Clinical Focus

  • Pediatric Endocrinology
  • Type 1 Diabetes Mellitus

Academic Appointments

Professional Education

  • Fellowship:Children's Hospital Los Angeles (1976) CA
  • Residency:Children's Hospital Los Angeles (1974) CA
  • Internship:Children's Hospital Los Angeles (1973) CA
  • Medical Education:UCSD School of Medicine (1972) CA
  • Board Certification: Pediatrics, American Board of Pediatrics (1977)
  • Board Certification: Pediatric Endocrinology, American Board of Pediatrics (1978)

Research & Scholarship

Current Research and Scholarly Interests

My major interest is in type 1 diabetes mellitus, continuous glucose sensor, and the development of an artificial pancreas. Other research interests include using continuous glucose monitoring and algorithms to control blood glucose levels in intensive care units.

Clinical Trials

  • A Randomized Control Trial Comparing Linjeta Versus Humalog in Pumps: Effect on Postprandial Blood Sugars. Not Recruiting

    The purpose of this study is to determine if the use of Linjeta(tm) insulin when compared to Humalog will result in significantly lower episodes of hyperglycemia and hypoglycemia after a breakfast meal.

    Stanford is currently not accepting patients for this trial. For more information, please contact Parul Patel, (650) 723 - 5791.

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  • Duration of Infusion Set Function: Quick-Set Teflon Catheter Versus Sure-T Steel Infusion Set Catheter Not Recruiting

    This is an open label cross over study looking to compare the length of infusion set wear using a teflon catheter or a steel catheter.

    Stanford is currently not accepting patients for this trial. For more information, please contact Parul Patel, (650) 723 - 5791.

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  • Medtronic Treat to Range (TTR) Closed-Loop Control Not Recruiting

    The purpose of this study is to evaluate a treat-to-range automated insulin management system using continuous glucose monitoring (CGM) and subcutaneous insulin pump infusion in individuals with type 1 diabetes.

    Stanford is currently not accepting patients for this trial. For more information, please contact Kari Benassi, RN, FNP, 650-736-8948.

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  • A Study to Evaluate a Multiple Model Probabilistic Predictive Controller (MMPPC) for Closed Loop Insulin Delivery Not Recruiting

    You are invited to participate in a research study for the development of an artificial pancreas. An artificial pancreas uses a program which takes information from a continuous blood glucose monitor and uses that information to tell an insulin infusion pump how much insulin to deliver. The primary purpose of this study is to gain experience with insulin delivery algorithms or programs program (algorithm) provides the best regulation of glucose levels so that there are no severe low blood glucose reactions and blood glucose levels are generally between 70 to 180 mg/dl.

    Stanford is currently not accepting patients for this trial. For more information, please contact Paula Clinton, (650) 736 - 2313.

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2014-15 Courses


Journal Articles

  • Recommendations for Standardizing Glucose Reporting and Analysis to Optimize Clinical Decision Making in Diabetes: The Ambulatory Glucose Profile (AGP) DIABETES TECHNOLOGY & THERAPEUTICS Bergenstal, R. M., Ahmann, A. J., Bailey, T., Beck, R. W., Bissen, J., Buckingham, B., Deeb, L., Dolin, R. H., Garg, S. K., Goland, R., Hirsch, I. B., Klonoff, D. C., Kruger, D. F., Matfin, G., Mazze, R. S., Olson, B. A., Parkin, C., Peters, A., Powers, M. A., Rodriguez, H., Southerland, P., Strock, E. S., Tamborlane, W., Wesley, D. M. 2013; 15 (3): 198-211


    Abstract Underutilization of glucose data and lack of easy and standardized glucose data collection, analysis, visualization, and guided clinical decision making are key contributors to poor glycemic control among individuals with type 1 diabetes. An expert panel of diabetes specialists, facilitated by the International Diabetes Center and sponsored by the Helmsley Charitable Trust, met in 2012 to discuss recommendations for standardization of analysis and presentation of glucose monitoring data, with the initial focus on data derived from CGM systems. The panel members were introduced to a universal software report, the Ambulatory Glucose Profile (AGP), and asked to provide feedback on its content and functionality, both as a research tool and in clinical settings. This paper provides a summary of the topics and issues discussed during the meeting and presents recommendations from the expert panel regarding the need to standardize glucose profile summary metrics and the value of a uniform glucose report to aid clinicians, researchers, and patients.

    View details for DOI 10.1089/dia.2013.0051

    View details for Web of Science ID 000316064500004

    View details for PubMedID 23448694

  • White Matter Structural Differences in Young Children With Type 1 Diabetes: A Diffusion Tensor Imaging Study DIABETES CARE Aye, T., Barnea-Goraly, N., Ambler, C., Hoang, S., Schleifer, K., Park, Y., Drobny, J., Wilson, D. M., Reiss, A. L., Buckingham, B. A. 2012; 35 (11): 2167-2173


    To detect clinical correlates of cognitive abilities and white matter (WM) microstructural changes using diffusion tensor imaging (DTI) in young children with type 1 diabetes.Children, ages 3 to <10 years, with type 1 diabetes (n = 22) and age- and sex-matched healthy control subjects (n = 14) completed neurocognitive testing and DTI scans.Compared with healthy controls, children with type 1 diabetes had lower axial diffusivity (AD) values (P = 0.046) in the temporal and parietal lobe regions. There were no significant differences between groups in fractional anisotropy and radial diffusivity (RD). Within the diabetes group, there was a significant, positive correlation between time-weighted HbA(1c) and RD (P = 0.028). A higher, time-weighted HbA(1c) value was significantly correlated with lower overall intellectual functioning measured by the full-scale intelligence quotient (P = 0.03).Children with type 1 diabetes had significantly different WM structure (as measured by AD) when compared with controls. In addition, WM structural differences (as measured by RD) were significantly correlated with their HbA(1c) values. Additional studies are needed to determine if WM microstructural differences in young children with type 1 diabetes predict future neurocognitive outcome.

    View details for DOI 10.2337/dc12-0017

    View details for Web of Science ID 000311424100015

    View details for PubMedID 22966090

  • Feasibility of prolonged continuous glucose monitoring in toddlers with type 1 diabetes. Pediatric diabetes Tsalikian, E., Fox, L., Weinzimer, S., Buckingham, B., White, N. H., Beck, R., Kollman, C., Xing, D., Ruedy, K. 2012; 13 (4): 301-307


    To examine the feasibility of continuous glucose monitoring (CGM) use in very young children with type 1 diabetes (T1D).Twenty-three children less than 4 yr of age with T1D were provided with a FreeStyle Navigator(®) (n = 21) or a Paradigm(®) (n = 2) CGM device. At baseline, mean age was 3.0 ± 0.8 yr, mean hemoglobin A1c (HbA1c) was 8.0 ± 0.8%, 10 were using an insulin pump and 13 were on multiple daily injections. CGM use was evaluated over a 6-month period.Three children dropped out of the study before the end of 6 months. Among the 20 children who completed 6 months of follow-up, CGM use in month 6 was ?6 d/wk in 9 (45%), 4 ? 6 d/wk in 2 (10%), and <4 d/wk in 9 (45%). Skin reactions were minimal. Although there was no detectable change in mean HbA1c between baseline and 6 months (7.9 and 8.0%, respectively), there was a high degree of parental satisfaction with CGM as measured on the CGM satisfaction scale questionnaire. A high percentage of glucose values were in the hyperglycemic range, and biochemical hypoglycemia was infrequent.More than 40% of very young children were able to safely use CGM on a near-daily basis after 6 months. CGM demonstrated frequent hyperglycemic excursions, with a large variability in glucose readings. Although improvement in glycemic control was not detected in the group as a whole, parental satisfaction with CGM was high.

    View details for DOI 10.1111/j.1399-5448.2011.00837.x

    View details for PubMedID 22151826

  • Use of continuous glucose monitoring in children and adolescents PEDIATRIC DIABETES Phillip, M., Danne, T., Shalitin, S., Buckingham, B., Laffel, L., Tamborlane, W., Battelino, T. 2012; 13 (3): 215-228
  • Achievement of Target A1C Levels With Negligible Hypoglycemia and Low Glucose Variability in Youth With Short-Term Type 1 Diabetes and Residual beta-Cell Function DIABETES CARE Sherr, J., Tamborlane, W. V., Xing, D., Tsalikian, E., Mauras, N., Buckingham, B., White, N. H., Arbelaez, A. M., Beck, R. W., Kollman, C., Ruedy, K. 2012; 35 (4): 817-820


    To determine exposure to hyper- and hypoglycemia using blinded continuous glucose monitoring (CGM) profiles in youth with type 1 diabetes (T1D) with residual ?-cell function during the first year of insulin treatment.Blinded, 3-7 day CGM profiles were obtained in 16 short-term T1D patients (age 8-18 years, T1D duration 6-52 weeks) who had peak C-peptide levels ranging from 0.46 to 1.96 nmol/L during a mixed-meal tolerance test. Results in this short-term group were compared with those in 34 patients with well-controlled, longer-term T1D (duration ?5 years), matched for age and A1C with the short-term T1D group, and with those in 26 age-matched nondiabetic individuals.Despite matching for A1C, and therefore similar mean sensor glucose levels in the two T1D groups, short-term T1D participants had a lower frequency of hypoglycemia (0.3 vs. 7.6%, P < 0.001), a trend toward less hyperglycemia (17 vs. 32%, P = 0.15), and a greater percentage in the target range (median 77 vs. 60%, P = 0.02). Indeed, the percentage of sensor glucose levels ?70 mg/dL in the short-term T1D group (0.3%) did not differ from those in the nondiabetic group (1.7%, P = 0.73). The coefficient of variation of sensor glucose levels (an index of glucose variability) was lower in short-term vs. longer-term T1D participants (27 vs. 42%, respectively, P < 0.001).In youth with short-term T1D who retain residual ?-cell function, there is negligible exposure to hypoglycemia and lower glucose variability than in youth with well-controlled T1D of longer duration.

    View details for DOI 10.2337/dc11-2190

    View details for Web of Science ID 000301959600027

    View details for PubMedID 22323414

  • Reduction in Duration of Hypoglycemia by Automatic Suspension of Insulin Delivery: The In-Clinic ASPIRE Study DIABETES TECHNOLOGY & THERAPEUTICS Garg, S., Brazg, R. L., Bailey, T. S., Buckingham, B. A., Slover, R. H., Klonoff, D. C., Shin, J., Welsh, J. B., Kaufman, F. R. 2012; 14 (3): 205-209


    The efficacy of automatic suspension of insulin delivery in induced hypoglycemia among subjects with type 1 diabetes was evaluated.In this randomized crossover study, subjects used a sensor-augmented insulin pump system with a low glucose suspend (LGS) feature that automatically stops insulin delivery for 2?h following a sensor glucose (SG) value ?70?mg/dL. Subjects fasted overnight and exercised until their plasma glucose (measured with the YSI 2300 STAT Plus™ glucose and lactate analyzer [YSI Life Sciences, Yellow Springs, OH]) value reached ?85?mg/dL on different occasions separated by washout periods lasting 3-10 days. Exercise sessions were done with the LGS feature turned on (LGS-On) or with continued insulin delivery regardless of SG value (LGS-Off). The order of LGS-On and LGS-Off sessions was randomly assigned. YSI glucose data were used to compare the duration and severity of hypoglycemia from successful LGS-On and LGS-Off sessions and to estimate the risk of rebound hyperglycemia after pump suspension.Fifty subjects attempted 134 sessions, 98 of which were successful. The mean±SD hypoglycemia duration was less during LGS-On than during LGS-Off sessions (138.5±76.68 vs. 170.7±75.91?min, P=0.006). During LGS-On compared with LGS-Off sessions, mean nadir YSI glucose was higher (59.5±5.72 vs. 57.6±5.69?mg/dL, P=0.015), as was mean end-observation YSI glucose (91.4±41.84 vs. 66.2±13.48?mg/dL, P<0.001). Most (53.2%) end-observation YSI glucose values in LGS-On sessions were in the 70-180?mg/dL range, and none was >250?mg/dL.Automatic suspension of insulin delivery significantly reduced the duration and severity of induced hypoglycemia without causing rebound hyperglycemia.

    View details for DOI 10.1089/dia.2011.0292

    View details for Web of Science ID 000300845600003

    View details for PubMedID 22316089

  • A Randomized Clinical Trial to Assess the Efficacy and Safety of Real-Time Continuous Glucose Monitoring in the Management of Type 1 Diabetes in Young Children Aged 4 to < 10 Years DIABETES CARE Mauras, N., Beck, R., Xing, D., Ruedy, K., Buckingham, B., Tansey, M., White, N. H., Weinzimer, S. A., Tamborlane, W., Kollman, C. 2012; 35 (2): 204-210


    Continuous glucose monitoring (CGM) has been demonstrated to improve glycemic control in adults with type 1 diabetes but less so in children. We designed a study to assess CGM benefit in young children aged 4 to 9 years with type 1 diabetes.After a run-in phase, 146 children with type 1 diabetes (mean age 7.5 ± 1.7 years, 64% on pumps, median diabetes duration 3.5 years) were randomly assigned to CGM or to usual care. The primary outcome was reduction in HbA(1c) at 26 weeks by ?0.5% without the occurrence of severe hypoglycemia.The primary outcome was achieved by 19% in the CGM group and 28% in the control group (P = 0.17). Mean change in HbA(1c) was -0.1% in each group (P = 0.79). Severe hypoglycemia rates were similarly low in both groups. CGM wear decreased over time, with only 41% averaging at least 6 days/week at 26 weeks. There was no correlation between CGM use and change in HbA(1c) (r(s) = -0.09, P = 0.44). CGM wear was well tolerated, and parental satisfaction with CGM was high. However, parental fear of hypoglycemia was not reduced.CGM in 4- to 9-year-olds did not improve glycemic control despite a high degree of parental satisfaction with CGM. We postulate that this finding may be related in part to limited use of the CGM glucose data in day-to-day management and to an unremitting fear of hypoglycemia. Overcoming the barriers that prevent integration of these critical glucose data into day-to-day management remains a challenge.

    View details for DOI 10.2337/dc11-1746

    View details for Web of Science ID 000299856000004

    View details for PubMedID 22210571

  • The Feasibility of Detecting Neuropsychologic and Neuroanatomic Effects of Type 1 Diabetes in Young Children DIABETES CARE Aye, T., Reiss, A. L., Kesler, S., Hoang, S., Drobny, J., Park, Y., Schleifer, K., Baumgartner, H., Wilson, D. M., Buckingham, B. A. 2011; 34 (7): 1458-1462


    To determine if frequent exposures to hypoglycemia and hyperglycemia during early childhood lead to neurocognitive deficits and changes in brain anatomy.In this feasibility, cross-sectional study, young children, aged 3 to 10 years, with type 1 diabetes and age- and sex-matched healthy control (HC) subjects completed neuropsychologic (NP) testing and magnetic resonance imaging (MRI) scans of the brain.NP testing and MRI scanning was successfully completed in 98% of the type 1 diabetic and 93% of the HC children. A significant negative relationship between HbA1c and Wechsler Intelligence Scale for Children (WISC) verbal comprehension was observed. WISC index scores were significantly reduced in type 1 diabetic subjects who had experienced seizures. White matter volume did not show the expected increase with age in children with type 1 diabetes compared with HC children (diagnosis by age interaction, P=0.005). A similar trend was detected for hippocampal volume. Children with type 1 diabetes who had experienced seizures showed significantly reduced gray matter and white matter volumes relative to children with type 1 diabetes who had not experienced seizures.It is feasible to perform MRI and NP testing in young children with type 1 diabetes. Further, early signs of neuroanatomic variation may be present in this population. Larger cross-sectional and longitudinal studies of neurocognitive function and neuroanatomy are needed to define the effect of type 1 diabetes on the developing brain.

    View details for DOI 10.2337/dc10-2164

    View details for Web of Science ID 000293261200003

    View details for PubMedID 21562318

  • Factors Predictive of Severe Hypoglycemia in Type 1 Diabetes Analysis from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized control trial dataset DIABETES CARE Fiallo-Scharer, R., Cheng, J., Beck, R. W., Buckingham, B. A., Chase, H. P., Kollman, C., Laffel, L., Lawrence, J. M., Mauras, N., Tamborlane, W. V., Wilson, D. M., Wolpert, H., Bode, B., Ruedy, K. J., Weinzimer, S., Xing, D. 2011; 34 (3): 586-590


    Identify factors predictive of severe hypoglycemia (SH) and assess the clinical utility of continuous glucose monitoring (CGM) to warn of impending SH.In a multicenter randomized clinical trial, 436 children and adults with type 1 diabetes were randomized to a treatment group that used CGM (N = 224), or a control group that used standard home blood glucose monitoring (N = 212) and completed 12 months of follow-up. After 6 months, the original control group initiated CGM while the treatment group continued use of CGM for 6 months. Baseline risk factors for SH were evaluated over 12 months of follow-up using proportional hazards regression. CGM-derived indices of hypoglycemia were used to predict episodes of SH over a 24-h time horizon.The SH rate was 17.9 per 100 person-years, and a higher rate was associated with the occurrence of SH in the prior 6 months and female sex. SH frequency increased eightfold when 30% of CGM values were ? 70 mg/dL on the prior day (4.5 vs. 0.5%; P < 0.001), but the positive predictive value (PPV) was low (<5%). Results were similar for hypoglycemic area under the curve and the low blood glucose index calculated by CGM.SH in the 6 months prior to the study was the strongest predictor of SH during the study. CGM-measured hypoglycemia over a 24-h span is highly associated with SH the following day (P < 0.001), but the PPV is low.

    View details for DOI 10.2337/dc10-1111

    View details for Web of Science ID 000288145400010

    View details for PubMedID 21266651

  • A closed-loop artificial pancreas based on risk management. Journal of diabetes science and technology Cameron, F., Bequette, B. W., Wilson, D. M., Buckingham, B. A., Lee, H., Niemeyer, G. 2011; 5 (2): 368-379


    Control algorithms that regulate blood glucose (BG) levels in individuals with type 1 diabetes mellitus face several fundamental challenges. Two of these are the asymmetric risk of clinical complications associated with low and high glucose levels and the irreversibility of insulin action when using only insulin. Both of these nonlinearities force a controller to be more conservative when uncertainties are high. We developed a novel extended model predictive controller (EMPC) that explicitly addresses these two challenges.Our extensions to model predictive control (MPC) operate in three ways. First, they explicitly minimize the combined risk of hypoglycemia and hyperglycemia. Second, they integrate the effect of prediction uncertainties into the risk. Third, they understand that future control actions will vary if measurements fall above or below predictions. Using the University of Virginia/Padova Simulator, we compared our novel controller (EMPC) against optimized versions of a proportional-integral-derivative (PID) controller, a traditional MPC, and a basal/bolus (BB) controller, as well as against published results of an independent MPC (IMPC). The BB controller was optimized retrospectively to serve as a bound on the possible performance.We tuned each controller, where possible, to minimize a published blood glucose risk index (BGRI). The simulated controllers (PID/MPC/EMPC/BB) provided BGRI values of 2.99/3.05/2.51/1.27 as compared to the published IMPC BGRI value of 4.10. These correspond to 73/79/84/92% of BG values lying in the euglycemic range (70-180 mg/dl), respectively, with mean BG levels of 151/156/147/140 mg/dl.The EMPC strategy extends MPC to explicitly address the issues of asymmetric glycemic risk and irreversible insulin action using estimated prediction uncertainties and an explicit risk function. This controller reduces the avoidable BGRI by 56% (p < .05) relative to a published MPC algorithm studied on a similar population.

    View details for PubMedID 21527108

  • Toward Closing the Loop: An Update on Insulin Pumps and Continuous Glucose Monitoring Systems ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA Aye, T., Block, J., Buckingham, B. 2010; 39 (3): 609-?


    This article reviews current pump and continuous glucose monitoring therapy and what will be required to integrate these systems into closed-loop control. Issues with sensor accuracy, lag time, and calibration are discussed as well as issues with insulin pharmacodynamics, which result in a delayed onset of insulin action in a closed-loop system. A stepwise approach to closed-loop therapy is anticipated, where the first systems will suspend insulin delivery based on actual or predicted hypoglycemia. Subsequent systems may control to range, limiting the time spent in hyperglycemia by mitigating the effects of a missed food bolus or underestimate of consumed carbohydrates, while minimizing the risk of hypoglycemia.

    View details for DOI 10.1016/j.ecl.2010.05.005

    View details for Web of Science ID 000282146100011

    View details for PubMedID 20723823

  • Insulin Pumps in Young Children DIABETES TECHNOLOGY & THERAPEUTICS Fuld, K., Conrad, B., Buckingham, B., Wilson, D. M. 2010; 12: S67-S71


    Insulin infusion pump therapy has dramatically improved over the past 20 years and can now address some of the specific challenges related to toddlers with diabetes. We discuss both the non-randomized and randomized controlled trials comparing continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) in this age group. There are advantages and disadvantages related to both CSII and MDI treatments, and ultimately the decision to use CSII should be individualized for each patient and family with the guidance of their diabetes team.

    View details for DOI 10.1089/dia.2009.0182

    View details for Web of Science ID 000278212300012

    View details for PubMedID 20515310

  • Prevention of Nocturnal Hypoglycemia Using Predictive Alarm Algorithms and Insulin Pump Suspension DIABETES CARE Buckingham, B., Chase, H. P., Dassau, E., Cobry, E., Clinton, P., Gage, V., Caswell, K., Wilkinson, J., Cameron, F., Lee, H., Bequette, B. W., Doyle, F. J. 2010; 33 (5): 1013-1017


    The aim of this study was to develop a partial closed-loop system to safely prevent nocturnal hypoglycemia by suspending insulin delivery when hypoglycemia is predicted in type 1 diabetes.Forty subjects with type 1 diabetes (age range 12-39 years) were studied overnight in the hospital. For the first 14 subjects, hypoglycemia (<60 mg/dl) was induced by gradually increasing the basal insulin infusion rate (without the use of pump shutoff algorithms). During the subsequent 26 patient studies, pump shutoff occurred when either three of five (n = 10) or two of five (n = 16) algorithms predicted hypoglycemia based on the glucose levels measured with the FreeStyle Navigator (Abbott Diabetes Care).The standardized protocol induced hypoglycemia on 13 (93%) of the 14 nights. With use of a voting scheme that required three algorithms to trigger insulin pump suspension, nocturnal hypoglycemia was prevented during 6 (60%) of 10 nights. When the voting scheme was changed to require only two algorithms to predict hypoglycemia to trigger pump suspension, hypoglycemia was prevented during 12 (75%) of 16 nights. In the latter study, there were 25 predictions of hypoglycemia because some subjects had multiple hypoglycemic events during a night, and hypoglycemia was prevented for 84% of these events.Using algorithms to shut off the insulin pump when hypoglycemia is predicted, it is possible to prevent hypoglycemia on 75% of nights (84% of events) when it would otherwise be predicted to occur.

    View details for DOI 10.2337/dc09-2303

    View details for Web of Science ID 000277631200011

    View details for PubMedID 20200307

  • Probabilistic evolving meal detection and estimation of meal total glucose appearance. Journal of diabetes science and technology Cameron, F., Niemeyer, G., Buckingham, B. A. 2009; 3 (5): 1022-1030


    Automatic compensation of meals for type 1 diabetes patients will require meal detection from continuous glucose monitor (CGM) readings. This is challenged by the uncertainty and variability inherent to the digestion process and glucose dynamics as well as the lag and noise associated with CGM sensors. Thus any estimation of meal start time, size, and shape is fundamentally uncertain. This uncertainty can be reduced, but not eliminated, by estimating total glucose appearance and using new readings as they become available.In this article, we propose a probabilistic, evolving method to detect the presence and estimate the shape and total glucose appearance of a meal. The method is unique in continually evolving its estimates and simultaneously providing uncertainty measures to monitor their convergence. The algorithm operates in three phases. First, it compares the CGM signal to no-meal predictions made by a simple insulin-glucose model. Second, it fits the residuals to potential, assumed meal shapes. Finally, it compares and combines these fits to detect any meals and estimate the meal total glucose appearance, shape, and total glucose appearance uncertainty.We validate the performance of this meal detection and total glucose appearance estimation algorithm both separately and in cooperation with a controller on the Food and Drug Administration-approved University of Virginia/Padova Type I Diabetes Simulator. In cooperation with a controller, the algorithm reduced the mean blood glucose from 137 to 132 mg/dl over 1.5 days of control without any increased hypoglycemia.This novel, extensible meal detection and total glucose appearance estimation method shows the feasibility, relevance, and performance of evolving estimates with explicit uncertainty measures for use in closed-loop control of type 1 diabetes.

    View details for PubMedID 20144415

  • Preventing Hypoglycemia Using Predictive Alarm Algorithms and Insulin Pump Suspension DIABETES TECHNOLOGY & THERAPEUTICS Buckingham, B., Cobry, E., Clinton, P., Gage, V., Caswell, K., Kunselman, E., Cameron, F., Chase, H. P. 2009; 11 (2): 93-97


    Nocturnal hypoglycemia is a significant problem. From 50% to 75% of hypoglycemia seizures occur at night. Despite the development of real-time glucose sensors (real-time continuous glucose monitor [CGM]) with hypoglycemic alarms, many patients sleep through these alarms. The goal of this pilot study was to assess the feasibility using a real-time CGM to discontinue insulin pump therapy when hypoglycemia was predicted.Twenty-two subjects with type 1 diabetes had two daytime admissions to a clinical research center. On the first admission their basal insulin was increased until their blood glucose level was <60 mg/dL. On the second admission hypoglycemic prediction algorithms were tested to determine if hypoglycemia was prevented by a 90-min pump shutoff and to determine if the pump shutoff resulted in rebound hyperglycemia.Using a statistical prediction algorithm with an 80 mg/dL threshold and a 30-min projection horizon, hypoglycemia was prevented 60% of the time. Using a linear prediction algorithm with an 80 mg/dL threshold and a 45-min prediction horizon, hypoglycemia was prevented 80% of the time. There was no rebound hyperglycemia following pump suspension.Further development of algorithms is needed to prevent all episodes of hypoglycemia from occurring.

    View details for DOI 10.1089/dia.2008.0032

    View details for Web of Science ID 000262811200006

    View details for PubMedID 19848575

  • Duration of Nocturnal Hypoglycemia Before Seizures DIABETES CARE Buckingham, B., Wilson, D. M., Lecher, T., Hanas, R., Kaiserman, K., Cameron, F. 2008; 31 (11): 2110-2112


    Despite a high incidence of nocturnal hypoglycemia documented by the use of continuous glucose monitoring (CGM), there are no reports in the literature of nocturnal hypoglycemic seizures while a patient is wearing a CGM device.In this article, we describe four such cases and assess the duration of nocturnal hypoglycemia before the seizure.In the cases where patients had a nocturnal hypoglycemic seizure while wearing a CGM device, sensor hypoglycemia (<60 mg/dl) was documented on the CGM record for 2.25-4 h before seizure activity.Even with a subcutaneous glucose lag of 18 min when compared with blood glucose measurements, glucose sensors have time to provide clinically meaningful alarms. Current nocturnal hypoglycemic alarms need to be improved, however, since patients can sleep through the current alarm systems.

    View details for DOI 10.2337/dc08-0863

    View details for Web of Science ID 000260565000007

    View details for PubMedID 18694975

  • Continuous glucose monitoring and intensive treatment of type 1 diabetes NEW ENGLAND JOURNAL OF MEDICINE Tamborlane, W. V., Beck, R. W., Bode, B. W., Buckingham, B., Chase, H. P., Clemons, R., Fiallo-Scharer, R., Fox, L. A., Gilliam, L. K., Hirsch, I. B., Huang, E. S., Kollman, C., Kowalski, A. J., Laffel, L., Lawrence, J. M., Lee, J., Mauras, N., O'Grady, M., Ruedy, K. J., Tansey, M., Tsalikian, E., Weinzimer, S., Wilson, D. M., Wolpert, H., Wysocki, T., Xing, D. 2008; 359 (14): 1464-U65


    The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined.In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks.The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference.Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. ( number, NCT00406133.)

    View details for Web of Science ID 000259631700007

    View details for PubMedID 18779236

  • Sensor-augmented insulin pump therapy: Results of the first randomized treat-to-target study DIABETES TECHNOLOGY & THERAPEUTICS Hirsch, I. B., Abelseth, J., Bode, B. W., Fischer, J. S., Kaufman, F. R., Mastrototaro, J., Parkin, C. G., Wolpert, H. A., Buckingham, B. A. 2008; 10 (5): 377-383


    The objective of the study was to evaluate the clinical effectiveness and safety of a device that combines an insulin pump with real-time continuous glucose monitoring (CGM), compared to using an insulin pump with standard blood glucose monitoring systems.This 6-month, randomized, multicenter, treat-to-target study enrolled 146 subjects treated with continuous subcutaneous insulin infusion between the ages of 12 and 72 years with type 1 diabetes and initial A1C levels of >or=7.5%. Subjects were randomized to pump therapy with real-time CGM (sensor group [SG]) or to pump therapy and self-monitoring of blood glucose only (control group [CG]). Clinical effectiveness and safety were evaluated.A1C levels decreased (P<0.001) from baseline (8.44+/-0.70%) in both groups (SG, -0.71+/-0.71%; CG, -0.56+/-0.072%); however, between-group differences did not achieve significance. SG subjects showed no change in mean hypoglycemia area under the curve (AUC), whereas CG subjects showed an increase (P=0.001) in hypoglycemia AUC during the blinded periods of the study. The between-group difference in hypoglycemia AUC was significant (P<0.0002). Greater than 60% sensor utilization was associated with A1C reduction (P=0.0456). Fourteen severe hypoglycemic events occurred (11 in the SG group and three in the CG group, P=0.04).A1C reduction was no different between the two groups. Subjects in the CG group had increased hypoglycemia AUC and number of events during blinded CGM use; however, there was no increase in hypoglycemia AUC or number of events in the SG group. Subjects with greater sensor utilization showed a greater improvement in A1C levels.

    View details for DOI 10.1089/dia.2008.0068

    View details for Web of Science ID 000259177600007

    View details for PubMedID 18715214

  • Clinical application of emerging sensor technologies in diabetes management: Consensus guidelines for continuous glucose monitoring (CGM) DIABETES TECHNOLOGY & THERAPEUTICS Hirsch, I. B., Armstrong, D., Bergenstal, R. M., Buckingham, B., Childs, B. P., Clarke, W. L., Peters, A., Wolpert, H. 2008; 10 (4)


    Continuous glucose monitoring (CGM) is an evolving technology poised to redefine current concepts of glycemic control and optimal diabetes management. To date, there are few randomized studies examining how to most effectively use this new tool. Therefore, a group of eight diabetes specialists heard presentations on continuous glucose sensor technology and then discussed their experience with CGM in order to identify fundamental considerations, objectives, and methods for applying this technology in clinical practice. The group concluded that routine use of CGM, with real-time data showing the rate and direction of glucose change, could revolutionize current approaches to evaluating and managing glycemia. The need for such progress is indicated by the growing prevalence of inadequately treated hyperglycemia. Coordinating financial and educational resources and developing clear protocols for using glucose sensor technology are urgent priorities in promoting wide adoption of CGM by patients and health care providers. Finally, researchers, manufacturers, payers, and advocacy groups must join forces on the policy level to create an environment conducive to managing continuous data, measuring outcomes, and formalizing best practices.

    View details for DOI 10.1089/dia.2008.0016

    View details for Web of Science ID 000258900000001

    View details for PubMedID 18699743

  • Statistical hypoglycemia prediction. Journal of diabetes science and technology Cameron, F., Niemeyer, G., Gundy-Burlet, K., Buckingham, B. 2008; 2 (4): 612-621


    Hypoglycemia presents a significant risk for patients with insulin-dependent diabetes mellitus. We propose a predictive hypoglycemia detection algorithm that uses continuous glucose monitor (CGM) data with explicit certainty measures to enable early corrective action.The algorithm uses multiple statistical linear predictions with regression windows between 5 and 75 minutes and prediction horizons of 0 to 20 minutes. The regressions provide standard deviations, which are mapped to predictive error distributions using their averaged statistical correlation. These error distributions give confidence levels that the CGM reading will drop below a hypoglycemic threshold. An alarm is generated if the resultant probability of hypoglycemia from our predictions rises above an appropriate, user-settable value. This level trades off the positive predictive value against lead time and missed events.The algorithm was evaluated using data from 26 inpatient admissions of Navigator(R) 1-minute readings obtained as part of a DirecNet study. CGM readings were postprocessed to remove dropouts and calibrate against finger stick measurements. With a confidence threshold set to provide alarms that correspond to hypoglycemic events 60% of the time, our results were (1) a 23-minute mean lead time, (2) false positives averaging a lowest blood glucose value of 97 mg/dl, and (3) no missed hypoglycemic events, as defined by CGM readings. Using linearly interpolated FreeStyle capillary glucose readings to define hypoglycemic events provided (1) the lead time was 17 minutes, (2) the lowest mean glucose with false alarms was 100 mg/dl, and (3) no hypoglycemic events were missed.Statistical linear prediction gives significant lead time before hypoglycemic events with an explicit, tunable trade-off between longer lead times and fewer missed events versus fewer false alarms.

    View details for PubMedID 19885237

  • Use of the DirecNet Applied Treatment Algorithm (DATA) for diabetes management with a real-time continuous glucose monitor (the FreeStyle Navigator) PEDIATRIC DIABETES Buckingham, B., Xing, D., Weinzimer, S., Fiallo-Scharer, R., Kollman, C., Mauras, N., Tsalikian, E., Tamborlane, W., Wysocki, T., Ruedy, K., Beck, R. 2008; 9 (2): 142-147


    There are no published guidelines for use of real-time continuous glucose monitoring data by a patient; we therefore developed the DirecNet Applied Treatment Algorithm (DATA). The DATA provides algorithms for making diabetes management decisions using glucose values: (i) in real time which include the direction and rate of change of glucose levels, and (ii) retrospectively based on downloaded sensor data.To evaluate the use and effectiveness of the DATA in children with diabetes using a real-time continuous glucose sensor (the FreeStyle Navigator).Thirty children and adolescents (mean +/- standard deviation age = 11.2 +/- 4.1 yr) receiving insulin pump therapy.Subjects were instructed on use of the DATA and were asked to download their Navigator weekly to review glucose patterns. An Algorithm Satisfaction Questionnaire was completed at 3, 7, and 13 wk.At 13 wk, all of the subjects and all but one parent thought that the DATA gave good, clear directions for insulin dosing, and thought the guidelines improved their postprandial glucose levels. In responding to alarms, 86% of patients used the DATA at least 50% of the time at 3 wk, and 59% reported doing so at 13 wk. Similar results were seen in using the DATA to adjust premeal bolus doses of insulin.These results show the feasibility of implementing the DATA when real-time continuous glucose monitoring is initiated and support its use in future clinical trials of real-time continuous glucose monitoring.

    View details for DOI 10.1111/j.1399-5448.2007.00301.x

    View details for Web of Science ID 000255130400011

    View details for PubMedID 18221427

  • Clinical overview of continuous glucose monitoring. Journal of diabetes science and technology Buckingham, B. 2008; 2 (2): 300-306


    Continuous glucose monitoring (CGM) is now available from several companies in the United States for purchase or research studies. This article provides an overview of these devices and reviews the use of sensors for managing diabetes in "real time," as well as the use of retrospective analysis of CGM results.

    View details for PubMedID 19885360

  • Detection of a Meal Using Continuous Glucose Monitoring implications for an artificial beta-cell DIABETES CARE Dassau, E., Bequette, B. W., Buckingham, B. A., Doyle, F. J. 2008; 31 (2): 295-300


    The purpose of this study was to introduce a novel meal detection algorithm (MDA) to be used as part of an artificial beta-cell that uses a continuous glucose monitor (CGM).We developed our MDA on a dataset of 26 meal events using records from 19 children aged 1-6 years who used the MiniMed CGMS Gold. We then applied this algorithm to CGM records from a DirecNet pilot study of the FreeStyle Navigator continuous glucose sensor. During a research center admission, breakfast insulin was withheld for 1 h, and discrete glucose levels were obtained every 10 min after the meal.Based on the Navigator readings, the MDA detected a meal at a mean time of 30 min from the onset of eating, at which time the mean serum glucose was 21 mg/dl above baseline (range 2-36 mg/dl), and >90% of meals were detected before the glucose had risen 40 mg/dl from baseline.The MDA will enable automated insulin dosing in response to meals, facilitating the development of an artificial pancreas.

    View details for DOI 10.2337/dc07-1293

    View details for Web of Science ID 000266563300023

    View details for PubMedID 17977934

  • Continuous glucose monitoring in children with type 1 diabetes JOURNAL OF PEDIATRICS Anonymous 2007; 151 (4): 388-393


    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).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.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.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.

    View details for DOI 10.1016/j.jpeds.2007.03.047

    View details for Web of Science ID 000249966800017

    View details for PubMedID 17889075

  • The medtronic MiniMed gold continuous glucose monitoring system: An effective means to discover hypo- and Hyperglycemia in children under 7 years of age DIABETES TECHNOLOGY & THERAPEUTICS Gandrud, L. M., Xing, D., Kollman, C., Block, J. M., Kunselman, B., Wilson, D. M., Buckingham, B. A. 2007; 9 (4): 307-316


    The glycemic patterns of children less than 7 years with type 1 diabetes have not been well studied using continuous glucose monitoring. Our goal was to assess the incidence of hypoglycemia as well as postprandial glycemic patterns in this age group utilizing continuous glucose monitoring.Nineteen children used the Medtronic MiniMed (Northridge, CA) CGMS System Gold on three to seven occasions over approximately 6 months.Nineteen children (nine girls and 10 boys; mean age 4.8 +/- 1.4 years, range 1.6-6.8 years) used the CGMS 102 times, providing 434 days of data; 79% of days were optimal based on CGMS Solutions software version 3.0. Mild hypoglycemia (glucose or=2 mg/dL/min following 50% of breakfasts. Children with hemoglobin A1c levels >or=8% had higher postprandial glucose concentrations. There was no significant advantage of continuous subcutaneous insulin infusion therapy over multiple daily injection therapy in decreasing postprandial hyperglycemia.CGMS tracings from young children with diabetes demonstrate frequent mild nocturnal hypoglycemia and significant postprandial hyperglycemia, with a rapid rise in glucose following the meal. The most rapid rate of rise and the most severe postprandial hyperglycemia occurred after breakfast.

    View details for DOI 10.1089/dia.2007.0026

    View details for Web of Science ID 000248811800001

    View details for PubMedID 17705686

  • Real-time continuous glucose monitoring. Current opinion in endocrinology, diabetes, and obesity Buckingham, B., Caswell, K., Wilson, D. M. 2007; 14 (4): 288-295


    To summarize the current literature on real-time continuous glucose monitors, focusing on devices that have been approved or are pending approval.Real-time continuous glucose sensors are new tools to assist in diabetes management. Several devices are currently being sold and additional monitors are expected to be available shortly. These sensors measure interstitial glucose - a distinct physiologic space when compared with the blood glucose. The ability to recognize trends in blood glucose levels provides a new paradigm for making insulin dose decisions and treating hypo- and hyperglycemia.Real-time continuous glucose monitoring systems are currently less accurate than home glucose meters, but provide information every 1-5 min throughout the day and night with alarms for hyper- and hypoglycemia, providing information on glucose trends and nocturnal glycemic excursions. Current real-time sensors are behavior modification tools. Thus, improvements in diabetes control depend on the willingness of patients to modify their diabetes management based on information provided by these devices.

    View details for PubMedID 17940454

  • Glucose control in pediatric intensive care unit patients using an insulin-glucose algorithm DIABETES TECHNOLOGY & THERAPEUTICS Wintergerst, K. A., Deiss, D., Buckingham, B., Cantwell, M., Kache, S., Agarwal, S., Wilson, D. M., Steil, G. 2007; 9 (3): 211-222


    Control of hyperglycemia in adult medical and surgical intensive care units (ICUs) has been shown to dramatically decrease morbidity and mortality. Algorithms to achieve glycemic control in the ICU setting are evolving. We have evaluated the use of a discrete proportional-integral-derivative (PID) algorithm to control hyperglycemia in pediatric ICU (PICU) patients both with and without diabetes.Six PICU patients [four with diabetic ketoacidosis (DKA) and two with glucocorticoid-induced hyperglycemia] with glucose values >150 mg/dL were enrolled. Their hyperglycemia was managed with a PID algorithm that provided recommendations for both changes in the intravenous insulin infusion rate and the time to obtain the next discrete glucose value. Glucose targets were adjusted based on clinical circumstances.Patients (mean age 9.2 years; range 1.8-14 years) utilized the algorithm for a total of 454.4 h. Mean time to the initial glucose target was 8.7 h (range 1.3-15.1 h) in five patients. One subject with hyperosmolar DKA did not achieve target before discharge from the PICU, and another was at target when the algorithm was initiated. After the glucose target was achieved, the mean SD was 23.5 mg/dL, and glucose values were >40 mg/dL above target 13% of the time and <40 mg/dL below target 1% of the time. There were no glucose values <55 mg/dL.The PID algorithm safely and effectively controlled hyperglycemia in a PICU, despite multiple changes in intravenous fluids, steroid doses (including high-dose pulses), and hemodialysis.

    View details for DOI 10.1089/dia.2006.0031

    View details for Web of Science ID 000247337800002

    View details for PubMedID 17561791

  • Increasing the accuracy of oral glucose tolerance testing and extending its application to individuals with normal glucose tolerance for the prediction of type 1 diabetes - The Diabetes Prevention Trial-Type 1 DIABETES CARE Sosenko, J. M., Palmer, J. P., Greenbaum, C. J., Mahon, J., Cowie, C., Krischer, J. P., Chase, H. P., White, N. H., Buckingham, B., Herold, K. C., Cuthbertson, D., Skyler, J. S. 2007; 30 (1): 38-42


    We assessed the extent to which both standard and alternative indexes from 2-h oral glucose tolerance testing predict type 1 diabetes and whether oral glucose tolerance tests (OGTTs) predict type 1 diabetes in individuals with normal glucose tolerance.The prediction of type 1 diabetes from baseline OGTTs was studied in 704 Diabetes Prevention Trial-Type 1 participants (islet-cell autoantibody [ICA]-positive relatives of type 1 diabetic patients). The maximum follow-up was 7.4 years. Analyses utilized receiver-operator curves (ROCs), proportional hazards models, and survival curves.ROC areas under the curve (ROCAUCs) for both the AUC glucose (0.73 +/- 0.02) and an OGTT prediction index (0.78 +/- 0.02) were higher (P < 0.001) than those for the fasting (0.53 +/- 0.02) and 2-h glucose (0.66 +/- 0.02). ROCAUCs for the 60- and 90-min glucose (0.71 +/- 0.02 and 0.72 +/- 0.02, respectively) were also higher (P < 0.01) than those for the fasting and 2-h glucose. Among individuals with normal glucose tolerance, OGTTs were highly predictive, with 4th versus 1st quartile hazard ratios for the 2-h glucose, AUC glucose, and OGTT prediction index ranging from 3.77 to 5.30 (P < 0.001 for all).Certain alternative OGTT indexes appear to better predict type 1 diabetes than standard OGTT indexes in ICA-positive relatives of type 1 diabetic patients. Moreover, even among those with normal glucose tolerance, OGTTs are strongly predictive. This suggests that subtle metabolic abnormalities are present several years before the diagnosis of type 1 diabetes.

    View details for DOI 10.2337/dc06-1615

    View details for Web of Science ID 000243469800007

    View details for PubMedID 17192330

  • Association of hypoglycemia, hyperglycemia, and glucose variability with morbidity and death in the pediatric intensive care unit PEDIATRICS Wintergerst, K. A., Buckingham, B., Gandrud, L., Wong, B. J., Kache, S., Wilson, D. M. 2006; 118 (1): 173-179


    We evaluated retrospectively plasma glucose levels and the degree of hypoglycemia, hyperglycemia, and glucose variability in a PICU and then assessed their association with hospital length of stay and mortality rates.Electronic medical records at the Packard Children's Hospital at Stanford University were reviewed retrospectively for all PICU admissions between March 1, 2003, and March 31, 2004. Patients with a known diagnosis of diabetes mellitus were excluded. The prevalence of hyperglycemia was defined with cutoff values of 110, 150, and 200 mg/dL. Hypoglycemia was defined as < or = 65 mg/dL. Glucose variability was assessed with a calculated glucose variability index.In 13 months, 1094 eligible admissions generated 18865 glucose values (median: 107 mg/dL; range: 13-1839 mg/dL). Patients in the highest maximal glucose quintile had a significantly longer median PICU length of stay, compared with those in the lowest quintile (7.5 days vs 1 day). Mortality rates increased as patients' maximal glucose levels increased, reaching 15.2% among patients with the greatest degree of hyperglycemia. Hypoglycemia was also prevalent, with 18.6% of patients (182 of 980 patients) having minimal glucose levels of < or = 65 mg/dL. There was an increased median PICU length of stay (9.5 days vs 1 day) associated with glucose values in the lowest minimal quintile, compared with those in the highest quintile. Hypoglycemia was correlated with mortality rates; 16.5% of patients with glucose levels of < or = 65 mg/dL died. Glucose variability also was associated with increased length of stay and mortality rates. In multivariate logistic regression analyses, glucose variability, taken with hyperglycemia and hypoglycemia, showed the strongest association with mortality rates.Hyperglycemia and hypoglycemia were prevalent in the PICU. Hypoglycemia, hyperglycemia, and, in particular, increased glucose variability were associated with increased morbidity (length of stay) and mortality rates.

    View details for DOI 10.1542/peds.2005-1819

    View details for Web of Science ID 000238726100021

    View details for PubMedID 16818563

  • Evaluation of factors affecting CGMS calibration DIABETES TECHNOLOGY & THERAPEUTICS Buckingham, B. A., Kollman, C., Beck, R. W., Kalajian, A., Fiallo-Scharer, R., Tansey, M. J., Fox, L. A., Wilson, D. M., Weinzimer, S. A., Ruedy, K. J., Tamborlane, W. V. 2006; 8 (3): 318-325


    The optimal number/timing of calibrations entered into the CGMS (Medtronic MiniMed, Northridge, CA) continuous glucose monitoring system have not been previously described.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.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).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.

    View details for Web of Science ID 000242531200007

    View details for PubMedID 16800753

  • Extended use of a new continuous glucose monitoring system with wireless data transmission in children with type 1 diabetes mellitus DIABETES TECHNOLOGY & THERAPEUTICS Wong, L. J., Buckingham, B. A., Kunselman, B., Istoc, E., Leach, J., Purvis, R. 2006; 8 (2): 139-145


    A new continuous glucose monitoring system (CGMS Datalogger, Medtronic MiniMed, Northridge, CA) potentiates extended sensor use by eliminating the cable connection to a monitor and by being waterproof. We evaluated the performance, safety, and patient tolerance of using the CGMS for 7 continuous days in children with type 1 diabetes mellitus who were encouraged to participate fully in their usual sports and activities in their home environment.Twenty pediatric subjects (12.2 +/- 4.6 years old [mean +/- SD] and glycosylated hemoglobin of 8.06 +/- 1.22%) wore two CGMS devices simultaneously for 7 days. Sensor function was assessed by paired sensor-meter values obtained from the CGMS and their Paradigm Link (Medtronic Minimed) home glucose meter and a daily patient log of sensor and Datalogger sites.Subjects were wearing 90% of the sensors at the end of 7 days. The devices were well tolerated except for pruritus at the adhesive sites in 29% of subjects, and one sensor site (3%) became infected. Once a correction was made to the connection between the cable and Datalogger, 89% of the 18 sensors that initialized were functional at the end of 5 days [r = 0.91; percent mean absolute relative difference (%MARD) = 12.4%], and 78% were functioning at the end of 7 days (r = 0.91; %MARD s 15.4%). Patient comfort while wearing the device decreased after 5 days of sensor wear.This study demonstrates that the life of the glucose sensor can be extended well beyond the current labeling of 72 h. Once the cable connection was corrected, there was no statistically significant change in sensor performance over 7 days. Patients preferred to wear the device for a maximum of 5-6 days.

    View details for Web of Science ID 000242405400002

    View details for PubMedID 16734544

  • Vitamin D deficiency in the San Francisco bay area JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM McAllister, J. C., Lane, A. T., Buckingham, B. A. 2006; 19 (3): 205-208

    View details for Web of Science ID 000236479400003

    View details for PubMedID 16607919

  • Patterns of metabolic progression to type 1 diabetes in the Diabetes Prevention Trial-Type 1 DIABETES CARE Sosenko, J. M., Palmer, J. P., Greenbaum, C. J., Mahon, J., Cowie, C., Krischer, J. P., Chase, H. P., White, N. H., Buckingham, B., Herold, K. C., Cuthbertson, D., Skyler, J. S. 2006; 29 (3): 643-649


    There is little information regarding the pattern of metabolic deterioration before the onset of type 1 diabetes. The goal of this study was to utilize data from the Diabetes Prevention Trial-Type 1 (DPT-1) to obtain a picture of the metabolic progression to type 1 diabetes over a period of approximately 2.5 years before its diagnosis.Fifty-four DPT-1 participants (22 in the parenteral trial and 32 in the oral trial) were studied. All had oral glucose tolerance tests (OGTTs) at 6-month intervals from approximately 30 to 6 months before diagnosis. The vast majority also had OGTTs at diagnosis. Changes in OGTT glucose and C-peptide indexes from 30 to 6 months before diagnosis were examined by calculating slopes of the indexes for each individual over that time period. Changes from 6 months before diagnosis to diagnosis were examined by paired comparisons of the OGTT metabolic indexes between the time points.Glucose levels increased gradually from 30 to 6 months before diagnosis in both the parenteral and oral groups (P < 0.001 for all indexes). Area under the curve (AUC) C-peptide (P < 0.05) and AUC C-peptide-to-AUC glucose ratio (P < 0.001) values decreased in the oral group; peak C-peptide-to-2-h glucose ratio values decreased in both groups (P < 0.001). In participants who also had OGTTs at diagnosis, AUC C-peptide (parenteral group, P < 0.05) and peak C-peptide (oral group, P < 0.05) values decreased from the last 6 months before diagnosis; stimulated C-peptide-to-glucose ratio values decreased in both groups (P < 0.001). Conversely, fasting C-peptide levels increased in both groups (oral group, P < 0.01). Fasting C-peptide-to-fasting glucose ratio values remained constant throughout the 30-month follow-up.These data indicate that over a period of at least 2 years, glucose tolerance gradually deteriorates as stimulated C-peptide levels slowly decline in a substantial number of individuals who develop type 1 diabetes. However, fasting C-peptide levels are maintained, even at diagnosis.

    View details for Web of Science ID 000235764100027

    View details for PubMedID 16505520

  • The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes DIABETES CARE Tansey, M. J. 2006; 29 (1): 20-25


    To examine the acute glucose-lowering effects of aerobic exercise in children and adolescents with type 1 diabetes.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.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.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.

    View details for Web of Science ID 000234349300004

    View details for PubMedID 16373890

  • Hypoglycemia detection, and better yet, prevention, in pediatric patients. Diabetes technology & therapeutics Buckingham, B. 2005; 7 (5): 792-796

    View details for PubMedID 16241885

  • Accuracy of newer-generation home blood glucose meters in a Diabetes Research in Children Network (DirecNet) inpatient exercise study. Diabetes technology & therapeutics Weinzimer, S. A., Beck, R. W., Chase, H. P., Fox, L. A., Buckingham, B. A., Tamborlane, W. V., Kollman, C., Coffey, J., Xing, D., Ruedy, K. J. 2005; 7 (5): 675-680


    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).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.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%.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.

    View details for PubMedID 16241867

  • Impact of exercise on overnight glycemic control in - Children with type 1 diabetes mellitus JOURNAL OF PEDIATRICS Tsalikian, E., Mauras, N., Beck, R. W., Tamborlane, W. V., Janz, K. F., Chase, H. P., Wysocki, T., Weinzimer, S. A., Buckingham, B. A., KOLLMAN, C., Xing, D. Y., Ruedy, K. J., Fiallo-Scharer, R., Fisher, J. H., Tallant, B., Tsalikian, E., Tansey, M. J., Larson, L. F., Coffey, J., Wysocki, T., Mauras, N., Fox, L. A., Bird, K., Lofton, K. L., Buckingham, B. A., Wilson, D. M., Block, J. M., Clinton, P., Doyle, E. A., Sikes, K., Kalajian, A., Stockdale, C. R., Steffes, M. W., Bucksa, J. M., Nowicki, M. L., Van Hale, C. A., Makky, V., Grave, G. D., Linder, B., Winer, K. K., Becker, D. M., Cox, C., Ryan, C. M., White, N. H., White, P. C. 2005; 147 (4): 528-534


    To examine the effect of exercise on overnight hypoglycemia in children with type 1 diabetes mellitus (T1DM).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.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.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.

    View details for DOI 10.1016/j.jpeds.2005.04.065

    View details for Web of Science ID 000232865300024

    View details for PubMedID 16227041

  • Response to nocturnal alarms using a real-time glucose sensor. Diabetes technology & therapeutics Buckingham, B., Block, J., Burdick, J., Kalajian, A., Kollman, C., Choy, M., Wilson, D. M., Chase, P. 2005; 7 (3): 440-447


    The objective of this study was to determine how subjects responded to alarms for hypo- and hyperglycemia while they were sleeping.Twenty subjects with type 1 diabetes (4-17 years old) were admitted to a clinical research center for approximately 24 h. Each subject wore two GlucoWatch G2 Biographers (GW2B) (Cygnus, Inc., Redwood City, CA) and was videotaped using an infrared camera from 9 p.m. to 7 a.m. The videotapes were reviewed to determine if the GW2B alarms were audible on the tape and to document the subject's response to the alarms. Because many alarms can occur surrounding a change in blood glucose, GW2B alarm "events" are defined as a one or more alarms separated from previous alarms by more than 30 min.Downloaded data from the biographers identified 240 individual alarms, 75% of which occurred while the subject was sleeping. Of the 240 alarms 68% were audible on the videotape. Subjects awoke to 29% of individual alarms and to 66% of alarm events. Subjects 4-6 years old responded to 17% of alarms, 7-11 year olds responded to 20% of alarms, adolescents responded to 53% of alarms, and parents responded to 37% of alarms. Subjects awoke to 40% of the first alarm during the night, but to only 28% of subsequent alarms. There were 11 events when the glucose was confirmed to be < or = 70 mg/dL, and in each case the subject was awoken. Fifty-five percent of alarm events occurred when there was no hypo- or hyperglycemia confirmed by a reference glucose value.Subjects awoke to 29% of individual alarms and to 66% of alarm events. Subjects awoke during all alarm events when hypoglycemia was confirmed, but there was a high incidence of false alarms.

    View details for PubMedID 15929675

  • A randomized multicenter trial comparing the GlucoWatch Biographer with standard glucose monitoring in children with type 1 diabetes. Diabetes care Chase, H. P., Beck, R., Tamborlane, W., Buckingham, B., Mauras, N., Tsalikian, E., Wysocki, T., Weinzimer, S., Kollman, C., Ruedy, K., Xing, D. 2005; 28 (5): 1101-1106


    This study assesses whether use of the GlucoWatch G2 Biographer (GW2B) in addition to standard glucose monitoring lowers HbA(1c) and reduces hypoglycemia compared with standard glucose monitoring alone.In all, 200 subjects aged 7 to <18 years with type 1 diabetes were randomly assigned at five centers to standard glucose monitoring (usual care) or standard glucose monitoring plus GW2B use for 6 months. Study outcomes included HbA(1c) values obtained at 6 months and occurrence of severe hypoglycemia.The mean HbA(1c) at baseline was 8.0% in both groups; at 6 months, HbA(1c) was 7.9% in the usual care group and 8.1% in the GW2B group (95% CI for mean reduction in the GW2B group compared with the usual care group -0.4 to 0.1%; P = 0.15). A decrease in HbA(1c) of > or =0.5% was achieved in 21% of the usual care group and 28% of the GW2B group (P = 0.29). Severe hypoglycemia events occurred in 7% of the GW2B group and in 2% of the usual care group (P = 0.10). In the GW2B group, sensor use declined throughout the study from a mean value of 2.1 times/week in the 1st month to 1.5 times/week in the 6th month. Reasons given for declining use included skin irritation (76%), frequent skips (56%), excessive alarms (47%), and inaccurate readings (33%).Use of the GW2B in addition to standard glucose monitoring did not improve glycemic control or reduce the frequency of severe hypoglycemia. Skin reactions and other problems led to decreasing sensor use over time.

    View details for PubMedID 15855573

  • Accuracy of the modified Continuous Glucose Monitoring System (CGMS) sensor in an outpatient setting: results from a diabetes research in children network (DirecNet) study. Diabetes technology & therapeutics Tansey, M. J., Beck, R. W., Buckingham, B. A., Mauras, N., Fiallo-Scharer, R., Xing, D., Killman, C., Tamborlane, W. V., Ruedy, K. J. 2005; 7 (1): 109-114


    We previously reported the results of an inpatient accuracy study in children with type 1 diabetes using the Continuous Glucose Monitoring System (CGMS, Medtronic MiniMed, Northridge, CA). During the course of that study, a new process was implemented for manufacturing the CGMS sensor. Accuracy from the resulting modified sensor used by only 14 children was significantly better than the original version [median relative absolute difference (RAD), 11% vs. 19%; P < 0.001]. Baseline data from a subsequent outpatient study provide an opportunity to further assess the accuracy of the modified sensor in a much larger sample of children with type 1 diabetes.As part of a randomized trial to assess the utility of the GlucoWatch G2 Biographer (Cygnus, Inc., Redwood City, CA), 200 children with type 1 diabetes were instructed to wear a CGMS for 48-72 h in an outpatient setting at baseline. Glucose measurements from a OneTouch UltraSmart (Lifescan, Inc., Milpitas, CA) home glucose meter were downloaded and used as reference values to calculate accuracy measures.The overall median RAD was 12%. Accuracy was better during hyperglycemia than during hypoglycemia (median RAD, 10% vs. 20%; P < 0.001) and on optimal versus non-optimal days but did not vary significantly by the number of calibrations entered.These data confirm the improved accuracy previously reported for the modified version of the CGMS sensor.

    View details for PubMedID 15738708

  • The extended Kalman filter for continuous glucose monitoring. Diabetes technology & therapeutics Knobbe, E. J., Buckingham, B. 2005; 7 (1): 15-27


    Glucose monitoring is a problem with evolving solutions using sensors and data processing techniques that are continually improving. This paper presents the development and application of the extended Kalman filter to the problem of real-time estimation of blood glucose levels and is consistent with sensors based on optical, electrical, or chemical processes. The structure of the extended Kalman filter provides the capability to systematically accommodate new information as it develops. This flexibility and the potential for performance improvement are demonstrated by processing patient data files generated using the Medtronic (Northridge, CA) MiniMed continuous glucose monitoring system (CGMS).

    View details for PubMedID 15738701

  • A two-center randomized controlled feasibility trial of insulin pump therapy in young children with diabetes DIABETES CARE Wilson, D. M., Buckingham, B. A., Kunselman, E. L., Sullivan, M. M., Paguntalan, H. U., Gitelman, S. E. 2005; 28 (1): 15-19


    Our goals were to determine if continuous subcutaneous insulin infusion (CSII), compared with those continuing multiple daily injections (MDIs), can be safely used in young children, if those on CSII will have superior glycemic control, if subjects using CSII will have less hypoglycemia for their level of control, and if families using CSII will report an improved quality of life.We conducted a randomized 1-year feasibility trial comparing CSII with continuing MDIs in preschool children with a history of type 1 diabetes for at least 6 months' duration. Prospective outcomes included measures of overall glycemic control (HbA1c and continuous glucose monitoring system), the incidence of severe hypoglycemia and diabetic ketoacidosis, the percent of glucose values below 3.9 mmol/l, and the parents' report of quality of life.The 19 subjects' ages ranged from 1.7 to 6.1 (mean 3.6) years, duration of diabetes ranged from 0.6 to 2.6 (mean 1.4) years, and baseline HbA1c ranged from 6.7 to 9.6% (mean 7.9%). Seven subjects were male. Nine subjects were randomized to start CSII and 10 to continue on MDI. All baseline characteristics were well balanced. Overall metabolic control, diabetes quality of life, and the incidence of hypoglycemia were similar in the two groups. No subject had diabetic ketoacidosis, while one subject in each group had an episode of severe hypoglycemia. No CSII subject discontinued using the pump during or after the study.CSII can be a safe and effective method to deliver insulin in young children.

    View details for Web of Science ID 000226247700004

    View details for PubMedID 15616227

  • GlucoWatch G2 Biographer alarm reliability during hypoglycemia in children. Diabetes technology & therapeutics Tsalikian, E., Kollman, C., Mauras, N., Weinzimer, S., Buckingham, B., Xing, D., Beck, R., Ruedy, K., Tamborlane, W., Fiallo-Scharer, R. 2004; 6 (5): 559-566


    The GlucoWatch G2 Biographer (GW2B) (Cygnus, Inc., Redwood City, CA) provides near-continuous monitoring of glucose values in near real time. This device is equipped with two types of alarms to detect hypoglycemia. The hypoglycemia alarm is triggered when the current glucose measurement falls below the level set by the user. The "down alert" alarm is triggered when extrapolation of the current glucose trend anticipates hypoglycemia to occur within the next 20 min.We used data from an inpatient accuracy study to assess the performance of these alarms. During a 24-h clinical research center stay, 89 children and adolescents with Type 1 diabetes mellitus (3.5-17.7 years old) wore 174 GW2B devices and had frequent serum glucose determinations during the day and night.Sensitivity to detect hypoglycemia (reference glucose < or = 60 mg/dL) during an insulin-induced hypoglycemia test was 24% with the hypoglycemia alarm alone and 88% when combined with the down alert alarm. Overnight sensitivity from 11 p.m. to 6 a.m. was 23% with the hypoglycemia alarm alone and 77% when combined with the down alert alarm. For 16% of hypoglycemia alarms, the reference glucose was above 70 mg/dL for 30 min before and after the time of the alarm. For the two alarm types combined, the corresponding false-positive rate increased to 62%.The down alert alarm substantially improves the sensitivity of the GW2B to detect hypoglycemia at the price of a large increase in the false alarm rate. The utility of these alarms in the day-to-day management of children with diabetes remains to be determined.

    View details for PubMedID 15628809

  • Severe infantile hypercalcemia associated with Williams syndrome successfully treated with intravenously administered pamidronate PEDIATRICS Cagle, A. P., Waguespack, S. G., Buckingham, B. A., Shankar, R. R., DiMeglio, L. A. 2004; 114 (4): 1091-1095


    Infantile hypercalcemia occurs in approximately 15% of children with Williams syndrome (WS) and is typically not clinically severe. We report on 3 children with WS (confirmed with fluorescent in situ hybridization probes) who presented with severe symptomatic hypercalcemia. The first patient's severe hypercalcemia resolved with traditional therapies, whereas the subsequent 2 patients were treated with intravenously administered pamidronate after traditional measures proved only partially successful. Besides asymptomatic mild hypocalcemia, there were no complications resulting from pamidronate administration. We conclude that WS-associated hypercalcemia can be quite severe and symptomatic and that it can be successfully and safely treated with intravenously administered bisphosphonate in some cases.

    View details for DOI 10.1542/peds.2003-1146-L

    View details for Web of Science ID 000224242200052

    View details for PubMedID 15466114

  • Lack of accuracy of continuous glucose sensors in healthy, nondiabetic children: Results of the Diabetes Research in Children Network (DirecNet) Accuracy study JOURNAL OF PEDIATRICS Mauras, N., Beck, R. W., Ruedy, K. J., KOLLMAN, C., Tamborlane, W. V., Chase, P., Buckingham, B. A., Tsalikian, E., Weinzimer, S. A., Booth, A. D., Xing, D. Y. 2004; 144 (6): 770-775


    The workup of hypoglycemia requires frequent glucose sampling. We designed these studies to determine if the Continuous Glucose Monitoring System (CGMS) and the GlucoWatch G2 Biographer (GW2B) are sufficiently accurate to use in nondiabetic children. Study design Fifteen healthy children (aged 9-17 years, 11 boys) wore a GW2B and a CGMS during a 24-hour period, and reference serum glucose was measured hourly during the day and half-hourly overnight.Compared with the reference glucose, the median absolute difference in concentrations measured by the GW2B (487 pairs) was 13 mg/dL, and the difference measured by the CGMS was 17 mg/dL (668 pairs), with 30% and 42% of values using the GW2B and CGMS, respectively, deviating >20 mg/dL from the reference value. The GW2B reported values <60 mg/dL in 73% of subjects, the CGMS in 60% of subjects. In none of these episodes was serum glucose truly low. Spurious high glucose concentrations also were observed with the sensors. The mean reference glucose was lowest at 5 am (89 mg/dL) and highest at 11:30 pm (106 mg/dL) during the 24-hour period.Neither the CGMS nor the GW2B is accurate enough to establish population standards of the glycemic profile of healthy children and cannot be recommended in the workup of hypoglycemia in nondiabetic youth.

    View details for DOI 10.1016/j.jpeds.2004.03.042

    View details for Web of Science ID 000222047900017

    View details for PubMedID 15192625

  • Initiation of insulin glargine in children and adolescents with type I diabetes PEDIATRIC DIABETES Tan, C. Y., Wilson, D. M., Buckingham, B. 2004; 5 (2): 80-86


    Glargine (Lantus) is a recently approved, long-acting insulin analog that is increasingly being used in children with diabetes. The aim of this retrospective chart review was to summarize our experience in starting glargine in children and adolescents with diabetes. SUBJECTS AND STUDY METHODS: We reviewed the medical records of 71 children with type 1 diabetes (29 boys and 42 girls) who initiated glargine therapy to improve glycemic control between 1 June 2001 and 30 June 2002. Data were collected for 6 months before and 6 months after adding glargine.Subjects' mean age [+/-standard deviation (SD)] at diagnosis of diabetes was 7.5 +/- 4.1 yr. Mean age at initiation of glargine therapy was 11.5 +/- 4.9 yr. The total daily long-acting insulin dose decreased by about 20% after initiating glargine therapy. There were no significant differences in hemoglobin A1c (HbA1c) and blood glucose control prior to and after initiating glargine therapy (HbA1c at baseline 8.9 +/- 1.6% and HbA1c after 6 months of glargine therapy was 8.9 +/- 1.5%). Overall, blood glucose concentrations did not differ significantly throughout the study. Patients who switched to glargine because of nocturnal hypoglycemia had a 65% decrease in nocturnal blood glucose reading less than 50 mg/dL. There were three seizures in the first week after initiating glargine therapy.This retrospective study suggests that glargine is at least as effective as other long-acting insulins but that care must be taken during the conversion process to avoid hypoglycemia.

    View details for Web of Science ID 000223649200004

    View details for PubMedID 15189493

  • Use of the Cygnus GlucoWatch biographer at a diabetes camp PEDIATRICS Gandrud, L. M., Paguntalan, H. U., Van Wyhe, M. M., Kunselman, B. L., Leptien, A. D., Wilson, D. M., Eastman, R. C., Buckingham, B. A. 2004; 113 (1): 108-111


    Detection and prevention of nocturnal hypoglycemia is a major medical concern at diabetes camps.We conducted an open-label trial of the Cygnus GlucoWatch biographer to detect nocturnal hypoglycemia in a diabetes camp, a nonclinical environment with multiple activities.Forty-five campers (7-17 years old) wore a biographer. The biographer was placed on the arm at 6:00 PM, with the low alarm set to 85 mg/dL (4.7 mmol/L). Overnight glucose monitoring occurred per usual camp protocol. Counselors were to check and record blood glucose values if the biographer alarmed.Biographers were worn for 154 nights by 45 campers. After a 3-hour warm-up period, 67% of biographers were calibrated, of which 28% were worn the entire night (12 hours). Thirty-four percent of readings were skipped because of: "data errors" (65%), sweat (20%), and temperature change (16%). Reported biographer values correlated with meter glucose values measured 11 to 20 minutes later (r = 0.90). Of 20 low-glucose alarms with corresponding meter values measured within 20 minutes, there were 10 true-positive alarms, 10 false-positive alarms, and no false-negative alarms. Campers reported sleep disruption 32% of the nights, and 74% found the biographer helpful. Campers reported they would wear the biographer 4 to 5 nights each week.Half of the biographer low-glucose alarms that had corresponding blood meter values were true-positive alarms, and the remaining were false-positive alarms. There was close correlation between the biographer and meter glucose values. The majority of campers found the biographer helpful and would use it at home.

    View details for Web of Science ID 000188010600032

    View details for PubMedID 14702457

  • How should we interpret "real life" conditions. Pediatric diabetes Eastman, R. C., Chase, H. P., Buckingham, B., Hathout, E., Tamada, J., Ginsberg, B. 2003; 4 (1): 59-?

    View details for PubMedID 14655525

  • Analysis: dawn of real-time continuous glucose sensing. Diabetes technology & therapeutics Buckingham, B. 2003; 5 (3): 381-383

    View details for PubMedID 12828821

  • Use of the GlucoWatch biographer in children and adolescents with diabetes. Pediatric diabetes Eastman, R. C., Chase, H. P., Buckingham, B., Hathout, E. H., Fuller-Byk, L., Leptien, A., Van Wyhe, M. M., Davis, T. L., Fermi, S. J., Pechler, H., Sahyun, G., Lopatin, M., Wang, B. Y., Wei, C., Bartkowiak, M., Ginsberg, B. H., Tamada, J. A., Pitzer, K. R. 2002; 3 (3): 127-134


    This study was done to evaluate the accuracy and safety of measuring glucose with the GlucoWatch biographer in children and adolescents with diabetes.Accuracy was assessed by comparing biographer glucose measurements with hourly blood glucose measurements using the HemoCue (Aktiebolaget Leo, Helsingborg, Sweden) Photometer for up to 12 h of monitoring. Safety was evaluated by examining the biographer application sites immediately upon removal of the devices, and then at regular intervals.Sixty-six subjects each wore three biographers at sites including the forearm, upper arm, leg, and torso. For forearm biographers, the mean absolute relative difference between biographer readings and blood glucose was 21%. Ninety-five per cent of biographer readings fell into the A or B regions of the Clarke error grid, and 97.3% into the A or B regions of the consensus error grid. Data from biographers worn at the alternative sites were similar to data from the forearm biographers. Two strong reactions to the adhesive pad of the biographer AutoSensor were observed. Most skin reactions were mild.The GlucoWatch biographer is well tolerated by children and adolescents with diabetes. Performance is similar when the device is worn at different anatomical sites, and is similar to the performance on the forearm, previously reported in adults.

    View details for PubMedID 15016152

  • Cognitive and behavioral characteristics of Turner syndrome: Exploring hormones in female sexual a role for ovarian differentiation HORMONES AND BEHAVIOR Collaer, M. L., Geffner, M. E., Kaufman, F. R., Buckingham, B., Hines, M. 2002; 41 (2): 139-155


    To better understand factors contributing to behavioral development, we studied patients with Turner syndrome (TS), a disorder typically marked by prenatal onset of ovarian dysfunction. We compared girls and women (ages 12 and up) with TS (n = 21) to matched controls (n = 21) in cognitive and motor skills, as well as sex-typed personality characteristics and activity preferences. Measures were categorized (based on prior studies) as showing an average male advantage (male-superior measures), female advantage (female-superior measures), or no sex difference (sex-neutral measures). It was hypothesized that, if gonadal function contributes to behavioral development, effects of this deficiency would be more prominent on sexually differentiated than sex-neutral measures and thus that patient-control differences would be most marked for measures that show sex differences. Our findings indicated that TS patients and controls differed more on cognitive and motor domains that show sex differences than on sex-neutral domains. Patients also had more "undifferentiated" personalities and showed reduced sex-typed interests and activities. Differing experiences, as indexed by interests and activities, did not explain the observed cognitive and motor differences. These results are consistent with a role for ovarian hormones acting on the brain to influence cognitive and behavioral development, although they do not rule out other possible interpretations.

    View details for DOI 10.1006/hbeh.2001.1751

    View details for Web of Science ID 000174171400003

  • Type 1 diabetes mellitus and epilepsia partialis continua in a 6-year-old boy with elevated anti-GAD65 antibodies PEDIATRICS Olson, J. A., Olson, D. M., Sandborg, C., Alexander, S., Buckingham, B. 2002; 109 (3)


    A 6-year-old boy presented with epilepsia partialis continua 6 months after diagnosis of type 1 diabetes. Anti-glutamic acid decarboxylase 65 antibodies were found in his serum and cerebrospinal fluid. Anti-epileptic agents did not improve his seizures. High-dose steroids, plasmapheresis, and intravenous immunoglobulin resulted in decreased anti-glutamic acid decarboxylase 65 antibody levels and resolution of his seizures.

    View details for Web of Science ID 000174202800012

    View details for PubMedID 11875178

  • Familial isolated hypoparathyroidism caused by a mutation in the gene for the transcription factor GCMB JOURNAL OF CLINICAL INVESTIGATION Ding, C. L., Buckingham, B., Levine, M. A. 2001; 108 (8): 1215-1220


    Hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and absent or markedly reduced circulating concentrations of parathyroid hormone. The transcription factor GCMB is predominantly, if not exclusively, expressed in parathyroid cells and is critical for development of the parathyroid glands in mice. Thus, in the present study we examined the GCMB gene, mapped to 6p23-24, as a candidate for isolated hypoparathyroidism. We defined the boundaries of the five exons of the human GCMB gene and then identified a large intragenic mutation in the GCMB genes of the proband of an extensive kindred with isolated hypoparathyroidism. Her parents and several other unaffected relatives were heterozygous for the mutation. Despite an absence of any history of consanguinity, microsatellite analysis showed shared genotypes that flanked the GCMB gene over a span of 5 cM, suggesting that both of the proband's GCMB alleles had been derived from a single common ancestor. Analysis of additional, unrelated cases did not disclose the same mutation. We conclude that homozygous loss of function of the GCMB gene impairs normal parathyroid gland embryology and is responsible for isolated hypoparathyroidism in a subset of patients with this disease.

    View details for Web of Science ID 000171614500016

    View details for PubMedID 11602629

  • Intensive diabetes management in pediatric patients. Current diabetes reports Buckingham, B., Bluck, B., Wilson, D. M. 2001; 1 (1): 11-18


    Intensive diabetes management requires frequent home glucose monitoring, multiple daily insulin injections or chronic subcutaneous insulin infusion, and adjustments of insulin doses in response to changes in blood glucose levels, food intake, and exercise. It also requires a periodic review of previous glucose results to recognize patterns of hyper- or hypoglycemia. The goals of intensive management are age dependent. In young children, avoidance of severe hypoglycemia is the major goal. In older children and adolescents, lowering hemoglobin A(1c) becomes an increasingly important goal. In children of all ages, the ability to have a flexible lifestyle and meal plan is often a priority. This article provides a brief overview of the rationale for implementing intensive diabetes management in pediatric patients, and practical guidelines for implementation.

    View details for PubMedID 12762952

  • Prevention of type 1a diabetes mellitus*. Pediatric diabetes Wilson, D. M., Buckingham, B. 2001; 2 (1): 17-24


    Type 1 diabetes begins with the progressive autoimmune mediated destruction of the insulin-producing beta cells. When sufficient beta cell function is lost, the endocrine phase, characterized by insulin deficiency and hyperglycemia, supervenes. While a genetic predisposition to diabetes is an important precondition, most believe an environmental factor or factors serve as the trigger for initiating this process. In this paper we review trials designed to prevent or delay the clinical onset of diabetes. In these studies, high-risk individuals are identified by their genetic predisposition to diabetes, and/or by the presence of immune markers indicating activation of the autoimmune process directed against islet cells. The Deutsche Nicotinamide Intervention Study (DENIS) randomized 55 high-risk subjects to either nicotinamide or placebo and found no significant benefit. The European Nicotinamide Diabetes Intervention Trial (ENDIT) completed enrollment in May 1998. ENDIT screened over 40 000 relatives, randomizing 552 to either nicotinamide or placebo. Results are expected in May of 2003. Designed to test if avoidance of cow's milk in infancy will decrease the incidence of diabetes, the Trial to Reduce Type I Diabetes in the Genetically at Risk (TRIGR). High-risk infants are randomly assigned to different supplemental formulas in the first 6 months of life. Initial results suggest that removing cow's milk has a protective effect. The ongoing, NIH funded, multicenter Diabetes Prevention Trial-Type 1 (DPT-1) is testing two antigen-based (insulin) interventions in relatives at high risk for diabetes. Now in its sixth year, the DPT-1 study group has screened over 84,000 individuals. As of November 2000, 339 subjects have been randomized in the parenteral insulin study, completing the enrollment phase. Enrollment continues in the oral insulin study. Results of this trial are not yet available. Different epitopes of insulin and its analogs, monoclonal antibodies, and cytokine-based therapy, among others, have all been proposed as potential new interventional agents. While a great deal of effort will be required to test these approaches, the potential benefits of prevention justify these research efforts.

    View details for PubMedID 15016206

  • A randomized trial of methotrexate in newly diagnosed patients with type 1 diabetes mellitus CLINICAL IMMUNOLOGY Buckingham, B. A., Sandborg, C. I. 2000; 96 (2): 86-90


    The aim of this study was to determine whether low-dose, oral methotrexate therapy would prolong the remission phase at the onset of Type 1 diabetes. Ten newly diagnosed, nonacidotic, ICA-positive, Type 1 diabetics were randomly assigned to receive either methotrexate (5 mg/m(2)/week) or no immunosuppressive treatment. The study was not blinded and no placebo was given. Endogenous insulin production was assessed every 3 months by fasting and Sustacal-stimulated C-peptide levels. Methotrexate therapy was not beneficial in prolonging islet survival as assessed by fasting and stimulated C-peptide levels. Insulin requirements were generally lower in the control group, and islet failure, determined by an insulin requirement of >0.7 u/kg/day, occurred earlier for those receiving MTX (P < 0.02). Side effects of methotrexate treatment were minimal. There was no benefit from methotrexate therapy, and methotrexate therapy was associated with an earlier increase in insulin requirements.

    View details for DOI 10.1006/clim.2000.4882

    View details for Web of Science ID 000088615500003

    View details for PubMedID 10900154

  • Decreased IL-4 production in new onset type I insulin-dependent diabetes mellitus JOURNAL OF IMMUNOLOGY Berman, M. A., Sandborg, C. I., Wang, Z. S., Imfeld, K. L., Zaldivar, F., Dadufalza, V., Buckingham, B. A. 1996; 157 (10): 4690-4696


    IL-4 has been shown to protect against diabetes development in rodent models of insulin-dependent (type I) diabetes mellitus (IDDM). To study IL-4 production in human IDDM, PBMC from IDDM patients and controls were stimulated in vitro with PHA, anti-CD3 mAb, or PMA and ionophore. IL-4 production by PBMC or T cells was strongly impaired in IDDM patients at diabetes onset (p < 0.0001). The mean IL-4 response of patients in the honeymoon stage was higher than the mean of the new onset patients, but significantly lower than the control group (p = 0.01). Patients with IDDM of longer duration (>2 yr) showed a wide range of IL-4 responses and their mean IL-4 response was lower than the controls; however, the difference was not statistically significant. IL-4 mRNA levels were measured using competitive reverse transcription PCR. The results showed greatly reduced mRNA levels in new onset IDDM. In contrast, IL-1 production (measured by ELISA) and IFN-gamma mRNA (measured by reverse transcription PCR) were not significantly different in IDDM. The results suggest an imbalance of inflammatory vs anti-inflammatory cytokine production at the onset of IDDM. Deficient IL-4 production as seen at the onset of IDDM may play a role in the development of diabetes by allowing the inflammatory/autoimmune process in pancreatic islets to progress.

    View details for Web of Science ID A1996VR79300053

    View details for PubMedID 8906850

  • Self-care behaviors in insulin-dependent diabetes: Evaluative tools and their associations with glycemic control JOURNAL OF PEDIATRIC PSYCHOLOGY Hanson, C. L., DEGUIRE, M. J., SCHINKEL, A. M., Kolterman, O. G., Goodman, J. P., Buckingham, B. A. 1996; 21 (4): 467-482


    Clarified the relationships between self-care behaviors and illness-specific outcomes in approximately 270 youths with IDDM. Youths were assessed at three points in time using a semistructured interview measure and multiple indices of dietary intake and physical activity with two different methodologies (i.e., recalls, logs). Glycemic control was most strongly related to the semistructured Self-Care Adherence Interview (SCAI); and second to the overall quality of the youth's dietary intake. The SCAI also predicted glycemic control over time. Physical activity levels and specific nutritional components from the logs and recalls were generally unrelated to glycemic control.

    View details for Web of Science ID A1996UZ76000001

    View details for PubMedID 8863457



    Congenial lipoid adrenal hyperplasia (lipoid CAH) is the most severe form of CAH. Affected individuals can make no adrenal or gonadal steroids. All affected individuals are phenotypic females irrespective of gonadal sex, and frequently die in infancy if mineralocorticoid and glucocorticoid replacements are not instituted. Recent data implicate the steroidogenic acute regulatory (StAR) protein in this disorder. We now describe a 46,XY patient of Vietnamese ancestry with lipoid CAH who had a somewhat milder form of the disease. Diagnosis was at 10 weeks of age, and low levels of plasma progesterone, corticosterone, 180H-corticosterone and androstenedione were detectable. Testicular RNA for StAR was reverse transcribed, amplified, cloned and sequenced, revealing a 185 bp deletion corresponding to all of exon 5. The corresponding mRNA did not encode active protein in transfected cells. Cloned genomic DNA from the patient revealed only a T-->A transversion in intron 4,11 bp from the splice acceptor site of exon 5. This transversion destroys an NcoI site; digestion of PCR-amplified genomic DNA from the patient and both parents confirmed that the patient was homozygous and the parents were heterozygous. Expression vectors for StAR minigenes were constructed containing all StAR exons plus introns 4, 5 and 6 either with or without the T-->A mutation in intron 4. RNase protection assays showed that expression of the vector with normal intron 4 yielded correctly spliced StAR mRNA in transfected COS-1 cells, while most, but not all StAR mRNA from the vector with the T-->A transversion in intron 4 was abnormally spliced. RNase protection of the patient's testicular RNA confirmed that most, but not all StAR mRNA was similarly spliced abnormally. Splicing errors appear to be a rare cause of genetic diseases, but subtle intronic mutations may be missed when genomic DNA is the only material available for study. The low level of normal StAR mRNA produced may account for the later clinical presentation and low levels of steroid hormones detected in this patient.

    View details for Web of Science ID A1995TK36300016

    View details for PubMedID 8634702

  • IL-4 EXPRESSION IN HUMAN T-CELLS IS SELECTIVELY INHIBITED BY IL-1-ALPHA AND IL-1-BETA JOURNAL OF IMMUNOLOGY Sandborg, C. I., Imfeld, K. L., Zaldivar, F., Wang, Z. S., Buckingham, B. A., Berman, M. A. 1995; 155 (11): 5206-5212


    Imbalances in anti-inflammatory and proinflammatory cytokines may be responsible for initiation or progression of diverse pathologic states including autoimmune and infectious diseases. IL-4 production of proinflammatory cytokines and IL-12 promotes differentiation and activation of IFN-gamma-producing T cells, but does a counter-regulatory effect of proinflammatory cytokines on IL-4 production exist? This study evaluates the effect of proinflammatory cytokines (IL-1 alpha, IL-1 beta, IL-6, IL-12, and TNF-alpha) on IL-4 production in primary human T cell cultures. PBMCs from healthy individuals were tested for IL-4 production in response to PHA and various cytokines. IL-4 was measured by proliferation of the IL-4-sensitive T cell line (CT.h4S) or ELISA. IL-1 alpha and IL-1 beta inhibited IL-4 production by 20 to 80% in > 92% of healthy individuals (p = 0.0001, paired t-test). IL-12 had an inhibitory effect on PBMC IL-4 production as previously described, but neither IL-6 nor TNF-alpha inhibited IL-4 production. IL-1 had no effect on PHA-induced PBMC or purified T cell proliferation or IL-2 production. IL-4 production by purified T cells stimulated by PHA or the combination of PMA with calcium ionophore (A23187) was inhibited by IL-1, and reconstitution with peripheral blood-derived adherent macrophages had no effect. IL-12 did not inhibit IL-4 production in stimulated purified T cells. Steady state IL-4 mRNA levels were determined by semiquantitative competitive reverse transcribed PCR (RT-PCR). Marked inhibition of IL-4 mRNA levels were seen at 5 h after exposure to IL-1. This interaction between IL-1 and IL-4 may be an important physiologic regulator of the balance between proinflammatory cytokines from activated macrophages and anti-inflammatory cytokines from T cells.

    View details for Web of Science ID A1995TF68600016

    View details for PubMedID 7594531



    Vitreous changes in diabetes can exacerbate proliferative diabetic retinopathy. These changes may be due to the effects of diabetes on vitreous collagen. Vitreous samples from 19 patients with proliferative diabetic retinopathy and 23 patients without diabetes were analyzed for collagen crosslinks, as well as for the early glycation products, glucitolyllysine and glucitolylhydroxylysine. Fluorometry was performed to measure advanced glycation end products. Vitreous collagen derived from diabetic patients was found to have significantly higher levels of the crosslink dihydroxylysinonorleucine (3.15 vs 1.24 mol/mol collagen, P<.01) than that of control subjects. Early glycation products were elevated in diabetic vitreous (1.65 vs 0.54 mol/mol collagen, P<.05). Levels of advanced glycation end products were 20 times higher in diabetic vitreous compared with the vitreous of controls. These diabetes-induced alterations of human vitreous may be of particular importance given the role of vitreous in proliferative diabetic retinopathy and vision loss.

    View details for Web of Science ID A1992JT34900029

    View details for PubMedID 1417549



    Earlier studies have shown direct effects of interleukin-1 (IL-1) on isolated pancreatic islets. Coculture of isolated rat pancreatic islets with human rIL-1 beta for 6 days resulted in dose-dependent cytotoxicity (up to 100%) and suppression of insulin secretion (up to 88.5%). The cytotoxic effects of rIL-1 beta beta were blocked by the simultaneous presence of a naturally occurring 6-9-kilodalton (kDa) inhibitor of IL-1-induced T-cell proliferation. However, the ability of rIL-1 beta to suppress insulin secretion was not blocked by the 6-9-kDa inhibitor of IL-1 activity. This IL-1 inhibitor is produced by mononuclear cells and is resistant to pH 2, sensitive to heating at 56 degrees C for 30 min, has a pI of 4.5-5.6, and appears to be different from other recognized IL-1 inhibitors in both composition and mechanism of action. Unlike this IL-1 inhibitor, a monoclonal antibody specific for rIL-1 beta was able to neutralize both the islet cytotoxic and insulin modulatory effects of rIL-1 beta. These results demonstrate the use of an IL-1 inhibitor to prevent at least one mechanism of islet destruction, and suggest separate pathways for IL-1 mediated islet cytotoxicity and suppression of insulin secretion.

    View details for Web of Science ID A1991FM89500004

    View details for PubMedID 1868042



    We assessed the heterogeneity in the islet cell cytoplasmic antibody (ICA) response of insulin-dependent diabetes mellitus (IDDM) patients via indirect immunofluorescence on frozen sections of human, bovine, and porcine pancreas. The three substrates detected comparable frequencies of ICA positives among the IDDM sera tested, whereas control sera were ICA negative on all three substrates. However, individual IDDM serum samples showed heterogeneity in ICA binding on the three pancreata. Of 28 sera tested on all three substrates, 22 were ICA positive on human pancreas, three were ICA positive on bovine pancreas, and two were ICA positive on porcine pancreas. Sensitivity of ICA epitopes to neuraminidase treatment and periodate oxidation suggests that glycoconjugates are recognized by serum ICA. Cholera toxin blocked ICA binding. However, the functional cholera toxin receptor ganglioside Gm1 is resistant to neuraminidase treatment and periodate oxidation. Therefore, it is unlikely that Gm1 is the ICA determinant. These data suggest that not all ICA antigens are equivalently expressed on islets from different pancreata and/or that each individual responds to a hierarchy of islet antigens such that restricted patterns of specific ICA binding are found.

    View details for Web of Science ID A1990EE50500003

    View details for PubMedID 1704123



    Many abnormalities in collagen have been reported in insulin-dependent diabetes mellitus, some or all of which have been attributed to increased cross-linking. Although recent work has focused on the role of glucose-derived collagen cross-links in the pathogenesis of diabetic complications, relatively few studies have investigated the role of lysyl oxidase-dependent (LOX) cross-links. In the present study, LOX cross-links and nonenzymatic glycosylation were quantified in skin collagen from diabetic subjects. There was an increase in the difunctional cross-link dihydroxylysinonorleucine (DHLNL) as well as in one of its trifunctional maturation products, hydroxypyridinium. All other LOX crosslinks were normal. Nonenzymatic glycosylation was increased in diabetic skin collagen, and this increase was correlated with increases in DHLNL (P less than 0.001). The biochemical results were examined for correlations with clinical data from the same subjects. Increases in DHLNL content were associated with duration of diabetes (P less than 0.003), glycohemoglobin levels (P less than 0.001), hand contractures (P less than 0.05), skin changes (P less than 0.005), and microalbuminuria (P less than 0.01). In nondiabetic subjects age was not correlated with collagen cross-link content with the exception that his-HLNL increased with age (r = 0.79, P less than 0.02). In diabetic subjects, PA levels decreased with age (r = 0.51, P less than 0.02). With increased duration of diabetes, DHLNL content was increased (r = 0.55, P less than 0.003) and OHP was increased (r = 0.59, P less than 0.01), whereas PA levels were decreased (r = -0.48, P less than 0.04). Nonenzymatic glycosylation of collagen was also increased with increased duration of diabetes (hex-lys, r = 0.47, P less than 0.02; hex-hyl, r = 0.39, P less than 0.05). We conclude that: (a) lysyl oxidase-dependent cross-linking is increased in skin collagen in diabetes and (b) that these changes in skin collagen are correlated with duration of diabetes, glycemic control, and long-term complications.

    View details for Web of Science ID A1990EE19900005

    View details for PubMedID 1976653



    Severe neonatal hypoglycemia due to nesidioblastosis demands prompt diagnosis and treatment to prevent mental retardation. Early central venous catheter placement is essential for a constant glucose infusion. At surgery, near-total (95%) pancreatectomy is done, starting at the tail and preserving the spleen. Bipolar electrocoagulation is very useful for the tiny vessels. The uncinate process is removed leaving a small amount of pancreas adjacent to the preserved common bile duct. Three patients, diagnosed shortly after birth, had surgery at 34 days, 2 years, and 17 days of life. Two patients developed staphylococcal infections, one of whom exhibited the "scalded baby" syndrome and required reoperation for evisceration. Insulin was required for one to seven days in two and for three months in one. Diazoxide was needed for 18 months in the initial patient, who did not have uncinate resection. All patients are healthy and off medication with a postoperative follow-up period of 11, 12, and 65 months.

    View details for Web of Science ID A1988N446800018

    View details for PubMedID 2837563

  • INTERFERON RESPONSIVENESS OF NATURAL-KILLER CELLS IN TYPE-I HUMAN DIABETES DIABETES RESEARCH CLINICAL AND EXPERIMENTAL Negishi, K., Gupta, S., Chandy, K. G., Waldeck, N., Kershnar, A., Buckingham, B., Charles, M. A. 1988; 7 (1): 49-52


    Abnormally low circulating numbers and function of NK cells are associated with new onset type I diabetes. Since alpha interferon is a stimulator of NK function, enriched T and non-T lymphocytes were incubated with 0, 100 and 1,000 units/ml of recombinant alpha interferon (rIFN alpha) and natural killing against K562 and pancreatic islet cell targets was measured. The killing of K562 (1:20 target:effector ratio) cells by non-T cells incubated with 0, 100 and 1,000 units/ml of rIFN alpha in patients was decreased to 27% (p less than 0.014 vs control), 34% (p less than 0.001) and 39% (p less than 0.003) when compared to killing by normal control non-T cells (48%, 74% and 58% respectively). T cell mediated killing of K562 cells in patients was decreased to 3.9% (p less than 0.03), 5.3% and 6.6% (p less than 0.003) when compared to that of controls (8.7%, 10-8% and 22.6% respectively). Non-T cell mediated killing of islet cells (1:20 target:effector ratio) following treatment of effector cells with 0, 100 and 1,000 units/ml of rIFN alpha in patients was 19%, 27%, and 26% which was comparable to control subjects killing of 31%, 18% and 37% respectively. Similar data were obtained using T-cells as effectors. These data indicate that in new onset type I diabetes; (a) NK cell functional activity is diminished in both T and non-T lymphocyte subpopulations and (b) NK activity is suboptimally enhanced with rIFN alpha.

    View details for Web of Science ID A1988N469200008

    View details for PubMedID 3402165

  • NATURAL-KILLER-CELL AND ISLET KILLER-CELL ACTIVITIES IN HUMAN TYPE-1 DIABETES EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY Negishi, K., Waldeck, N., Chandy, G., Buckingham, B., Kershnar, A., Fisher, L., Gupta, S., Charles, A. M. 1987; 89 (3): 345-353


    Peripheral blood mononuclear cells from 14 type 1 diabetic patients were examined for natural killer cell activity using the K562 cell line as 51Cr labeled targets. Mean cytotoxicity of K562 cells by unseparated mononuclear cells derived from new onset type 1 patients (12 +/- 1.6%) was lower (P less than .01) than that observed in non diabetic controls, (25 +/- 4.2%). Mean natural killer cell cytotoxicity mediated by enriched non-T cells from patients (41 +/- 5.8%) was also lower (P less than 0.03) than in the control group (56 +/- 3.7%). Specificity of these findings was evaluated by also examining other diabetic patient subgroups. Mean non T cell mediated natural killer cell activity in type 2 diabetic patients and type 1 patients with long term disease was 65 +/- 5.4% and 62 +/- 4.8% respectively (p less than 0.001 vs new onset type 1 patients). Longitudinal studies of new onset type 1 patients during the remission (honeymoon) phase revealed no improvement of impaired natural killer cell activity. In 30 new onset and 11 remission diabetic patients, mean non-T cell-mediated cytotoxicity was also measured using dispersed 51Cr labeled pancreatic islet target cells. Mean islet cytotoxicity mediated by cells from new onset patients was 34 +/- 2.4%, whereas in nondiabetic control subjects mean cytotoxicity was 25 +/- 1.8% (p less than 0.005). During remission, islet cytotoxicity returned to normal values in over half of the patients. There was no correlation between K562 and islet cell cytotoxicity in either of the latter two patient groups.(ABSTRACT TRUNCATED AT 250 WORDS)

    View details for Web of Science ID A1987K252900017

    View details for PubMedID 3311777

  • NATURAL-KILLER-CELL AND ISLET KILLER-CELL ACTIVITIES IN TYPE-1 (INSULIN-DEPENDENT) DIABETES DIABETOLOGIA Negishi, K., Waldeck, N., Chandy, G., Buckingham, B., Kershnar, A., Fisher, L., Gupta, S., Charles, M. A. 1986; 29 (6): 352-357


    Peripheral blood mononuclear cells from 20 Type 1 (insulin-dependent) diabetic patients were examined for natural killer cell activity using the K562 cell line as 51Cr labeled targets. Mean natural killer cell cytotoxicity mediated by enriched non-T cells from patients (37 +/- 4.0%) was lower (p less than 0.03) than in controls (56 +/- 3.7%). Specificity was evaluated by examining other patient subgroups. Mean non-T cell mediated natural killer cell activity in Type 2 (non-insulin-dependent) diabetic patients and Type 1 patients with long term disease was 65 +/- 5.4% and 62 +/- 4.8% respectively (p less than 0.003 vs new onset Type 1 patients). Longitudinal studies of new onset Type 1 patients during the remission (honeymoon) phase revealed persistently impaired natural killer cell activity in 3 of 4 patients. In 30 new onset and 11 remission Type 1 diabetic patients, mean non-T cell-mediated cytotoxicity was also measured using dispersed 51Cr labeled islet target cells. Mean islet cytotoxicity mediated by cells from new onset patients was 34 +/- 2.4%, whereas in non-diabetic control subjects mean cytotoxicity was 25 +/- 1.8% (p less than 0.005). During remission, islet cytotoxicity remained at similar or elevated levels in most patients. In patients evaluated simultaneously for K562 and islet cell cytotoxicity, natural killer cell activity was decreased, whereas islet killing was increased. These results suggest a dichotomy in natural killer cell and islet killer cell activities in new onset Type 1 diabetes that could have an important role in the pathogenesis of Type diabetes.

    View details for Web of Science ID A1986D148400002

    View details for PubMedID 3527835



    Peripheral blood mononuclear cells from patients with Type 1 diabetes mellitus were examined for the proportion of monoclonal antibody-defined T-cell subsets, natural killer (NK) cells, and macrophages and the proliferative response to phytohemagglutinin (PHA), Concanavalin A (Con A), pokeweed mitogen (PWM) and in the autologous mixed lymphocyte reaction (AMLR) and allogeneic mixed lymphocyte reaction (MLR). The in vitro response of purified IL-2 on PHA- and PWM-induced proliferative response was also examined. Total T cells (Leu 1+), helper/inducer phenotype (Leu 3+) T cells, suppressor/cytotoxic phenotype (Leu 2+) T cells, surface Ig+ B lymphocytes and monoclonal antibody-defined monocytes (Mac +) in patient group were comparable to the control group. The Leu 7+ NK cells were, however significantly (p less than 0.05) decreased in the diabetic group. The NK function was also deficient in the diabetic group when compared to healthy non-diabetic controls. The proliferative responses to all 3 concentrations of PHA, PWM, and Con A, and in the MLR were similar in 2 groups. However, the proliferative response in the AMLR was significantly reduced (p less than 0.05) in the diabetic group. Exogenous purified IL-2 failed to induce any enhancement in the PHA- and PWM-induced proliferative response; this was in contrast to control group in which IL-2 enhanced proliferative response to both mitogens. This study demonstrates deficiency of the AMLR, Leu 7+ and of natural killer cell function and unresponsiveness of mitogen-activated T cells to purified IL-2. The significance of these findings is discussed.

    View details for Web of Science ID A1986D364800001

    View details for PubMedID 2943547



    Three hundred seventy-five patients with diabetes mellitus were examined for the presence of sclerodermalike skin changes, limited joint mobility, and vital capacity changes. Nineteen percent of patients had vital capacities 2 SDs below the mean of predicted values. There was no significant relationship between decreased vital capacities and duration of diabetes, sclerodermalike skin changes, limited joint mobility, smoking history, proteinuria, or retinopathy. Cutaneous involvement consisting of thickening, tightening, and/or a waxy quality of the skin was noted in 190 patients (51%). The severity of skin involvement correlated positively with the patients' duration of diabetes, age, severity of joint contractures, and diabetic retinopathy. Thus, sclerodermalike skin changes appear to reflect generalized connective tissue alterations in diabetes and may indicate increased risk for diabetic microvascular complications.

    View details for Web of Science ID A1986C085200017

    View details for PubMedID 3962933

  • COMPLEMENT ACTIVATION IN TYPE-1 HUMAN DIABETES CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY Sundsmo, J. S., PAPIN, R. A., Wood, L., Hirani, S., Waldeck, N., Buckingham, B., Kershnar, A., Ascher, M., Charles, M. A. 1985; 35 (2): 211-225


    Complement activation was quantitated in serum and plasma of diabetic and normal subjects by sensitive competitive equilibrium radioimmunoassays (RIA) for C3a, C4a, C5a, Factor B, and a newly described C5 neoantigen (termed C5 activation antigen, and abbreviated C5-AA) in a stable 54-kDa fragment of C5. Plasma C3a levels were significantly elevated in 8 of 16 patients with newly diagnosed Type 1 diabetes (P less than 0.0005) with the mean C3a concentration for these patients being more than 10-times greater than the mean value of normal controls. C4a levels were also elevated in 2 of these patients (P less than 0.02), but C5a levels, although higher than normal, were not significantly increased. In contrast, the levels of C5-AA in the serum of all patients (11/11) with chronic Type 1 diabetes were significantly higher than in control Type 2 patients (noninsulin-dependent diabetes) (P less than 0.0005) and 4 of 7 patients with new onset insulin-dependent diabetes mellitus also had significantly higher levels of C5-AA than the Type 2 patients (P less than 0.01). The levels of Factor B in the serum of 5 of 9 patients with new onset diabetes were significantly higher than normal (P less than 0.0025). Five recent onset Type 1 diabetes patients were evaluated longitudinally for C3a, C4a, and C5a: in 3 the levels of C3a were elevated during new onset disease decreasing into the normal range during remission; in 2 of these patients C4a was also significantly elevated and the levels decreased during remission; and in 3 patients the levels of C5a were not significantly elevated but they decreased during remission. Purified human complement proteins and complement hemolytic assays were used to measure complement activation in serum during incubation with rat pancreatic islet cells. With diluted normal human serum, less than 20% of C3 or Factor B were consumed during 30 min at 37 degrees C, while with new onset Type 1 diabetic patient sera up to 90% of C3 and Factor B were consumed in 5/6 sera and 4/6 sera, respectively. These findings suggest (a) that complement activation fragments C3a, C4a, and C5a are generated in vivo in new onset Type 1 diabetes; (b) that both the classical and the alternative complement pathways may be activated; and (c) that this may result in a measurable activation of C5 generating biologically and immunologically active C5a and other C5 activation fragments.(ABSTRACT TRUNCATED AT 400 WORDS)

    View details for Web of Science ID A1985AFY6200008

    View details for PubMedID 3907907



    The autologous mixed lymphocyte response (AMLR) and the allogeneic mixed lymphocyte response were deficient in a subset of patients with newly diagnosed insulin-dependent diabetes mellitus (IDDM). Using a single set of HLA-identical twins, the cellular and molecular basis of deficient AMLR was investigated and appears to be due to a defect in both responder T cells and stimulator non-T cells. Interleukin-2 production was diminished in the patient but not in the healthy twin. The in vitro addition of purified interleukin-2 enhanced the depressed AMLR in the diseased twin. This suggests that the deficient AMLR in IDDM may be in part due to a deficiency in the production of interleukin-2.

    View details for Web of Science ID A1984TV30600002

    View details for PubMedID 6239872

  • SCLERODERMA-LIKE CHANGES IN INSULIN-DEPENDENT DIABETES-MELLITUS - CLINICAL AND BIOCHEMICAL-STUDIES DIABETES CARE Buckingham, B. A., UITTO, J., Sandborg, C., Keens, T., Roe, T., Costin, G., KAUFMAN, F., Bernstein, B., Landing, B., Castellano, A. 1984; 7 (2): 163-169


    Children with insulin-dependent diabetes mellitus (IDDM) were examined for scleroderma-like changes of digital sclerosis and joint contractures. Of the 104 patients, 19 (18%) demonstrated these features; five patients had both multiple joint involvement and skin changes; three were studied in detail. All three had restrictive pulmonary disease. Histopathology of skin in these three patients demonstrated increased accumulation of collagen in the lower dermis. In two of the patients, the extractability of collagen in 0.5 N acetic acid was decreased by about 50% as compared with normal controls, which suggests increased cross-linkage of collagen. In addition, the mean nonenzymatic glycosylation of collagen in these three patients was 13 times that of controls. The results indicate that distinct histopathologic and biochemical changes can be detected in the skin of these patients. The results further support the hypothesis that nonenzymatic glycosylation may alter the turnover of collagen, thus contributing to the development of a scleroderma-like syndrome with skin, joint, and pulmonary findings in patients with IDDM.

    View details for Web of Science ID A1984SN20800012

    View details for PubMedID 6734383

  • IMMUNOLOGICAL EVENTS IN NEW ONSET DIABETES BIOMEDICA BIOCHIMICA ACTA CHARLES, M., Suzuki, M., SUNDSMO, J., Waldeck, N., Negishi, K., Slater, L., Ong, K., Buckingham, B., Kershnar, A. 1984; 43 (5): 615-619


    Data from our laboratory are reviewed showing that both cell-mediated cytotoxicity, complement-dependent antibody-mediated cytotoxicity, antibody-dependent cellular cytotoxicity, and complement-augmented antibody-dependent cellular cytotoxicity may provide mechanisms which kill pancreatic islets during pathogenesis of insulin-dependent (type I) diabetes. Xenogenic test systems employing dispersed rat islet target cells were employed. Most of the findings were reversible during clinical remission of diabetes.

    View details for Web of Science ID A1984TA00700010

    View details for PubMedID 6383365



    Peripheral blood from 11 newly diagnosed patients with insulin-dependent diabetes mellitus (IDDM) was studied for the proportion of monoclonal antibody (HNK 1, Leu 7) defined natural killer (NK) cells using a fluorescence-activated cell sorter analyzer. The proportion of Leu 7+ cells in patients with IDDM (7.0 +/- 4.0) was significantly (P less than 0.001) lower than in simultaneously studied healthy controls (16.8 +/- 7.0). A 2-yr-old boy with recent onset IDDM had a deficiency of Leu 7+ NK cells (6.1%), while his healthy identical twin had normal proportions of Leu 7+ cells (22.2%), when compared to a simultaneously studied healthy control. Two patients reexamined in remission and one other studied in remission alone, showed deficiency of Leu 7+ NK cells. This study demonstrates a quantitative deficiency of monoclonal antibody (Leu 7+) defined NK cells in newly diagnosed patients with IDDM that persists during remission of the disease and therefore appears to be independent of metabolic abnormality. The deficiency of NK cells may predispose genetically susceptible individuals to viral-induced islet cell injury, contributing to the pathogenesis of IDDM.

    View details for Web of Science ID A1984TA79600007

    View details for PubMedID 6746020



    Because immune mechanisms are associated with insulin-dependent diabetes, multiple organ specific and xenogeneic cytotoxicity assays were developed. Human cellular and antibody effector systems were incubated with 51Cr-labeled dispersed normal rat islet target cells. In eight of 11 diabetic patients, nonenriched mononuclear cells incubated with islet target cells were more cytotoxic than cells from age- and sex-matched controls (p less than 0.01). When non-T cell-enriched mononuclear cells were used at diabetes onset, seven of 11 patients' cells showed excessive islet cytotoxicity (p less than 0.05). In four patients showing elevated cytotoxicity at diabetes onset, cytotoxicity decreased to control levels during diabetes remission. Islet specificity was suggested in that mononuclear cells derived from diabetic subjects did not mediate cytotoxicity against rat spleen or macrophage target cells. Three cytotoxic antibody mechanisms were also evaluated. C-dependent antibody-mediated cytotoxicity with the use of patient serum-coated islet target cells was elevated above control levels in four of 14 patients. Antibody-dependent cellular cytotoxicity exceeded control values in only two of 16 patients, although four assay systems were evaluated. C-augmented antibody-dependent cellular cytotoxicity was elevated in three of 14 patients. No differences were observed for antibody-mediated mechanisms in four patients evaluated at both diabetes onset and remission. Cytotoxic antibody was present in only about one-half of the patients showing increased cellular cytotoxicity, whereas most patients expressing increased cytotoxic antibody had cellular cytotoxicity. Islet cell cytotoxicity assays with the use of effector systems from patients with recent onset insulin-dependent diabetes suggest that direct cellular cytotoxicity is more active than antibody-mediated cytotoxic mechanisms, and that cellular cytotoxicity can correlate with disease activity.

    View details for Web of Science ID A1983QC72100033

    View details for PubMedID 6337213



    The results of medical and surgical therapy were determined in 107 hyperthyroid children. After surgery, 85% of patients were rendered free of hyperthyroidism; however, 62% became hypothyroid. After medical treatment, 30% of patients were euthyroid and 2% became hypothyroid. The relapse rate, however, was higher after medical (22%) than after surgical (9%) therapy. Serious drug-related complications (arthritis-, hepatitis-, and collagen disease-like syndromes) occurred in 14% of patients. Complications occurred in 9% of surgically treated patients, but recurrent laryngeal nerve injury or permanent hypoparathyroidism did not occur. In medically treated patients, both a goiter size less than three times normal prior to treatment and a reduction in goiter size to less than two times normal at the completion of therapy correlated with a successful outcome.

    View details for Web of Science ID A1981LC02800003

    View details for PubMedID 7468542


    View details for Web of Science ID A1981LN88700006

    View details for PubMedID 7012624



    A 2-year-old boy became ill with diabetic ketoacidosis complicated by severe rhabdomyolysis. He completely recovered from the rhabdomyolysis, but has persistent insulin-dependent diabetes mellitus (IDDM). Serological studies showed that the patient's serum contained high titers of coxsackievirus B4 antibody, suggesting that the development of rhabdomyolysis and IDDM may have been related to this infection. A review of the records of 133 patients admitted with onset of IDDM disclosed one additional patient with marked myoglobinuria, and 11 patients with orthotolidine-positive urine in the absence of hematuria. These findings suggest that myoglobinuria may not be uncommon at the onset of IDDM.

    View details for Web of Science ID A1981LL30700013

    View details for PubMedID 6782859

  • THYROIDECTOMY FOR HYPERTHYRODISM IN CHILDREN JOURNAL OF PEDIATRIC SURGERY Andrassy, R. J., Buckingham, B. A., Weitzman, J. J. 1980; 15 (4): 501-504


    Between November 1964 and August 1978, 66 patients underwent subtotal thyroidectomy for hyperthyroidism. Fifty-seven of these patients have been followed for more than 2 yr postoperatively and form the basis for this report. The mean age of these patients was 11 7/12 yr. There wre no deaths in this series and no recurrent laryngeal nerve injuries. Hyperthyroidism recurred in 4 patients from 10 to 60 mo following surgery (mean of 30 mo). Patients with relapse had a significantly larger gland at operation, but no difference in estimated thyroid remnant. Those patients with larger glands at exploration need a relatively larger percentage of the gland removed to prevent recurrent hyperthyroidism.

    View details for Web of Science ID A1980KD65400024

    View details for PubMedID 7411364

  • THYROID-FUNCTION IN CHILDREN WITH CHRONIC RENAL-FAILURE NEPHRON Wassner, S. J., Buckingham, B. A., KERSHNAR, A. J., MALEKZADEH, M. H., Pennisi, A. J., Fine, R. N. 1977; 19 (4): 236-241


    Thyroid function was evaluated in 24 children (aged 4-18 years) with chronic renal failure either before institution of hemodialysis or after more than 3 months of hemodialysis. 22 patients were clinically euthyroid and 2 were hypothyroid; in one case hypothyroidism was secondary to cystinosis and in the other it followed radiation therapy. The 2 hypothyroid patients had subnormal levels of T4, T3, FTI and FT4 as well as elevated serum TSH levels. Mean values for T4, T3, FTI and FT4 for the remaining 22 patients were within the normal range, but were significantly decreased, (all p values less than 0.01) when compared to controls. TSH and TBG levels were not significantly different from those of the normal population. Eleven of the euthyroid patients (50%) had either T3 or FT4, but not both, below the normal range without elevation of their TSH levels. These findings suggest that in the absence of other causes of hypothyroidism, children with chronic renal failure are able to maintain a clinically euthyroid state with either normal FT4 or T3 serum levels and can respond to primary gland failure with elevated TSH secretion.

    View details for Web of Science ID A1977DW21800009

    View details for PubMedID 917171

  • SURGICAL TREATMENT OF HYPERTHYROIDISM IN CHILDREN SURGERY GYNECOLOGY & OBSTETRICS Wesley, J. R., Buckingham, B. A., GAHR, J. A., Isaacs, H., KOGUT, M. D., Weitzman, J. J. 1977; 145 (3): 343-346


    During the past ten years, subtotal thyroidectomy for hyperthyroidism was performed upon 43 children at Childrens Hospital of Los Angeles. There were no deaths, no recurrent laryngeal nerve injuries and no permanent hypoparathyroidism. During the one to ten year follow-up period, one patient had recurrent hyperthyroidism develop and was treated with 131I. Twenty-five patients are hypothyroid and require thyroid supplement; 14 are euthyroid and receiv no medication. Postoperative thyroid function did not correlate well with gland remnant size, degree of fibrosis or the extent of lymphoid follicle formation. Lymphocytic infiltration was more severe in patients who had hypothyroidism develop postoperatively. Transient hypocalcemia developed in 22 patients. The effectiveness and safety of the surgical treatment for hyperthyroidism in children is reaffirmed, and it is advocated for consideration over 131I or prolonged medical therapy.

    View details for Web of Science ID A1977DT66200005

    View details for PubMedID 888053

  • PATHOLOGIC AND IMMUNE FACTORS IN THYROID DISEASE JOURNAL OF PEDIATRICS Buckingham, B. A., Costin, G., KOGUT, M. D., Isaacs, H., Landing, B. H. 1977; 91 (5): 728-733


    Thyroid glands from 33 children with hyperthyroidism and nine with juvenile lymphocytic thyroiditis were examined histologically and for IgG, IgA, IgM, and C3 by immunofluorescent staining. There was no significant difference between glands with JLT and those with hyperthyroidism in the degree of lymphoid infiltration or lymphoid follicle formation. In thyroiditis there was no correlation between the degree of histologic abnormalities and the presence of immunofluorescent staining for IgG, IgM, or IgA. In hyperthyroidism there was a correlation between the degree of histologic abnormalities and the presence of IgG. In both groups of patients LI and LFF were distinctly more severe in glands positive for C3. Postsurgical hypothyroidism correlated with LI but not with LFF, IgG, or C3.

    View details for Web of Science ID A1977DZ51600008

    View details for PubMedID 333076

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