Cheril Clarson

Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis

OBJECTIVE Nocturnal hypoglycemia can cause seizures and is a major impediment to tight glycemic control, especially in young children with type 1 diabetes. We conducted an in-home randomized trial to assess the efficacy and safety of a continuous glucose monitor–based overnight predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS In two age-groups of children with type 1 diabetes (11–14 and 4–10 years of age), a 42-night trial for each child was conducted wherein each night was assigned randomly to either having the PLGS system active (intervention night) or inactive (control night). The primary outcome was percent time <70 mg/dL overnight. RESULTS Median time at <70 mg/dL was reduced by 54% from 10.1% on control nights to 4.6% on intervention nights (P < 0.001) in 11–14-year-olds (n = 45) and by 50% from 6.2% to 3.1% (P < 0.001) in 4–10-year-olds (n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 ± 18 vs. 152 ± 19 mg/dL [P < 0.001] and 153 ± 14 vs. 160 ± 16 mg/dL [P = 0.004], respectively). Mean morning blood glucose was 159 ± 29 vs. 176 ± 28 mg/dL (P < 0.001) in the 11–14-year-olds and 154 ± 25 vs. 158 ± 22 mg/dL (P = 0.11) in the 4–10-year-olds, respectively. No differences were found between intervention and control in either age-group in morning blood ketosis. CONCLUSIONS In 4–14-year-olds, use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia without an increase in morning ketosis, although overnight mean glucose is slightly higher.

Placental weight in diabetic pregnancies

The placenta from 30 women with diabetes mellitus were examined and weighed at delivery. Nineteen of these were from women with overt and eleven from women with gestational diabetes. Eleven placentae from normal pregnancies served as controls. There was no difference between the mean +/- s.d. placental weight for the diabetic group and the control group (609 +/- 148 versus 591 +/- 93 g, NS). The mean placental weight ratios for the diabetic group and the control group were also similar (0.98 +/- 0.23 versus 0.89 +/- 0.15, NS). Moreover, there was no difference between the weights and weight ratios of placentae from women with overt (622 +/- 173 g, 1.02 +/- 0.27) and those with gestational diabetes (586 +/- 90 g, versus 0.90 +/- 0.13). Placental weights correlated with birthweights (r = 0.70, P less than 0.01) and with skinfold thickness measurements fo the infants (r = 0.40, P less than 0.05), but neither with gestational ages (r = 0.15, NS) nor with maternal glycosylated haemoglobin levels in the third trimester (r = 0.24, NS). Among the women with overt diabetes, placental weights were greater in those in Whites class B and C than those in class D and R (689 +/- 143 versus 530 +/- 177 g; P less than 0.05). In general, placentae from well controlled diabetic patients were not heavier than those from normal pregnant women, although there was an increase in placental weight in Whites class B and C, as compared with those in class D and R.

Residual β-Cell Function in Children With IDDM: Reproducibility of Testing and Factors Influencing Insulin Secretory Reserve

Reproducibility of C-peptide secretion was assessed in 20 children (group 1) by their responses to two Sustacal- (a mixed liquid meal) stimulation tests performed 7–14 days apart. For the 12 C-peptide-positive children (basal C-peptide ≥0.03 pmol/ml) there were no differences in the basal or stimulated values between tests 1 and 2. The effect of exogenous insulin on C-peptide secretion was assessed in 20 other children (group 2) by their responses to two Sustacal tests, one test without and one with soluble insulin (0.25 U/kg) injected subcutaneously before testing. Eleven children were C-peptide positive and had no differences in C-peptide response between tests 1 and 2. The results from test 1 in groups 1 and 2 were combined with those from 44 others undergoing a single Sustacal test (group 3, N = 84). There was a close correlation between basal and peak C-peptide concentrations in the 44 C-peptide-positive children (r = .88, P < .001). Peak C-peptide concentrations correlated inversely with HbA1 (r = −.29, P < .01), insulin dose in units per kilogram (r = −.40, P < .001), and duration of diabetes (r = .33, P < .001) and positively with age at onset of diabetes (r = .34, P < .001). The C-peptide-positive children had reduced glucose response to Sustacal, lower HbA1 concentration, lower insulin requirement, later age of onset, and shorter duration of diabetes than children who were C-peptide negative.

Self-Monitoring of Blood Glucose: How Accurate Are Children with Diabetes at Reading Chemstrip bG?

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.

Lifestyle modification and metformin as long-term treatment options for obese adolescents: study protocol

BackgroundChildhood obesity is a serious health concern affecting over 155 million children in developed countries worldwide. Childhood obesity is associated with significantly increased risk for development of type 2 diabetes, cardiovascular disease and psychosocial functioning problems (i.e., depression and decreased quality of life). The two major strategies for management of obesity and associated metabolic abnormalities are lifestyle modification and pharmacologic therapy. This paper will provide the background rationale and methods of the REACH childhood obesity treatment program.Methods/designThe REACH study is a 2-year multidisciplinary, family-based, childhood obesity treatment program. Seventy-two obese adolescents (aged 10-16 years) and their parents are being recruited to participate in this randomized placebo controlled trial. Participants are randomized to receive either metformin or placebo, and are then randomized to a moderate or a vigorous intensity supervised exercise program for the first 12-weeks. After the 12-week exercise program, participants engage in weekly exercise sessions with an exercise facilitator at a local community center. Participants engage in treatment sessions with a dietitian and social worker monthly for the first year, and then every three months for the second year. The primary outcome measure is change in body mass index and the secondary outcome measures are changes in body composition, risk factors for type 2 diabetes and cardiovascular disease, changes in diet, physical activity, and psychosocial well-being (e.g., quality of life). It is hypothesized that participants who take metformin and engage in vigorous intensity exercise will show the greatest improvements in body mass index. In addition, it is hypothesized that participants who adhere to the REACH program will show improvements in body composition, physical activity, diet, psychosocial functioning and risk factor profiles for type 2 diabetes and cardiovascular disease. These improvements are expected to be maintained over the 2-year program.DiscussionThe findings from this study will advance the knowledge regarding the long-term efficacy and sustainability of interventions for childhood obesity.Trial RegistrationClinicalTrials.gov number NCT00934570

Effects of a group-based exercise and self-regulatory intervention on obese adolescents’ physical activity, social cognitions, body composition and strength: A randomized feasibility study

This feasibility study assessed the effects of an exercise plus group-based self-regulatory skills intervention on obese youths’ physical activity, social cognitions, body composition and strength. Forty-three obese youth (male = 13, BMI > 95th percentile; 10–16 yrs) completed this 12-week intervention. Assessments were taken at baseline, week 6, 13 and 12 weeks post-intervention (week 24). Although no attention control group (i.e. exercise only) was included in this study, participants engaged in significantly more self-reported physical activity at weeks 13 and 24 as compared to baseline. Social cognitions, body composition and strength were also positively impacted suggesting this intervention technique may be feasible for treating obese adolescents.

Evaluation of an affinity chromatographic procedure for the determination of glycosylated hemoglobin (HbA1)

An affinity chromatographic method for the determination of glycosylated hemoglobin (HbA1) was evaluated. The procedure was shown to be precise, the within- and between-assay coefficients of variation being less than 5%. It was also shown to correlate well with electrophoresis (r = 0.968) and ion-exchange chromatography (r = 0.916). An inverse relationship was shown to exist between increasing temperature and HbA1 levels measured by affinity chromatography. A statistically significant difference was found for samples run at 20 degrees C and 25 degrees C respectively, suggesting that the method should be run in a temperature-controlled environment. The affinity procedure was also shown not to be affected by the type of anticoagulant, the concentration of hemoglobin in the hemolysate, and acetylation.

Relationship between Birth Weight and Metabolic Status in Obese Adolescents

Objective. To examine the relationships between birth weight and body mass index, percent body fat, blood lipids, glycemia, insulin resistance, adipokines, blood pressure, and endothelial function in a cohort of obese adolescents. Design and Methods. Ninety-five subjects aged 10–16 years (mean age 13.5 years) with a body mass index >95th centile (mean [±SEM] 33.0 ± 0.6) were utilized from two prospective studies for obesity prevention prior to any interventions. The mean term birth weight was 3527 ± 64 g (range 1899–4990 g;). Results. Body mass index z-score correlated positively with birth weight (r 2 = 0.05, P = 0.03), but not percent body fat. Insulin resistance negatively correlated with birth weight (r 2 = 0.05, P < 0.001), as did fasting plasma insulin (r 2 = 0.05, P < 0.001); both being significantly greater for subjects of small versus large birth weight (Δ Homeostasis Model Assessment = 2.5 and Δ insulin = 10 pmol/L for birth weight <2.5 kg versus >4.5 kg). Adiponectin, but not leptin, blood pressure z-scores or peripheral arterial tomography values positively correlated with birth weight (r 2 = 0.07, P = 0.008). Conclusions. Excess body mass index in obese adolescents was positively related to birth weight. Birth weight was not associated with cardiovascular risk factors but represented a significant determinant of insulin resistance.

Effects of a Comprehensive, Intensive Lifestyle Intervention Combined with Metformin Extended Release in Obese Adolescents

Objective. To assess a comprehensive, intensive lifestyle intervention in combination with metformin extended release (MXR) or placebo on body mass index (BMI) and risk factors for type 2 diabetes and cardiovascular disease in obese adolescents. Study Design. Sixty-nineobese adolescents (mean BMI 32.5) received a comprehensive lifestyle intervention with structured dietary, physical activity, and behavioral components for 24 months. Subjects were randomized to 1 of 4 groups: MXR (33) 2,000 mg daily or placebo, with either moderate or vigorous intensity exercise for the first 3 months. Subsequently the exercise intervention was the same for all 4 groups. Results. Anthropometry measurements did not differ with initial exercise intensity at any time. At 3 months % body fat decreased in all 4 groups (P < 0.006). BMI and % body fat decreased in the MXR groups, but not the placebo groups, at 6 (−0.88, −3.16) and 12 months (−0.56, −2.34) (P < 0.05). Insulin resistance, fasting blood glucose, and leptin improved in all groups at 6 and 12 months. A high subject attrition rate (58%) occurred by 24 months. Conclusion. A comprehensive, intensive lifestyle intervention combined with MXR led to a decline in BMI and % body fat at 1 year independent of initial exercise intensity. This trial is registered with ClinicalTrials.gov NCT00934570 .

Elevated Leukocyte Azurophilic Enzymes in Human Diabetic Ketoacidosis Plasma Degrade Cerebrovascular Endothelial Junctional Proteins.

Objective: Diabetic ketoacidosis in children is associated with vasogenic cerebral edema, possibly due to the release of destructive polymorphonuclear neutrophil azurophilic enzymes. Our objectives were to measure plasma azurophilic enzyme levels in children with diabetic ketoacidosis, to correlate plasma azurophilic enzyme levels with diabetic ketoacidosis severity, and to determine whether azurophilic enzymes disrupt the blood-brain barrier in vitro. Design: Prospective clinical and laboratory study. Setting: The Children’s Hospital, London Health Sciences Centre. Subjects: Pediatric type 1 diabetes patients; acute diabetic ketoacidosis or age-/sex-matched insulin-controlled. Measurements and Main Results: Acute diabetic ketoacidosis in children was associated with elevated polymorphonuclear neutrophils. Plasma azurophilic enzymes were elevated in diabetic ketoacidosis patients, including human leukocyte elastase (p < 0.001), proteinase-3 (p < 0.01), and myeloperoxidase (p < 0.001). A leukocyte origin of human leukocyte elastase and proteinase-3 in diabetic ketoacidosis was confirmed with buffy coat quantitative real-time polymerase chain reaction (p < 0.01). Of the three azurophilic enzymes elevated, only proteinase-3 levels correlated with diabetic ketoacidosis severity (p = 0.002). Recombinant proteinase-3 applied to human brain microvascular endothelial cells degraded both the tight junction protein occludin (p < 0.05) and the adherens junction protein VE-cadherin (p < 0.05). Permeability of human brain microvascular endothelial cell monolayers was increased by recombinant proteinase-3 application (p = 0.010). Conclusions: Our results indicate that diabetic ketoacidosis is associated with systemic polymorphonuclear neutrophil activation and degranulation. Of all the polymorphonuclear neutrophil azurophilic enzymes examined, only proteinase-3 correlated with diabetic ketoacidosis severity and potently degraded the blood-brain barrier in vitro. Proteinase-3 might mediate vasogenic edema during diabetic ketoacidosis, and selective proteinase-3 antagonists may offer future vascular- and neuroprotection.