Multicenter, Randomized Trial of a Bionic Pancreas in Type 1 Diabetes.

BACKGROUND: Currently available semiautomated insulin-delivery systems require individualized insulin regimens for the initialization of therapy and meal doses based on carbohydrate counting for routine operation. In contrast, the bionic pancreas is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. METHODS: In this 13-week, multicenter, randomized trial, we randomly assigned in a 2:1 ratio persons at least 6 years of age with type 1 diabetes either to receive bionic pancreas treatment with insulin aspart or insulin lispro or to receive standard care (defined as any insulin-delivery method with unblinded, real-time continuous glucose monitoring). The primary outcome was the glycated hemoglobin level at 13 weeks. The key secondary outcome was the percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter; the prespecified noninferiority limit for this outcome was 1 percentage point. Safety was also assessed. RESULTS: A total of 219 participants 6 to 79 years of age were assigned to the bionic-pancreas group, and 107 to the standard-care group. The glycated hemoglobin level decreased from 7.9% to 7.3% in the bionic-pancreas group and did not change (was at 7.7% at both time points) in the standard-care group (mean adjusted difference at 13 weeks, -0.5 percentage points; 95% confidence interval [CI], -0.6 to -0.3; P<0.001). The percentage of time that the glucose level as assessed by continuous glucose monitoring was below 54 mg per deciliter did not differ significantly between the two groups (13-week adjusted difference, 0.0 percentage points; 95% CI, -0.1 to 0.04; P<0.001 for noninferiority). The rate of severe hypoglycemia was 17.7 events per 100 participant-years in the bionic-pancreas group and 10.8 events per 100 participant-years in the standard-care group (P = 0.39). No episodes of diabetic ketoacidosis occurred in either group. CONCLUSIONS: In this 13-week, randomized trial involving adults and children with type 1 diabetes, use of a bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT04200313.).

Impact of the COVID-19 pandemic on management of children and adolescents with Type 1 diabetes.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic had widespread impacts on the lives of parents and children. We determined how the pandemic affected Type 1 diabetes patients at a large urban pediatric teaching hospital. METHODS: We compared patient characteristics, glycemic control, PHQ-9 depression screen, in person and virtual outpatient encounters, hospitalizations and continuous glucose monitor (CGM) utilization in approximately 1600 patients in 1 year periods preceding and following the local imposition of COVID-related restrictions on 3/15/2020 ("2019" and "2020" groups, respectively). RESULTS: In a generalized linear model, increasing age, non-commercial insurance, Black and Hispanic race/ethnicity, and non-utilization of CGMs were all associated with higher hemoglobin A1c (HbA1c), but there was no difference between the 2019 and 2020 groups. The time in range in CGM users was lower with non-commercial insurance and in Black and Hispanic patients; it improved slightly from 2019 to 2020. CGM utilization by patients with non-commercial insurance (93% of such patients were in government programs, 7% uninsured or "other") increased markedly. In 2020, patients with commercial insurance (i.e., private-pay or provided by an employer) had fewer office visits, but insurance status did not influence utilization of the virtual visit platform. There was no change in hospitalization frequency from 2019 to 2020 in either commercially or non-commercially insured patients, but patients with non-commercial insurance were hospitalized at markedly higher frequencies in both years. PHQ-9 scores were unchanged. CONCLUSIONS: Hospitalization frequency, glycemic control and depression screening were unchanged in our large urban pediatric teaching hospital during the COVID pandemic. Increased utilization of CGM and rapid adoption of telemedicine may have ameliorated the impact of the pandemic on disease management.

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency.

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

Risk factors for hospitalization in youth with type 1 diabetes: Development and validation of a multivariable prediction model.

OBJECTIVE: To develop a multivariable prediction model to identify patients with type 1 diabetes at increased risk of hospitalization for diabetic ketoacidosis or hyperglycemia with ketosis in the 12 months following assessment. METHODS: Retrospective review of clinical data from patients with type 1 diabetes less than 17 years old at a large academic children's hospital (5732 patient years, 652 admissions). Data from the previous 12 months were assessed on October 15, 2015, 2016, 2017, and 2018, and used to predict hospitalization in the following 12 months using generalized estimating equations. Variables that were significant predictors of hospitalization in univariate analyses were entered into a multivariable model. 2014 to 2016 data were used as a training dataset, and 2017 to 2019 data for validation. Discrimination of the model was assessed with receiver operator characteristic curves. RESULTS: Admission in the preceding year, hemoglobin (Hb)A1c, non-commercial insurance, female sex, and non-White race were all individual predictors of hospitalization, but age, duration of diabetes and number of office visits in the preceding year were not. In multivariable analysis with threshold P < .0033, admissions in the previous 12 months, HbA1c, and non-commercial insurance remained as significant predictors. The model identified a subset of ~8% of the patients with a collective 42% risk of hospitalization, thus increased 5-fold compared with the 8% risk of hospitalization in the remaining 93% of patients. Similar results were obtained with the validation dataset. CONCLUSION: Our multivariable prediction model identified patients at increased risk of admission in the 12 months following assessment.

Impact of insulin reduction on glycemic control in children attending a residential diabetes camp.

BACKGROUND/OBJECTIVES: Children attending diabetes camp are more active, increasing the risk of hypoglycemia. Decreasing initial insulin doses may reduce this risk. The objectives of our study were to compare glycemic control between campers receiving multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII), and analyze the impact of decreasing basal insulin by 10%. METHODS: We analyzed 849 camp sessions (599 children, 5-19 years old) from Camp Sweeney's 2016/2017 summers. Campers were separated into groups by year and insulin route (MDI_2016, MDI_2017, CSII_2016, and CSII_2017). The MDI_2016 group had initial basal insulin decreased 10%, while CSII_2016, MDI_2017, and CSII_2017 did not. Time spent in blood glucose ranges and area under the curve (AUC) were compared by year and insulin route using ANOVA. We also performed repeated measures ANOVA using campers who attended both years. RESULTS: No significant differences in time spent in any glucose range could be attributed to the initial 10% basal decrease, including on paired analysis. MDI_2017 had more decreases to basal insulin than the other groups. CSII campers had higher AUC and more hyperglycemia than MDI campers. CONCLUSIONS: Campers on MDI may benefit from decreasing basal insulin, either at the beginning of camp or during the first week. Future research is needed to optimize glycemic control in the camp setting.

Parental Involvement and Executive Function in Emerging Adults with Type 1 Diabetes.

OBJECTIVE: To examine (a) changes in parental involvement across early emerging adulthood, (b) whether yearly fluctuations in parental involvement were associated with adherence and glycated hemoglobin (HbA1c) over time, and (c) whether higher involvement was more beneficial for those with poorer executive function (EF). METHODS: A total of 228 high school seniors (M age = 17.76) with type 1 diabetes reported on mothers' and fathers' acceptance, knowledge of diabetes activities, disclosure to mothers and fathers regarding diabetes, and adherence at four yearly time points. At baseline, participants completed performance-based measures of EF. HbA1c was collected from assay kits. RESULTS: Growth curve models revealed significant declines in disclosure to fathers and mothers' and fathers' knowledge of diabetes activities; no changes were found in mothers' or fathers' acceptance nor disclosure to mothers. Multilevel models indicated significant between-person effects for nearly all aspects of parental involvement with more acceptance, knowledge, and disclosure associated with better HbA1c and adherence. Within-person effects for disclosure to fathers, and mothers' and fathers' knowledge indicated that in years when emerging adults perceived higher amounts of these types of involvement (compared with their own average), HbA1c was lower. Within-person effects were found for acceptance to mothers, disclosure to mothers and fathers, and mothers' diabetes knowledge for adherence. Disclosure to fathers and mothers' knowledge of diabetes activities were especially beneficial for HbA1c for those with poorer EF performance. CONCLUSIONS: Parental involvement in diabetes management remains important during the high-risk time of emerging adulthood, especially for those with poorer EF.

Weight gain after treatment of Graves' disease in children.

OBJECTIVE: The frequency of and risk factors for weight gain in children treated for Graves' disease have not been described. We evaluated change in BMI-Z score and predictors of weight gain in this population. DESIGN: Retrospective review of data from January 2000 to July 2011. PATIENTS: Two hundred and twenty two children and adolescents with Graves' disease (ages 2-18 years) evaluated following radioactive iodine administration (RAI); (n = 101), thyroidectomy (n = 9) and initiation of medical therapy (n = 112). MEASUREMENTS: Changes in body mass index Z score over 12 months (ΔBMI-Z0-12 ). RESULTS: All treatment groups in each gender and race increased BMI-Z (median ΔBMI-Z0-12 was positive). T3 levels following RAI (P = .04) and weight lost at the time of administration (P = .02) in the RAI group and free T4 levels in the medical therapy group (P = .03) were positively correlated with ΔBMI-Z0-12 . Race was a significant predictor only in the medical therapy group (P = .01). Age negatively correlated with ΔBMI-Z0-12 in both the RAI (P < .001) and medical therapy groups (P = .003). Gender, maximum TSH in the 12 months after RAI and initial dose of LT4 replacement did not correlate with ΔBMI-Z0-12 . The prevalence of overweight and obesity in our cohort was similar to US children. CONCLUSIONS: Weight gain during treatment for Graves' disease is common in children, and many children become overweight or obese during treatment. Risk factors include greater degree of hyperthyroidism at presentation and time of RAI and younger age. Weight lost upon presentation may also predict greater weight gain. Control of subsequent hypothyroidism does not appear to affect weight gain.

A phase I study of anti-inflammatory therapy with rilonacept in adolescents and adults with type 1 diabetes mellitus.

BACKGROUND: The innate immune system may be activated around the time of diagnosis of type 1 diabetes (T1D). Components of this system, including cytokines such as interleukin-1ß (IL-1ß) represent potential therapeutic targets for disease modifying therapy. OBJECTIVE: We conducted a phase 1 trial of rilonacept, an IL-1 cytokine trap, in patients with T1D. SUBJECTS AND METHODS: Thirteen T1D patients (10 males) with median age (interquartile range, IQR) of 17 years (16-18), a median (IQR) of 5 months (5-7) since diagnosis. Rilonacept was administered subcutaneously for 26 weeks. Incidence of infections was the primary end-point. RESULTS: There were 85 adverse events; 13 were Grade 2, of which 9 (8 infectious) were judged "possibly related" to the drug. The mean (SD) C-peptide on 2-hour mixed meal tolerance tests decreased from 0.87 (0.42) to 0.59 (0.29) ng/mL (P = .01 by paired t test) during 6 months on treatment. Hemoglobin A1c (HbA1c) increased from 6.8 (1.1) to 7.3 (1.1) (P = .05), but there was not a significant change in daily insulin dose (0.41 ± 0.23 to 0.47 ± 0.18), or in insulin dose-adjusted HbA1c (IDAA1c, 8.4 ± 1.8 to 9.0 ± 1.5). Subjects in "remission," defined as HbA1c <6.5 and a total daily insulin dose <0.5 units/kg/24 h, decreased from 5 to 4. There were no significantly differentially expressed genes in peripheral blood leukocytes before and after rilonacept. CONCLUSIONS: Rilonacept treatment for 6 months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function.

Effects of residential summer camp on body mass index and body composition in type 1 diabetes.

BACKGROUND: Body mass index (BMI) and fat mass may be higher in children with diabetes compared to healthy peers. It is not certain how diabetic children respond to exercise and diet interventions. OBJECTIVE: To investigate the effect of summer camp on BMI and body composition in children with type 1 diabetes. METHODS: Five hundred eighty-six children (5-19 years, 518 with type 1 diabetes, 68 without diabetes) were followed while attending camp. BMI z-scores (BMIz) and body composition (bioelectrical impedance analysis) were measured at the beginning and end of each 19-day session. Diet and activity were directly supervised, blood glucose closely monitored. A nested diabetic/non-diabetic sib pair analysis was also conducted. Changes in BMIz and percent fat mass (%FM) were the primary outcomes. Findings were confirmed by analysis of data from 612 campers (549 with diabetes) the following summer. RESULTS: At entry, campers with diabetes had higher BMIz and %FM. They tended to gain BMIz (0.04 ± 0.01) whereas non-diabetic campers lost (-0.16 ± 0.11, P < .0001). BMIz increases were positively correlated with precamp hemoglobin A1c values. The differences in initial values and changes in BMIz remained when campers with diabetes were compared to their siblings. All experienced a similar reduction in %FM. Similar results were obtained the following summer. CONCLUSIONS: Children with diabetes may, therefore, accrue more lean body tissue with increased exercise and a healthy diet than those without diabetes. This effect is greatest in those with initially poor metabolic control.

Camp-based multi-component intervention for families of young children with type 1 diabetes: A pilot and feasibility study.

BACKGROUND: Managing type 1 diabetes mellitus (T1DM) in preschool-aged children has unique challenges that can negatively impact glycemic control and parental coping. OBJECTIVE: To evaluate the impact of a camp-based multi-component intervention on glycated hemoglobin A1c (HbA1c) in young children with T1DM and psychosocial measures for their parents. SUBJECTS AND METHODS: Two separate cohorts of 18 children (ages 3-5 years) and their families participated in a camp-based intervention that included didactic and interactive parent education, child-centered education and family-based recreational activities. In Camp 1.0, measures of HbA1c, parental fear of hypoglycemia, mealtime behaviors and quality of life (QOL) were compared before and after an initial session (I) and follow-up booster session (II) 6 months later. Based on these results, the intervention was consolidated into 1 session (Camp 2.0) and repeated with additional measures of parental stress and parental self-efficacy with diabetes management tasks. RESULTS: Participants in Camp 2.0 exhibited a significant decrease in mean HbA1c level (-0.5%, P = .002) before and after camp. Mothers exhibited a significant improvement in diabetes-specific QOL (Camp 1.0/Session I and Camp 2.0) and reduction in stress as measured on the Pediatric Inventory for Parent (PIP) assessment (Camp 2.0). The booster session in Camp 1.0 showed no added benefit. CONCLUSIONS: A family centered, camp-based multi-component intervention in young children with T1DM improved HbA1c and perceived QOL and stress in their mothers.

Adolescent Information Management and Parental Knowledge in Non-Latino White and Latino Youth Managing Type 1 Diabetes.

Objectives: The objective of this study is to examine associations between adolescents' regulation of information about their type 1 diabetes (adolescent disclosure, secrecy), parental knowledge about their adolescent's diabetes management, diabetes outcomes (adherence, HbA1c), and depressive symptoms in Non-Latino White and Latino families. Methods: In all, 118 adolescents (56 = Latino, 62 = Non-Latino White) completed surveys of disclosure to and secrecy from parents, parental knowledge of adolescent diabetes management, adherence, and depressive symptoms, and mothers completed measures of maternal knowledge and adolescent adherence. Glycemic control was extracted from medical records. Adolescents also completed structured interviews about parental knowledge about their diabetes-related problems. Results: Interviews revealed that adolescent disclosure is the primary method by which parents gain knowledge about adolescent diabetes management problems. Adolescent disclosure to and secrecy from parents were uniquely associated with diabetes management and depressive symptoms independent of parental knowledge across ethnic groups; maternal reports of knowledge about her adolescent's diabetes care activities were associated with diabetes management independent of adolescent disclosure and secrecy. Conclusions: Adolescent information management strategies are a primary means by which parents gain knowledge about diabetes, which may facilitate more effective management.

Risk factors for hospitalization of children with congenital adrenal hyperplasia.

BACKGROUND AND OBJECTIVES: Patients with congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency are prone to potentially life-threatening adrenal crises. We tried to identify risk factors for postdiagnosis hospitalization for children with the salt-wasting form of CAH. METHODS: We reviewed medical records of all children who presented to Children's Medical Center, Dallas, from 1999 to 2013 with CAH (ICD-9 code 255·2). RESULTS: Five hundred and twenty-two unique patients were coded for ICD-9 code of 255·2 (CAH) from 1999 to 2013; 155 patients had salt-wasting disease. Fifty-five patients were hospitalized a total of 105 times. Patients who were hospitalized were more likely to have noncommercial insurance (RR = 1·8; 95% CI [1·1-2·8]; P = 0·02); this included five patients hospitalized a total of 37 times. Children younger than 2 years (RR = 3·3 [2·2-4·8]; P < 0·0001) were more likely to be hospitalized. In a nested case-control analysis, the risk of hospitalization was correlated with daily fludrocortisone dose (P ≤ 0·0001) but not hydrocortisone dose; no outpatient laboratory test predicted hospitalization. Gastroenteritis was the most frequent admitting diagnosis. CONCLUSIONS: Younger children may be at greater risk of hospitalization owing to increased susceptibility to viral infections and decreased ability to withstand stress and dehydration. A minority of patients with noncommercial insurance may have higher risk owing to social barriers that interfere with treatment compliance. Those requiring higher daily fludrocortisone dosages likely have inherently more severe disease leading to higher rates of hospitalization.

Iowa Gambling Task Performance Prospectively Predicts Changes in Glycemic Control among Adolescents with Type 1 Diabetes.

OBJECTIVES: Good glycemic control is an important goal of diabetes management. Late adolescents with type 1 diabetes (T1D) are at risk for poor glycemic control as they move into young adulthood. For a subset of these patients, this dysregulation is extreme, placing them at risk for life-threatening health complications and permanent cognitive declines. The present study examined whether deficiency in emotional decision making (as measured by the Iowa Gambling Task; IGT) among teens with T1D may represent a neurocognitive risk factor for subsequent glycemic dysregulation. METHODS: As part of a larger longitudinal study, a total of 241 high-school seniors (147 females, 94 males) diagnosed with T1D underwent baseline assessment that included the IGT. Glycated hemoglobin (HbA1c), which reflects glycemic control over the course of the past 2 to 3 months, was also assessed at baseline. Of the 241,189 (127 females, 62 males, mean age=17.76, mean HbA1c=8.11) completed HbA1c measurement 1 year later. RESULTS: Baseline IGT performance in the impaired range (per norms) was associated with greater dysregulation in glycemic control 1 year later, as evidenced by an average increase in HbA1c of 2%. Those with normal IGT scores (per norms) exhibited a more moderate increase in glycemic control, with an HbA1c increase of 0.7%. Several IGT scoring approaches were compared, showing that the total scores collapsed across all trials was most sensitive to change in glycemic control. CONCLUSIONS: IGT assessment offers promise as a tool for identifying late adolescents at increased risk for glycemic dysregulation. (JINS, 2017, 23, 204-213).

Graves' disease in children: long-term outcomes of medical therapy.

BACKGROUND AND OBJECTIVES: Management options are limited for the treatment of Graves' disease, and there is controversy regarding optimal treatment. We describe the demographic and biochemical characteristics of children with Graves' disease and the outcomes of its management. METHODS: This is a retrospective study reviewing medical records from 2001 to 2011 at a tertiary-care paediatric hospital. Diagnostic criteria included elevated free T4 and total T3, suppressed TSH, and either positive thyroid-stimulating immunoglobulin or thyroid receptor antibodies or clinical signs suggestive of Graves' disease, for example exophthalmos. Patients were treated with antithyroid drugs (ATD), radioactive iodine, or thyroidectomy. The main outcome measures were remission after medical therapy for at least 6 months and subsequent relapse. RESULTS: A total of 291 children met diagnostic criteria. A total of 62 were male (21%); 117 (40%) were Hispanic, 90 (31%) Caucasian, and 59 (20%) African American. Mean age (±standard deviation) at diagnosis was 12·3 ± 3·8 (range 3-18·5) years. At diagnosis, 268 patients were started on an antithyroid drug and 23 underwent thyroid ablation or thyroidectomy. Fifty-seven (21%) children achieved remission and 16 (28%) of these patients relapsed, almost all within 16 months. Gender and ethnicity did not affect rates of remission or relapse. Of 251 patients treated with methimazole, 53 (21%) had an adverse reaction, including rash, arthralgias, elevated transaminases, or neutropenia. CONCLUSIONS: Most children with Graves' disease treated with ATD do not experience remission, but most remissions do not end in relapse. Adverse reactions to methimazole are common but generally mild.

Associations of parent-adolescent relationship quality with type 1 diabetes management and depressive symptoms in Latino and Caucasian youth.

OBJECTIVE: To examine associations of parent-adolescent relationship quality (parental acceptance and parent-adolescent conflict) with adolescent type 1 diabetes management (adherence and metabolic control) and depressive symptoms in Latinos and Caucasians. METHODS: In all, 118 adolescents and their mothers (56 = Latino, 62 = Caucasian) completed survey measures of parental acceptance, diabetes conflict, adolescent adherence, and adolescent depressive symptoms. Glycemic control was obtained from medical records. RESULTS: Across ethnic groups, adolescent-reported mother and father acceptance were associated with better diabetes management, whereas mother-reported conflict was associated with poorer diabetes management and more depressive symptoms. Independent of socioeconomic status, Latinos reported lower parental acceptance and higher diabetes conflict with mothers than Caucasians. Ethnicity moderated some associations between relationship quality and outcomes. Specifically, diabetes conflicts with mothers (mother and adolescent report) and fathers (adolescent report) were associated with poorer mother-reported adherence among Caucasians, but not among Latinos. CONCLUSIONS: Parent-adolescent relationship quality differs and may have different relations with diabetes management across Latinos and Caucasians.

Individual differences and day-to-day fluctuations in perceived self-regulation associated with daily adherence in late adolescents with type 1 diabetes.

OBJECTIVE: To examine whether individual differences and intraindividual (within-person day-to-day) fluctuations in late adolescents' self-regulation were associated with daily adherence to the type 1 diabetes regimen. METHODS: 110 school seniors (M age = 17.78 years) and their mothers assessed adolescents' skills underlying self-regulation (executive function, attention, self-control, behavioral inhibition and activation, emotion regulation) and adherence, with glycosylated hemoglobin from medical records. Teens completed daily diaries reporting self-regulation failures surrounding monitoring blood glucose, adherence, and number of blood glucose checks each day for 14 days. RESULTS: Hierarchical Linear Models indicated that better daily adherence was associated with teen and mother reports of better self-regulation skills and teens' reports of fewer daily self-regulation failures. Daily adherence was unrelated to temperamental differences in behavioral inhibition and activation. CONCLUSIONS: Results indicate that both individual and intraindividual differences in self-regulation contribute to daily adherence highlighting the importance of daily self-regulatory challenges to adherence.

Low morbidity and mortality in children with diabetic ketoacidosis treated with isotonic fluids.

OBJECTIVE: To assess current rates of complications of diabetic ketoacidosis (DKA), particularly cerebral edema, in a large tertiary-care pediatric hospital with a consistent management protocol. STUDY DESIGN: We report our single-center retrospective experience with 3712 admissions with DKA in 1999-2011. Our DKA protocol features a "3-bag" system using 2 bags of rehydration fluids, identical except for the presence in 1 bag of 10% dextrose, to allow rapid adjustment of glucose infusion rate. The third bag contains insulin. Fluids are administered at a total rate of 2-2.5 times "maintenance" fluid requirements. Total electrolyte concentration is kept approximately isotonic. Billing and medical records databases at Children's Medical Center Dallas were examined for cases of DKA, cerebral edema, other morbidities, and death. RESULTS: We ascertained 20 cases of cerebral edema (0.5%). Most presented early (median duration of treatment 2 hours). Only 10 of 20 computed tomography scans were graded as moderate edema or worse. Only 10 patients received treatment other than routine DKA management. There was 1 death in a patient with sickle cell trait who developed intravascular sickling. Two patients had neurologic sequelae at hospital discharge but both recovered fully. CONCLUSIONS: Compared with data in recent consensus statements, the Dallas protocol is associated with extremely low rates of death and disability (0.08% vs 0.3%) from DKA.

Longer HSD11B2 CA-repeat in impaired glucose tolerance and type 2 diabetes.

Type 2 11ß-hydroxysteroid dehydrogenase encoded by the HSD11B2 gene converts cortisol to inactive cortisone, and alteration in this enzymatic activity might affect glucose homeostasis by affecting circulating levels or tissue availability of glucocorticoids. We investigated the association of HSD11B2 variant with glucose homeostasis. Subjects with normal glucose tolerance (n=585), impaired glucose tolerance (n=202) and type 2 diabetes (n=355) were genotyped for a highly polymorphic CA-repeat polymorphism in the first intron of HSD11B2. Allele and genotype frequencies differed between normal and impaired glucose tolerance (P = 0.0014 and 0.0407, respectively; 4 degree of freedom) or type 2 diabetes (P = 0.0053 and 0.0078), with significant linear trends between the repeat length and the phenotype fraction. In normal subjects, total CA-repeat length was negatively correlated with fasting insulin and HOMA-ß. Thus, subjects having more CA repeats are susceptible to developing abnormal glucose tolerance, whereas normal subjects carrying more CA repeats appeared to have frugal characteristics in insulin secretion.

P53 and cellular glucose uptake.

OBJECTIVES: Tumor protein p53 is a transcription factor involved with cellular responses to stressors including limited glucose availability. We hypothesized that modulating p53 levels would affect cellular glucose uptake. METHODS AND RESULTS: Transfecting cultured primary mouse hepatocytes with p53 siRNA suppressed p53 mRNA expression >90%. Control hepatocytes (transfected with non-targeting siRNA) increased glucose uptake (2.28 ± 1.02-fold vs basal, p 0.009) in response to 100 nM insulin, but p53 siRNA-treated hepatocytes had a blunted response (0.92 ± 0.11-fold vs basal; between group difference p 0.0012). In adipocytes differentiated from the pre-adipocyte line 3T3-L1, knockdown of p53 had no effect on insulin-stimulated glucose uptake. There were no differences in Glut 1 or Glut 2 expression in the plasma membrane fraction or in the levels of phosphorylated AKT in cell lysates between primary hepatocytes transfected with p53 siRNA or control siRNA. Glycemic responses to insulin tolerance, glucose tolerance, and pyruvate tolerance tests did not differ between p53 knockout and wild type mice. DISCUSSION: Thus, inhibition of p53 has pleiotropic effects, inhibiting glucose uptake in the liver but having no effect on adipocytes. Knockout of p53 has no apparent effect on glucose homeostasis in intact lean mice. An explanation for the association between p53 expression and hepatocyte glucose uptake remains to be elucidated.