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Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

To assess the hypothesis that ondansetron administration to children with type 1 diabetes mellitus (T1DM) presenting for emergency department (ED) care with intercurrent illness and vomiting improves clinical outcomes by reducing hospitalization rates (primary), length of ED stay, intravenous fluid (IVF) administration, and revisits (secondary outcomes).We conducted a single-center, 10-year retrospective cohort study of 345 ED encounters of children aged 6 months-8 years with T1DM and vomiting. We compared outcomes among children receiving and not receiving ondansetron. To avoid selection bias related to ondansetron administration, we also investigated outcomes by conducting comparisons by ondansetron usage periods (ie, low [2002-2004] vs high [2009-2011]).Ondansetron usage increased from 0% to 67% of ED encounters between 2002 and 2011. Admission rates were similar among those administered [54% (58/107)] and not administered ondansetron [55% (131/238)]. Length of stay was longer in children receiving ondansetron (409 vs 315 minutes; P = .03). IVF administration (77% vs 77%) and revisits (5.6% vs 5.9%) were similar. Ondansetron administration was not associated with reduced admission in logistic regression modeling. Admission rate (62%; 56/91 vs 49%; 57/111) (-13%, 95% CI -23%, 3%), length of stay (395 vs 327 minutes [IQR 164 501]; P.001), and IVF administration decreased (84% [77/91] to 70% [78/111]; P = .02] when comparing low and high ondansetron usage periods.Ondansetron administration was not independently associated with lower admission rates. Over time, along with increasing ondansetron use, there have been reductions in admissions, length of stay, and IVF administration in children with T1DM.

Rachmiel M, Rubio-Cabezas O, Ellard S, Hattersley AT, Perlman K. Early-onset, severe lipoatrophy in a patient with permanent neonatal diabetes mellitus secondary to a recessive mutation in the INS gene. We describe a case of neonatal diabetes due to a homozygous mutation (c.3 G>T) at the INS gene, leading to lack of insulin expression and severe hyperglycemia from day one of life requiring permanent insulin replacement therapy. The genetic loss of endogenous insulin production likely led to lack of immune tolerance to insulin, with resultant autoantibody production against exogenous insulin and progressive immune-mediated lipoatrophy at injection sites.

Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man.

Infantile hemangiomas (IHs) are common, although systemic therapy has been generally limited to circumstances of potential compromise of vital functions (airway, vision, feeding, or cardiac), risk of disfigurement, or bleeding. IHs have previously been shown to express high levels of type III deiodinase, which catabolizes active thyroid hormone, resulting in a state of severe hypothyroidism, termed “consumptive hypothyroidism.” We describe an infant with diffuse hepatic hemangiomas who developed consumptive hypothyroidism who was initially treated successfully with systemic glucocorticoids and β-blockers. Several efforts to wean her medications were unsuccessful. She subsequently developed severe growth restriction and treatment alternatives were sought. Although previously limited to treatment of life-threatening hemangiomas, a trial of vincristine was initiated. She was ultimately weaned from all systemic therapies, with recovery of a normal growth trajectory. This case highlights broader indications for vincristine as a safe and effective systemic therapy for treatment of IHs. It also stresses the importance of close anthropometric monitoring of infants and toddlers receiving glucocorticoid therapy and intervention when growth compromise becomes evident.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

BACKGROUND Hyperinsulinism-hyperammonemia syndrome (HI/HA) is a rare autosomal dominant disorder presenting with hypoglycemia and hyperammonemia. It is caused by activating mutations in the GLUD1 gene. CASE REPORTS Three patients from two different centers, a 14-month-old female, a 28-year-old female (mother of the first patient) from Toronto and an unrelated 2.5-year-old male from Vienna, presented with multiple episodes of seizures associated with hypoglycemia. RESULTS All patients had mild to moderate hypoglycemia, inappropriate insulin levels and mild hyperammonemia, thus suggesting a disorder of glutamate dehydrogenase (GDH). Molecular genetic testing of the GLUD1 gene identified heterozygous mutations in all patients (patient 1 and her mother a novel c.1526G>C mutation; patient 3 a known c.809C>G mutation). CONCLUSION We present three new patients with GDH caused by heterozygous mutation in the GLUD1 gene. Mild hyperammonemia and inappropriately elevated insulin levels should suggest a GLUD1 mutation. Early onset hypoglycemia associated with seizures, and especially a good response to diazoxide treatment, should include this disorder in the differential diagnosis of hyperinsulinemic hypoglycemia.

This article reviews the advantages to and caveats of the use of newer insulin formulations (insulin analogues) and regimens in children and teens who have type 1 diabetes, their affect on glycemic control, frequency of hypoglycemic events, daily insulin requirements, and adverse affects such as excessive weight gain, which provides a further major challenge in adolescents. We also address briefly the use of adjunctive agents in the treatment of type 1 diabetes in children and teens.

Improved metabolic control has unequivocally been demonstrated to delay the onset and slow the progression of microvascular complications in adolescents and adults with diabetes mellitus. Growing evidence also supports the association of tighter glucose control and more frequent blood glucose monitoring. Therefore, self-monitoring of blood glucose (SMBG) has become a fundamental part of diabetes care in children. Here, we review recent advances and ongoing trends in glucose monitoring in children with diabetes. Technologies have been developed to improve patient compliance with recommended monitoring, requiring less blood, involving less pain, and providing results more quickly. Alternate-site testing (AST) is also a potential means of improving patient compliance with SMBG by avoiding the sensitive fingertip area. The Continuous Glucose Monitoring System (CGMS) and the GlucoWatch Biographer are two recent tools that can track glucose levels continuously. However, inconsistency in their accuracy and precision remain challenges when using these technologies to guide management.

Objective. This study compared the glucose-lowering effect of insulin lispro, given before or after meals, with regular human insulin given before meals in prepubertal children with diabetes. Research Design and Methods. A 3-way crossover, open-label study involving 61 prepubertal children (ages 2.9–11.4 years) with type 1 diabetes. The children were randomly assigned to receive regular human insulin 30 to 45 minutes before meals, insulin lispro within 15 minutes before or immediately after meals, combined with basal insulin. Each treatment lasted 3 months. Hemoglobin A1c levels and home glucose monitoring profiles were measured at the end of each treatment period. Results. Treatment with insulin lispro before breakfast resulted in lower 2-hour postprandial glucose values than regular human insulin (11.7 ± 4.4 mmol/L vs 15.0 ± 5.4 mmol/L). Similarly, insulin lispro given before dinner resulted in lower blood glucose values 2 hours postprandially (8.8 ± 5.0 mmol/L vs 10.8 ± 5.4 mmol/L) than regular human insulin. When insulin lispro was administered after meals, the 2-hour glucose levels were between those seen with either insulin lispro or regular human insulin given before meals. The number and types of adverse events, the rates of hypoglycemia, and the HbA1c levels did not differ among the 3 therapies. Conclusions. In prepubertal children, insulin lispro given before meals is safe and significantly lowers postprandial glucose levels after breakfast and dinner compared with regular human insulin, and insulin lispro given after the meal provides similar benefits as regular human insulin before the meal.

We examined the patterns of TSH, T(4), and treatment schedules from diagnosis to 4 yr of age in 125 children (50 males anf 75 females) with congenital hypothyroidism (CH). Subjects were divided into 3 groups based on their thyroid scans: 1) athyreosis (n = 31), 2) dysgenesis (n = 54; 49 lingual and 5 hypoplastic), and 3) dyshormonogenesis (n = 40). Follow-up evaluation was carried out at 2-4 wk and 3, 6, 9, 12, 24, 36, and 48 months of age. Median gestational age, age at onset of therapy, and starting L-T(4) dose were similar in the three groups. In infants with athyreosis median screening TSH levels were higher (P < 0.02) and confirmatory T(4) levels were lower than in the other two groups (P < 0.01 vs. dysgenetic; P < 0.05 vs. dyshormonogenetic CH). During the first 6 months of therapy, mean TSH levels were highest in the athyrotic group, intermediate in the dysgenetic group, and lowest in the dyshormonogenetic group. In children with athyreosis, TSH levels normalized by 12 months of age. At 12 months dysgenetic patients had the highest TSH levels (P < 0.05). During the entire study period, TSH levels were lowest in patients with dyshormonogenesis (except at 48 months) and normalized earlier. Mean T(4) levels normalized by 2-4 weeks in all groups. At 3 and 6 months, the percentage of patients who required dose changes was highest in the athyrotic group, and at 12 months it was highest in the dysgenetic group. The athyrotic group received the highest dose of L-T(4), and dyshormonogenetic group received the lowest dose. We conclude that treatment and follow-up schedules for CH may differ in the three etiological categories based on the different hormonal patterns and responses to therapy. Children with athyreosis need close monitoring particularly early in life, whereas those with dysgenesis and dyshormonogenesis require more attention later in life.

Infants and toddlers comprise a small minority of individuals with type 1 diabetes. However, epidemiological data provide evidence of a trend towards diagnosis at a younger age. These very young children pose significant challenges to both the health care professionals involved in their care as well as to their families. At diagnosis, younger children often do not present with classical symptoms of diabetes. Unless health professionals remain alert to the possibility of diabetes being the underlying cause of a child’s illness, the diagnosis may be missed. Once the diabetes has been diagnosed, the major challenge is to set up a treatment regimen that is both reasonable and realistic; in the youngest children, the goal of very tight metabolic control may expose them to episodes of severe hypoglycemia which may lead to subtle cognitive impairments later in life. The therapeutic regimen must balance the naturally erratic eating and exercise patterns of very young children with the need to maintain adequate metabolic control. Setting a blood glucose target range of 6 to 12 mmol/L usually allows this to be accomplished. Diabetes during early childhood creates a psychosocial challenge to the families of these children. Successful management of infants and toddlers with diabetes depends on a well functioning and educated family, the availability of diabetes health care team experienced in the treatment of these youngsters, and the involvement of the extended family, child care personnel and others who play a role in their daily care.

A new form of congenital hyperinsulinism characterized by hypoglycemia and hyperammonemia was described recently. We hypothesized that this syndrome of hyperinsulinism and hyperammonemia was caused by excessive activity of glutamate dehydrogenase, which oxidizes glutamate to alpha-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver.We measured glutamate dehydrogenase activity in lymphoblasts from eight unrelated children with the hyperinsulinism-hyperammonemia syndrome: six with sporadic cases and two with familial cases. We identified mutations in the glutamate dehydrogenase gene by sequencing glutamate dehydrogenase complementary DNA prepared from lymphoblast messenger RNA. Site-directed mutagenesis was used to express the mutations in COS-7 cells.The sensitivity of glutamate dehydrogenase to inhibition by guanosine 5'-triphosphate was a quarter of the normal level in the patients with sporadic hyperinsulinism-hyperammonemia syndrome and half the normal level in patients with familial cases and their affected relatives, findings consistent with overactivity of the enzyme. These differences in enzyme insensitivity correlated with differences in the severity of hypoglycemia in the two groups. All eight children were heterozygous for the wild-type allele and had a mutation in the proposed allosteric domain of the enzyme. Four different mutations were identified in the six patients with sporadic cases; the two patients with familial cases shared a fifth mutation. In two clones of COS-7 cells transfected with the mutant sequence from one patient, the sensitivity of the enzyme to guanosine 5'-triphosphate was reduced, findings similar to those in the child's lymphoblasts.The hyperinsulinism-hyperammonemia syndrome is caused by mutations in the glutamate dehydrogenase gene that impair the control of enzyme activity.

The presence of cystic fibrosis (CF)-related diabetes was evaluated in 19 adolescents with CF by continuous glucose monitoring system (CGMS) and oral glucose tolerance testing. CGMS confirmed diabetic glucose excursions in 7/19 subjects deemed diabetic on oral glucose tolerance testing. CGMS is a useful tool for detecting hyperglycemia in CF.

GOALS The aim of this report is to delineate the clinical, pathologic, and enteroendocrine (EE) features of prohormone convertase 1/3 (PC1/3) deficiency in children. BACKGROUND Prohormone convertases play a pivotal role in the activation of biologically inactive hormones. Congenital defects in the EE axis, such as PC1/3 deficiency, have been rarely reported and their pathophysiological mechanisms are largely unknown. STUDY EE function and pathology was evaluated in 4 males (1, 2, 7, and 10 y old) from 2 families with PC1/3 deficiency at a university children's hospital. Clinical course, pathology analysis including immunohistochemistry for PC1/3, PC2, and glucagon-like peptide 1 (GLP-1) and electron microscopy, as well as EE function tests (GLP-1, GLP-2, oral glucose tolerance test) were performed. RESULTS All (n=4) suffered from congenital severe diarrhea associated with malabsorption. The diarrhea improved during the first year of life and hyperphagia with excessive weight gain (BMI>97th percentile) became the predominant phenotype at an older age. Analysis of the enteroendocrine axis revealed high proinsulin levels (57 to 1116 pmol/L) in all patients, low serum GLP-2 levels, and impaired insulin and GLP-1 secretion after an oral glucose tolerance test at a young age, with improvement in 1 older child tested. Electron microscopy showed normal ultrastructure of enterocytes and EE cells. Immunohistochemistry revealed normal expression of chromogranin A, a marker of EE cells but markedly reduced immunostaining for PC1/3 and PC2 in all patients. CONCLUSIONS PC1/3 deficiency is associated with an age dependent, variable clinical phenotype caused by severe abnormalities in intestinal and EE functions. Serum level of proinsulin can be used as an effective screening tool.

Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and by parathyroid carcinoma in 15% of cases. Inactivating mutations of the tumour suppressor CDC73/HRPT2 gene have been found in HPT-JT patients and also as genetic determinants of sporadic parathyroid carcinoma/atypical adenomas and, rarely, typical adenomas, in familial PHPT. Here we report the genetic and molecular analysis of the CDC73/HRPT2 gene in three patients affected by PHPT due to atypical and typical parathyroid adenomas, in one case belonging to familial PHPT. Flag-tagged WT and mutant CDC73/HRPT2 proteins were transiently transfected in HEK293 cells and functional assays were performed in order to investigate the effect of the variants on the whole protein expression, nuclear localization and cell overgrowth induction. We identified four CDC73/HRPT2 gene mutations, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro). In three cases the mutation was located within the Nucleolar Localisation Signals (NoLS). The three NoLS variants led to instability either of the corresponding mutated protein or mRNA or both. When transfected in HEK293 cells, NoLS mutated proteins mislocalized with a predeliction for cytoplasmic or nucleo-cytoplasmic localization and, finally, they resulted in overgrowth, consistent with a dominant negative interfering effect in the presence of the endogenous protein.

A rare case of possible primary ectopic adrenocorticotropic hormone (ACTH)-producing tumor in the liver mimicking a liver hemangioma is reported. A 9-year-old boy, with Cushing syndrome, was referred for the assessment of ectopic ACTH-producing tumor. Ultrasound, CT scan, and MRI of the abdomen revealed a liver lesion suggestive of a hemangioma. (111)In-octreotide scintigraphy revealed focal activity in the liver, indicative of a somatostatin-positive lesion. (99m)Tc-labeled RBC scintigraphy was negative for hemangioma. After surgical resection of the tumor, the cortisol level converted to a normal range indicative of a rare possible primary ACTH-producing tumor in the liver, which was confirmed by histopathology.

Necrotizing fasciitis (NF) is a potentially fatal bacterial infection of the subcutaneous soft tissues. Two cases of polymicrobial NF in adolescents with type 1 diabetes mellitus and poor glycemic control are reported. The perineal region was involved in both cases. One case was precipitated by apparently minimal trauma, the other by high-impact trauma. Diabetes mellitus has been identified as a common comorbidity and predictor of increased mortality in adult patients with NF. The associations between diabetes and the incidence or outcome of NF in children and adolescents are not known. In all cases, early identification and aggressive surgical intervention are important for limiting morbidity and mortality.

Data were reviewed from 73 consecutive medical charts of children and adolescents with type 1 diabetes mellitus using insulin pumps for more than 6 months at The Hospital for Sick Children, Toronto, Canada. Statistically significant differences in HbA1c (-0.8%), body mass index (+1.45 kg/m2) and total daily dose of insulin (-0.23 U/kg/day) were found between the start of pump use and evaluation 6-30 months later. There was a close correlation between the HbA1c before and after 6-30 months of pump therapy.

A 9-week-old infant presented with severe postnatal hypothyroidism. His hypothyroidism corrected only after his l-thyroxine dose was progressively increased to 28 μg/kg/d. At 6 months of age, multiple clinically asymptomatic hepatic hemangiomas were detected and support a diagnosis of consumptive hypothyroidism as a result of increased type 3 iodothyronine deiodinase activity in the hemangiomas. Coincident with the involution of the hemangiomas, the child’s hypothyroidism improved and l-thyroxin replacement could be stopped at the age of 3 years. Despite some degree of hypothyroidism for several weeks during infancy, his growth and development have been normal.

Minimal information exists on the education and follow-up required to successfully initiate intensive diabetes management (IDM) in adolescents with type 1 diabetes. We performed a retrospective analysis of HbA1c 3 and 15 months after initiation of IDM in two cohorts: (1) 17 patients who received individualised education in IDM and intensive early follow-up, and (2) 11 patients who participated in group education for initiation of IDM with standard follow-up. Entry HbA1c was higher in the individualised education patients (9.5 +/- 0.3% [mean +/- SE] versus 8.2 +/- 0.4%, p = 0.02). After 3 months of IDM, HbA1c improved in both cohorts reaching similar levels (individualised: 7.0 +/- 0.1%, p < 0.0001 vs entry; group: 7.3 +/- 0.2%, p = 0.05). During the following year, with routine follow-up for both cohorts, HbA1c levels rose approximately 1% as patients reverted to a multiple daily injection regimen. Irrespective of the educational approach, we believe maintenance of IDM and optimal HbA1c requires long-term intensive follow-up.

Objective To evaluate how intrauterine and neonatal thyroid hormone deficiencies affect infant cognitive abilities. Method 26 infants with intrauterine or neonatal thyroid hormone deficiency and 20 full-term infants with normal thyroid economies were studied at 6 months of age or corrected age. Reasons for thyroid hormone deficiency were maternal hypothyroidism, maternal hyperthyroidism treated with antithyroid medication, congenital hypothyroidism, and low-risk prematurity. A computer-generated task during which infants' eye-movements were videotaped was used to assess attention, memory, and learning abilities Results Data from transcribed videotapes showed the study group was significantly less attentive and had longer reaction times than controls but did not differ on indices of sustaining attention or learning. Within thyroid-deficient groups, offspring of treated hyperthyroid mothers showed an atypical profile suggestive of hypervigilance. Conclusion A decreased fetal or maternal thyroid hormone supply in pregnancy is associated with infants' poorer attention and altered rates of information processing.

Four patients with lingual thyroid glands presenting beyond the neonatal period have been evaluated at the Hospital for Sick Children, Toronto since the advent of neonatal TSH screening. All were female, clinically euthyroid at diagnosis and presented with symptoms of a lingual mass. We estimate that 1.6% of lingual thyroids are missed by this TSH based thyroid screening program and approximately 1/600,000 live births present in childhood or adolescence with a lingual thyroid. Physicians should still include lingual thyroid in the differential diagnosis of a mass at the base of the tongue.

A 95% pancreatectomy became the treatment of choice for persistent hyperinsulinemic hypoglycemia of the neonate (PHHN, Nesidioblastosis) at the author's institution, when lesser resections failed to prevent hypoglycemia in 25% to 50% of cases. With few outcome data available in the literature, the authors reviewed their 25-year experience to assess the efficacy and the long-term consequences of this procedure. Since 1971, 27 infants underwent a 95% pancreatectomy for the treatment of PHHN. None had responded to medical treatment (glucose infusion, glucagon, octreotide, diazoxide), and two had 85% pancreatectomy that failed. The procedure consisted of resecting the pancreas including the uncinate process, leaving only the gland lying between the common bile duct (CBD) and the duodenum and a small rim of pancreas along the duodenal sweep. Hyperinsulinemia and hypoglycemia recurred in nine children (33%), all within 2 to 5 days. Seven of them were subsequently cured with near-total pancreatic resection. Partial pancreatic regrowth was evident at reoperation. In two cases hypoglycemia was controlled with diazoxide and frequent feedings because reoperation was refused. The gross anatomic findings and the histopathology were not predictive of treatment failure. Perioperative complications occurred in four of 27 children (15%) after 95% pancreatectomy and in four of seven children (57%) after near-total pancreatectomy. Clinical follow-up ranged from 0.5 to 18 years (mean, 8 years; median, 8 years). To date, diabetes has developed in 15 children (56%), nine of 20 (45%) after 95% pancreatectomy (mean age, 9.7 years) and six of seven (86%) after a near-total pancreatectomy (mean age, 1.7 years). After 95% pancreatectomy, the incidence of diabetes increased with age, developing in nine of the 13 (69%) children followed up for more than 4 years. The failure of 95% pancreatectomy to prevent hypoglycemia in one third of children with PHHN and the ultimate development of diabetes in a minimum of two-thirds, indicates that an alternative treatment strategy is needed for this disease.

We have observed 4 cases of hypoglycemia associated with clonidine stimulation of growth hormone secretion; only one patient had growth hormone deficiency. Significant drowsiness after administration of clonidine may prolong the period of fasting in these children and mask early signs and symptoms, leading to severe hypoglycemia.

It has been proposed that lowering glomerular pressure in children with insulin-dependent diabetes mellitus will reduce microalbuminuria and that this reduction may preserve renal function. We therefore conducted a double-blind, placebo-controlled, crossover trial to compare 3 months of treatment with the angiotensin converting enzyme inhibitor captopril (0.9 mg/kg/day), and 3 months of placebo administration to 12 normotensive adolescents with insulin-dependent diabetes mellitus, 11 with microalbuminuria (albumin excretion rate of 15 to 200 micrograms/min) and one with early overt nephropathy. Mean age (+/- SD) was 14.4 +/- 1.7 years, and disease duration was 5.1 +/- 2.5 years. Albumin excretion rate decreased significantly during captopril therapy (baseline 78 +/- 114 micrograms/min; mean of monthly measurements 38 +/- 55 micrograms/min vs placebo 78 +/- 140 micrograms/min; p less than 0.001). During captopril therapy, albumin excretion was reduced by 41 +/- 44% and decreased in 10 of 12 subjects, but was unchanged in two, one with a borderline albumin excretion rate (16.3 micrograms/min) and one with diabetes of short duration (2.9 years). Plasma renin activity rose significantly during captopril therapy, and mean arterial pressure decreased slightly (placebo 81 +/- 7 mm Hg; captopril 76 +/- 5 mm Hg; p = 0.004). After 3 months of captopril treatment, glomerular filtration rate and renal plasma flow did not change significantly. Hemoglobin Alc values remained stable during the study. The only side effect of captopril was diarrhea in one patient. We conclude that, in the short term, captopril is effective in decreasing albumin excretion rate in normotensive children with insulin-dependent diabetes mellitus and microalbuminuria, without significant side effects. Longer trials are indicated in an attempt to delay or prevent overt nephropathy.

We surveyed 311 children with insulin-dependent diabetes mellitus to evaluate the frequency and characteristics of those children experiencing severe hypoglycemia (defined by an episode of coma, convulsion, or both). The children and their parents completed a questionnaire, and we reviewed the hospital records to confirm reported episodes. Ninety-seven (31%) reported severe hypoglycemia, and a further 50 (16%) reported moderate hypoglycemia requiring the assistance of another person but not resulting in coma or convulsion. In 164 children (53%) there was no history of either moderate or severe hypoglycemia. Sixty-nine (22%) reported the occurrence of more than one severe hypoglycemic episode (range 2 to 20); 52 (16%) reported such an event in a single year. A total of 285 episodes were reported, 39% during sleep and 61% while awake. Children reporting such events tended to have diabetes of longer duration and be younger at the time of the first episode. Hemoglobin A 1c concentration at the time closest to the severe episode was significantly lower than in children reporting no hypoglycemia. All families had been taught to use glucagon to reverse severe hypoglycemia at home, but it was available in only 80 of the 97 homes and used in only 30. These data suggest that severe hypoglycemia is common in children with insulin-dependent diabetes mellitus who are treated conventionally. Greater vigilance and education are required both to prevent and to treat severe hypoglycemia in children with insulin-dependent diabetes mellitus.

A case is reviewed of precocious puberty associated with hypothalamic hamartoma in a 15-month-old boy. The authors believe this to be the first documented case in which significant reductions occurred in the level of serum testosterone and in the result of the luteinizing hormone-releasing hormone (LHRH) infusion test following surgical removal of the turner. Such surgery appears to be safe when a planned micro-surgical course is employed.

The impact on remission of normalizing blood glucose levels immediately after diagnosis of type I diabetes was studied in 14 adolescents. Accordingly, in this randomized prospective primary intervention study, 7 of the subjects (i.v. group) received insulin by continuous intravenous (i.v.) infusion via a portable preprogrammed system for 28–62 days and 7 (s.c. group) received conventional subcutaneous (s.c.) therapy. Before therapy, the two groups did not differ significantly with respect to glycosylated hemoglobin, fasting plasma C-peptide, or 24-h urinary C-peptide excretion. During the infusion period, the overall mean fasting plasma glucose (FPG) concentration for the i.v. group was 84 mg/dl with a mean coefficient of variation of 18 ± 4% (mean ± SD). During the comparable period for the s.c. group, the mean FPG was 253 mg/dl with a coefficient of variation of 30 ± 20%. Twenty-four-hour urinary glucose excretions for the two groups were 0.29 ± 0.06 (mean ± SEM) and 59 ± 11 g/day, respectively. Daily insulin requirements in the i.v. group decreased from 1.47 ± 0.19 U/kg body wt/day at the start to 0.47 ± 0.10 U/kg/day at the end of the infusion period. Notably, 10–25 days after the infusion period, 5 of 7 subjects experienced a further decrease to a low of 0.27 ± 0.01 U/kg/day. The mean peak and low requirements in the s.c. group were 0.71 ± 0.15 and 0.33 ± 0.13 U/kg/day, respectively, with the only peak requirements being significantly different (P < 0.01). No patient was able to discontinue insulin therapy. The fasting plasma C-peptide level rose significantly (P < 0.05) by 1 mo in the i.v. group, but only achieved similar levels by 4 mo in the s.c. group. In the i.v. group, 24-h urinary C-peptide excretion decreased during the first week of therapy, rose through the infusion period, and finally peaked at 60 ± 14 μg day 3–30 days later. In the s.c group, the urinary C-peptide excretion gradually increased reaching a significantly lower peak (P < 0.05) of 36 ± 8 μg day at 113 ± 38 days. Glycosylated hemoglobin levels declined significantly only in the i.v. group with 4 subjects achieving normal levels. At 1 mo after diagnosis, the i.v. group had significantly higher (P < 0.05) fasting plasma C-peptide levels and lower (P < 0.005) glycosylated hemoglobin levels than did the s.c. group. Inspite of the higher peak urinary C-peptide excretion for the i.v. group, 4 and 12 mo after diagnosis the groups did not differ in mean 24-h urinary C-peptide excretion, fasting plasma C-peptide, insulin requirements, or glycosylated hemoglobin. We conclude that sustained strict glycemie control within normal limits at diagnosis of type I diabetes does not of itself augment the remission phase.

Accuracy of self-monitoring of blood glucose (SMBG) using Chemstrip bG (Bio-Dynamics, Indianapolis, Indiana) was studied in 90 randomly selected children with insulin-dependent diabetes mellitus (IDDM). For 28 children (mean age 8.3 ± 3.6 yr) a parent routinely read the Chemstrip at home. The remaining 62 children (mean age 13.7 ± 2.8 yr) read the Chemstrip themselves. Each child or parent analyzed 20 capillary blood samples using Chemstrips and answered a questionnaire on SMBG. The accuracy of SMBG of the group was high (mean correlation coefficient = 0.89 ± 0.05), but consistency of measurement was variable (mean standard deviation = 1.90 ± 0.57) and there was a general tendency to underread Chemstrips (mean y-intercept = 1.05 ± 1.48; mean slope = 0.80 ± 0.17). For each subject, 0–65% (mean of 34%) of readings were within 10% of the laboratory measurement, and 17–100% (mean 68%) within 20%. These results indicate that most subjects were fairly accurate in reading Chemstrips; however, analysis of accuracy is useful in identifying individuals who are inaccurate or inconsistent in SMBG. Continuing supervision of SMBG is necessary in children with IDDM.

Devices and methods for long-term intravenous (i.v.) insulin infusion in ambulatory patients have recently been developed. However, to date optimal waveforms for open-loop insulin administration in severely insulin deficient patients have not been defined. We studied 7 nonobese uncomplicated type 1 diabetics aged 16.5 ± 0.2 yr who received insulin continuously for 14–23 days by central venous infusion. A pattern of i.v. insulin administration was developed and eventually refined to include a constant basal infusion rate augmented at meal time by a series of 3 pulses. The first pulse lasted 10–15 min with an infusion rate 1.5–2 times the basal rate. The second pulse was 60–100 min in duration with a rate 4–6 times the basal infusion rate. The third pulse lasted 40–100 min with an infusion rate 1.5–3 times the basal rate. Accompanying the evolution of this waveform, the mean fasting plasma glucose fell from 262 ± 40 mg/dl on conventional therapy to 92 ± 9 mg/dl during infusion with normal meal excusions (mean a.c. glucose 80 ± 3 mg/dl with a rise of 35 ± 3 mg/dl at 41 ± 3 min). Mean urinary glucose excretion decreased from 55 before to 1.9 g/day during the infusion period. Fasting serum cholesterol and triglycerides dropped from 220 ± 28 and 281 ± 94 to 138 ± 13 and 115 ± 24 mg/dl, respectively.Mean HbA, declined from 14.8% before to 10.7% at the conclusion of the infusion period. All indices of control showed improvement significant at P < 0.05. There were no catheter-related complications and the system was well accepted by all subjects. These studies confirm that continuous central venous insulin infusion with a relatively simple waveform is feasible for the prolonged normalization of glycemia and other indices of metabolic control in ambulatory adolescent diabetics.

• Hyperglycemia and glycosuria are known to occur in some children receiving corticosteroids. In a retrospective study 24 such episodes were identified in 17 patients receiving steroids for a variety of primary diseases from 1968 to 1979. Detection based on symptoms averaged 26 days from initiation of steroid treatment, whereas detection based on the presence of glycosuria or hyperglycemia averaged 4.5 days. Acidosis, ketosis, and hyperglycemia (glucose level, > 500 mg/dL) occurred in 2, 4, and 8 patients, respectively. Insulin therapy was necessary in 15 episodes in 11 patients, but in three episodes the insulin dosage was reduced while the steroid dosage remained high. Permanent insulin dependence developed immediately in one patient and eventually in three others. Steroid-precipitated diabetes must be anticipated but should not interfere with the treatment of the primary disease. ( Am J Dis Child 1982;136:64-68)

Devices and methods for long term intravenous insulin infusion in ambulatory patients have recently been developed. With informed consent we studied 7 non-obese uncomplicated Type I diabetics (aged 15-17y) who received insulin for 14-23 days by central venous infusion (CVII). All subjects were studied in hospital with otherwise unrestricted activity and received 3 daily meals and an evening snack of constant caloric content. Under local anesthesia, a thin silicone rubber catheter was inserted into a branch of the external jugular vein, advanced to the SVC and tunnelled subcutaneously to exit in the supramammary region, where it was connected to the portable system consisting of a small peristaltic pump, a flow rate controller and a reservoir of soluble insulin. Insulin was infused at a constant basal rate of 17±3 mU/min. The rate was increased 15 minutes from the start of a meal 4-5 fold for 60-120 min then returned to the basal rate in a 2 step fashion over 40-120 min. Fasting plasma glucose (mean±SEM) was 262±40 prior to infusion and fell to 92±9 mg/dl on CVII with increases during mealtimes from 80±3 to 115±3 mg/dl at 41±3 min pc. Mean urinary glucose excretion of 55 g/day fell to 1.9 during CVII and fasting serum cholesterol of 220±28 and triglycerides of 281±94 fell to 138±13 and 115±24 mg/dl respectively. Mean HgbAl (N:6.5 - 8.5%) fell from 14.8 to 10.7% by the end of the study period. All indices of control showed improvement with p