Stuart A Weinzimer

Yale University, New Haven, Connecticut, United States

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Publications (138)622.71 Total impact

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    ABSTRACT: Early-onset type 1 diabetes may affect the developing brain during a critical window of rapid brain maturation. Structural magnetic resonance imaging was performed on 141 children with diabetes (ages 4-10 years at study entry) and 69 age-matched controls at two time points spaced 18 months apart. For the children with diabetes, HbA1c was 7.9±0.9% (63±9.8 mmol/mol)(mean±SD) at both time points. Relative to controls, children with diabetes had significantly less growth of cortical gray matter volume and cortical surface area, and significantly less growth of white matter volume throughout the cortex and cerebellum. For the diabetic population, the change across longitudinal time points of the blood glucose level at the time of scan was negatively correlated with the change in gray and white matter volumes, suggesting that fluctuating glucose levels in children with diabetes may be associated with corresponding fluctuations in brain volume. In addition, measures of hyperglycemia and glycemic variation were significantly negatively correlated with development of surface curvature. These results demonstrate that early-onset type 1 diabetes has widespread effects on the growth of gray and white matter for children whose blood glucose levels are well within the current treatment guidelines for management of diabetes.
    No preview · Article · Oct 2015 · Diabetes
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    Kathleen H Ang · William V Tamborlane · Stuart A Weinzimer
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    ABSTRACT: Despite the widespread availability of insulin pumps, continuous glucose sensors, and insulin analogs with rapid-acting pharmacokinetic profiles, most people with type 1 diabetes fail to meet recommended glycemic targets, rates of severe hypoglycemia remain unacceptably high, and the burden of care on patients and loved ones exacts an enormous psychosocial toll. The combination of continuous glucose monitoring with insulin delivery into an integrated automated system promises to improve diabetes control while at the same time reduce the burden of care. A wide variety of automated insulin delivery systems, ranging in scope from simple pump suspension to reduce hypoglycemia, to complex multiple hormone systems under separate regulation and delivery, have been studied in both controlled inpatient settings and more free-ranging outpatient environments. Preliminary findings have been positive, with most studies demonstrating reduction in overall glucose levels, increased time-in-target range, and reductions in exposure to hypoglycemia. As these systems move closer to commercialization, the focus of ongoing efforts will need to address the continuing challenges of sensor accuracy and reliability, connectivity issues, and human factors considerations.
    Preview · Article · Sep 2015 · Expert Opinion on Drug Delivery
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    ABSTRACT: Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.
    No preview · Article · Apr 2015 · Diabetes
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    ABSTRACT: The aim of this work was to assess the association between continuous glucose monitoring (CGM) data, HbA1c, insulin-dose-adjusted HbA1c (IDAA1c) and C-peptide responses during the first 2 years following diagnosis of type 1 diabetes. A secondary analysis was conducted of data collected from a randomised trial assessing the effect of intensive management initiated within 1 week of diagnosis of type 1 diabetes, in which mixed-meal tolerance tests were performed at baseline and at eight additional time points through 24 months. CGM data were collected at each visit. Among 67 study participants (mean age [± SD] 13.3 ± 5.7 years), HbA1c was inversely correlated with C-peptide at each time point (p < 0.001), as were changes in each measure between time points (p < 0.001). However, C-peptide at one visit did not predict the change in HbA1c at the next visit and vice versa. Higher C-peptide levels correlated with increased proportion of CGM glucose values between 3.9 and 7.8 mmol/l and lower CV (p = 0.001 and p = 0.02, respectively) but not with CGM glucose levels <3.9 mmol/l. Virtually all participants with IDAA1c < 9 retained substantial insulin secretion but when evaluated together with CGM, time in the range of 3.9-7.8 mmol/l and CV did not provide additional value in predicting C-peptide levels. In the first 2 years after diagnosis of type 1 diabetes, higher C-peptide levels are associated with increased sensor glucose levels in the target range and with lower glucose variability but not hypoglycaemia. CGM metrics do not provide added value over the IDAA1c in predicting C-peptide levels.
    Full-text · Article · Mar 2015 · Diabetologia
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    ABSTRACT: Prior studies examining beta-cell preservation in type 1 diabetes have predominantly assessed stimulated C-peptide concentrations approximately 10 wk after diagnosis. We examined whether earlier assessments might aid in prediction of beta cell function over time. Using data from a multi-center randomized trial assessing the effect of intensive diabetes management initiated within 1 wk of diagnosis, we assessed which clinical factors predicted 90-min mixed-meal tolerance test (MMTT) stimulated C-peptide values obtained 2 and 6 wk after diagnosis. We also studied associations of these factors with C-peptide values at 1- and 2-year post-diagnosis. Data from intervention and control groups were pooled. Among 67 study participants (mean age 13.3 ± 5.7 yr, range 7.8-45.7 yr) in multivariable analyses, C-peptide increased from baseline to 2 wks and then 6 wk. C-peptide levels at these times were significantly correlated with 1- and 2-yr C-peptide concentrations (all p < 0.001), with the strongest observed associations between 6-wk C-peptide and the 1- and 2-yr values (r = 0.66 and r = 0.61, respectively). In multivariable analyses, greater baseline and 6-wk C-peptide, and older age independently predicted greater 1- and 2-yr C-peptide concentrations. C-peptide assessments close to diagnosis were predictive of subsequent C-peptide production. Our data demonstrate a clear increase in C-peptide over the initial 6 wk after diabetes diagnosis followed by a plateau. Our data do not suggest that MMTT assessments performed closer to diagnosis than 6 wk would improve prediction of subsequent residual beta cell function. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
    No preview · Article · Feb 2015 · Pediatric Diabetes

  • No preview · Article · Feb 2015 · Diabetes Technology & Therapeutics

  • No preview · Article · Feb 2015 · Diabetes Technology & Therapeutics

  • No preview · Article · Feb 2015 · Diabetes Technology & Therapeutics

  • No preview · Article · Feb 2015 · Diabetes Technology & Therapeutics
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    ABSTRACT: Objectives The aim of the study was to characterize glucose levels and variability in young children with type 1 diabetes (T1D).MethodsA total of 144 children of 4–10 yr old diagnosed with T1D prior to age 8 were recruited at five DirecNet centers. Participants used a continuous glucose monitor (CGM) every 3 months during an 18-month study. Among the 144 participants, 135 (mean age 7.0 yr, 47% female) had a minimum of 48 h of CGM data at more than five of seven visits and were included in analyses. CGM metrics for different times of day were analyzed.ResultsMean hemoglobin A1c (HbA1c) at the beginning and end of the study was 7.9% (63 mmol/mol). Fifty percent of participants had glucose levels >180 mg/dL (10.0 mmol/L) for >12 h/d and >250 mg/dL (13.9 mmol/L) for >6 h/d. Median time <70 mg/dL (3.9 mmol/L) was 66 min/d and <60 mg/dL (3.3 mmol/L) was 39 min/d. Mean amplitude of glycemic excursions (MAGE) was lowest overnight (00:00–06:00 hours). The percent of CGM values 71–180 mg/dL (3.9–10.0 mmol/L) and the overall mean glucose correlated with HbA1c at all visits. There were no differences in CGM mean glucose or coefficient of variation between the age groups of 4 and <6, 6 and <8, and 8 and <10.Conclusions Suboptimal glycemic control is common in young children with T1D as reflected by glucose levels in the hyperglycemic range for much of the day. New approaches to reduce postprandial glycemic excursions and increase time in the normal range for glucose in young children with T1D are critically needed. Glycemic targets in this age range should be revisited.
    No preview · Article · Dec 2014 · Pediatric Diabetes
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    Garry M. Steil · John J. Mastrototaro · Stuart A. Weinzimer · D. Barry Keenan

    Full-text · Dataset · Aug 2014
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    ABSTRACT: OBJECTIVE To examine the evolution of the dysregulated glucagon responses to mixed-meal tolerance tests (MMTTs) in youth with recent-onset type 1 diabetes (T1D).RESEARCH DESIGN AND METHODSMMTTs were performed in 25 youth (9-18 years of age) with 1.5-12 months disease duration (year 1); 22 subjects were restudied 1 year later (year 2). Twenty nondiabetic (ND) control children were also studied.RESULTSIn T1D children, MMTT-stimulated increases in glucagon were significantly greater than that in ND children (median increments: year 1, 21 pg/mL [16-30]; year 2, 25 pg/mL [16-30]; ND, 9 pg/mL [5-16]; P = 0.001 and P < 0.001, respectively).CONCLUSIONS In comparison with ND control children, exaggerated plasma glucagon responses to mixed-meal feedings are observed in youth with T1D within the first 2 years of diagnosis. Further studies to determine whether suppression of these abnormal responses may help to improve glycemic control are warranted.
    Full-text · Article · Apr 2014 · Diabetes care
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    ABSTRACT: Objective: This study was undertaken to investigate the effect of an insulin infusion site warming device, the InsuPatch(40)(™) (IP(40)) (InsuLine Medical Ltd., Petach-Tikvah, Israel), on insulin aspart pharmacodynamics (PD) and pharmacokinetics (PK) in adolescents with type 1 diabetes. Subjects and methods: Seventeen subjects with type 1 diabetes (age, 15±1 years; hemoglobin A1c, 7.5±0.2% [58±2.2 mmol/mol]) underwent two euglycemic clamps performed on separate mornings with and without IP(40) activation with warming temperature at 40°C. On both days, the basal infusion was suspended, and glucose levels were maintained between 90 and 100 mg/dL by a variable rate dextrose infusion for up to 5 h after a 0.2 U/kg bolus of insulin aspart. Results: Time to peak insulin action and time to half-maximal action occurred earlier with a greater early glucodynamic effect (area under the curve [AUC] for glucose infusion rate from 0 to 30 min) with IP(40) than without the IP(40), whereas the AUC for the time-action profile and the peak action did not differ with and without infusion site warming. PK parameters were in agreement with PD parameters, namely, a significantly earlier time to reach the maximum increment in insulin concentrations and greater early bioavailability (AUC for the change in insulin concentration from 0 to 30 min) with the IP(40). The tail of the plasma insulin response curve was also shortened with infusion site warming, with the time to reach baseline insulin concentration occurring significantly earlier (P=0.04). Conclusions: Our data demonstrate that skin warming around the infusion site to 40°C with the IP(40) is an effective means to accelerate absorption and action of rapid-acting insulin. These improvements in time-action responses have the potential to enhance the performance of open- and closed-loop insulin delivery systems.
    No preview · Article · Dec 2013 · Diabetes Technology & Therapeutics
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    ABSTRACT: OBJECTIVE To investigate whether type 1 diabetes affects white matter (WM) structure in a large sample of young children.RESEARCH DESIGN AND METHODS Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.RESULTSBetween-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects.CONCLUSIONS These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.
    Full-text · Article · Dec 2013 · Diabetes care
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    ABSTRACT: This paper investigates the expected clinical performance and robustness envelope (e.g., postprandial blood glucose peak and low blood glucose condition risk) of an artificial pancreas (AP) with respect to the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of different insulin delivery options (i.e., combinations of insulin formulations and routes). Specifically, an insulin PK/PD based design method that enables the investigation of the clinical performance and robustness envelope using the internal model control methodology is introduced. The controller based on the proposed method was evaluated on the Universities of Virginia and Padova FDA-accepted metabolic simulator. The robustness analyses suggest that the controller can achieve safe glucose regulation over a wide range of insulin PK/PD characteristics. The simulation results suggest that the controller with only two parameters (the pharmacokinetic time constant and the controller time constant) can achieve satisfactory performance (meal disturbance rejection within 3.5 h) over the PK/PD range, demonstrating that a faster acting insulin delivery option achieves superior meal disturbance rejection without inducing a dangerous overshoot (i.e., low blood glucose condition). Additionally, two sample clinical results using fast acting insulin delivery options (inhaled and intraperitoneal) are given to illustrate the benefit of improving PK/PD characteristics.
    No preview · Conference Paper · Dec 2013
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    ABSTRACT: Objective An integrated sensor-augmented pump system has been introduced that interrupts basal insulin infusion for 2-hrs if patients fail to respond to low glucose alarms. It has been suggested that such interruptions of basal insulin due to falsely low sensor glucose levels could lead to diabetic ketoacidosis. We hypothesized that random suspension of basal insulin for 2-hrs in the overnight period would not lead to clinically important increases in blood β-hydroxybutyrate (BHB) levels despite widely varying glucose values prior to the suspension.Research Design and Methods Subjects measured meter blood glucose (BG) and BHB levels each night at 9PM and fasting the next morning. On control nights, usual basal rates were continued; on experimental nights, the basal insulin infusion was re-programmed for a 2-hr zero basal rate at random times after 11:30PM.ResultsIn seventeen type 1 diabetes subjects (age 24±9yr, duration 14±11yr, A1c 7.3±0.5 [56mmol/mol]) BG and BHB levels were similar at 9PM on suspend (144±63mg/dL and 0.09±0.07mmol/L) and non-suspend (151±65mg/dL and 0.08±0.06mmol/L) nights (p=0.39 and p=0.47, respectively). Fasting morning BG increased following suspend nights compared to non-suspend nights (191±68mg/dL vs. 141±75mg/dL, p<0.0001) and the frequency of fasting hypoglycemia decreased the morning following suspend nights (p<0.0001). Morning BHB levels were slightly higher after suspension (0.13±0.14mmol/L vs. 0.09±0.11mmol/L, p=0.053) but the difference was not clinically important.Conclusions Systems that suspend basal insulin for 2-hrs are safe and do not lead to clinically significant ketonemia even if BG is elevated at the time of the suspension.
    Full-text · Article · Oct 2013 · Diabetes care
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    ABSTRACT: OBJECTIVE To assess effectiveness of inpatient hybrid closed-loop control (HCLC) followed by outpatient sensor-augmented pump (SAP) therapy initiated within 7 days of diagnosis of type 1 diabetes on the preservation of β-cell function at 1 year.RESEARCH DESIGN AND METHODS Sixty-eight individuals (mean age 13.3 ± 5.7 years; 35% female, 92% Caucasian) were randomized to HCLC followed by SAP therapy (intensive group; N = 48) or to the usual-care group treated with multiple daily injections or insulin pump therapy (N = 20). Primary outcome was C-peptide concentrations during mixed-meal tolerance tests at 12 months.RESULTSIntensive-group participants initiated HCLC a median of 6 days after diagnosis for a median duration of 71.3 h, during which median participant mean glucose concentration was 140 mg/dL (interquartile range 134-153 mg/dL). During outpatient SAP, continuous glucose monitor (CGM) use decreased over time, and at 12 months, only 33% of intensive participants averaged sensor use ≥6 days/week. In the usual-care group, insulin pump and CGM use were initiated prior to 12 months by 15 and 5 participants, respectively. Mean HbA1c levels were similar in both groups throughout the study. At 12 months, the geometric mean (95% CI) of C-peptide area under the curve was 0.43 (0.34-0.52) pmol/mL in the intensive group and 0.52 (0.32-0.75) pmol/mL in the usual-care group (P = 0.49). Thirty-seven (79%) intensive and 16 (80%) usual-care participants had a peak C-peptide concentration ≥0.2 pmol/mL (P = 0.30).CONCLUSIONS In new-onset type 1 diabetes, HCLC followed by SAP therapy did not provide benefit in preserving β-cell function compared with current standards of care.
    Full-text · Article · Oct 2013 · Diabetes care
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    ABSTRACT: The ability to lie still in an MRI scanner is essential for obtaining usable image data. To reduce motion, young children are often sedated, adding significant cost and risk. We assessed the feasibility of using a simple and affordable behavioral desensitization program to yield high-quality brain MRI scans in sedation-free children. 222 children (4-9.9 years), 147 with type 1 diabetes and 75 age-matched non-diabetic controls, participated in a multi-site study focused on effects of type 1 diabetes on the developing brain. T1-weighted and diffusion-weighted imaging (DWI) MRI scans were performed. All children underwent behavioral training and practice MRI sessions using either a commercial MRI simulator or an inexpensive mock scanner consisting of a toy tunnel, vibrating mat, and video player to simulate the sounds and feel of the MRI scanner. 205 children (92.3%), mean age 7 ± 1.7 years had high-quality T1-W scans and 174 (78.4%) had high-quality diffusion-weighted scans after the first scan session. With a second scan session, success rates were 100% and 92.5% for T1-and diffusion-weighted scans, respectively. Success rates did not differ between children with type 1 diabetes and children without diabetes, or between centers using a commercial MRI scan simulator and those using the inexpensive mock scanner. Behavioral training can lead to a high success rate for obtaining high-quality T1-and diffusion-weighted brain images from a young population without sedation.
    Full-text · Article · Oct 2013 · Pediatric Radiology
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    ABSTRACT: Hyperglycemia is a significant problem for critically ill children. Treatment for hyperglycemia remains contro-versial. This study explores the effect of controlling blood glucose (BG) in hyperglycemic critically ill children. A retrospective cohort of nondiabetic critically ill children (defined as requiring mechanical ventilation and/or vasopressors) with BG persistently ≥150 mg/dl and treated with insulin (treatment group) were compared with a historical cohort of similar children who did not receive interventions to control hyperglycemia (baseline group). There were 130 children in the treatment group and 137 children in the baseline group. Mean BG in the treatment group was 140 ± 24 mg/dl compared with 179 ± 47 mg/dl in the baseline group (p < .001). After adjusting for patient characteristics, cointerventions, and glucose metrics, patients in the treatment group had 2.5 fewer intensive care unit (ICU)-free days (i.e., number of days alive and discharged from ICU within 28 days after inclusion) than the baseline group (p = .023). Glucose control was not independently associated with duration of ICU stay, ventilator-free days, vasopressor-free days, or mortality. Blood glucose control appears associated with worse outcomes in critically ill children. Our data combined with conflicting results in adults leads us to strongly advocate for the conduct of randomized trials on glucose control in critically ill children.
    Preview · Article · Sep 2013 · Journal of diabetes science and technology
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    ABSTRACT: We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes (T1D). Seventy-four oral insulin trial progressors to T1D of the Diabetes Prevention Trial-Type 1 with at least one FPIR measurement after baseline and before diagnosis were studied. The FPIR was examined longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis. The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was studied in the remainder (n=48). The 74 progressors had lower baseline FPIR values than non-progressors (n=270) with adjustments for age and BMI. In the longitudinal analysis of the 26 progressors, there was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before diagnosis. This accelerated decline was also evident in a regression analysis of the 48 remaining progressors in whom the rate of decline became more marked with the approaching diagnosis. The patterns of decline were similar between the longitudinal and regression analyses. There is an acceleration of decline in the FPIR during the progression to T1D which becomes especially marked between 1.5 and 0.5 years before diagnosis.
    Full-text · Article · Jul 2013 · Diabetes

Publication Stats

4k Citations
622.71 Total Impact Points

Institutions

  • 2003-2015
    • Yale University
      • • Department of Pediatrics
      • • Center for Children's Surgical Research
      New Haven, Connecticut, United States
  • 2003-2011
    • Yale-New Haven Hospital
      • Endocrinology and Diabetes Program
      New Haven, Connecticut, United States
  • 2005-2009
    • Jaeb Center for Health Research
      Tampa, Florida, United States
  • 1993-2003
    • The Children's Hospital of Philadelphia
      • • Department of Emergency Medicine
      • • Department of Pediatrics
      Philadelphia, Pennsylvania, United States
  • 2001
    • William Penn University
      Filadelfia, Pennsylvania, United States
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States