals, the ages at peak velocity for the different variables being highly correlated, particularly for IGF‐1 vs height (r = 0·74 for girls, 0·92 for boys). Conclusions IGF‐1, like height, the sex steroids and Tanner stages, rises steeply in individuals during puberty, with the timings of the rises tightly synchronized within individuals. This suggests that IGF‐1 may play an important role in determining the timing of puberty.

Patients with the highest albumin:creatinine ratio within the normal range are at an increased risk for developing microalbuminuria. The mechanistic basis for this is unknown, but may be related to renal inflammation. Our goal was to characterize the urinary excretion of cytokines/chemokines in normoalbuminuric adolescents with Type 1 diabetes to determine whether higher range normoalbuminuria is associated with evidence of renal inflammation.Forty-two urinary cytokines/chemokines were measured in subjects who were screened for the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Urinary cytokines/chemokines were compared across low (n = 50), middle (n = 50) or high (n = 50) albumin:creatinine ratio tertile groups.At baseline, participants in the upper tertile were younger and had shorter diabetes duration compared with the other groups. Other clinical characteristics were similar. Urinary levels of interleukin 6, interleukin 8, platelet-derived growth factor-AA and RANTES differed across albumin:creatinine ratio tertiles, with higher values in patients in the middle and high tertiles compared with the lower tertile (ANCOVA P ≤ 0.01).Within the normal albumin:creatinine ratio range, higher urinary albumin excretion is associated with elevated urinary levels of inflammatory markers. Ultimately, this may provide mechanistic insights into disease pathophysiology and stratify the risk of nephropathy in Type 1 diabetes.

Asymmetric dimethylarginine (ADMA) is an independent risk factor for cardiovascular disease and its concentrations are increased in several diseases, including diabetes. However, there is limited information on this plasma marker in young people, particularly in those with Type 1 diabetes. The aim of the present study was therefore to perform a longitudinal evaluation of plasma ADMA and of its determinants in young people with childhood-onset Type 1 diabetes.For measurement of ADMA using mass spectrometry, 1018 longitudinal stored blood samples were available from 330 young people with Type 1 diabetes followed in the Oxford Regional Prospective Study. Additional data concerning annual assessments of HbA(1c) , height, weight, insulin dose and three early morning urine samples for measurement of the albumin/creatinine ratio were available.ADMA levels were significantly higher in males than in females (mean ± SD: 0.477 ± 0.090 vs. 0.460 ± 0.089 μmol/l, P=0.002) and declined with chronological age (estimate ± SE: -0.0106 ± 0.0008, P0.001). A significant inverse association was detected between ADMA and HbA(1c) (estimate ± SE:-0.0113 ± 0.001, P0.001). ADMA levels were lower in subjects developing microalbuminuria (mean ± SD: 0.455 ± 0.093 vs. 0.476 ± 0.087 μmol/l, P=0.001) than in subjects with normoalbuminuria, but this difference disappeared after adjusting for HbA(1c) .In this longitudinal study, ADMA concentrations decreased with age and were significantly higher in males and lower in subjects developing microalbuminuria. These associations were largely explained by a paradoxical negative association between HbA(1c) and ADMA. We suggest that chronic hyperglycaemia might down-regulate mechanisms implicated in ADMA production or stimulate its metabolism confounding short-term associations with complications risk.

Aims Using compartment modelling, we assessed the time delay between blood glucose and sensor glucose measured by the Guardian® RT continuous glucose monitoring system in young subjects with Type 1 diabetes (T1D). Methods Twelve children and adolescents with T1D treated by continuous subcutaneous insulin infusion (male/female 7/5; age 13.1 ± 4.2 years; body mass index 21.9 ± 4.3 kg/m2; mean ± sd) were studied over 19 h in a Clinical Research Facility. Guardian® RT was calibrated every 6 h and sensor glucose measured every 5 min. Reference blood glucose was measured every 15 min using a YSI 2300 STAT Plus Analyser. A population compartment model of sensor glucose–blood glucose kinetics was adopted to estimate the time delay, the calibration scale and the calibration shift. Results The population median of the time delay was 15.8 (interquartile range 15.2, 16.5) min, which was corroborated by correlation analysis between blood glucose and 15-min delayed sensor glucose. The delay has a relatively low intersubject variability, with 95% of individuals predicted to have delays between 10.4 and 24.3 min. Population medians (interquartile range) for the scale and shift are 0.800 (0.777, 0.823) (unitless) and 1.66 (1.47, 1.84) mmol/l, respectively. Conclusions In young subjects with T1D, the total time delay associated with the Guardian® RT system was approximately 15 min. This is twice that expected on physiological grounds, suggesting a 5- to 10-min delay because of data processing. Delays above 25 min are rarely to be observed.

Bodyweight is an important prognostic indicator in children with cystic fibrosis (CF), but the relationships between body composition and clinical outcomes are less clear. We have investigated the role of leptin (a potential satiety factor) and changes in body composition, height and weight with respect to age and clinical outcome.143 children (77 boys) with CF and a median age (range) of 5.99 (2.27-17.98) y were followed with annual measurements of height, weight, skinfolds, forced expiratory volume (FEV1), Shwachman score assessment and fasting blood sample. Our control group comprised 40 children (20 boys, 20 girls) aged 8.6-10.2 y at recruitment who were participating in a longitudinal study of growth and puberty.SD scores for height, weight and BMI decreased with age; fat and fat-free mass was lower in both sexes compared to controls. Shwachman score decreased with age in both sexes and was related to fat-free mass in girls, and to both fat-free and fat mass in boys. FEV1 decreased with age only in boys and was related to fat-free mass. Leptin levels by age and by fat mass were higher in CF children compared to controls.Despite improvements in management, contemporary children with CF still gain less body fat and fat-free mass and are shorter than controls. The higher leptin levels we observed may be due to stimulatory effects of inflammatory cytokines and we postulate that they may contribute to the anorexia, poor weight gain and growth of these children.

To determine the clinical and psychological course of diabetes through adolescence and the relationship with glycemic control in young adulthood.A longitudinal cohort study of adolescents recruited from the register of the outpatient pediatric diabetes clinic. A total of 76 individuals (43 male patients, 33 female patients) aged 11-18 years completed baseline assessments, and 65 individuals (86%) were reinterviewed as young adults (20-28 years of age). Longitudinal assessments were made of glycemic control (HbA(1c)), weight gain (BMI), and development of complications. Adolescents completed self-report questionnaires to assess emotional and behavioral problems as well as self-esteem. As young adults, psychological state was assessed by the Revised Clinical Interview Schedule and the self-report Brief Symptom Inventory.Mean HbA(1c) levels peaked in late adolescence and were worse in female participants (average 11.1% at 18-19 years of age). The proportion of individuals who were overweight (BMI25.0 kg/m(2)) increased during the 8-year period from 21 to 54% in female patients and from 2 to 28% in male patients. Serious diabetes-related events included death in one patient and cognitive impairment in two patients. Individuals in whom diabetic complications developed (25% of male patients and 38% of female patients) had significantly higher mean HbA(1c) levels than those without complications (difference 1.9%, 95% CI 1.1-2.7, P0.0001). Behavioral problems at baseline were related to higher mean HbA(1c) during the subsequent 8 years (beta = 0.15, SEM (beta) 0.04, P0.001, 95% CI 0.07-0.24).The outcome for this cohort was generally poor. Behavioral problems in adolescence seem to be important in influencing later glycemic control.

Although growth hormone (GH) has well documented insulin antagonistic effects, GH deficient adults often demonstrate insulin resistance. In young GH deficient children, increased susceptibility to hypoglycaemia might indicate increased insulin sensitivity; however, this has not been documented. We therefore determined insulin sensitivity in GH deficient and GH sufficient children.Prospective study of children undergoing insulin tolerance tests for clinical investigation of GH or cortisol secretion at a regional Paediatric Endocrine/Growth Clinic between October 1986 and December 1997. Ninety-one tests were performed in children with GH deficiency and 142 tests in children with normal GH response to insulin (peak GHor = 20 IU/l).The standard insulin tolerance test was modified to permit frequent measurements of glucose (0, 5, 10, 15, 20, 30, 45, 60 and 90 minutes). Rate of log glucose disappearance in the first 15 minutes was calculated as a direct measure of insulin sensitivity.GH deficient children were more insulin sensitive than GH sufficient children (P = 0.004) and had lower glucose nadirs post-insulin (P = 0.005). Subgroup analysis revealed that these differences were greater in younger (12 years old) or pre/early pubertal children. In 14 prepubertal children, exogenous sex steroid priming resulted in lower insulin sensitivity (P0.05) compared to nonprimed tests.Young GH deficient children were more insulin sensitive than children with normal GH secretion. This difference attenuated with age and puberty, possibly secondary to pubertal sex steroids; however, insulin resistance as reported in GH deficient adults, was not observed in adolescents.

To examine whether a rise in blood pressure could be detected before the onset of microalbuminuria (MA) in a cohort of children followed from diagnosis of type 1 diabetes.The Oxford Regional Prospective Study is an incident cohort study of children with type 1 diabetes aged (mean +/- SD) 9.8 +/- 3.7 years at diagnosis. Subjects were assessed annually from diagnosis, with measurement of HbA1c, arterial blood pressure (random zero), and three urine samples for estimation of the albumin/creatinine ratio. During follow-up, 63 of 494 children developed MA at one or more annual assessments and were designated as cases for a nested case-control study. Each case was matched for sex and age at diagnosis with two normoalbuminuric control subjects. Blood pressure (BP) data were compared at corresponding years of diabetes duration.Cases with MA were similar to normoalbuminuric control subjects with respect to age and BMI, but they had higher mean HbA1c levels (mean difference 1.1%, P0.001). In the years before the onset of MA, the diastolic BP standard deviation score (SDS) was significantly higher than zero in cases (mean 0.49, P0.001) and in control subjects (0.50, P0.001). No difference could be detected between cases and control subjects before the onset of MA in either systolic or diastolic BP (mean difference systolic -1.2 mmHg [95% CI -4.7 to 2.7], mean difference diastolic 0.1 mmHg [-2.4 to 2.6]). However, within the cases, the onset of MA was associated with elevations in systolic and diastolic BP SDSs (F = 16.1, P0.001; and F = 18.0, P0.001). BMI, but not HbA1c, was associated with systolic and diastolic BP SDSs in the subjects with MA (F = 0.6, P = 0.4; and F = 12.3, P = 0.001). However, the association of BP with MA remained signifcant for systolic BP (P = 0.001) and for diastolic BP (P0.001) after adjusting for BMI.A rise in systemic BP cannot be detected before the first appearance of MA in children with type 1 diabetes. BP rises concurrently with the onset of MA and is also closely related to BMI.

Dramatically high rates of type 2 diabetes mellitus (DM) have been observed in historically undernourished, recently urbanized populations. A comparable model is the high risk of DM in individuals who were growth restrained in utero and subsequently catch up in size. While it is proposed that undernutrition may somehow adversely program metabolism, both models could also be explained by genotypes that promoted survival during earlier nutritional adversity but later add to the risk of DM. Our recent studies in a contemporary birth cohort have identified two different candidate thrifty genotypes. The insulin gene VNTR III/III genotype promotes fetal growth and historically could thereby have enhanced survival during infancy. In contrast, the maternally inherited 16189 mitochondrial DNA variant is associated with restrained fetal growth and may therefore enhance the likelihood of maternal survival. Both genotypes are associated with an increased risk of adult type 2 DM in historical cohorts. However, the development of DM in individuals from contemporary birth cohorts may prove to be influenced more by genetic and other early determinants of childhood obesity.

In cystic fibrosis, reduced body mass is related to low levels of IGF-I and changes in the IGF binding proteins. Our aim was to determine whether these abnormalities are linked to pancreatic endocrine dysfunction.We measured serum levels of insulin, IGF-I, IGFBP-I, IGFBP-3 and IGF bioactivity in 77 fasting subjects (43 male) mean age 9.6 years (range 2.99-17.98 years). Data were analysed with respect of body mass, puberty and stature and compared with control data established in the same laboratory.The mean height standard deviation score (SDS (SD)) was -0.54 (0.97) and the body mass index SDS -0.24 (1.09). Both body mass index SDS (r = -0.40, P = 0.0003) and IGF-I SDS (r = - 0.32, P = 0.009) declined with age. Insulin levels were also low and correlated with IGF-I and IGFBP-3 (r = 0.42, P = 0.0004, and r = 0.45, P = 0.0002, respectively) whereas levels of IGFBP-I were inversely related to those of IGF-I and insulin (r = - 0.43, P = 0. 0004, r = - 0.52, P0.0001). IGF bioactivity was reduced and inversely related to IGFBP-I (r = - 0.31, P = 0.009). In multiple regression analysis, body mass index SDS was negatively related to age (P0.0001) and positively related to insulin and IGF-I (P = 0. 04, P = 0.03, respectively). Height SDS was correlated with IGF bioactivity (P = 0.003) and negatively with IGFBP-I (P = 0.01).We conclude that progressive insulin deficiency may result in reduced IGF-I levels and IGF-bioactivity and may determine weight gain and statural growth in cystic fibrosis.

To determine whether abnormal lipid levels in children with Type 1 diabetes mellitus are the result of poor metabolic control or may in part be determined by genetic factors.Non-fasting lipid levels were measured in 141 children with Type 1 diabetes (age range 7.7-19 years) 3 years after diagnosis, and in 192 of their parents. Glycosylated haemoglobin and the urinary albumin-creatinine ratio (three urine samples) were estimated in each child annually.The children had a mean total cholesterol of 4.46 +/- 1.25 mmol/l (+/- SD) and a median triacylglycerol of 1.18 mmol/l (range 0.32-4.7). A total of 15.3% of the population had a total cholesterol5.2 mmol/l and 17.9% had a triacylglycerol1.7 mmol/l; in 5.6% both total cholesterol and triacylglycerol were greater than these cut-off points. Total cholesterol, triacylglycerol and very low density lipoprotein-cholesterol were significantly correlated to glycaemic control. However, total cholesterol was also significantly related to parental total cholesterol either as analysed separately or as mean parental total cholesterol (r = 0.37, P = 0.0001). In stepwise multiple regression analysis both mean parental total cholesterol (P = 0.001) and HbA1c (P = 0.015) were significant determinants of the child's total cholesterol. The children studied were being followed prospectively for the development of microalbuminuria and there was a weak association across tertiles of total cholesterol, linking higher levels to the development of microalbuminuria (P0.05).We conclude that both glycaemic control and familial factors may be important determinants of lipid levels in young people with diabetes. Both may contribute to the subsequent risk of cardiovascular disease and possibly the development of incipient diabetic nephropathy.

Leptin may have a role in the initiation of puberty and the regulation of subsequent weight gain, but this hypothesis has not been tested by longitudinal study. We report data from 40 normal children (20 boys and 20 girls) followed from 8-16 yr of age with hormone measurements and auxology every 6 months. Before the onset of puberty, leptin levels were similar in boys and girls: G1, mean (95% confidence interval), 2.63 (2.17-3.20) ng/mL; B1, 2.47 (2.08-2.94) ng/mL (P = 0.64) and increased with age in both sexes (B, 0.107 +/- 0.042; P = 0.02). With the onset of puberty, leptin levels increased in girls (B2-B5, P0.0005), but decreased in boys (G2-G5, P0.0005). Similar positive independent relationships were seen between leptin and fat mass in girls (B, 0.106 +/- 0.022; P0.0005) and boys (B, 0.121 +/- 0.020; P0.0005), and negative relationships were found with fat-free mass [girls: B, -1.104 +/- 0.381 (P0.005); boys: B, -1.288 +/- 0.217 (P0.0005)]. Girls gained more fat mass than boys, whereas boys gained more fat-free mass, and this explained the sex difference in leptin levels. Leptin levels correlated significantly with a large number of other hormones, but none was independent of changes in body composition. In girls, but not in boys, low leptin levels during prepuberty (B1) predicted subsequent gains in the percent body fat during puberty (r = -0.75; P = 0.005). The sexual dimorphism in leptin levels during puberty reflects differential changes in body composition. Prepubertal leptin levels in girls also predict gains in the percent body fat.

We surveyed the clinical presentation, initial management and subsequent course of a prospectively registered, population-based cohort of 230 patients with Type 1 (insulin-dependent) diabetes mellitus diagnosed before age 21 years in the Oxford Regional Health Authority area in 1985 and 1986. Clinical details from the time of diagnosis were available on 219 patients. Thirty-four (16%) were in severe ketoacidosis with pH less than 7.10 or plasma bicarbonate less than 10 mmol/l, and 21 (10%) had mild to moderate ketoacidosis with pH 7.10-7.35 or plasma bicarbonate 10-21 mmol/l. One child died in ketoacidosis. Presentation in severe ketoacidosis was most common in children under age 5 years (p0.05), and ketoacidosis of any degree was less frequent in older children (0.05p0.01) and those with a parent or sibling with diabetes (p0.01). Within 4 years of diagnosis, 55 of 211 patients (26%) experienced severe hypoglycaemia, which in 31 (15%) led to one or more admissions. Readmission for unstable glycaemic control excluding acute hypoglycaemia occurred at least once within 1 year of diagnosis in 13% and within 4 years in 28%, and was more common in girls, in children aged less than 10 years at diagnosis, and those with a history of severe hypoglycaemia. A second cohort of 97 similar patients was recruited in 1990. The rates of admission at diagnosis (79%), severe ketoacidosis (13%) and mild to moderate ketoacidosis (13%) did not differ from the 1985/1986 cohort.(ABSTRACT TRUNCATED AT 250 WORDS)

A syndrome of disordered hypothalamic function with abnormal control of temperature, appetite, and thirst, hyperprolactinaemia, and inappropriate vasopressin release is described in a 13-year-old boy who, in addition, had insensitivity to pain and a more general disorder affecting mood, sleep, and control of respiration. A disturbance of the opioid peptide system is postulated. Naloxone reversed central analgesia, altered urine fluid and electrolyte excretion, modified the hormonal response to gonadotrophin-releasing and thyrotrophin-releasing hormones, and improved the auditory and visual reaction times. Specific opioid antagonists may have a therapeutic role.

• Clinical, hematologic, and immunologic findings were reviewed in 21 patients with glycogenosis lb. Fifteen of the patients suffered from moderate to severe bacterial infections. Ten patients had excessive epistaxis or bleeding from surgical sites, and eight suffered oral and anal mucosal ulceration. Sixteen of 21 patients exhibited chronic neutropenia associated with abnormalities In myelold maturation and decreases in the bone marrow storage and peripheral marginating pools. Diminished neutrophil motility was documented in 14 of 15 patients tested, and adherence was decreased in three patients studied. Neutrophil microbicidal activity, reduction of nitroblue tetrazolium, and ingestion were normal in all patients tested. Bleeding times were prolonged in five of eight patients, and results of platelet function studies were abnormal in five individuals. Excessive bleeding in patients with glycogenoses la and lb are similar and may be secondary to the functional deficiency of glucose-6-phosphatase. However, neutropenia, neutrophil dysfunction, and the resulting Infectious complications are specific for lb disease and may be related to abnormal glucose-6-phosphate transport. (AJDC1985;139:691-697)