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Background: Ethanol modulates glutamate and γ-aminobutyric (GABA) function. However, little is known about the acute pharmacologic effects of ethanol on levels of GABA, glutamate, and other metabolites measurable in the human cortex in vivo with proton magnetic resonance spectroscopy ((1)H-MRS)., Methods: Eleven healthy social drinkers received two intravenous ethanol infusions that raised breath alcohol levels to a clamped plateau of 60 mg/dL over 60-70 min. The first infusion established tolerability of the procedure, and the second procedure, conducted 15 ± 12 days later, was performed during (1)H-MRS of occipital GABA, glutamate, and other metabolites., Results: The time course of brain ethanol approximated that of breath ethanol, but venous ethanol lagged by approximately 7 min. The GABA fell 13 ± 8% after 5 min of the ethanol infusion and remained reduced (p = .003) throughout the measurement. The combination of N-acetylaspartate and N-acetylaspartyl glutamate (summed as NAA) fell steadily during the infusion by 8 ± 3% (p = .0036)., Conclusions: Ethanol reduced cortical GABA and NAA levels in humans. Reductions in GABA levels are consistent with facilitation of GABA(A) receptor function by ethanol. The gradual decline in NAA levels suggests inhibition of neural or metabolic activity in the brain., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Commercialization of a closed-loop artificial pancreas system that employs continuous subcutaneous insulin infusion and interstitial fluid glucose sensing has been encumbered by state-of-the-art technology. Continuous glucose monitoring (CGM) devices with improved accuracy could significantly advance development efforts. However, the current accuracy of CGM devices might be adequate for closed-loop control., Methods: The influence that known CGM limitations have on closed-loop control was investigated by integrating sources of sensor inaccuracy with the University of Virginia Padova Diabetes simulator. Non-glucose interference, physiological time lag and sensor error measurements, selected from 83 Enlite™ glucose sensor recordings with the Guardian® REAL-Time system, were used to modulate simulated plasma glucose signals. The effect of sensor accuracy on closed-loop controller performance was evaluated in silico, and contrasted with closed-loop clinical studies during the nocturnal control period., Results: Based on n = 2472 reference points, a mean sensor error of 14% with physiological time lags of 3.28 ± 4.62 min (max 13.2 min) was calculated for simulation. Sensor bias reduced time in target for both simulation and clinical experiments. In simulation, additive error increased time <70 mg/dl and >180 mg/dl by 0.2% and 5.6%, respectively. In-clinic, the greatest low blood glucose index values (max = 5.9) corresponded to sensor performance., Conclusion: Sensors have sufficient accuracy for closed-loop control, however, algorithms are necessary to effectively calibrate and detect erroneous calibrations and failing sensors. Clinical closed-loop data suggest that control with a higher target of 140 mg/dl during the nocturnal period could significantly reduce the risk for hypoglycemia., (© 2011 Diabetes Technology Society.)

Objective: To describe clinical outcomes in youth with new-onset type 1 diabetes mellitus (T1DM) treated with a modified, twice-daily regimen of a mixture of NPH insulin and rapid-acting insulin analogue at breakfast and separate injections of rapid-acting insulin analogue and insulin detemir at dinner., Methods: Our clinic database was used to describe changes in insulin doses, hemoglobin A1c (A1C) levels, and frequency of severe hypoglycemia during the first year of therapy in young patients with T1DM diagnosed between September 2006 and April 2009. Data are presented as median values (25%, 75%)., Results: Overall, 108 patients (62 girls; mean age, 10.0 ± 0.4 years) were eligible for inclusion. Total daily insulin doses at 3, 6, and 12 months were 0.6 (0.4, 0.8), 0.7 (0.4, 0.9), and 0.8 (0.6, 0.9) U/kg, respectively. A1C levels were 9.8% (8.5%, 10.8%) at 2 weeks (baseline). Of the 108 patients, 19 had switched to insulin pump therapy by 3 months and 49 had switched by 12 months after initial diagnosis of T1DM. The 49 pump-treated patients had an A1C of 6.9% (6.6%, 7.3%), whereas the 59 injection-treated patients had an A1C of 7.2% (6.7%, 7.7%) by 12 months. There were only 6 severe hypoglycemic events in 5 patients; none occurred during the first 3 months, none occurred during the night, and all occurred in patients receiving insulin injection treatment., Conclusion: A twice-daily insulin regimen that uses insulin detemir for overnight basal replacement and morning NPH insulin to avoid lunch and afternoon snack doses is an effective initial treatment for young patients with new-onset T1DM that can provide a smooth transition to intensive basal/bolus insulin pump therapy.

Diabetes is one of the most common chronic disorders with an increasing incidence worldwide. Technologic advances in the field of diabetes have provided new tools for clinicians to manage this challenging disease. For example, the development of continuous subcutaneous insulin infusion systems have allowed for refinement in the delivery of insulin, while continuous glucose monitors provide patients and clinicians with a better understanding of the minute to minute glucose variability, leading to the titration of insulin delivery based on this variability when applicable. Merging of these devices has resulted in sensor-augmented insulin pump therapy, which became a major building block upon which the artificial pancreas (closed-loop systems) can be developed. This article summarizes the evolution of sensor-augmented insulin pump therapy until present day and its future applications in new-generation diabetes management.

In this issue of Journal of Diabetes Science and Technology, Davey and coauthors present encouraging data that even short-term use of a real-time continuous glucose monitor can lead to marked reduction in hypoglycemia exposure. In this analysis, two particular issues will be discussed: the distinction between short- and long-term experiences with sensors and the use of standardized diabetes treatment algorithms for use with continuous glucose monitoring (CGM) devices. An understanding of both of these aspects of CGM devices is necessary for placing clinical diabetes technology products into the context of how they will be used in "real life.", (© 2010 Diabetes Technology Society.)

OBJECTIVE Clinicians who treat children with type 1 diabetes often try to minimize the number of daily injections to reduce treatment burden and improve compliance. Despite the manufacturer's cautions against mixing glargine with rapid-acting insulin analogs, clinical studies have failed to demonstrate deleterious effects of mixing on glucose excursions or A1C levels. However, no formal glucose clamp studies have been performed to determine whether mixing with glargine has an adverse effect on the early pharmacodynamic action of rapid-acting insulin in humans. RESEARCH DESIGN AND METHODS To examine this question, euglycemic glucose clamps were performed twice, in random order, in 11 youth with type 1 diabetes (age 15.1 +/- 3 years, A1C 7.6 +/- 0.6%) with 0.2 units/kg lispro and 0.4 units/kg glargine, given either as separate or as a single mixed injection. RESULTS Mixing the two insulins shifted the time action curve to the right, with significantly lower glucose infusion rate (GIR) values after the mixed injections between 60 and 190 min and significantly higher values between 270 and 300 min, lowered the GIR(max) (separate 7.1 +/- 1 vs. mix 3.9 +/- 1, P = 0.03), and markedly delayed the time to reach GIR(max) (separate 116 +/- 8 min vs. mix 209 +/- 15 min, P = 0.004). The GIR area under the curve was significantly lower after the mixed injections. Mixing had similar effects on plasma insulin pharmacokinetics. CONCLUSIONS These data demonstrate that mixing lispro with glargine markedly flattens the early pharmacodynamic peak of lispro and causes a shift to the right in the GIR curve changes that might lead to difficulties in controlling meal-related glucose excursions.

OBJECTIVE The potential benefits of continuous glucose monitoring (CGM) in the management of adults and children with well-controlled type 1 diabetes have not been examined. RESEARCH DESIGN AND METHODS A total of 129 adults and children with intensively treated type 1 diabetes (age range 8-69 years) and A1C <7.0% were randomly assigned to either continuous or standard glucose monitoring for 26 weeks. The main study outcomes were time with glucose level < or =70 mg/dl, A1C level, and severe hypoglycemic events. RESULTS At 26 weeks, biochemical hypoglycemia (< or =70 mg/dl) was less frequent in the CGM group than in the control group (median 54 vs. 91 min/day), but the difference was not statistically significant (P = 0.16). Median time with a glucose level < or =60 mg/dl was 18 versus 35 min/day, respectively (P = 0.05). Time out of range (< or =70 or >180 mg/dl) was significantly lower in the CGM group than in the control group (377 vs. 491 min/day, P = 0.003). There was a significant treatment group difference favoring the CGM group in mean A1C at 26 weeks adjusted for baseline (P < 0.001). One or more severe hypoglycemic events occurred in 10 and 11% of the two groups, respectively (P = 1.0). Four outcome measures combining A1C and hypoglycemia data favored the CGM group in comparison with the control group (P < 0.001, 0.007, 0.005, and 0.003). CONCLUSIONS Most outcomes, including those combining A1C and hypoglycemia, favored the CGM group. The weight of evidence suggests that CGM is beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C <7.0%.

Objectives: It has been proposed that the first step towards a closed-loop artificial pancreas might be to use a continuous glucose sensor to automatically suspend the basal insulin delivery based on projected low sensor glucose values., Methods: We reviewed our recent experience with an artificial pancreas system, utilizing a proportional-integrative-derivative (PID) algorithm, in 17 adolescents with type 1 diabetes (T1D) to assess the safety and efficacy of this maneuver., Results: During 34 h of closed-loop automated insulin delivery, 18 pump suspensions > or =60 min (90 +/- 18 min) occurred in eight subjects. Sensor glucose levels fell from 159 +/- 42 mg/dL to a nadir of 72 +/- 13 mg/dL. Corresponding plasma glucose levels fell from 168 +/- 51 to 72 +/- 16 mg/dL, with values <60 mg/dL recorded in only four of the 18 events., Conclusions: These data suggest that automatic pump suspension using the PID algorithm may be an effective means to prevent hypoglycemia in youth with T1D.

Objective: The purpose of this study was to examine the effect of type of insulin analog and age of insertion site on the pharmacodynamic characteristics of a standard insulin bolus in youth with type 1 diabetes receiving insulin pump therapy., Research Design and Methods: Seventeen insulin pump-treated adolescents with type 1 diabetes underwent two euglycemic clamp procedures after a 0.2 unit/kg bolus of either insulin aspart or lispro on day 1 and day 4 of insulin pump site insertion. The glucose infusion rate (GIR) required to maintain euglycemia was the primary pharmacodynamic measure., Results: There were no statistically significant differences in any of the pharmacodynamic parameters between aspart and lispro during day 1 and day 4. However, when the two groups were combined, time to discontinuation of exogenous glucose infusion, and time to half-maximal onset and offset of insulin action were observed significantly earlier during day 4 compared with day 1 (P = 0.03-0.0004), but the overall area under the GIR curve was similar on day 1 and day 4., Conclusions: With both insulin aspart and lispro, there is an earlier peak and shorter duration of action with increasing duration of infusion site use, but overall insulin action is not affected.

Objective: The most promising beta-cell replacement therapy for children with type 1 diabetes is a closed-loop artificial pancreas incorporating continuous glucose sensors and insulin pumps. The Medtronic MiniMed external physiological insulin delivery (ePID) system combines an external pump and sensor with a variable insulin infusion rate algorithm designed to emulate the physiological characteristics of the beta-cell. However, delays in insulin absorption associated with the subcutaneous route of delivery inevitably lead to large postprandial glucose excursions., Research Design and Methods: We studied the feasibility of the Medtronic ePID system in youth with type 1 diabetes and hypothesized that small manual premeal "priming" boluses would reduce postprandial excursions during closed-loop control. Seventeen adolescents (aged 15.9 +/- 1.6 years; A1C 7.1 +/- 0.8%) underwent 34 h of closed-loop control; 8 with full closed-loop (FCL) control and 9 with hybrid closed-loop (HCL) control (premeal priming bolus)., Results: Mean glucose levels were 135 +/- 45 mg/dl in the HCL group versus 141 +/- 55 mg/dl in the FCL group (P = 0.09); daytime glucose levels averaged 149 +/- 47 mg/dl in the HCL group versus 159 +/- 59 mg/dl in the FCL group (P = 0.03). Peak postprandial glucose levels averaged 194 +/- 47 mg/dl in the HCL group versus 226 +/- 51 mg/dl in the FCL group (P = 0.04). Nighttime control was similar in both groups (111 +/- 27 vs. 112 +/- 28 mg/dl)., Conclusions: Closed-loop glucose control using an external sensor and insulin pump provides a means to achieve near-normal glucose concentrations in youth with type 1 diabetes during the overnight period. The addition of small manual priming bolus doses of insulin, given 15 min before meals, improves postprandial glycemic excursions.

Purpose of Review: Recent developments in technology have ushered in a new era of managing type 1 diabetes. Continuous glucose monitoring is rapidly becoming an accepted adjunct to traditional self-monitoring of plasma glucose, and the marriage of continuous glucose sensors to continuous subcutaneous insulin infusion is the first step towards the development of a true artificial pancreas. The purpose of this review is to familiarize the reader with the new glucose sensors and discuss the literature evaluating their accuracy and effectiveness., Recent Findings: Current models of continuous glucose sensors are still less accurate than traditional methods of blood glucose monitoring but provide information regarding trends that cannot be obtained with blood testing. Short-term studies of continuous glucose sensors have demonstrated reduction in glycosylated hemoglobin levels and time spent in hypo- and hyperglycemic ranges. Patient acceptance and satisfaction with sensors has been shown to depend on the quality of the data, comfort of wear, and ease of use., Summary: Sensor-augmented pump therapy represents a landmark improvement in diabetes treatment and will likely become the standard of care. Future work should focus on improvements in sensor accuracy and development of user-friendly algorithms to assist patients with self-management.

Objective: The safety and efficacy of insulin aspart continuous subcutaneous insulin infusion (CSII) was compared with that of insulin lispro CSII in children and adolescents with type 1 diabetes., Research Design and Methods: Children and adolescents aged 4-18 years with diagnosed type 1 diabetes >or=1 year previously and treated with insulin analog in a CSII >or=3 months were randomly assigned 2:1 to 16 weeks of insulin aspart CSII (n = 198) or insulin lispro CSII (n = 100) in this open-label, parallel-group, multicenter study. Standard diabetes safety and efficacy parameters were assessed., Results: Baseline demographics, subject characteristics, and diabetes history were similar between treatment groups. After 16 weeks of treatment, insulin aspart CSII was noninferior to insulin lispro CSII as measured by change in A1C from baseline (aspart, -0.15 +/- 0.05%; lispro, -0.05 +/- 0.07% [95% CI of the treatment difference -0.27 to 0.07]; P = 0.241). No significant differences between treatment groups were observed in fasting plasma glucose, hyperglycemia, and rates of hypoglycemic episodes. At week 16, 59.7% of subjects in the aspart group and 43.8% of subjects in the lispro groups achieved age-specific American Diabetes Association A1C goals (<8.5% for subjects aged <6 years; <8% for subjects aged 6-18 years) (P = 0.040, corrected for baseline). Daily insulin dose (units per kilogram) was significantly lower at week 16 for subjects treated with aspart compared with those treated with lispro (0.86 +/- 0.237 vs. 0.94 +/- 0.233, P = 0.018)., Conclusions: Insulin aspart was as safe and effective as insulin lispro for use in a CSII in children and adolescents with type 1 diabetes.

Aim: To identify patients aged 10-30 years with probable hyperglycemic hyperosmolar syndrome (HHS), to describe demographic and clinical profiles, and to attempt to assess risk factors for poor outcomes., Study Design: Retrospective cohort study (medical records review)., Setting: A 944-bed tertiary care teaching and research hospital and a 425-bed affiliated facility., Patients: 10-30 year-old patients with a primary or secondary discharge diagnosis of HHS or diabetic ketoacidosis (DKA). Patients with a serum glucose >600 mg/dl in the absence of significant ketoacidosis (possible HHS) were profiled. Further stratification based on measured or calculated serum osmolarity >320 mOsm/kg (probable HHS) was undertaken., Interventions: Patients received treatment for hyperglycemic crises, consisting primarily of fluids, electrolyte replacement and insulin., Measurements and Main Results: Of the 629 admissions, 10 with a diagnosis of HHS and 33 with a diagnosis of DKA met the initial study criteria for HHS. 60% were African Americans and 89% were new-onset diabetics. From this group, 20 admissions had serum osmolarity > or =320 mOsm/kg. Fisher's exact test and Pearson coefficients were used to examine associations between risk factor and poor outcomes and correlations between admission data and length of hospital stay, respectively. Serious complications occurred in four patients (including two deaths, 10% mortality) and were limited to those with unreversed shock over the first 24 hours of admission and who received <40 ml/kg of intravenous fluids over the first 6 hours of treatment., Conclusions: HHS was underdiagnosed in this population and occurred disproportionately in African Americans. Serious complications occurred exclusively in those with unreversed shock and inadequate fluid resuscitation.

Objective: To examine the feasibility of daily use of a continuous glucose monitor, the FreeStyle Navigator Continuous Glucose Monitoring System ("Navigator"), in children with type 1 diabetes (T1D)., Study Design: After a masked Navigator was used for 4 to 7 days to establish a baseline level of glycemic control, 30 insulin pump users with T1D (average age 11.2 years) were asked to use the Navigator daily for 13 weeks., Results: Subjects averaged 149 h/wk of Navigator use during the first 4 weeks, which decreased slightly to 134 h/wk during weeks 9 to 13 (P = .006). Mean hemoglobin A1c improved from 7.1% at baseline to 6.8% at 13 weeks (P = .02), and the percentage of glucose values between 71 and 180 mg/dL increased from 52% to 60% (P = .01). Subjects and parents reported high satisfaction with the Navigator on the Continuous Glucose Monitor Satisfaction Scale. Two subjects had severe skin reactions related to sensor mount adhesive., Conclusion: This study indicates that incorporating real-time continuous glucose monitoring into the daily treatment of children with T1D is feasible. The results provide a compelling rationale for conducting a randomized trial of daily use of a continuous glucose monitor in children with T1D.

Objective: Our objective was to describe the first case of the successful use of pegvisomant during pregnancy in a woman with acromegaly., Design: We present the case of a 26-yr-old female with acromegaly who had failed surgical and subsequent medical therapy but whose disease was well controlled on pegvisomant. She then conceived and was continued on pegvisomant throughout pregnancy. We then collected both maternal and cord blood samples at parturition, and later analyzed her breast milk., Results: Maternal IGF-I was well controlled during gestation. Fetal GH and IGF-I were within the normal range. Maternal pegvisomant levels were consistent with a 25-mg daily dosage. Fetal pegvisomant levels were minimal and near the range detected in untreated acromegalic patients, likely representing minimal cross-reactivity from endogenous GH or spurious contamination by maternal blood. GH variant levels in the maternal blood and the cord blood were both within the normal ranges. Pegvisomant levels in breast milk were below the lower limit of quantification of the assay and similar to those observed when analyzing breast milk samples from normal mothers in the same assay. Fetal growth parameters were normal; the baby was healthy and showed no adverse signs., Conclusions: Pegvisomant therapy during gestation was safe and effective in our patient. Transplacental passage of pegvisomant is either absent or minimal, with a concentration highly unlikely to convey any significant pharmacodynamic effects on the fetal GH and IGF-I system. In addition, there is no evidence of substantial secretion of pegvisomant into breast milk.

Objective: To evaluate the accuracy and precision of the FreeStyle Navigator continuous glucose monitoring system in children with type 1 diabetes., Research Design and Methods: In 30 children with type 1 diabetes (mean age 11.2 +/- 4.1 years), the Navigator glucose values were compared with reference serum glucose values of blood samples obtained in an inpatient clinical research center and measured in a central laboratory using a hexokinase enzymatic method and in an outpatient setting with a FreeStyle meter. Median absolute difference (AD) and median relative absolute difference (RAD) were computed for sensor-reference and sensor-sensor pairs., Results: The median AD and RAD were 17 mg/dl and 12%, respectively, for 1,811 inpatient sensor-reference pairs and 20 mg/dl and 14%, respectively, for 8,639 outpatient pairs. The median RAD between two simultaneous Navigator measurements (n = 1,971) was 13%. Ninety-one percent of sensors in the inpatient setting and 81% of sensors in the outpatient setting had a median RAD < or = 20%., Conclusions: The Navigator's accuracy does not yet approach the accuracy of current-generation home glucose meters, but it is sufficient to believe that the device has the potential to be an important adjunct to treatment of youth with type 1 diabetes.

Recent studies have shown that continuous subcutaneous insulin infusion (CSII), or insulin pump therapy, provides a treatment option that can assist in the attainment of current goals of treatment in children and adolescents with type 1 diabetes (T1DM). In pediatric patients, CSII has been demonstrated to reduce both glycosylated hemoglobin levels and frequency of severe hypoglycemia, without sacrifices in safety, quality of life, or excessive weight gain, particularly in conjunction with the use of new insulin analogs and improvements in pump technology. Clinical studies of safety and efficacy of CSII in children are reviewed.

Objective: Strategies for preventing hypoglycemia during exercise in children with type 1 diabetes have not been well studied. The Diabetes Research in Children Network (DirecNet) Study Group conducted a study to determine whether stopping basal insulin could reduce the frequency of hypoglycemia occurring during exercise., Research Design and Methods: Using a randomized crossover design, 49 children 8-17 years of age with type 1 diabetes on insulin pump therapy were studied during structured exercise sessions on 2 days. On day 1, basal insulin was stopped during exercise, and on day 2 it was continued. Each exercise session, performed from approximately 4:00-5:00 p.m., consisted of four 15-min treadmill cycles at a target heart rate of 140 bpm (interspersed with three 5-min rest breaks over 75 min), followed by a 45-min observation period. Frequently sampled glucose concentrations (measured in the DirecNet Central Laboratory) were measured before, during, and after the exercise., Results: Hypoglycemia (< or = 70 mg/dl) during exercise occurred less frequently when the basal insulin was discontinued than when it was continued (16 vs. 43%; P = 0.003). Hyperglycemia (increase from baseline of > or = 20% to > or = 200 mg/dl) 45 min after the completion of exercise was more frequent without basal insulin (27 vs. 4%; P = 0.002). There were no cases of abnormal blood ketone levels., Conclusions: Discontinuing basal insulin during exercise is an effective strategy for reducing hypoglycemia in children with type 1 diabetes, but the risk of hyperglycemia is increased.

Current goals for the treatment of children and adolescents with type 1 diabetes mellitus include achieving near-normal blood sugar levels, minimizing the risk of hypoglycemia, optimizing quality of life, and preventing or delaying long-term microvascular and macrovascular complications. Continuous subcutaneous insulin infusion (CSII), or insulin pump therapy, provides a treatment option that can assist in the attainment of all of these goals in all ages of children. In pediatric patients, CSII has been demonstrated to reduce both glycosylated hemoglobin levels and frequency of severe hypoglycemia, without sacrifices in safety, quality of life, or weight gain, particularly in conjunction with the use of new insulin analogs and improvements in pump technology. Clinical studies of safety and efficacy of CSII in children are reviewed, as well as criteria for patient selection and practical considerations using pump therapy in youth with T1DM.

Insulin pump therapy has, within the last 10 years, emerged as an increasingly popular modality of treatment to achieve intensive glycemic targets in type 1 diabetes (T1D). The evidence for the benefits of pump therapy has been demonstrated in adults and adolescents; however, until recently there has been a paucity of studies examining the efficacy and safety in pump therapy in very young children. The purpose of this article is to discuss the rationale for insulin pump therapy in infants and toddlers, review the available studies of pump therapy in this population, and show that the data support the use of insulin pumps in our very youngest of patients.

Objective: To investigate the impact of factors that might interfere with optimal glycemic control in youth with type 1 diabetes mellitus (T1DM) in the current era of intensive management, including the interplay of race/ethnicity and socioeconomic status (SES) on HbA1c levels., Study Design: This study comprised a database review of all patients under age 18 years with T1DM for at least 6 months duration. Sex, age, race/ethnicity, duration of diabetes, mode of insulin administration (pump vs injection), body mass index, SES, and HbA1c level were recorded at each patient's most recent visit between January and September 2003., Results: Mean HbA1c level for the 455 patients was 7.6% +/- 1.4%; only 31% of patients failed to meet the therapeutic goal of < 8.0%. Multiple linear regression analysis identified female sex (P = .02), older age (P = .001), longer duration of diabetes (P < .001), injection therapy (P < .001), and lower SES (P = .001) as significantly associated with higher HbA1c level. After adjustment for SES, race/ethnicity was not a determinant of HbA1c level., Conclusions: Low SES had a greater association with poor metabolic control than did race/ethnicity, which was not associated with differences in HbA1c level after controlling for SES. Most children were able to attain glycemic targets at least as good as the Diabetes Control and Complications Trial recommendations in a large clinical practice.

Background: The optimal number/timing of calibrations entered into the CGMS (Medtronic MiniMed, Northridge, CA) continuous glucose monitoring system have not been previously described., Methods: Fifty subjects with Type 1 diabetes mellitus (10-18 years old) were hospitalized in a clinical research center for approximately 24 h on two separate days. CGMS and OneTouch Ultra meter (LifeScan, Milpitas, CA) data were obtained. The CGMS was retrospectively recalibrated using the Ultra data varying the number and timing of calibrations. Resulting CGMS values were compared against laboratory reference values., Results: There was a modest improvement in accuracy with increasing number of calibrations. The median relative absolute deviation (RAD) was 14%, 15%, 13%, and 13% when using three, four, five, and seven calibration values, respectively (P < 0.001). Corresponding percentages of CGMS-reference pairs meeting the International Organisation for Standardisation criteria were 66%, 67%, 71%, and 72% (P < 0.001). Nighttime accuracy improved when daytime calibrations (pre-lunch and pre-dinner) were removed leaving only two calibrations at 9 p.m. and 6 a.m. (median difference, -2 vs. -9 mg/dL, P < 0.001; median RAD, 12% vs. 15%, P = 0.001). Accuracy was better on visits where the average absolute rate of glucose change at the times of calibration was lower. On visits with average absolute rates <0.5, 0.5 to <1.0, 1.0 to <1.5, and >or=1.5 mg/dL/min, median RAD values were 13% versus 14% versus 17% versus 19%, respectively (P = 0.05)., Conclusions: Although accuracy is slightly improved with more calibrations, the timing of the calibrations appears more important. Modifying the algorithm to put less weight on daytime calibrations for nighttime values and calibrating during times of relative glucose stability may have greater impact on accuracy.

Objective: To examine the acute glucose-lowering effects of aerobic exercise in children and adolescents with type 1 diabetes., Research Design and Methods: Fifty children and adolescents with type 1 diabetes (ages 10 to <18 years) were studied during exercise. The 75-min exercise session consisted of four 15-min periods of walking on a treadmill to a target heart rate of 140 bpm and three 5-min rest periods. Blood glucose and plasma glucagon, cortisol, growth hormone, and norepinephrine concentrations were measured before, during, and after exercise., Results: In most subjects (83%), plasma glucose concentration dropped at least 25% from baseline, and 15 (30%) subjects became hypoglycemic (< or = 60 mg/dl) or were treated for low glucose either during or immediately following the exercise session. The incidence of hypoglycemia and/or treatment for low glucose varied significantly by baseline glucose, occurring in 86 vs. 13 vs. 6% of subjects with baseline values <120, 120-180, and >180 mg/dl, respectively (P < 0.001). Exercise-induced increases in growth hormone and norepinephrine concentrations were marginally higher in subjects whose glucose dropped < or = 70 mg/dl. Treatment of hypoglycemia with 15 g of oral glucose resulted in only about a 20-mg/dl rise in glucose concentrations., Conclusions: In youth with type 1 diabetes, prolonged moderate aerobic exercise results in a consistent reduction in plasma glucose and the frequent occurrence of hypoglycemia when preexercise glucose concentrations are <120 mg/dl. Moreover, treatment with 15 g of oral glucose is often insufficient to reliably treat hypoglycemia during exercise in these youngsters.

Current goals for the treatment of children and adolescents with type 1 diabetes mellitus include achieving near-normal blood sugar levels, minimizing the risk of hypoglycemia, optimizing quality of life, and preventing or delaying long-term microvascular complications. Continuous subcutaneous insulin infusion (CSII) provides a treatment option that can assist in the attainment of all of these goals in all ages of children. Usage of CSII has been demonstrated to reduce glycosylated hemoglobin levels and frequency of severe hypoglycemia, without sacrifices in safety, quality of life, or weight gain, particularly in conjunction with the use of new insulin analogs and improvements in pump technology. Clinical studies of safety and efficacy of CSII in children are reviewed.

Objective: To examine the effect of exercise on overnight hypoglycemia in children with type 1 diabetes mellitus (T1DM)., Study Design: At 5 clinical sites, 50 subjects with T1DM (age 11 to 17 years) were studied in a clinical research center on 2 separate days. One day included an afternoon exercise session on a treadmill. On both days, frequently sampled blood glucose levels were measured at the DirecNet central laboratory. Insulin doses were similar on both days., Results: During exercise, plasma glucose levels fell in almost all subjects; 11 (22%) developed hypoglycemia. Mean glucose level from 10 pm to 6 am was lower on the exercise day than on the sedentary day (131 vs 154 mg/dL; P=.003). Hypoglycemia developed overnight more often on the exercise nights than on the sedentary nights (P=.009), occurring on the exercise night only in 13 (26%), on the sedentary night only in 3 (6%), on both nights in 11 (22%), and on neither night in 23 (46%). Hypoglycemia was unusual on the sedentary night if the pre-bedtime snack glucose level was>130 mg/dL., Conclusions: These findings indicate that overnight hypoglycemia after exercise is common in children with T1DM and support the importance of modifying diabetes management after afternoon exercise to reduce the risk of hypoglycemia.

Background: The objective of this study was to assess how the accuracy of the FreeStyle Flash (Abbott Diabetes Care, Alameda, CA) meter compares with that of the One Touch Ultra (Lifescan, Milpitas, CA) home glucose meter (HGM)., Research Design and Methods: Fifty children with type 1 diabetes (T1D), 10-17 years old, were admitted for two separate 24-h periods to assess the effect of exercise on subsequent nocturnal hypoglycemia. Resulting data were used in a preplanned analysis of the accuracy of the Ultra and FreeStyle HGMs. Glucose levels were measured throughout the day and night and every 15-20 min during a standardized exercise protocol. Reference samples were assayed in a central laboratory using a hexokinase enzymatic method. These reference glucose measurements were paired with HGM values from venous blood obtained within +/- 5 min., Results: The median relative absolute difference was 5% for both the Ultra and FreeStyle HGMs, and the percentages of pairs meeting the International Organisation for Standardization criteria were 99% and 98%, respectively. The FreeStyle tended to read slightly higher than the reference method (median difference = +3 mg/dL; P < 0.001), and there was trend in this direction for the Ultra (median difference = +2 mg/dL, P = 0.15). Sensitivities for detection of hypoglycemia (reference < or = 60 and HGM < or = 70 mg/dL) were 96% and 100% for the Ultra and FreeStyle, respectively, and corresponding false-positive rates were both 5%., Conclusions: In a controlled clinical setting using venous blood samples, both the Ultra and FreeStyle meters demonstrated a high degree of accuracy compared with the laboratory reference over a broad range of glucose concentrations in children with T1D.

Objective: Hyperglycemic hyperosmolar non-ketotic (HHNK) syndrome is thought to be a rare entity in the pediatric population, associated with significant mortality based on case reports in the literature. As obesity and type 2 diabetes in childhood grow in prevalence, such related complications may also increase. This study will serve to provide updated information regarding typical clinical course and sequelae of HHNK syndrome in childhood., Methods: Patients diagnosed with type 2 diabetes at Children's Hospital of Philadelphia (CHOP) over a period of 5 yr were screened retrospectively for any laboratory evidence of previous episodes of HHNK syndrome. The standard diagnostic criteria of blood glucose >600 mg/dL and serum osmolality >330 mOsm/L with only mild acidosis (serum bicarbonate >15 mmol/L and small ketonuria 15 mg/dL or less) were utilized., Results: The records of all patients with type 2 diabetes mellitus (DM) diagnosed over a 5-yr period were reviewed (n=190). Seven patients were found to have one episode of HHNK syndrome by diagnostic criteria (five males, mean age at presentation 13.3 yr, age range 10.1--16.9 yr), yielding a frequency of 3.7%. All were African-American. HHNK syndrome was the clinical presentation at diagnosis of new onset diabetes for all seven children. Three of seven children had a previously diagnosed developmental delay. The average Glasgow Coma Scale (GCS) score at presentation was 13 (range 9--15). Mean body mass index (BMI) at presentation was 32.7 kg/m(2) (n=6). Mean serum osmolality was 393 mOsm/L (n=7), and mean blood glucose was 1604 mg/dL (n = 7). The average time until mental status returned to baseline among survivors was 3 d (range 1--7 d). The average number of hospital days for survivors was 10 (range 5--24 d). Four of seven patients had an uncomplicated course. One patient developed multisystem organ failure and died on hospital day 4. The case fatality rate was 14.3% (one of seven). Survivors had no appreciable neurodevelopmental sequelae., Conclusions: This retrospective chart review provides updated information regarding the entity of HHNK syndrome in children. This study supports the need for increased awareness of type 2 diabetes in children so that morbidity and mortality related to HHNK syndrome can be prevented.

Type 1 diabetes mellitus was thought to be the prevalent type of diabetes in children and adolescents; however, increasing numbers of juvenile patients appear to have type 2 diabetes. Management of all diabetes in young patients should include regular assessment, careful monitoring for glycemic control and the presence of hypoglycemia, and educational training on disease management. Hypoglycemic episodes, especially nocturnal events, are frequent in the young diabetic patient. Improvements in glycemic control and nocturnal hypoglycemia have been observed with continuous subcutaneous insulin infusion and insulin glargine. A continuous glucose-monitoring system can provide important insight into 24-hour glycemic control. Overall, careful management, monitoring, and education can improve glycemic control and yield positive treatment outcomes in the child or adolescent with diabetes.

Objective: Use of continuous subcutaneous insulin infusion (CSII) has increased dramatically in recent years, and pump therapy has been shown to be a safe and effective alternative to multiple daily injections in adults and older pediatric patients with type 1 diabetes. Its use in very young children, however, has been limited, although this group might be expected to benefit the most from CSII. The objective of this study was to analyze the CSII efficacy and safety data in very young children with type 1 diabetes from our Diabetes Clinic database., Methods: Glycosylated hemoglobin (HbA1c), severe hypoglycemia (SH), and ketoacidosis (DKA) in the year before CSII were compared with corresponding values during pump treatment in all children who started CSII before age 7., Results: Sixty-five children (mean age: 4.5 y at CSII initiation; range: 1.4-6.9 years; 28 girls; 3 black, 1 Hispanic) were analyzed for >162 patient-years of follow-up. Mean HbA(1c) (7.4 +/- 1.0 prepump) decreased to 7.0 +/- 0.9 after 12 months of CSII and continued to improve even after 4 years on CSII. The rate of SH was reduced by 53% (from 78 to 37/100 patient-years). Children who received daytime care from paid caregivers (n = 26) experienced significant reductions in HbA1c and hypoglycemia frequency. There were no episodes of DKA requiring emergency treatment in the year before CSII and 4 episodes (4 per 100 patient-years) after transition to pump., Conclusions: CSII is a durable and effective means of optimizing glycemic control in very young patients with type 1 diabetes and may be superior to multiple daily injections in minimizing the risk of severe hypoglycemia in this age group. Employment of paid caregivers does not preclude safe and effective use of CSII.

Objective: The efficacy of the insulin analogs now available for multiple daily injection (MDI) and continuous subcutaneous insulin infusion (CSII) therapy in type 1 diabetes has not yet been established in pediatric patients. Our principal aim in this short-term study was to compare the efficacy of CSII to MDI with glargine in lowering HbA(1c) levels in children and adolescents with type 1 diabetes., Research Design and Methods: Thirty-two youth with type 1 diabetes (age 8-21 years) were randomly assigned to receive either MDI treatment with once-daily glargine and premeal/snack insulin aspart or CSII with insulin aspart. Dose titration in both groups was based on home self-monitored blood glucose measurements and monthly HbA(1c). HbA(1c), total daily insulin dose (TDD), self-monitored blood glucose readings, and adverse events were compared after 16 weeks of therapy., Results: While there was no significant change in the glargine group (HbA(1c) 8.2% at baseline vs. 8.1% at 16 weeks), youth randomized to CSII had a sharp reduction in HbA(1c) levels, from 8.1 to 7.2% after 16 weeks of therapy (P < 0.02 vs. baseline and <0.05 vs. glargine group). TDD was unchanged in the glargine group, but significantly dropped with CSII (1.4 units/kg at baseline vs. 0.9 units/kg at 16 weeks, P < 0.01). Both groups had similar basal doses and insulin-to-carbohydrate ratios. Fasting self-monitored blood glucose was similar in both groups, but lunch, dinner, and bedtime readings were significantly lower in the CSII group (P < 0.01)., Conclusions: Lower HbA(1c) and premeal glucose levels were more achievable in this short-term study with CSII than with glargine-based MDI treatment. CSII is an efficacious treatment to improve metabolic control in youth with type 1 diabetes.

Continuous glucose monitoring is becoming increasingly more widespread for the routine care of people with type 1 diabetes mellitus and may eventually be used in closed-loop artificial beta-cell systems. The current "state of the art" of this technology, including accuracy, performance in clinical trials, limitations, and recommendations for use, is discussed for the two currently approved continuous glucose monitoring devices.

Idiopathic ketotic hypoglycemia (IKH) is an important cause of emergent hypoglycemia among children. We present a case series of 24 patients with IKH in an effort to provide a current clinical description of this disorder. Secondly, we provide a crude lower-bound estimate of the incidence of IKH in an Emergency Department (ED) setting. The charts of 94 non-diabetic patients presenting to an ED during a period of 64 months with a diagnosis of hypoglycemia as identified via ICD-9 codes were reviewed. Eleven patients, accounting for 24.4% of all significant hypoglycemic episodes unrelated to diabetes in children over 6 months of age, were diagnosed with IKH. These patients accounted for 31.4% of hypoglycemic episodes among previously heathy children older than 6 months. A further review of 13 individuals with IKH identified from an endocrinology specialty clinic was also performed. Among all 24 individuals identified with IKH, the mean age of presentation was 30.8 months. We have found IKH to be the most common cause of hypoglycemia among previously healthy ED patients during childhood. In our series, patients with IKH presented initially before 5 years of age with symptomatic hypoglycemia during the morning hours after a moderate fast. These patients were found to have ketonuria with symptoms resolving after glucose administration. Patients with IKH were more likely to be Caucasian, male gender, and have a low body weight.

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) possesses both growth-inhibitory and -potentiating effects on cells, which are independent of IGF action and mediated through specific IGFBP-3 binding proteins/receptors located at the cell membrane, cytosol, or nuclear compartments as well as in the extracellular matrix. We here characterized type Ialpha collagen as one of these IGFBP-3 binding proteins. Human serum was fractionated over an IGFBP-3 affinity column, and bands at 70-100 kDa were eluted as IGFBP-3 ligands. The 100-kDa band was extracted, subjected to N-terminal amino acid sequencing, and identified through database searching as the N-terminal chain of type Ialpha collagen protein. In a separate screening approach, using a yeast two-hybrid system, we cloned the type Ialpha collagen cDNA from a human liver cDNA library as an IGFBP-3 protein partner. Anti-IGFBP-3 antibodies co-immunoprecipitated type Ialpha collagen and IGFBP-3 from the conditioned media of human fibroblasts and vice versa. We demonstrated through ligand dot blot analysis that type Ialpha collagen binds IGFBP-3. IGFBP-3 mutants, with altered sequence at the nuclear localization sequence, bound type Ialpha collagen poorly. Western immunoblot showed that type Ialpha collagen binds only IGFBP-3 but not IGF-I, suggesting an IGF-I-independent mechanism of this interaction. Physiological effects of IGFBP-3-collagen interactions may include modulation of cell adhesion and migration.

Use of the Medtronic MiniMed Continuous Glucose Monitoring System (CGMS) in non-diabetic children has revealed many low and high sensor glucose (SG) values, suggesting that the original analytical algorithm (Solutions 2.0) might be overreading glycemic excursions. A revised algorithm (Solutions 3.0) was introduced in 2001. Our aim was to compare analyses of the same sensor profiles using both programs. Twenty-five lean, non-diabetic subjects (mean age 14 +/- 4 years) underwent continuous glucose monitoring with CGMS for up to 72 h. Sensor tracings were analyzed with both algorithms and compared. Separate analyses were performed for nocturnal readings (12-6 a.m.). Mean SG values were similar (103 +/- 24 mg/dL for version 2.0 vs. 100 +/- 14 for version 3.0), but the distribution was significantly different: 13.8% of total SG were <70 mg/dL by version 2.0 versus 8.2% by version 3.0 (p < 0.001), and 7.7% of total SG were >150 mg/dL by version 2.0 versus 4.7% by version 3.0 (p = 0.02). Of nocturnal SG values, 25.8% were <70 mg/dL by version 2.0 compared with 17.9% by version 3.0, and 9.4% were >150 mg/dL by version 2.0 compared with 4.0% by version 3.0. In lean non-diabetic children, Solutions 2.0 identified significantly more hypoglycemia and hyperglycemia than Solutions 3.0. Similar analyses in 40 children with type 1 diabetes revealed no significant differences. Solutions 3.0 may be a more useful algorithm for preventing over-reading of low and high SG readings in non-diabetic children, whereas both algorithms give similar results in children with diabetes.