Howard Zisser

University of California, Santa Barbara, Santa Barbara, California, United States

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Publications (134)307.43 Total impact

  • L.M. Huyett · E. Dassau · H.C. Zisser · F.J. Doyle
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    ABSTRACT: A closed-loop artificial pancreas (AP) to provide automated treatment for people with type 1 diabetes mellitus has the potential to improve patient health outcomes; however, the system's success hinges on its ability to quickly detect and react to changing blood glucose concentrations (BG). In this study, the impact of measurement lag on AP robust stability, performance, and time-domain disturbance rejection was investigated and compared to the case of an ideal BG sensor. The analysis was performed for an AP using either intraperitoneal (IP) or subcutaneous (SC) insulin delivery routes. Decreasing the sensor lag resulted in a higher tolerance for model uncertainty for robust stability and performance. In the case of a 20 min sensor lag, the time spent in hyperglycemia after a meal disturbance was 59±19 min and 120 ±22 min for IP and SC insulin, respectively. Switching the sensor to the ideal case decreased the time spent in hyperglycemia by 21±8 min for IP insulin and by 13±3 min for SC insulin. Since the SC system already contains large actuation delays, a faster sensor is not as important to improved performance as it is in the IP case. Significant gains in AP performance can be achieved with the use of IP insulin, but these improvements will not be fully realized unless faster glucose sensing is implemented as well.
    No preview · Article · Jul 2015 · Proceedings of the American Control Conference
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    ABSTRACT: Closed-loop control (CLC) relies on an individual's open-loop insulin pump settings to initialize the system. Optimizing open-loop settings prior to use of CLC usually requires significant time and effort. To investigate the effects of a one-time algorithmic adjustment of basal rate and insulin to carbohydrate ratio (CR) open-loop settings on the performance of CLC. Multicenter, outpatient, randomized, crossover clinical trial. 37 adults with type 1 diabetes were enrolled at 3 clinical sites. Each subject'ss insulin pump settings were subject to a one-time algorithmic adjustment based on one week of open-loop (i.e., home care) data collection. Subjects then underwent two 27-hr periods of CLC in random order with either unchanged (control) or algorithmic adjusted basal rate and CR settings (adjusted) used to initialize the zone-MPC artificial pancreas controller. Subject'ss followed their usual meal-plan and had an unannounced exercise session. Time in glucose range 80-140 mg/dL, compared between both arms. 32 subjects completed the protocol. Median time in CLC was 25.3 hrs. Median time in range 80-140 mg/dL was similar in both groups (39.7% control, 44.2% adjusted). Subjects in both arms of CLC showed minimal time spent <70 mg/dL (median 1.34% and 1.37% respectively). There were no significant differences time >140 mg/dL. A one-time algorithmic adjustment of open-loop settings did not alter glucose control in a relatively short duration outpatient closed-loop study. The CLC system proved very robust and adaptable, with minimal (<2%) time spent in the hypoglycemic range in either arm.
    Full-text · Article · Jul 2015 · The Journal of Clinical Endocrinology and Metabolism
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    ABSTRACT: Treatment of type 1 diabetes mellitus could be greatly improved by applying a closed-loop control strategy to insulin delivery, also known as an artificial pancreas (AP). In this work, we outline the design of a fully implantable AP using intraperitoneal (IP) insulin delivery and glucose sensing. The design process utilizes the rapid glucose sensing and insulin action offered by the IP space to tune a PID controller with insulin feedback to provide safe and effective insulin delivery. The controller was tuned to meet robust performance and stability specifications. An anti-reset windup strategy was introduced to prevent dangerous undershoot toward hypoglycemia after a large meal disturbance. The final controller design achieved 78% of time within the tight glycemic range of 80-140 mg/dL, with no time spent in hypoglycemia. The next step is to test this controller design in an animal model to evaluate the in vivo performance.
    Preview · Article · Jun 2015 · Industrial & Engineering Chemistry Research
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    ABSTRACT: The purpose of this study was to investigate whether or not adding a fixed preprandial dose of inhaled insulin to a fully automated closed loop artificial pancreas would improve the postprandial glucose control without adding an increased risk of hypoglycemia. Nine subjects with T1DM were recruited for the study. The patients were on closed-loop control for 24 hours starting around 4:30 pm. Mixed meals (~50 g CHO) were given at 6:30 pm and 7:00 am the following day. For the treatment group each meal was preceded by the inhalation of one 10 U dose of Technosphere Insulin (TI). Subcutaneous insulin delivery was controlled by a zone model predictive control algorithm (zone-MPC). At 11:00 am, the patient exercised for 30 ± 5 minutes at 50% of predicted heart rate reserve. The use of TI resulted in increasing the median percentage time in range (70-180 mg/dl, BG) during the 5-hour postprandial period by 21.6% (81.6% and 60% in the with/without TI cases, respectively, P = .06) and reducing the median postprandial glucose peak by 33 mg/dl (172 mg/dl and 205 mg/dl in the with and without TI cases, respectively, P = .004). The median percentage time in range 80-140 mg/dl during the entire study period was 67.5% as compared to percentage time in range without the use of TI of 55.2% (P = .03). Adding preprandial TI (See video supplement) to an automated closed-loop AP system resulted in superior postprandial control as demonstrated by lower postprandial glucose exposure without addition hypoglycemia. © 2015 Diabetes Technology Society.
    No preview · Article · Apr 2015 · Journal of diabetes science and technology
  • Howard Zisser · Jennifer E. Lane · Joseph P. Shivers
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    ABSTRACT: Continuous glucose monitors are a valuable tool to obtain tight glycemic control in people with diabetes. Since 1999 when the first continuous glucose monitor became commercially available, continuous glucose monitors have continued to evolve, becoming more accurate and user-friendly. Novel uses have also been discovered, including tracking glucose during sleep and finding trends in glucose levels that may lead to diet or exercise changes. While continuous glucose monitors are continually advancing in accuracy and reliability, their 'hassle factor' and invasiveness have investigators seeking alternative routes of glucose measurement. New models of continuous glucose monitors are being pursued including implantable, intraperitoneal, and fluorescence-based glucose sensors, as well as noninvasive models that are used on the surface of the skin. Regardless of system type, the ultimate goal is to find the continuous glucose monitor that is best-suited for use in systems that automate insulin delivery partially (e.g. low glucose suspend) or entirely (e.g. 'fully closed-loop' artificial pancreas).
    No preview · Article · Jan 2015 · Frontiers in Diabetes
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    ABSTRACT: Prandial glucose regulation is a major challenge for the artificial pancreas using subcutaneous insulin (without a feedforward bolus) due to insulin's slow absorption-peak (50-60 [min]). Intraperitoneal insulin, with a fast absorption peak (20-25 [min]), has been suggested as an alternative to address these limitations. An artificial pancreas using intraperitoneal insulin was designed and evaluated on 100 in silico subjects and compared with two designs using subcutaneous insulin with and without a feedforward bolus, following the three meal (40-70 g-carbohydrates) evaluation protocol. The design using intraperitoneal insulin resulted in a significantly lower postprandial blood glucose peak (38 [mg/dL]) and longer time in the clinically accepted region (13%) compared to the design using subcutaneous insulin without a feedforward bolus and comparable results to a subcutaneous feedforward bolus design. This superior regulation with minimal user interaction may improve the quality of life for people with type 1 diabetes mellitus.
    Preview · Article · Nov 2014 · Computers & Chemical Engineering
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    Preview · Article · Oct 2014 · Diabetes Care
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    ABSTRACT: Background: This study evaluated meal bolus insulin delivery strategies and associated postprandial glucose control while using an artificial pancreas (AP) system. Subjects and methods: This study was a multicenter trial in 53 patients, 12-65 years of age, with type 1 diabetes for at least 1 year and use of continuous subcutaneous insulin infusion for at least 6 months. Four different insulin bolus strategies were assessed: standard bolus delivered with meal (n=51), standard bolus delivered 15 min prior to meal (n=40), over-bolus of 30% delivered with meal (n=40), and bolus purposely omitted (n=46). Meal carbohydrate (CHO) intake was 1 g of CHO/kg of body weight up to a maximum of 100 g for the first three strategies or up to a maximum of 50 g for strategy 4. Results: Only three of 177 meals (two with over-bolus and one with standard bolus 15 min prior to meal) had postprandial blood glucose values of <60 mg/dL. Postprandial hyperglycemia (blood glucose level >180 mg/dL) was prolonged for all four bolus strategies but was shorter for the over-bolus (41% of the 4-h period) than the two standard bolus strategies (73% for each). Mean postprandial blood glucose level was 15.9 mg/dL higher for the standard bolus with meal compared with the prebolus (baseline-adjusted, P=0.07 for treatment effect over the 4-h period). Conclusions: The AP handled the four bolus situations safely, but at the expense of having elevated postprandial glucose levels in most subjects. This was most likely secondary to suboptimal performance of the algorithm.
    Full-text · Article · Sep 2014 · Diabetes Technology & Therapeutics
  • Howard Zisser
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    ABSTRACT: This article reviews the concept of using the proper methods for the proper task, in this case measuring dose-to-dose accuracy of continuous subcutaneous insulin infusion pumps.
    No preview · Article · Aug 2014 · Journal of diabetes science and technology
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    ABSTRACT: Background: The Control to Range Study was a multinational artificial pancreas study designed to assess the time spent in the hypo- and hyperglycemic ranges in adults and adolescents with type 1 diabetes while under closed-loop control. The controller attempted to keep the glucose ranges between 70 and 180 mg/dL. A set of prespecified metrics was used to measure safety. Research design and methods: We studied 53 individuals for approximately 22 h each during clinical research center admissions. Plasma glucose level was measured every 15-30 min (YSI clinical laboratory analyzer instrument [YSI, Inc., Yellow Springs, OH]). During the admission, subjects received three mixed meals (1 g of carbohydrate/kg of body weight; 100 g maximum) with meal announcement and automated insulin dosing by the controller. Results: For adults, the mean of subjects' mean glucose levels was 159 mg/dL, and mean percentage of values 71-180 mg/dL was 66% overall (59% daytime and 82% overnight). For adolescents, the mean of subjects' mean glucose levels was 166 mg/dL, and mean percentage of values in range was 62% overall (53% daytime and 82% overnight). Whereas prespecified criteria for safety were satisfied by both groups, they were met at the individual level in adults only for combined daytime/nighttime and for isolated nighttime. Two adults and six adolescents failed to meet the daytime criterion, largely because of postmeal hyperglycemia, and another adolescent failed to meet the nighttime criterion. Conclusions: The control-to-range system performed as expected: faring better overnight than during the day and performing with variability between patients even after individualization based on patients' prior settings. The system had difficulty preventing postmeal excursions above target range.
    Full-text · Article · Jul 2014 · Diabetes Technology & Therapeutics
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    ABSTRACT: Objective: We estimate the effect size of hypoglycemia risk reduction on closed-loop control (CLC) versus open-loop (OL) sensor-augmented insulin pump therapy in supervised outpatient setting. Research design and methods: Twenty patients with type 1 diabetes initiated the study at the Universities of Virginia, Padova, and Montpellier and Sansum Diabetes Research Institute; 18 completed the entire protocol. Each patient participated in two 40-h outpatient sessions, CLC versus OL, in randomized order. Sensor (Dexcom G4) and insulin pump (Tandem t:slim) were connected to Diabetes Assistant (DiAs)-a smartphone artificial pancreas platform. The patient operated the system through the DiAs user interface during both CLC and OL; study personnel supervised on site and monitored DiAs remotely. There were no dietary restrictions; 45-min walks in town and restaurant dinners were included in both CLC and OL; alcohol was permitted. Results: The primary outcome-reduction in risk for hypoglycemia as measured by the low blood glucose (BG) index (LGBI)-resulted in an effect size of 0.64, P = 0.003, with a twofold reduction of hypoglycemia requiring carbohydrate treatment: 1.2 vs. 2.4 episodes/session on CLC versus OL (P = 0.02). This was accompanied by a slight decrease in percentage of time in the target range of 3.9-10 mmol/L (66.1 vs. 70.7%) and increase in mean BG (8.9 vs. 8.4 mmol/L; P = 0.04) on CLC versus OL. Conclusions: CLC running on a smartphone (DiAs) in outpatient conditions reduced hypoglycemia and hypoglycemia treatments when compared with sensor-augmented pump therapy. This was accompanied by marginal increase in average glycemia resulting from a possible overemphasis on hypoglycemia safety.
    Full-text · Article · Jun 2014 · Diabetes Care
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    ABSTRACT: Background: This feasibility study investigated the insulin-delivery characteristics of the Hypoglycemia-Hyperglycemia Minimizer (HHM) System-an automated insulin delivery device-in participants with type 1 diabetes. Methods: Thirteen adults with type 1 diabetes were enrolled in this nonrandomized, uncontrolled, clinical-research-center-based feasibility study. The HHM System comprised a continuous subcutaneous insulin infusion pump, a continuous glucose monitor (CGM), and a model predictive control algorithm with a safety module, run on a laptop platform. Closed-loop control lasted approximately 20 hours, including an overnight period and two meals. Results: When attempting to minimize glucose excursions outside of a prespecified target zone, the predictive HHM System decreased insulin infusion rates below the participants' preset basal rates in advance of below-zone excursions (CGM < 90 mg/dl), and delivered 80.4% less insulin than basal during those excursions. Similarly, the HHM System increased infusion rates above basal during above-zone excursions (CGM > 140 mg/dl), delivering 39.9% more insulin than basal during those excursions. Based on YSI, participants spent a mean ± standard deviation (SD) of 0.2 ± 0.5% of the closed-loop control time at glucose levels < 70 mg/dl, including 0.3 ± 0.9% for the overnight period. The mean ± SD glucose based on YSI for all participants was 164.5 ± 23.5 mg/dl. There were nine instances of algorithm-recommended supplemental carbohydrate administrations, and there was no severe hypoglycemia or diabetic ketoacidosis. Conclusions: Results of this study indicate that the current HHM System is a feasible foundation for development of a closed-loop insulin delivery device.
    Preview · Article · May 2014 · Journal of diabetes science and technology
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    ABSTRACT: The Hypoglycemia-Hyperglycemia Minimizer (HHM) System aims to mitigate glucose excursions by preemptively modulating insulin delivery based on continuous glucose monitor (CGM) measurements. The "aggressiveness factor" is a key parameter in the HHM System algorithm, affecting how readily the system adjusts insulin infusion in response to changing CGM levels. Twenty adults with type 1 diabetes were studied in closed-loop in a clinical research center for approximately 26 hours. This analysis focused on the effect of the aggressiveness factor on the insulin dosing characteristics of the algorithm and, to a lesser extent, on the glucose control results observed. As the aggressiveness factor increased from conservative to medium to aggressive: the maximum observed insulin dose delivered by the algorithm-which is designed to give doses that are corrective in nature every 5 minutes-increased (1.00 vs 1.15 vs 2.20 U, respectively); tendency to adhere to the subject's nominal basal dose decreased (61.9% vs 56.6% vs 53.4%); and readiness to decrease insulin below basal also increased (18.4% vs 19.4% vs 25.2%). Glucose analyses by both CGM and Yellow Springs Instruments (YSI) indicated that the aggressive setting of the algorithm resulted in the least time spent at levels >180 mg/dL, and the most time spent between 70-180 mg/dL. There was no severe hyperglycemia, diabetic ketoacidosis, or severe hypoglycemia for any of the aggressiveness values investigated. These analyses underscore the importance of investigating the sensitivity of the HHM System to its key parameters, such as the aggressiveness factor, to guide future development decisions.
    Full-text · Article · May 2014 · Journal of diabetes science and technology
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    ABSTRACT: Background: Artificial pancreas (AP) systems are currently an active field of diabetes research. This pilot study examined the attitudes of AP clinical trial participants toward future acceptance of the technology, having gained firsthand experience. Subjects and methods: After possible influencers of AP technology adoption were considered, a 34-question questionnaire was developed. The survey assessed current treatment satisfaction, dimensions of clinical trial participant motivation, and variables of the technology acceptance model (TAM). Forty-seven subjects were contacted to complete the survey. The reliability of the survey scales was tested using Cronbach's α. The relationship of the factors to the likelihood of AP technology adoption was explored using regression analysis. Results: Thirty-six subjects (76.6%) completed the survey. Of the respondents, 86.1% were either highly likely or likely to adopt the technology once available. Reliability analysis of the survey dimensions revealed good internal consistency, with scores of >0.7 for current treatment satisfaction, convenience (motivation), personal health benefit (motivation), perceived ease of use (TAM), and perceived usefulness (TAM). Linear modeling showed that future acceptance of the AP was significantly associated with TAM and the motivation variables of convenience plus the individual item benefit to others (R(2)=0.26, P=0.05). When insulin pump and continuous glucose monitor use were added, the model significance improved (R(2)=0.37, P=0.02). Conclusions: This pilot study demonstrated that individuals with direct AP technology experience expressed high likelihood of future acceptance. Results support the factors of personal benefit, convenience, perceived usefulness, and perceived ease of use as reliable scales that suggest system adoption in this highly motivated patient population.
    Preview · Article · May 2014 · Diabetes Technology & Therapeutics
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    ABSTRACT: In this two-part Bench to Clinic narrative, recent advances in both the preclinical and clinical aspects of artificial pancreas (AP) development are described. In the preceding Bench narrative, Kudva and colleagues provide an in-depth understanding of the modified glucoregulatory physiology of type 1 diabetes that will help refine future AP algorithms. In the Clinic narrative presented here, we compare and evaluate AP technology to gain further momentum toward outpatient trials and eventual approval for widespread use. We enumerate the design objectives, variables, and challenges involved in AP development, concluding with a discussion of recent clinical advancements. Thanks to the effective integration of engineering and medicine, the dream of automated glucose regulation is nearing reality. Consistent and methodical presentation of results will accelerate this success, allowing head-to-head comparisons that will facilitate adoption of the AP as a standard therapy for type 1 diabetes.
    Preview · Article · May 2014 · Diabetes care
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    ABSTRACT: The Glucose Rate Increase Detector (GRID), a module of the Health Monitoring System (HMS), has been designed to operate in parallel to the glucose controller to detect meal events and safely trigger a meal bolus. The GRID algorithm was tuned on clinical data with 40-70 g CHO meals and tested on simulation data with 50-100 g CHO meals. Active closed- and open-loop protocols were executed in silico with various treatments, including automatic boluses based on a 75 g CHO meal and boluses based on simulated user input of meal size. An optional function was used to reduce the recommended bolus using recent insulin and glucose history. For closed-loop control of a 3-meal scenario (50, 75, and 100 g CHO), the GRID improved median time in the 80-180 mg/dL range by 17% and in the >180 range by 14% over unannounced meals, using an automatic bolus for a 75 g CHO meal at detection. Under open-loop control of a 75 g CHO meal, the GRID shifted the median glucose peak down by 73 mg/dL and earlier by 120 min and reduced the time >180 mg/dL by 57% over a missed-meal bolus scenario, using a full meal bolus at detection. The GRID improved closed-loop control in the presence of large meals, without increasing late postprandial hypoglycemia. Users of basal-bolus therapy could also benefit from GRID as a safety alert for missed meal corrections.
    Preview · Article · Mar 2014 · Journal of diabetes science and technology
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    ABSTRACT: The paramount goal in the treatment of type 1 diabetes is the maintenance of normoglycemia. Continuous glucose monitoring (CGM) technologies enable frequent sensing of glucose to inform exogenous insulin delivery timing and dosages. The most commonly available CGMs are limited by the physiology of the subcutaneous (SQ) space in which they reside. The very same advantages of this minimally invasive approach are disadvantages with respect to speed. Because SQ blood flow is sensitive to local fluctuations (e.g., temperature, mechanical pressure), SQ sensing can be slow and variable. We propose the use of a more central, physiologically stable body space for CGM: the intraperitoneal space (IP). We compared the temporal response characteristics of simultaneously placed SQ and IP sensors during intravenous (IV) glucose tolerance tests in eight swine. Using compartmental modeling based on simultaneous IV sensing, blood draws, and intra-arterial sensing, we found that IP kinetics were more than twice as fast as SQ kinetics (mean time constant of 5.6 min IP vs. 12.4 min for SQ). Combined with the known faster kinetics of IP insulin delivery over SQ delivery, our findings suggest that artificial pancreas technologies may be optimized by both sensing glucose and delivering insulin in the IP space.
    Preview · Article · Mar 2014 · Diabetes
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    Preview · Article · Feb 2014 · Diabetes Technology & Therapeutics
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    ABSTRACT: Online glucose prediction which can be used to provide important information of future glucose status is a key step to facilitate proactive management before glucose reaches undesirable concentrations. Based on frequency‐band separation (FS) and empirical modeling approaches, this article considers several important aspects of on‐line glucose prediction for subjects with type 1 diabetes mellitus. Three issues are of particular interest: (1) Can a global (or universal) model be developed from glucose data for a single subject and then used to make suitably accurate on‐line glucose predictions for other subjects? (2) Does a new FS approach based on data filtering provide more accurate models than standard modeling methods? (3) Does a new latent variable modeling method result in more accurate models than standard modeling methods? These and related issues are investigated by developing autoregressive models and autoregressive models with exogenous inputs based on clinical data for two groups of subjects. The alternative modeling approaches are evaluated with respect to on‐line short‐term prediction accuracy for prediction horizons of 30 and 60 min, using independent test data. © 2013 American Institute of Chemical Engineers AIChE J 60: 574–584, 2014
    Full-text · Article · Feb 2014 · AIChE Journal
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    ABSTRACT: Background: This study was performed to evaluate the safety and efficacy of a fully automated artificial pancreas using zone-model predictive control (zone-MPC) with the health monitoring system (HMS) during unannounced meals and overnight and exercise periods. Subjects and methods: A fully automated closed-loop artificial pancreas was evaluated in 12 subjects (eight women, four men) with type 1 diabetes (mean±SD age, 49.4±10.4 years; diabetes duration, 32.7±16.0 years; glycosylated hemoglobin, 7.3±1.2%). The zone-MPC controller used an a priori model that was initialized using the subject's total daily insulin. The controller was designed to keep glucose levels between 80 and 140 mg/dL. A hypoglycemia prediction algorithm, a module of the HMS, was used in conjunction with the zone controller to alert the user to consume carbohydrates if the glucose level was predicted to fall below 70 mg/dL in the next 15 min. Results: The average time spent in the 70-180 mg/dL range, measured by the YSI glucose and lactate analyzer (Yellow Springs Instruments, Yellow Springs, OH), was 80% for the entire session, 92% overnight from 12 a.m. to 7 a.m., and 69% and 61% for the 5-h period after dinner and breakfast, respectively. The time spent < 60 mg/dL for the entire session by YSI was 0%, with no safety events. The HMS sent appropriate warnings to prevent hypoglycemia via short and multimedia message services, at an average of 3.8 treatments per subject. Conclusions: The combination of the zone-MPC controller and the HMS hypoglycemia prevention algorithm was able to safely regulate glucose in a tight range with no adverse events despite the challenges of unannounced meals and moderate exercise.
    Preview · Article · Jan 2014 · Diabetes Technology & Therapeutics

Publication Stats

3k Citations
307.43 Total Impact Points

Institutions

  • 2006-2015
    • University of California, Santa Barbara
      • Department of Chemical Engineering
      Santa Barbara, California, United States
  • 2014
    • Stanford University
      • Department of Biology
      Palo Alto, California, United States
  • 2004-2014
    • Sansum Diabetes Research Institute
      Santa Barbara, California, United States
  • 2013
    • York University
      • School of Kinesiology and Health Sciences
      Toronto, Ontario, Canada
  • 2011
    • University of California, Irvine
      Irvine, California, United States
  • 2009
    • Rensselaer Polytechnic Institute
      • Department of Chemical and Biological Engineering
      Troy, New York, United States