Endocrinol Metab Clin N Am 33 (2004) 175195

Glucose sensors: toward closed loop insulin delivery

Chee W. Chia, MD, Christopher D. Saudek, MD*
Division of Endocrinology and Metabolism, Department of Medicine, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Osler 575, Baltimore, MD 21287, USA

Although the symptoms of severe hyperglycemia have been known for millennia, the laboratory measurement of blood glucose was a lengthy and labor-intensive process until 1915, when Lewis and Benedict [1] were credited with simplifying the analysis to a point that glycemia could be documented relatively quickly. This advance is considered a crucial step in the chain of events that led up to the isolation of insulin by Banting and Best in 1921 [2]. Glucose measurements remained laboratory-based until the 1940s, however, when self-assessment of glucosuria became feasible by measuring total reducing substance in the urine at home. It took sophisticated physical chemistry to x glucose oxidase to a reagent strip with a development of color proportional to glucose in a drop of blood, initiating the era of self-monitoring of blood glucose (SMBG) with reectance meters in the 1970s [3,4]. This technology was made faster and more accurate with electrochemical sensors that replaced reectance meters in the 1990s. SMBG now requires small amounts of blood (0.310 lL), is rapid (515 seconds), and relatively accurate (less than 10% analytical error) [5]. The 10% error is still higher, however, than the American Diabetes Association (ADA) goal of less than 5% error [6]. The importance of SMBG in diabetes self-care, as the rst step in blood glucose sensor development, can hardly be overemphasized. Along with hemoglobin A1c (HbA1c), it is a basic pillar in assessing diabetic control, and by allowing hour-to-hour measurement, it makes practical the sort of intensive self-care regimen that prevents

This work was supported by National Institute of Health grant R01 DK55132 and General Clinical Research Center grant RR00051. Dr. Saudek is on the Medical Advisory Board for DexCom, Inc., the advisory panel for Cygnus, Inc., and has received research support from Medtronic MiniMed, Inc. * Corresponding author. E-mail address: csaudek@jhu.edu (C.D. Saudek). 0889-8529/04/$ - see front matter 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ecl.2003.12.001

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complications [7]. About 56% of people with diabetes are now performing SMBG on a regular basis, at least once a day [8]. The main limitations of SMBG from the patients view are inconvenience and discomfort, but the main limitations in terms of information obtained are that SMBG is intermittent and depends on the patients initiative. At best, SMBG provides 2, 4, or rarely over 10 data points in a day, but blood glucose itself varies continuously and unpredictably, up to as much as sixfold in the course of 24 hours. The values obtained by SMBG are always only snapshots of a continuous variable. The next major step in diabetes self-care will therefore be practical use of continuous glucose monitoring. The idea of continuous glucose monitoring is not new. Clark and Lyons [9] and Updike and Hicks [10] rst described the electrochemical enzymatic glucose sensors in the 1960s. The concept of articial pancreas with continuous glucose monitoring and automated insulin delivery was proposed by Kadish in 1964 [11], and made a reality by two dierent research teams in 1974, Albisser and colleagues [12,13] and Pfeier and colleagues [14,15]. Pfeier and colleagues [14,15] developed the Biostator, a large, bedside device widely used in research and for clinical assessment of blood glucose patterns in individuals. Using a continuous withdrawal of venous blood, with an online glucose oxidasecontaining membrane that provided real-time glucose values, the Biostator was limited by its sheer size and the need for constant attention of a technician. Thus, despite over 30 years of research in this area, the eld of continuous glucose monitoring for clinical use did not prosper until the turn of this century. This article assesses the uses and requirements of continuous glucose sensing and reviews the dierent glucose sensor technologies now clinically available and that may become available in the near future. The authors close with an assessment of prospects for the fully automatic articial pancreas.

Uses of continuous glucose monitoring Continuous glucose monitoring could help avoid severe highs and lows (the alarm function), identify patterns in diabetic control, and, ultimately, control an insulin delivery system. The requirements for each role dier in detail, although in the end an accurate, precise, and robust sensor is the ideal. Any sensor that can signal when blood glucose is too low or too high serves an obvious purpose. The set point to trigger high or low alarms could be programmed individually, and could include rate-of-decline or rate-ofrise to anticipate the highs and lows. Accuracy may be less of a requirement in this application than reliable avoidance of false alarms. Some years ago, a wristwatch-like device called the Sleep Sentry (Teledyne Avionics, Charlottesville, Virginia) monitored changes in skin temperature and sweating, but it had far too many false alarms to serve as a reliable indication of hypoglycemia [16,17].

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Patterns of blood glucose control should be apparent from use of a continuous glucose monitor. The main challenge in this use, particularly when applied to type 1 diabetes mellitus, will be data management: what patterns are identiable when glycemia seems to vary almost at random? The nal application, driving an articial pancreas, is the most dicult challenge.

Assessment of glucose sensors Glucose sensors can be assessed quantitatively in terms of precision, accuracy, sensitivity, and stability. Among the important performance characteristics are calibration requirements, availability of results, longevity, and robustness. In vivo use is to be distinguished from in vitro, or factory operation. Accuracy assesses how close sensor results are to some gold standard, and can be expressed as mean error (eg, mg/dL) or relative error (% error). Precision is a dierent measure, indicating how closely grouped the sensor results are around the mean result, and is expressed as variance, standard deviation, or range [18]. For example, accuracy may be excellenton average the sensor readings are close (eg, within 5% of the gold standard), but precision may be poorthe sensor readings vary widely (eg, 20% above and below the gold standard). The results of sensor measures commonly are displayed on the backdrop of Clarkes Error Grid Analysis [19,20], although the authors and others [2123], including Clarke, discourage using this analysis alone. An important issue in assessing a sensor is the applicable gold standard. Usually, the accepted method is to test against whole blood or plasma glucose. When subcutaneous tissue uid or extracted interstitial uid is tested, however, the results may dier systematically or in time kinetics from blood glucose.

General approaches to continuous glucose monitoring The general approaches to glucose-sensing technology are summarized in Table 1. Over 100 universities and companies are working on the subject to develop these technologies [24], none of which is yet either ready to drive an articial pancreas or ideally suited to routine clinical use. Sensors based on the enzyme glucose oxidase are the most reliable compared, for example, to spectroscopic or viscosity-based sensors, because glucose oxidase is specic for glucose. Most of the sensors under development today are amperometric, stemming from the work of Clark and Lyons [9], Updike and Hicks [10], and Gough and colleagues [25]. The hydrogen peroxidebased enzyme electrode sensor [2628] has a membrane with immobilized glucose oxidase coupled to a peroxide-sensitive catalytic anode. Hydrogen peroxide is generated when glucose and oxygen react with the membrane. The hydrogen peroxide diuses to the anode where it is

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Table 1 Various approaches to glucose-sensing technology Technique Subcutaneous Insertion (short-term) Basic principle Electrochemical sensor with hydrogen peroxide based enzyme electrode inserted or implanted subcutaneously Device/company CGMS/Medtronic MiniMed Invasivenessa + + Duration $3 d Calibration frequency 4/d Human trials Yes Clinical use Yes References [3437]

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Implanted (long-term) Microdialysis Microdialysis catheter is inserted subcutaneously and perfused with dialysate, which is collected outside the body for measurement of glucose using electrochemical sensor

TGMS/Medtronic MiniMed DexCom

+ + + + +

$2 d Months

2/d Yes

Yes Yes

No No

[70]

GlucoDay/Menarini Diagnostics

+ +

$2 d

Once

Yes

Yes (in Europe)

[69]

SCGM1/RocheDiagnostics GluOnline/ Disetronic

+ + + +

$4 d Days

1/d Data N/A

Yes Yes

No No

[6668] [72]

Open-ow Microperfusion Similar concept as microdialysis except the dialysate is in direct contact with interstitial uid Disetronic + + Days Data N/A Yes No [76,77] C.W. Chia, C.D. Saudek / Endocrinol Metab Clin N Am 33 (2004) 175195

Transdermal Reverse iontophoresis

Interstitial uid is extracted through the skin using various techniques and glucose is measured using electrochemical sensor

GlucoWatch/ Cygnus

$13 h

Once

Yes

Yes

[5558]

Biophotonic Intravenous Long-term

SpectRx

$2 d

1/d

Yes

No

[79]

Electrochemical sensor with oxygen-based enzyme electrode inserted through the subclavian vein and positioned in the superior vena cava

Medtronic MiniMed

+ + + +

Months

Data N/A

Yes

No

[86]

Short-term

VGMS/ Medtronic MiniMed

+ + + +

Days

Data N/A

Yes

No

From least invasive (+) to most invasive (+ + + +). Abbreviations: CGMS, Continuous Glucose Monitoring System; N/A, not available; SCGM1, Subcutaneous Continuous Glucose Monitoring System; TGMS, Telemetered Glucose Monitoring System; VGMS, Vascular Glucose Monitoring System.

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oxidized to produce an electrical current. The amount of current generated is proportional to the glucose concentration. The hydrogen peroxide sensors have several limitations, such as the dependence on oxygen concentration, interference from other chemical compounds, and inactivation of enzyme over time [29]. The most recent sensor developed by Updike and colleagues [30] may have overcome most of these limitations. Another design is the oxygen-based enzyme electrode sensor [10,25]. This design has a membrane with immobilized glucose oxidase coupled to an electrochemical oxygen sensor. The glucose and oxygen from the reagent rst come into contact and react with the glucose oxidase. As a result, the amount of oxygen detected by the oxygen sensor is reduced. The signal current generated by the oxygen sensor is subtracted from that of a reference oxygen sensor without the glucose oxidase, and the dierence is proportional to the glucose concentration. The design of the oxygen-based enzyme sensor makes it less susceptible to oxygen concentration [29]. There are a number of comprehensive reviews of dierent types of electrochemical sensors [29,31,32].

Source of analyte measured Although many uid sources can be imagined (eg, tears, saliva, urine, cerebrospinal uid), two locations are used commonly for measuring glucose: interstitial and intravascular. For continuous monitoring, the interstitial approach is the most popular because it is less invasive and less prone to triggering a clotting reaction. There are several ways to measure interstitial glucose: (1) inserting the glucose sensor into the subcutaneous tissues, either short- or long-term; (2) microdialysis technique; and (3) openow microperfusion. The analyte most familiar to patients, clinicians, and researchers, however, is blood or plasma, and the relationship between plasma and interstitial glucose is still not completely understood [33]. All the current sensors that measure interstitial glucose are calibrated using blood glucose measurement (obtained from capillary glucose meter) so the glucose readings are meant to represent plasma glucose equivalents. Exposure of the sensor to blood is relatively straightforward: either the blood is externally accessed, as in SMBG or the Biostator, or the sensor is placed intravenously. The latter procedure can be potentially dangerous (if an externalized line is in place long-term), and always prone to walling o by the clotting mechanisms.

Clinically available subcutaneous glucose sensors Regulatory approval and market availability of medical devices changes from month to month, but it is useful to consider which continuous glucose monitors are available, which may become available soon, and which are

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less certain or unlikely to be available for some years. There are three currently available glucose sensors. Continuous Glucose Monitoring System The Continuous Glucose Monitoring System (CGMS; Medtronic MiniMed, Northridge, California) is the rst commercially available continuous glucose sensor and the most extensively studied. This rstgeneration sensor is a Holter-style device, with data collected in memory for up to 3 days and then downloaded for graphic display; the glucose data are not available in real time. CGMS is an electrochemical sensor placed subcutaneously and connected to a pager-sized monitor worn on the belt. Physically, it looks like an external insulin pump. This sensor is placed subcutaneously with a needle insert and held in place by clear tape. Sensing is based on the hydrogen peroxidebased enzyme electrode technology described above [34]. The glucose sensor signal is measured in nanoamperes, acquired every 10 seconds. An average of these signals is saved in the CGMS monitor every 5 minutes. At least four calibrations by SMBG per day are recommended, each entered into the CGMS monitor. These SMBG readings are used to calibrate the sensor readings retrospectively when the data are downloaded to a computer [35]. The clinical trials on the rst-generation CGMS showed good correlation between sensor readings and SMBG [36,37]. There have been a number of small trials to evaluate whether CGMS use improves metabolic control, and to assess the incidence of undiscovered hypoglycemia. Two studies showed an improvement in HbA1c with CGMS use [38,39] although one showed no dierence between CGMS versus frequent SMBG alone [40]. A recent randomized multi-center study involving 128 patients with type 1 diabetes mellitus found improvement in HbA1c in both the control group and the CGMS group, but signicantly less hypoglycemia in the CGMS group [41]. Others have questioned whether the CGMS data are reproducible [42], or whether the asymptomatic nocturnal hypoglycemia may be spurious [43]. With the introduction of a redesigned sensor and an updated software package by Medtronic MiniMed in 2002, there was improvement in correlation with mean absolute dierence and improved performance [44]. More studies need to be done using the current improved CGMS. Its intended use is to provide glucose trend information and to supplement SMBG [45,46]. The limitations of the CGMS include the requirement for frequent (four times daily) calibration, sensor warm-up period of an hour or more, and the rare possibility of irritation and infection at the sensor insertion site. Nevertheless, since its availability in 1999, CGMS has been used relatively widely by clinicians and researchers, and has been shown to be useful in detecting glycemic patterns even in children with type 1 diabetes

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mellitus [47,48], as well as asymptomatic hyper- and hypoglycemia in adults with well-controlled type 2 diabetes mellitus [49]. It also has been used as a research tool in various studies looking at glycemic excursions under dierent conditions ranging from the drug eect of pramlintide in type 1 diabetes mellitus [50] to patients who underwent islet cell transplant [51]. In many ways, CGMS has ushered in the era of continuous glucose monitoring on a clinical basis. GlucoWatch Biographer The second continuous glucose monitor to become available in the United States was the GlucoWatch Biographer (Cygnus, Redwood City, California). Unlike the CGMS, the GlucoWatch is worn on the arm like a wristwatch, and provides a real-time glucose display. It extracts interstitial uid through the skin using a process called reverse iontophoresis [52,53]. The glucose concentration of the extracted uid is measured by hydrogen peroxidebased enzyme electrode sensor in the disposable membrane on the back of the device. The new version of GlucoWatch G2 Biographer takes 2 hours to equilibrate, and then it is calibrated using a single SMBG value. Thereafter, it provides a glucose reading every 10 minutes for up to 13 hours [54]. The glucose readings displayed in real time have a mean lag time of about 15 minutes [55]. Clinical trials in dierent patient populations (type 1 and type 2 diabetes mellitus) and dierent environments (controlled versus home) showed good correlations between Biographer readings and capillary blood glucose readings [5558]. To optimize the trade-o between true positives and false positives for hypoglycemic alarms, the best setting of the alarm level was found to be 1.1 to 1.7 mmol/L (2030 mg/dL) above the level of concern [59]. A recent study in a pediatric population showed statistically signicant improvement in HbA1c in the biographer group compared with the control group where the biographer was worn four times a week for 3 months [60]. The clear advantages of the GlucoWatch system include the real-time display of data and the need to calibrate only once. Its limitations include the relatively short duration of function and the variable comfort of wearing the device. GlucoDay The GlucoDay system (Menarini Diagnostics, Florence, Italy) is currently available in Europe, not in the United States. It is the rst continuous sensor to be clinically available that uses a microdialysis technique to obtain interstitial uid. In the early 1990s, several groups in Europe began using the microdialysis approach for glucose monitoring [6163]. Pfeiers group [64,65] in Germany developed the so-called Ulm Zucker Uhr System. As summarized in an excellent review of microdialysis-based glucose sensing by

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Heinemann [66], a small catheter is inserted into the subcutaneous tissue and perfused with an isotonic solution without glucose. Glucose in the interstitial uid surrounding the catheter diuses down the concentration gradient across a semipermeable membrane into the catheter. This dialysate is collected outside the skin, and an amperometric glucose sensor measures glucose concentration of the dialysate [66]. The limitations of this system include problems with catheter insertion sites, signal drift caused by local tissue trauma and inammation [67], and an inevitable lag time, dependent on the dialysate ow rate [66,68,69]. The GlucoDay systems dialysate is pumped through the catheter at 10 lL/min, and the glucose concentration in the euent dialysate is measured ex vivo by an electrochemical sensor with immobilized glucose oxidase enzymes. The dialysate and waste uid are stored in two small plastic bags carried by the patient [69]. The physical lag time for this system is under 3 minutes because of the high dialysate ow rate, but this high ow rate may cause incomplete equilibrium of the dialysate with the interstitial uid and thus incomplete recovery of the interstitial glucose [66]. The device is calibrated at 2 hours after catheter insertion. It acquires glucose level every second with an average glucose value stored every 3 minutes, and can be used for up to 48 hours. The glucose values are available in real time along with hypo- and hyperglycemia alarm. They can be also be downloaded to a computer at the end of the monitoring period. A multicenter trial involving 70 subjects with diabetes showed promising results [66,69].

Systems approaching clinical availability The exact status of clinical availability changes from month to month. The authors describe the clinical availability of the systems as of this writing, but specic devices may move in (and out) of clinical availability quickly. Telemetered Glucose Monitoring System Medtronic MiniMeds Telemetered Glucose Monitoring System (TGMS) is a next generation of the CGMS. Its main new features are real-time glucose values and hypo- and hyperglycemic alarms according to preset, adjustable parameters [70]. Otherwise, the TGMS will operate like the CGMS, with a sensor placed subcutaneously, lasting about 3 days, and requiring SMBG calibration. Subcutaneous Continuous Glucose Monitoring System 1 The Subcutaneous Continuous Glucose Monitoring System 1 (SCGM1) (Roche Diagnostics GmbH, Mannheim, Germany), like the GlucoDay system, uses the microdialysis technique coupled to an external amperometric glucose sensor. With a low ow rate (0.3 lL/min) of the perfusate, it

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is said to last for up to 4 days with glucose value calculated every second and the average stored every minute [66]. According to plans, the system will be calibrated with a SMBG glucose value no more than once a day. It will provide trend information and hypo- and hyperglycemic alarms. The sensor unit holds the microdialysis catheter that is attached to the patient, and the waste uids from the dialysate. The glucose measurements obtained in this sensor unit are displayed, stored, and can be transmitted wirelessly to a data manager [66]. Some limitations of the SCGM1 include a warm-up time of about 12 hours [67], and because of the low perfusate pump rate, an inherent lag time of 31 minutes (2 minutes) [68]. A feasibility study of this device in 23 ambulatory inpatients, however, showed promising results [71], and a multicenter clinical study is reportedly underway [67].

External continuous glucose monitoring systems under development GluOnline The GluOnline system is being developed by Disetronic Medical Systems (Burgdorf, Switzerland). It uses microdialysis to obtain interstitial uid, but the analysis is coupled to a unique nonenzymatic glucose sensor referred to as the viscometric-anity sensor. The working principle is that the viscosity of a liquid containing dextran and concanavalin A (ConA) is highly glucosedependent [72]. Free glucose modulates the viscosity of this uid by competing with dextran to bind at the glycoligand binding site of ConA [73]. The glucose-sensitive liquid is pumped through the dialysis catheter at a ow rate of 5 lL/h. Viscosity after equilibration with interstitial uid is compared with the viscosity of the reference uid, and the dierence in the measured viscosity signals is transformed into glucose concentration. There is a technical delay of 5 to 10 minutes and the read-out of the implanted sensor has a time shift of 10 to 15 minutes [72]. An open-ow microperfusion approach Using yet another novel approach, Disetronic Medical System is developing the Open-ow Microperfusion technique as part of the Advanced Insulin Infusion with a Control Loop (ADICOL) project. This is a European Union research program sponsored by a consortium of partners from six European nations representing universities, research institutes, and industry. The goal is to provide the rst subcutaneous glucose-sensing/ subcutaneous insulin delivery (SC-SC) closed-loop insulin delivery system [74]. The open-ow microperfusion technique is based on a double lumen catheter with macroscopic (0.5 mm diameter) perforations, inserted into the subcutaneous adipose tissue. The perfusate enters the double lumen catheter

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through the inner cannula and then into the annular space between the inner cannula and the outer perforated catheter. With the perforated outer catheter, the perfusate is able to equilibrate with the interstitial uid while in the annular space. The outer lumen is connected to a peristaltic pump, which pumps the euent perfusate to a collecting system [75,76]. Currently, the technique acquires a glucose reading every 30 minutes [76,77]. Results from six patients with type 1 diabetes mellitus showed good performance, at least on the Clarke Error Grid [77]. SpectRx: a transdermal, biophotonic approach The SpectRxs biophotonic technology developed by SpectRx, Inc. (Norcross, Georgia) uses a laser device to create micropores (less than 100 lm in diameter) in the stratum corneum of the skin. Interstitial uid is collected through these micropores with mild suction, and glucose is measured in a biosensor patch containing an enzyme-based glucose assay. The patch is disposable, lasting up to 3 or more days. This system requires at least one calibration a day. Preliminary ndings showed better results on the rst day than subsequent days, and more trials are currently underway [78,79]. Other techniques Sonophoresis or phonophoresis techniques are in early development. The principle is that applying ultrasound to the skin can increase its permeability and transdermal transport [80]. The use of ultrasound pretreatment for noninvasive monitoring has also been investigated [81]. Whether this will ever function practically as a glucose sensor remains to be seen. Another technique for collection of uid transdermally is the suction blister technique to extract dermal interstitial uid for glucose analysis [82,83]. Noninvasive optical glucose sensors Each of the systems described above requires obtaining an interstitial or blood uid to analyze. A truly noninvasive glucose sensor, however, would not break the skin barrier at all. Optical glucose sensors fall into this category, and sensing glucose by transmitting light into or through the skin has a long, rocky history. There are two basic approaches to optical glucose sensing: absorbance of light and optical rotation of light. Each presents considerable technical challenges because glucose provides an extremely small signal relative to water and solutes other than glucose in tissue and blood. Several areas of the electromagnetic spectrum (wavelengths) have been used, including infrared and near-infrared spectroscopy. The specic techniques include Raman spectroscopy, uorescence spectroscopy, and polarimetry, each beyond the scope of this article. Interested readers are referred to several excellent reviews [24,84].

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At present, several groups continue to develop optical-based sensors, but in general they have involved large, bedside equipment rather than portable sensors. If they are to become practical, the optical sensors will have to be miniaturized and show that they function with various skin thicknesses and colors, states of tissue hydration, and levels of potentially interfering substances, whether endogenous (eg, urea) or exogenous (eg, drugs).

Implanted glucose sensors Implanted glucose sensors would have the obvious advantage of requiring no transdermal uid collection, and no risk for infection or irritation once the device is implanted. Because they involve an initial surgical procedure, they must function for much longer periods than is the case if they can be changed every few days, and because they cannot be removed as easily in the event of failure, they must be more robust. Medtronic MiniMed long-term intravenous glucose sensor The long-term intravenous glucose sensor currently under development by Medtronic MiniMed is based on the oxygen-based enzymatic glucose sensor by Gough and colleagues [85]. The sensor is percutaneously implanted by way of subclavian vein catheterization, with the sensor tip radiographically positioned into the superior vena cava or right atrium (ie, in areas of high blood ow). An external electronic module is used to record sensor output every minute. Small clinical trials in human are underway. Preliminary ndings based on the use of 15 sensors in 10 people with type 1 diabetes mellitus over a total of 11.8 patient-years showed encouraging results. In a preliminary report, no clotting or venous trauma was noted with average sensor duration of 287 days (range 89431 days) [86]. Although it shows great technical promise, the device has not moved into larger clinical trials as quickly as expected. Short-term intravenous glucose sensor Long-term intravenous sensors raise dicult issues of brin deposition, stability of placement, and so forth, but essentially the same technology could be used in short-term applications such as intensive care unit glucose monitoring. At the 2003 ADA 63rd Scientic Sessions, Medtronic MiniMed presented a late-breaking abstract (unpublished ndings, 2003) on the results of a feasibility study looking at intravenous glucose monitoring in critically ill patients. This is particularly attractive use of sensing because it is used in an already highly controlled, medically sophisticated environment; intravenous (even triple-lumen) lines are often already in place; and blood glucose swings may be particularly dangerous. Medtronic MiniMeds Vascular Glucose Monitoring System (VGMS) consists of an intravenous glucose sensor

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placed into the sheath port of a multilumen central venous catheter, with sensor tip position at the superior vena cava/right atrial junction. The sensor is calibrated using a standard glucose meter, and glucose data are collected every minute. The preliminary results from eight patients are promising, and the application could prove extremely valuable in intensive care units. Dexcoms long-term implantable subcutaneous glucose sensor Subcutaneous implantation is easier and less risky than long-term intravenous implantation, but the issue with long-term subcutaneous implantation has always been that devices (such as pacemakers or implanted insulin pumps) are quickly walled o by a thick capsule of scar tissue. How does a sensor device maintain contact with the rapidly changing glucose concentration of interstitial uid if it is walled o? DexCom (San Diego, California) is developing a device, based on technology developed by Updike and colleagues [30], that not only resists tissue encapsulation but promotes vascularization of the subcutaneously placed device. The prototype developed by Updike and colleagues [10,27,30,87] has a hydrogen peroxidebased enzyme electrode sensor [27]. It maintains longterm activity when implanted subcutaneously because of an angiogenic layer that encourages formation of capillaries, rather than brous tissue, adjacent to the sensor on the tissue surface of the membrane. There is also a special bioprotective membrane layer that prevents macrophages from contacting the enzyme-active membrane. The prototype reportedly can measure glucose at levels ranging from 40 mg/dL to 700 mg/dL (2.238.9 mmol/L), has a recalibration interval of 20 days, and has a maximum lifetime of over 160 days [30]. Results are telemetered externally. Preliminary data from a DexCom clinical trial involving 15 patients with type 1 diabetes mellitus, presented as a late-breaking abstract at the 2003 ADA 63rd Scientic Sessions (unpublished), showed promising results, with patients able to better manage their blood glucose with fewer hypoglycemic and hyperglycemic excursions. A simply implanted, accurate, and reliable long-term subcutaneous sensor would be a valuable addition to sensor development.

Closing the loop: the articial endocrine pancreas Since insulin pump and sensor work began, the notion of a fully automated articial pancreas has been the nal goal. The basic elements of the closed loop articial pancreas are not hard to imagine: a sensor, a delivery system, and programming to link the two. The delivery systems, external and implanted, have developed far more successfully over the past decades, but sensor technology is now moving forward quickly. As with most advances in medicine, the closed-loop insulin delivery based on sensor-derived glucose values is not likely to come as a single

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breakthrough, but incrementally. This discussion notes the status of various steps in closing the loop. Controlling external insulin pumps In 1976, Pickup and colleagues [88] were among the pioneers in developing continuous insulin infusion (CSII) (ie, use of the external insulin pump). By 2001, an estimated 200,000 people worldwide and over 130,000 people in the United States [89] were using CSII. Although all these pumps normally are controlled on an entirely open-loop basis (with the patient deciding proper dosing based on SMBG), a meta-analysis of randomized controlled trials showed small but statistically signicant lower mean blood glucose level, lower HbA1c, and lower insulin dose in the CSII groups compared with intensive insulin injections [90]. Health care professionals have taught and written a variety of sliding scales, but it has always depended on the patient to close the loop (ie, to judge what dose of insulin is needed when). In 2003, Medtronic MiniMed, in partnership with BD (Becton, Dickinson & Co., Franklin Lakes, New Jersey), gained regulatory approval in the United States to market an external pump that begins to automate the process of dose selection. The system establishes a communication between a blood glucose meter (Paradigm Link Blood Glucose Monitor) and the Paradigm 512 external pump. With this telemetered link, the pump records the blood glucose value. If the health care professional has programmed into the pump the estimated insulin requirement for a given blood glucose and a given amount of carbohydrate to be consumed, and if the patient accurately estimates and enters the meal size, the pump then displays a suggested insulin dose, which the patient can accept or modify. The programming can consider factors such as a recent dose that is still having an eect. This new device can be considered the rst practical step in closing the loop because it involves communication of a blood glucose value and translation into a recommended insulin dose. Clearly, it is far from a fully automated system. Next steps could include telemetry between a continuous glucose sensor (such as the Medtronic MiniMed TGMS or the Cygnus GlucoWatch) and an insulin pump. Implantable pumps The development of open-loop implantable insulin pumps (IIP) has stretched over the past 25 years, but intraperitoneal insulin delivery by IIP is now largely successful. Blackshear and colleagues [91,92] pioneered the investigational use of IIP for the treatment of diabetes in humans in the 1970s. Currently, the only available device is the Medtronic MiniMed MMT-2007C, which is available in selected centers in France [93]; trials are still underway in the United States. Over the years, studies in types 1 and 2 diabetes mellitus patients have shown consistently that HbA1c is modestly

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reduced, and glycemic uctuations and hypoglycemic events are markedly reduced [9497]. Interested readers are referred to several comprehensive reviews on IIPs [98,99]. A recent short-term closed-loop trial of 10 patients with type 1 diabetes mellitus is reported in an abstract [86]. IIPs were linked to an intravenous glucose sensor for fully automated 48-hour closed-loop insulin delivery. The results were promising with the time recorded, with glucose levels less than 70 mg/dL reduced from 18% to 6%, and glucose values greater than 240 mg/dL levels reduced from 17% to 2%. The report is preliminary, however, and more research is needed to demonstrate the ecacy and practicality of this system. Other approaches to closing the loop If both the potential sensors and delivery systems can be classied as external or implanted, then there are four conceivable approaches to closing the loop: (1) external sensor/external pump, (2) external sensor/ implanted pump, (3) implanted sensor/external pump, and (4) implanted sensor/implanted pump. All studies with closed loop systems are preliminary and in early stages. In one feasibility study, CGMS was modied and used in real time to control blood glucose with intravenous insulin infusion using a closed-loop algorithm in ve critically ill patients. The results showed that the closedloop system performed comparably to manual control [100]. Another, the ADICOL project, uses the external/external approach, with subcutaneous sensing and subcutaneous, closed-loop insulin delivery system [74]. Using a model predictive control (MCP) algorithm with simulated subcutaneous glucose values (intravenous glucose values+30 minutes delay) in six people with type 1 diabetes mellitus, mean blood glucose levels were 123 17 mg/dL in the fasting state and 116 32 mg/dL in the postprandial state, compared with 179 70 mg/dL in the observation period (without closed-loop control) [101]. In another study, the intravenous-subcutaneous route was compared with the subcutaneoussubcutaneous route using the MCP algorithm with six subjects in each group. There was no signicant dierence in blood glucose values between the two routes at any time during blood glucose control with the systems [102]. Importantly, however, the subcutaneous glucose values used in both studies were only simulated, meaning they were derived by intravenous glucose values +30 minutes delay, greatly limiting their interpretation.

Summary Sensor-driven, closed-loop insulin delivery has been a long-term goal of many researchers. Delivery systems (insulin pumps), both external and implanted, are used widely and successfully, but the sensor component has

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been more dicult to bring to practical reality. Over the past few years, however, rapid progress has been made in glucose sensing. CGMS was the rst continuous glucose monitor to be approved for use by the US Food and Drug Administration, and the GlucoWatch was the second. Each has generated considerable clinical and research interest, and undoubtedly there will be more continuous glucose sensors on the market over the next few years. Indeed, we seem to be entering an era in which continuous glucose monitoring will be a standard part of diabetes care, revolutionizing clinical management. Many questions remain, and research will be stimulated by the easy availability of continuous monitoring. The goal of the fully automated, closed-loop, IIP remains years away. But when it is attained, implanting a long-term, reliable, low-maintenance, closed-loop device could rightly be categorized as a technological cure for diabetes mellitus.

References
[1] Lewis RC, Benedict SR. A method for the estimation of sugar in small quantities of blood. J Biol Chem 1915;20:6172. [2] Bliss M. The discovery of insulin. Chicago: The University of Chicago Press; 1982. [3] Skyler JS, Lasky IA, Skyler DL, Robertson EG, Mintz DH. Home blood glucose monitoring as an aid in diabetes management. Diabetes Care 1978;1(3):1507. [4] Sonksen PH, Judd SL, Lowy C. Home monitoring of blood-glucose. Method for improving diabetic control. Lancet 1978;1(8067):72932. [5] Solnica B, Naskalski JW, Sieradzki J. Analytical performance of glucometers used for routine glucose self-monitoring of diabetic patients. Clin Chim Acta 2003;331(12):2935. [6] American Diabetes Association. Self-monitoring of blood glucose. Diabetes Care 1994; 17(1):816. [7] The Diabetes Control and Complications Trial Research Group. The eect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329(14):97786. [8] Preventive-care practices among persons with diabetesUnited States, 1995 and 2001. MMWR Morb Mortal Wkly Rep 2002;51(43):9659. [9] Clark LC Jr, Lyons C. Electrode systems for continuous monitoring in cardiovascular surgery. Ann N Y Acad Sci 1962;102:2945. [10] Updike SJ, Hicks GP. The enzyme electrode. Nature 1967;214(92):9868. [11] Kadish AH. Automation control of blood glucose: a servo mechanism for glucose monitoring and control. Am J Med Electron 1964;3:826. [12] Albisser AM, Leibel BS, Ewart TG, Davidovac Z, Botz CK, Zingg W. An articial endocrine pancreas. Diabetes 1974;23(5):38996. [13] Albisser AM, Leibel BS, Ewart TG, Davidovac Z, Botz CK, Zingg W, et al. Clinical control of diabetes by the articial pancreas. Diabetes 1974;23(5):397404. [14] Pfeier EF, Thum C, Clemens AH. The articial beta cella continuous control of blood sugar by external regulation of insulin infusion (glucose controlled insulin infusion system). Horm Metab Res 1974;6(5):33942. [15] Clemens AH, Chang PH, Myers RW. The development of Biostator, a glucose controlled insulin infusion system (GCIIS). Horm Metab Res 1977;(Suppl 7):2333. [16] Hansen KA, Duck SC. Teledyne Sleep Sentry: evaluation in pediatric patients for detection of nocturnal hypoglycemia. Diabetes Care 1983;6(6):597600.

C.W. Chia, C.D. Saudek / Endocrinol Metab Clin N Am 33 (2004) 175195

191

[17] Clarke WL, Carter WR, Moll M, Cox DJ, Gonder-Frederick LA, Cryer PE. Metabolic and cutaneous events associated with hypoglycemia detected by sleep sentry. Diabetes Care 1988;11(8):6305. [18] Guide for Measures of Precision and Accuracy. Anal Chem 1968;40(14):2271. [19] Cox DJ, Clarke WL, Gonder-Frederick L, Pohl S, Hoover C, Snyder A, et al. Accuracy of perceiving blood glucose in IDDM. Diabetes Care 1985;8(6):52936. [20] Clarke WL, Cox D, Gonder-Frederick LA, Carter W, Pohl SL. Evaluating clinical accuracy of systems for self-monitoring of blood glucose. Diabetes Care 1987;10(5):6228. [21] Gough DA, Botvinick EL. Reservations on the use of error grid analysis for the validation of blood glucose assays. Diabetes Care 1997;20(6):10346. [22] Cox DJ, Gonder-Frederick LA, Kovatchev BP, Julian DM, Clarke WL. Understanding error grid analysis. Diabetes Care 1997;20(6):9112. [23] Brunner GA, Ellmerer M, Sendlhofer G, Wutte A, Trajanoski Z, Schaupp L, et al. Validation of home blood glucose meters with respect to clinical and analytical approaches. Diabetes Care 1998;21(4):58590. [24] McNichols RJ, Cote GL. Optical glucose sensing in biological uids: an overview. J Biomed Opt 2000;5(1):516. [25] Gough DA, Leypoldt JK, Armour JC. Progress toward a potentially implantable, enzyme-based glucose sensor. Diabetes Care 1982;5(3):1908. [26] Shichiri M, Kawamori R, Yamasaki Y, Hakui N, Abe H. Wearable articial endocrine pancrease with needle-type glucose sensor. Lancet 1982;2(8308):112931. [27] Gilligan BJ, Shults MC, Rhodes RK, Updike SJ. Evaluation of a subcutaneous glucose sensor out to 3 months in a dog model. Diabetes Care 1994;17(8):8827. [28] Johnson KW, Mastrototaro JJ, Howey DC, Brunelle RL, Burden-Brady PL, Bryan NA, et al. In vivo evaluation of an electroenzymatic glucose sensor implanted in subcutaneous tissue. Biosens Bioelectron 1992;7(10):70914. [29] Gough DA, Armour JC. Development of the implantable glucose sensor. What are the prospects and why is it taking so long? Diabetes 1995;44(9):10059. [30] Updike SJ, Shults MC, Gilligan BJ, Rhodes RK. A subcutaneous glucose sensor with improved longevity, dynamic range, and stability of calibration. Diabetes Care 2000; 23(2):20814. [31] Gough DA, Armour JC, Baker DA. Advances and prospects in glucose assay technology. Diabetologia 1997;40(Suppl 2):S1027. [32] Heller A. Implanted electrochemical glucose sensors for the management of diabetes. Annu Rev Biomed Eng 1999;1:15375. [33] Zierler K. Whole body glucose metabolism. Am J Physiol 1999;276(3 Pt 1):E40926. [34] Rebrin K, Steil GM, van Antwerp WP, Mastrototaro JJ. Subcutaneous glucose predicts plasma glucose independent of insulin: implications for continuous monitoring. Am J Physiol 1999;277(3 Pt 1):E56171. [35] Mastrototaro J. The MiniMed Continuous Glucose Monitoring System (CGMS). J Pediatr Endocrinol Metab 1999;12(Suppl 3):7518. [36] Gross TM, Mastrototaro JJ. Ecacy and reliability of the continuous glucose monitoring system. Diabetes Technol Ther 2000;2(Suppl 1):S1926. [37] Gross TM, Ter Veer A. Continuous glucose monitoring in previously unstudied population subgroups. Diabetes Technol Ther 2000;2(Suppl 1):S2734. [38] Ludvigsson J, Hanas R. Continuous subcutaneous glucose monitoring improved metabolic control in pediatric patients with type 1 diabetes: a controlled crossover study. Pediatrics 2003;111(5 Pt 1):9338. [39] Chase HP, Kim LM, Owen SL, MacKenzie TA, Klingensmith GJ, Murtfeldt R, et al. Continuous subcutaneous glucose monitoring in children with type 1 diabetes. Pediatrics 2001;107(2):2226. [40] Chico A, Vidal-Rios P, Subira M, Novials A. The continuous glucose monitoring system is useful for detecting unrecognized hypoglycemias in patients with type 1 and type 2

192

C.W. Chia, C.D. Saudek / Endocrinol Metab Clin N Am 33 (2004) 175195 diabetes but is not better than frequent capillary glucose measurements for improving metabolic control. Diabetes Care 2003;26(4):11537. Bode B, Lane W, Levetan C, Mestman J, Peters Harmel A, Tanenberg R, et al. Therapy adjustments based on CGMS data lower HbA1c with less hypoglycemia than blood glucose meter data alone. Diabetes 2003;52(S1):A90. Metzger M, Leibowitz G, Wainstein J, Glaser B, Raz I. Reproducibility of glucose measurements using the glucose sensor. Diabetes Care 2002;25(7):118591. McGowan K, Thomas W, Moran A. Spurious reporting of nocturnal hypoglycemia by CGMS in patients with tightly controlled type 1 diabetes. Diabetes Care 2002;25(9): 1499503. Gross T, Mastrototaro J, Shin J, Phongpharnich P, Shi M. Improved performance of the Metronic MiniMed CGMS using redesigned glucose sensors and updated calibration software. Diabetes 2003;52(S1):A95. Mastrototaro JJ, Gross TM. Reproducibility of the continuous glucose monitoring system matches previous reports and the intended use of the product [author reply: 256 7]. Diabetes Care 2003;26(1):256. Guerci B, Floriot M, Bohme P, Durain D, Benichou M, Jellimann S, et al. Clinical performance of CGMS in type 1 diabetic patients treated by continuous subcutaneous insulin infusion using insulin analogs. Diabetes Care 2003;26(3):5829. Kaufman FR, Gibson LC, Halvorson M, Carpenter S, Fisher LK, Pitukcheewanont P. A pilot study of the continuous glucose monitoring system: clinical decisions and glycemic control after its use in pediatric type 1 diabetic subjects. Diabetes Care 2001; 24(12):20304. Boland E, Monsod T, Delucia M, Brandt CA, Fernando S, Tamborlane WV. Limitations of conventional methods of self-monitoring of blood glucose: lessons learned from 3 days of continuous glucose sensing in pediatric patients with type 1 diabetes. Diabetes Care 2001;24(11):185862. Hay LC, Wilmshurst EG, Fulcher G. Unrecognized hypo- and hyperglycemia in wellcontrolled patients with type 2 diabetes mellitus: the results of continuous glucose monitoring. Diabetes Technol Ther 2003;5(1):1926. Levetan C, Want LL, Weyer C, Strobel SA, Crean J, Wang Y, et al. Impact of pramlintide on glucose uctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 2003;26(1):18. Kessler L, Passemard R, Oberholzer J, Benchamou PY, Bucher P, Toso C, et al. Reduction of blood glucose variability in type 1 diabetic patients treated by pancreatic islet transplantation: interest of continuous glucose monitoring. Diabetes Care 2002; 25(12):225662. Glikfeld P, Hinz RS, Guy RH. Noninvasive sampling of biological uids by iontophoresis. Pharm Res 1989;6(11):98890. Rao G, Glikfeld P, Guy RH. Reverse iontophoresis: development of a noninvasive approach for glucose monitoring. Pharm Res 1993;10(12):17515. GlucoWatch G2 Automatic Glucose Biographer. Available at: http://www.glucowatch. com. Accessed January 12, 2004. Tamada JA, Garg S, Jovanovic L, Pitzer KR, Fermi S, Potts RO. Noninvasive glucose monitoring: comprehensive clinical results. Cygnus research team. JAMA 1999;282(19): 183944. Garg SK, Potts RO, Ackerman NR, Fermi SJ, Tamada JA, Chase HP. Correlation of ngerstick blood glucose measurements with GlucoWatch biographer glucose results in young subjects with type 1 diabetes. Diabetes Care 1999;22(10):170814. Tierney MJ, Tamada JA, Potts RO, Eastman RC, Pitzer K, Ackerman NR, et al. The GlucoWatch biographer: a frequent automatic and noninvasive glucose monitor. Ann Med 2000;32(9):63241.

[41]

[42] [43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52] [53] [54] [55]

[56]

[57]

C.W. Chia, C.D. Saudek / Endocrinol Metab Clin N Am 33 (2004) 175195

193

[58] Tierney MJ, Tamada JA, Potts RO, Jovanovic L, Garg S. Clinical evaluation of the GlucoWatch biographer: a continual, non-invasive glucose monitor for patients with diabetes. Biosens Bioelectron 2001;16(912):6219. [59] Pitzer KR, Desai S, Dunn T, Edelman S, Jayalakshmi Y, Kennedy J, et al. Detection of hypoglycemia with the GlucoWatch biographer. Diabetes Care 2001;24(5):8815. [60] Chase HP, Roberts MD, Wightman C, Klingensmith G, Garg SK, Van Wyhe M, et al. Use of the GlucoWatch biographer in children with type 1 diabetes. Pediatrics 2003; 111(4 Pt 1):7904. [61] Bolinder J, Hagstrom E, Ungerstedt U, Arner P. Microdialysis of subcutaneous adipose tissue in vivo for continuous glucose monitoring in man. Scand J Clin Lab Invest 1989; 49(5):46574. [62] Keck FS, Kerner W, Meyerho C, Zier H, Pfeier EF. Combination of microdialysis and Glucosensor permits continuous (on line) s.c. glucose monitoring in a patient operated device: I. In vitro evaluation. Horm Metab Res 1991;23(12):6178. [63] Schoonen AJ, Schmidt FJ, Hasper H, Verbrugge DA, Tiessen RG, Lerk CF. Development of a potentially wearable glucose sensor for patients with diabetes mellitus: design and in-vitro evaluation. Biosens Bioelectron 1990;5(1):3746. [64] Meyerho C, Bischof F, Sternberg F, Zier H, Pfeier EF. On line continuous monitoring of subcutaneous tissue glucose in men by combining portable glucosensor with microdialysis. Diabetologia 1992;35(11):108792. [65] Pfeier EF. The Ulm Zucker Uhr System and its consequences. Horm Metab Res 1994; 26(11):5104. [66] Heinemann L. Continuous glucose monitoring by means of the microdialysis technique: underlying fundamental aspects. Diabetes Technol Ther 2003;5(4):54561. [67] Wientjes KJ, Grob U, Hattemer A, Hoogenberg K, Jungheim K, Kapitza C, et al. Eects of microdialysis catheter insertion into the subcutaneous adipose tissue assessed by the SCGM1 system. Diabetes Technol Ther 2003;5(4):61520. [68] Schoemaker M, Andreis E, Roper J, Kotulla R, Lodwig V, Obermaier K, et al. The SCGM1 system: subcutaneous continuous glucose monitoring based on microdialysis technique. Diabetes Technol Ther 2003;5(4):599608. [69] Maran A, Crepaldi C, Tiengo A, Grassi G, Vitali E, Pagano G, et al. Continuous subcutaneous glucose monitoring in diabetic patients: a multicenter analysis. Diabetes Care 2002;25(2):34752. [70] Mastrototaro J, Shin J, Ter Veer A, Shi M, Phongpharnich P. The Telemetered Glucose Monitoring System (TGMS) reliably and accurately alerts users to hypo- and hyperglycemia based on real-time glucose values. Diabetes 2003;52(S1):A36. [71] Jungheim K, Wientjes KJ, Heinemann L, Lodwig V, Koschinsky T, Schoonen AJ. Subcutaneous continuous glucose monitoring: feasibility of a new microdialysis-based glucose sensor system. Diabetes Care 2001;24(9):16967. [72] Beyer U, Schafer D, Thomas A, Aulich H, Haueter U, Reihl B, et al. Recording of subcutaneous glucose dynamics by a viscometric anity sensor. Diabetologia 2001;44(4): 41623. [73] Beyer U, Ehwald R. Compensation of temperature and concanavalin A concentratration eects for glucose determination by the viscometric anity assay. Biotechnol Prog 2000; 16(6):111923. [74] Advanced insulin infusion with a control loop. Available at: http://www.adicol.org. Accessed January 12, 2004. [75] Trajanoski Z, Brunner GA, Schaupp L, Ellmerer M, Wach P, Pieber TR, et al. Open-ow microperfusion of subcutaneous adipose tissue for on-line continuous ex vivo measurement of glucose concentration. Diabetes Care 1997;20(7):111421. [76] Schaupp L, Ellmerer M, Brunner GA, Wutte A, Sendlhofer G, Trajanoski Z, et al. Direct access to interstitial uid in adipose tissue in humans by use of open-ow microperfusion. Am J Physiol 1999;276(2 Pt 1):E4018.

194

C.W. Chia, C.D. Saudek / Endocrinol Metab Clin N Am 33 (2004) 175195

[77] Schaupp L, Schaller HC, Bodenlenz M, Haueter U, Vering T, Wutte A, et al. Simultaneous glucose measurement in interstitial uid with s.c. glucose and open-ow microperfusion in patients with Type 1 DM. Diabetologia 2002;45(S2):A2789. [78] SpectRx: an innovative medical technology company. Available at: http://www.spectrx. com. Accessed January 12, 2004. [79] Burdick J, Chase HP, Fialloscharer R, Faupel M, Wangness M, Gebhart S. Optimization of the SpectRx Continuous Glucose Monitoring System (SCGMS) in pediatric patients with type 1 diabetes. Diabetes 2003;52(S1):A901. [80] Kost J. Ultrasound-assisted insulin delivery and noninvasive glucose sensing. Diabetes Technol Ther 2002;4(4):48997. [81] Kost J, Mitragotri S, Gabbay RA, Pishko M, Langer R. Transdermal monitoring of glucose and other analytes using ultrasound. Nat Med 2000;6(3):34750. [82] Thennadil SN, Rennert JL, Wenzel BJ, Hazen KH, Ruchti TL, Block MB. Comparison of glucose concentration in interstitial uid, and capillary and venous blood during rapid changes in blood glucose levels. Diabetes Technol Ther 2001;3(3):35765. [83] Jensen BM, Bjerring P, Christiansen JS, Orskov H. Glucose content in human skin: relationship with blood glucose levels. Scand J Clin Lab Invest 1995;55(5):42732. [84] Klono DC. Noninvasive blood glucose monitoring. Diabetes Care 1997;20(3):4337. [85] Armour JC, Lucisano JY, McKean BD, Gough DA. Application of chronic intravascular blood glucose sensor in dogs. Diabetes 1990;39(12):151926. [86] Renard E, Shah R, Miller M, Kolopp M, Costalat G, Bringer J. Sustained safety and accuracy of central IV glucose sensors connected to implanted insulin pumps and short term closed-loop trials in diabetic patients. Diabetes 2003;52(S1):A36. [87] Rhodes RK, Shults MC, Updike SJ. Prediction of pocket-portable and implantable glucose enzyme electrode performance from combined species permeability and digital stimulation analysis. Anal Chem 1994;66(9):15209. [88] Pickup JC, Keen H, Parsons JA, Alberti KG. Continuous subcutaneous insulin infusion: an approach to achieving normoglycaemia. Br Med J 1978;1(6107):2047. [89] Pickup J, Keen H. Continuous subcutaneous insulin infusion at 25 years: evidence base for the expanding use of insulin pump therapy in type 1 diabetes. Diabetes Care 2002; 25(3):5938. [90] Pickup J, Mattock M, Kerry S. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: metaanalysis of randomised controlled trials. BMJ 2002;324(7339):705. [91] Blackshear PJ, Dorman FD, Blackshear PL Jr, Varco RL, Buchwald H. The design and initial testing of an implantable infusion pump. Surg Gynecol Obstet 1972;134(1): 516. [92] Blackshear PJ, Shulman GI, Roussell AM, Nathan DM, Minaker KL, Rowe JW, et al. Metabolic response to three years of continuous, basal rate intravenous insulin infusion in type II diabetic patients. J Clin Endocrinol Metab 1985;61(4):75360. [93] Selam JL. External and implantable insulin pumps: current place in the treatment of diabetes. Exp Clin Endocrinol Diabetes 2001;109(Suppl 2):S33340. [94] Broussolle C, Jeandidier N, Hanaire-Broutin H. French multicentre experience of implantable insulin pumps. The EVADIAC Study Group. Evaluation of active implants in diabetes society. Lancet 1994;343(8896):5145. [95] Saudek CD, Duckworth WC, Giobbie-Hurder A, Henderson WG, Henry RR, Kelley DE, et al. Implantable insulin pump vs multiple-dose insulin for non-insulin-dependent diabetes mellitus: a randomized clinical trial. Department of Veterans Aairs Implantable Insulin Pump Study Group. JAMA 1996;276(16):13227. [96] Jeandidier N, Selam JL, Renard E, Guerci B, Lassman-Vague V, Rocher L, et al. Decreased severe hypoglycemia frequency during intraperitoneal insulin infusion using programmable implantable pumps. Evadiac Study Group. Diabetes Care 1996;19(7):780.

C.W. Chia, C.D. Saudek / Endocrinol Metab Clin N Am 33 (2004) 175195

195

[97] Hanaire-Broutin H, Broussolle C, Jeandidier N, Renard E, Guerci B, Haardt MJ, et al. Feasibility of intraperitoneal insulin therapy with programmable implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Evaluation dans le Diabete du Traitement par Implants Actifs. Diabetes Care 1995;18(3):38892. [98] Saudek CD, Chia CW. Implantable pumps. In: De Fronzo RA, Ferrannini E, Keen H, Zimmet P, editors. International texbook of diabetes mellitus. 3rd edition. Chichester: John Wiley & Sons, Ltd; 2004, in press. [99] Lassmann-Vague V, Guerci B, Hanaire-Broutin H, Pinget M, Renard E, Selam JL, et al. Use of implantable insulin pumps: the EVADIAC position. Recommendations of ALFEDIAM (French Language Association for the Study of Diabetes and Metabolic Diseases). Evaluation dans le Diabete du Traitement par Implants Actifs. Diabetes Metab 1997;23(3):23450. [100] Chee F, Fernando T, van Heerden PV. Closed-loop glucose control in critically ill patients using continuous glucose monitoring system (CGMS) in real time. IEEE Trans Inf Technol Biomed 2003;7(1):4353. [101] Canonico V, Orsini Federici M, Ferolla P, Celleno R, Akwe J, Timi A, et al. Evaluation of a feedback model based on simulated interstitial glucose for continuous insulin infusion. Diabetologia 2002;45(S2):A322. [102] Schaller HC, Schaupp LA, Bodenlenz M, Sommer R, Wutte A, Semilitsch B, et al. Feasibility of the SC-SC route for an extracorporeal articial pancreas. Diabetes 2002; 51(S2):A114.