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Monitoring Technologies- Continuous Monitoring, Biomarkers of Control, Artificial Pancreas

Page history last edited by Robert Rushakoff, MD 13 years, 11 months ago


The Web diabetesmanager



Monitoring Technologies- Continuous Glucose Monitoring, Biomarkers Of Glycemic Control, Artificial Pancreas


Gloria Yee, RN, CDE 

David C Klonoff, MD


 Last Author Revision:  2010 





Three trends are emerging in self-monitoring of diabetes during the early 21st century. At this time we are seeing the increasing availability and use of: 1) continuous glucose monitoring; 2) home testing of biomarkers of glycemic control; and 3) the early stages of development of closed loop control systems.


The current technology for self monitoring of blood glucose levels has been well established since the 1980's. This practice is beneficial to patients with diabetes from both a clinical and an economic standpoint. Knowledge of the blood glucose levels that are measured can allow a patient to select an appropriate dose of insulin to regulate the blood glucose levels. Continuous glucose monitoring is the next step in glucose monitoring. This practice is not yet widely established, but evidence supporting its use is accumulating. The data available through continuous glucose monitoring can permit significantly more fine-tune adjustments in insulin dosing and other therapies than spot testing from self monitoring of blood glucose can provide. Continuous glucose monitoring technologies for automatic collection of data have spurred interest in alternate site testing of blood glucose and noninvasive glucose monitoring, as additional tools for obtaining information about glucose levels.

In recent years, self monitoring of additional analytes besides glucose is becoming established. Many patients are now self-testing other biomarkers of glycemic control. The number of these tests is increasing and the convenience of making these measurements is also increasing.


The next step in determining insulin dosing is not yet commercially available but will revolutionize diabetes management. The future technology that will permit adjustment of insulin dosage and with automatic control is closed loop control. This approach, also known as the artificial pancreas, is currently being developed. An artificial pancreas will link continuous blood glucose measurement with automatically controlled insulin delivery, using non-living components made of silicon, plastic, and metal. This chapter analyzes the technology, benefits, and problems with the use of continuous glucose monitoring, home testing of biomarkers of glycemic control, and the artificial pancreas.



Continuous Glucose Monitors (CGM) measures interstitial glucose levels continuously and updates the glucose level every 1 to 5 minutes.  Most CGMs consist of 1) a monitor to display the information, 2) a sensor that is usually inserted into the subcutaneous tissue, and 3) a transmitter that transmits the sensor data to the monitor.  CGM can provide both retrospective as well as real-time information to detect: 1) hypoglycemic and hyperglycemic excursions; 2) predict impending hypoglycemia; and 3) wide fluctuations in glucose levels, also known as glycemic variability.  24 hour telephone support is available for all the FDA approved CGM devices.  Use of CGM can help both the patient and their medical provider  make fine tune adjustments to medication therapy and provide insight to the patient on behavioral changes to acheive glycemic control  Additionally, current efforts to link continuous blood glucose measurement with automatically controlled insulin delivery, using non-living components made of silicon, plastic, and metal will lead to an artificial pancreas.  


Overview of Available Systems


Six continuous glucose monitors have been approved by the US Food and Drug Administration (FDA) for use in the United States or carry CE marking for use in Europe. They are: 1) the Continuous Glucose Monitoring System Gold (CGMS Gold) (Medtronic Diabetes, Northridge, CA) [1] (Figure 1); 2) the GlucoWatch G2 Biographer ("GlucoWatch") (formerly Cygnus, Inc., Redwood City, CA) [2] (Figure 2); 3) the Guardian Telemetered Glucose Monitoring System ("Guardian") (Medtronic Diabetes, Northridge, CA) [3]; 4) Guardian RT (Medtronic Diabetes, Northridge, CA) [4]; 5) GlucoDay-S (A. Menarini Diagnostics, Florence, Italy) [5] (Figure 3); and 6) Dexcom Seven Plus (Dexcom, San Diego, CA) [6] (Figure 4). All but GlucoDay are available in the US. FreeStyle Navigator (Abbott Diabetes Care, Alameda, California) [7] (Figure 5).




Figure 1. Continuous Glucose Monitoring System. A - Sensor. B - Sensor inserter known as a Senserter. C - Monitor. D - Monitor connected to a docking station and downloading data into a computer.




Figure 2. GlucoWatch G2 Biographer.





Figure 3. GlucoDay S continuous glucose monitor...





Figure 4. STS: A - Receiver. B - Applicator containing a Sensor ready for insertion. C - Transmitter which will be attached to the Sensor, after the Sensor is inserted.





Figure 5. Insertion of the FreeStyle Navigator: A - Attach sensor mount to the skin. B - Press to insert sensor. C - Attach transmitter to the sensor mount. D - Data is transmitted to the receiver.





The first device for reading blood glucose levels continuously was approved by the FDA in June 1999. This device was the Continuous Glucose Monitor System (CGMS) manufactured by Medtronic MiniMed. A second generation version of this device, containing the same sensor but improved software for smoothing out calculated glucose levels from the end of one day leading into the beginning of the next day, was approved in 2003. This device is known as the CGMS Gold, but over the past few years, many users have omitted the term "Gold" when they use it and write about it. This chapter will also omit the word "Gold". The CGMS measures interstitial fluid glucose continuously. It calculates and stores a reading every five minutes over a 72-hour period. The CGMS does not provide the glucose results in real time, but rather downloads the readings after they have been collected, the way a 24-hour cardiac holter monitor provides information about cardiac rhythms after they have occurred. The data can be studied retrospectively after the data is downloaded. The diabetes caregiver should look for patterns of intermittent hyperglycemia (especially after meals), intermittent hypoglycemia (especially during the night), and wide fluctuations of glucose levels, all of which should be treated.


Continuous glucose data can demonstrate patterns that that can be used as a basis for adjustments in therapy. An example of a patient who used continuous monitoring (with a CGMS Gold) is presented in Figure 6. The continuous glucose monitor demonstrated high glucose levels from 11:00-13:30 and low glucose levels from 16:00 - 21:00. Recognition of these patterns allowed appropriately timed treatment interventions.



Figure 6. CGMS Gold three-day tracing of a patient whose glucose levels were high from 11:00 - 3:30 and low from 16:00 - 1:00.


Three features of the continuous glucose data should be analyzed in particular. These are: 1) the overnight period; 2) the pre prandial period; and 3) the post prandial period. Out-of-target overnight glucose levels can be modified by adjusting the basal dose. Out-of-target preprandial glucose levels can be modified by adjusting the previous meal bolus, meal or exercise pattern. Out-of-target postprandial glucose levels can be modified by adjusting the immediate meal bolus, meal or exercise pattern. In certain special situations, such as hypoglycemia unawareness, the target glucose levels must be raised, and during pregnancy the target glucose levels must be lowered. For patients at extremes of the age spectrum, target glucose levels may need to be raised.


The CGMS contains a wire with a supply of glucose oxidase at the tip, which is inserted subcutaneously into the anterior abdominal wall with a dedicated inserting device, the Senserter. This same enzyme for recognizing glucose molecules is used in many portable blood glucose monitors. Glucose oxidase catalyses a biochemical reaction in the presence of glucose and Oxygen that transfers electrons to a receiving molecule and creates an electronic current, whose magnitude can be measured and converted into a glucose concentration. After 72 hours of measurements, the device is removed and plugged into a docking station to download its readings into a computer.

The docking station can be connected to a computer that contains dedicated software, called Solutions, for use with the system. The computer will then print out a graph of the three days' blood glucose readings. The CGMS must be recalibrated with a fingerstick blood glucose reading at least four times per day.


The greatest number of studies describing the performance of continuous glucose monitoring has been reported with the CGMS. The biosensor in this system has been reported to have a median average relative deviation of 11-12%. [8][9] The accuracy of all commercially available continuous glucose monitors is the lowest in the hypoglycemic range, which is where the need for sensitivity and specificity is great in terms of serving as an alarm for hypoglycemia. Software is being developed that will predict 15-30 minutes into the future and alert the user of pending hypoglycemia. As the time window into the future increases, the accuracy of these predictions will decline.



The Guardian was approved February 11, 2004. This device contains the same sensor as the CGMS system, but the sensor and monitor are not connected by a wire. Rather the sensor communicates with the monitor by a wireless transmitter. The Guardian system, like the CGMS, provides retrospective glucose data, but a significant difference is that this device also contains a real time alarm. This 50 db alarm sounds and vibrates if the glucose level becomes higher or lower than preset limits determined by the patient. The Guardian provides a realtime audible alert in such a situation, but does never displays a real time glucose reading, even when the alarm sounds for hypoglycemia or hyperglycemia. In case of an alarm, the patient is advised by the manufacturer to check a SMBG reading and take action based on that reading.


A hypoglycemia alarm will demonstrate both sensitivity and specificity at correctly identifying every true hypoglycemic event. The user will experience a tradeoff between a high alarm sensitivity (which is a tendency to identify every true hypoglycemic even at the expense of also sounding sometimes during periods of normal glucose); and a high alarm specificity (which is a tendency for the alarm to be correct when sounded, at the expense of failing to sound for some hypoglycemic events) (Figure 7).



Figure 7. Tradeoffs between emphasis on high sensitivity compared to emphasis on high specificity in a hypoglycaemic alarm that is part of a continuous glucose monitor.



The Guardian was never commercially marketed. It was a developed as a proof of concept bridge product in preparation for the launch of the Guardian RT (real time).


Guardian RT

The Guardian RT was approved on June 11, 2005 for patients over 18 years of age. This system resembles the Guardian, except that the monitor displays realtime glucose results every five minutes. The continuous data can be stored up to 21 days and downloaded any time into a computer. The data can then be reviewed with proprietary software provided by the Guardian's manufacturer. Exposure to realtime glucose values can allow the patient to make proactive decisions not only to recover from hypoglycemia and hyperglycemia, but also to take preventative steps to prevent these unwanted excursions. Current and recent glucose levels, trend information, and a visual alarm if needed are all presented so that a patient can predict future low or high glucose excursions. (Figure 8) Using this information will allow the patient to take actions to spend more time in the euglycemic range and less time in the hypoglycemic or hyperglycemic ranges. This potential decrease in glycemic variability will not necessarily be reflected in an improved Hemoglobin A1c value, because this test reflects mean glycemic levels. Glycemic variability has been hypothesized to be a risk factor for diabetic complications and even poor outcomes following trauma. [10]  Much research is currently underway to express continuous glucose data in a useful way that describes the mean level of glycemia, the frequency and duration of hypoglycemia, the frequency and duration of hyperglycemia, and the overall variability. Furthermore, it is important for patterns to be described so that a patient can modify the regimen to avoid unwanted future glycemic excursions.



Figure 8. The Guardian RT Monitor Screen displays information about: A - the glucose level; B - An alarm warning; C - Trend arrows for the direction and magnitude of trends in glycemia; and D - A trend graph portraying recent patterns of glycemia.


The original Guardian and Guardian RT devices contained a large transmitter piece to communicate from the sensor to the monitor. These versions were used primarily for research. (Figure 9) A smaller data transmission system, known as the Minilink, to send glucose information from the sensor to the belt-attached monitor, was approved in 2007. (Figure 10) This component was immediately incorporated into the Guardian RT. The Minilink transmitter, which has not been available with any other Medtronic continuous glucose monitors, makes the sensor hub less cumbersome. The Minilink is about the thickness of four quarters stacked on top of each other. After the Minilink transmitter was approved, the manufacturer began commercial rollout of the Guardian RT system.



Figure 9. Original Guardian RT: Original Transmitter, Monitor, and Sensor (which is connected to the Transmitter), a system that was never marketed because the Original Transmitter was replaced by the Minilink transmitter in the commercial version of the Guardian RT.



Figure 10. Guardian RT with Minilink Transmitter attached to the Sensor. A) Minilink Transmitter; B) Sensor.


The greatest barrier to the adoption of this technology has been poor reimbursement. The literature contains many studies demonstrating improved Hemoglobin A1c levels or a decreased burden of hypoglycemia with the use of realtime continuous glucose monitoring technology; however payers have been reluctant to provide reimbursement coverage to patients for using this technology. Payers have also been reluctant to cover physicians' time for applying and removing this device, educating patients about how to use this technology, and interpreting the additional data that becomes part of the patient's medical record.


Diabetes Technology Society and other medical organizations have proposed the establishment of clinical guidelines for use of continuous glucose monitors, to be written by expert clinicians and representatives of professional diabetes organizations, which will set a minimum degree of coverage for this technology, according to an evidence-based review of the medical literature. [11] As additional trials using this technology for additional indications are completed in the future, the guidelines can be revisited and modified.


Some insurance companies have approved coverage for the use continuous glucose monitors under certain specific conditions. Continuous glucose monitors have been considered medically necessary by some insurance companies when one of the following criteria is met: 1) unexplained hypoglycemia; 2) hypoglycemia unawareness; 3) suspected hypoglycemia due to a disorder other than diabetes, such as insulinoma or nesidioblastosis; 4)  noctural hypoglycemia; 5) suspected postprandial hyperglycemia with discordantly elevated Hemoglobin A1c levels and normal fasting blood glucose levels; 6) morning hyperglycemia suspected to be due to the dawn phenomenon; 7) pump therapy to determine a proper basal insulin dose; 8) diabetes in women about to conceive or already pregnant; and/or 9) frequent hyperglycemia or ketoacidosis. Because of real time hypoglycemia alarms, CGM have been considered medically necessary by many insurance companies for patients with the complications listed above.

In April, 2007 Centers for Medicare and Medicaid took a step toward approving a code that will help patients receive reimbursement for continuous glucose monitoring devices. A preliminary decision was made then that allows for companies to develop Healthcare Common Procedure Coding System codes for the devices. The codes describe specific health care items and procedures and are necessary for processing health insurance claims. A final decision is expected by late 2007. If the codes are issued, then they could go into effect as early as Jan. 1, 2008. After the coding problem is solved, then the technology must receive coverage.


Most of the clinical trials of continuous glucose monitoring have demonstrated improved Hemoglobin A1c levels in users, compared to controls. Many of these studies have been dismissed by payers because of small cohort sizes, lack of randomization or controls, or failure to achieve statistical significance. Several well designed randomized controlled clinical trials are currently underway that are intended to test the hypothesis that using the Guardian RT results in improved control and less glycemic variability. An important multinational randomized controlled trial of the Guardian RT was reported in 2006. The seven-country GuardControl Study was the first randomized controlled trial to ever demonstrate statistically significant improvement in Hemoglobin A1c levels with the use of realtime continuous glucose monitoring. The Guardian RT was used either continuously or biweekly for three months and both regimens wee compared to control treatment which did not include use of continuous glucose monitoring. At one month and at three months the continuous users had significantly lower A1c levels than the controls. The biweekly users had intermediate improvement which did not reach statistical significance compared to the outcomes in the control group. [12]


Seven Plus

The Seven Plus Continuous Glucose Monitoring System is a continuous glucose monitor that utilizes a glucose oxidase sensor at the tip of a wire that is implanted in the subcutaneous space. The Seven Plus sensor is inserted via a dedicated applicator by the user or clinician just under the skin where it is held in place by an adhesive to the skin. The transmitter is snapped into a platform located on top of the sensor.  The data is transmitted wirelessly and displayed on a separate monitor, or the Seven Plus Receiver.  This device is FDA approved to provide glucose readings for 168 hours or 7 days. After seven days, a patient can remove the implanted sensor, discard the sensor, and reinsert another sensor. The new sensor is utilized with the reusable Seven Plus Transmitter and Seven Plus Receiver. The Seven Plus comes with software called DexCom DM3 Consumer Data Manager for retrospective downloading and analysis of glucose data after the sensor has been removed.


The median average relative difference for the STS has been reported to be 15.9% after three days of use [13]and 15.7% after seven days of use [14]. Two randomized controlled trials of the STS sensor demonstrated decreased time spent in both the hypoglycemic and hyperglycemic ranges and more time in the euglycemic zone when unblinded realtime continuous glucose data was provided to subjects with diabetes. The subjects were issued no instructions on how to respond to glycemic fluctuations, and they could react as they saw fit. No significant improvement in Hemoglobin A1c was reported in either study. Such a decrease in glycemic variability with the use of STS would be expected to result in fewer microvascular complications.


FreeStyle Navigator

The FreeStyle Navigator continuous glucose monitoring device utilizes an implanted sensor wire.  It utilizes Wired Enzyme (tm) technology, and the enzyme and mediator co-immobilized on the sensor. The sensor is implanted into the skin at a 90 degree angle to the skin surface by a disposable insertion device.  The implanted portion of the sensor is 5mm long, 0.6 mm wide, and 0.25 mm thick.  A transmitter is slid into a platform located on top of the sensor.  It is currently the only CGM that offers glucose readings every minute and has a built-in blood glucose meter.  The data is transmitted wirelessly and displayed on a separate monitor.  It is FDA approved for 5 days of use.  Its software is the CoPilot Health Management System is available for downloading the glucose data. The device provides real time data, retrospective data.   The median relative absolute difference for Navigator has been reported to be 12% for inpatients and 14% for outpatients. [15]




The GlucoDay-S by Menarini, Inc. is the only currently available continuous glucose monitor that does not use an implanted sensor. This product is approved in Europe but not in the US. The device utilizes a microdialysis process to pump a continuous flow of perfusion fluid through a microdialysis system, which includes a microfiber that is inserted in the abdominal wall. This fluid, in effect, rinses the interstitial fluid of the abdominal wall. The device then measures the concentration of glucose in the effluent dialysis filtrate with an in line biosensor that generates a current signal proportionate to the glucose concentration. The patient wears two bags of crystalloid fluid fastened around the trunk. The perfusion bag contains the fluid before it is part of the dialysis process and the storage bag contains the fluid after it is part of the dialysis process. The device provides real time information. The microfiber must be removed and replaced every 48 hours.


Sensor Augmented Pump

Real-time continuous glucose monitoring and the insulin pump have been combined into the Sensor-Augmented Pump system (Medtronic Diabetes, Northridge, CA) (Figure 11). The first system was not widely released and it used a large transmitter, which was part of the original Guardian RT continuous glucose monitoring system. When the Minilink transmitter component of the Guardian RT monitor was approved in 2007, at that point the Medtronic Sensor Augmented Pump system was launched for marketing. Pilot studies have demonstrated improvements in mean glycemia in users of this technology. [16]



Figure 11. Sensor-augmented pump consisting of a Guardian RT sensor (A), which is attached to a Minilink transmitter (B) and they communicate with an insulin infusion pump (C).


Future Minimally Invasive Continuous Glucose Monitors

Continuous hypoglycemia detection systems using current sensing technology must be either implanted (subcutaneously or into a blood vessel), or else wrapped around or attached to the body. Implantation is more secure, but may be associated with biocompatibility problems or local irritation. Wrapping around or attaching a monitor to the body avoids biocompatibility problems, but may be uncomfortable or cause an unpleasant sensation to the wearer of being constantly tethered to a device. Other continuous glucose monitoring devices are currently being developed that will wrap around the upper extremities, the trunk, or be in contact with the eye in the form of a contact lens. Methods for harvesting interstitial fluid from the body to measure with an external non-implanted sensor, in addition to microdialysis, are being developed that disrupt the skin barrier and trap the fluid that rises to the surface. Besides microdialysis methods, none are close to being marketed. One company, SpectRx, which was developing a laser microporation system to harvest interstitial fluid for continuous glucose monitoring, recently terminated its glucose monitoring program after more than a decade of effort.


Alternate Site Blood Glucose Testing

The availability of alternate site blood glucose testing is a major advance for patients who wish to avoid the pain, blood waste, and trauma to the fingertips of finger stick blood glucose testing [17]. The forearm and palm are good sites for blood glucose sampling when the patient wants a break from fingertip trauma.

The accuracy of alternate site blood glucose testing can be adversely affected by a lag between rapid changes in fingertip glucose levels and alternate site (i.e. upper extremity or abdominal wall) glucose levels.  Alternate site testing should therefore be avoided when: 1) the blood glucose level is rising or falling rapidly; 2) the blood glucose level is very low; 3) within two hours of eating; and 4) when a continuous glucose monitor is being calibrated with capillary blood glucose values.  The physiology is not adequately understood as to of why alternate site testing may lag at detecting a downward trend or an upward trend when blood glucose levels are fluctuating rapidly or when they are at an absolute low level. To what extent vigorous rubbing, local application of heat, chemical irritation, or other forms of agitation to the alternate site, or even drawing blood through a vacuum harvesting system can increase circulation to the alternate site to overcome the lag phenomenon, is unclear.


Noninvasive Glucose Monitoring

No monitor is currently approved by the FDA to measure blood glucose noninvasively [18]. Devices under development can be classified as taking a measurement either intermittently or continuously. A large device that is not portable would have to be utilized on an intermittent basis, whereas a small monitoring device would have the potential to be wrapped around a body appendage or the waist to make continuous noninvasive readings. Noninvasive glucose monitoring depends either upon on application of optical energy into tissue followed by measurement of the interaction of the optical energy with glucose in the intravascular, interstitial fluid, and intracellular compartments; or else measurement of a physiologic phenomenon which is proportionate to the blood glucose level. The optical energy is typically applied to an appendage, such as a fingertip, an earlobe, or a forearm.


Interest has been expressed in applying optical energy to the buccal mucosa within the mouth because this region contains no stratum corneum, the outermost dead layer of skin, to absorb the optical energy. A lollipop type of sensor has been proposed that would read buccal mucosa glucose levels. Such a device might become covered with saliva and food particles, however.


The anterior chamber of the eye has been studied with various types of optical energy. Applications of light that interacts with ocular glucose must be carefully constructed to avoid excessive energy transmission and damage to the eyes. Optical measurement of glucose will avoid the problem of confounding analytes whose chemical properties resemble those of glucose. With optical measurement, however, other analytes that are not a problem for existing invasive monitors can be confounding if their optical properties overlap those of glucose. Noninvasive testing using infrared light spectroscopy to measure reflection of infrared light from the skin in proportion to the glucose concentration must distinguish the signal of water (which is very large) from that of glucose (which is much smaller).


Any physiological phenomenon which becomes increasingly more abnormal as the blood glucose falls or rises from normal to hypoglycemic or hyperglycemic levels could be a physiological marker for indirect identification of blood glucose, by way of noninvasive measuring technology. During states of abnormal glycemia, decreased function of the brain, cranial nerves, or peripheral nerves might lead to declining performance in specific tests of neurologic performance. Progressively more severe hypoglycemia or hyperglycemia would likely be associated with increasingly abnormal physiological performance. In that case, either a depressed or an elevated glucose level would both lead to the same type of offset from the normal range of functioning. Decreased performance of this physiological marker could then indicate either elevated or depressed blood glucose levels.


A promising physiological qualitative test for hypoglycemia is being developed by the Australian company, Aimedics. This company is currently testing the HypoMon hypoglycemia monitor. The HypoMon consists of: 1) a battery powered chest-belt unit that contains four skin surface bio-sensor electrodes; and 2) a hand-held receiver computer. EKG information and sweating are measured by the sensors. The information is digitized by the belt and transmitted to the receiver unit using a wireless communication link. The collected data is analyzed by a detection algorithm in the receiver computer, to determine whether physiological responses to hypoglycemia are present. An alarm will sound when severe hypoglycemia is present. This device is being investigated and is not approved anywhere for use.





Hemoglobin A1c

Hemoglobin A1c is the best biomarker indicator of glycemic control over the past 2-3 months. [19] Two devices are approved by the FDA for measurement of Hemoglobin A1c by a patient at home. The Micromat II device (BioRad, Hercules, California; <http://diabetes.bio-rad.com>) was the first to be approved, but the product is intended primarily for use by healthcare professionals. The A1cNow+ device (Metrika, Inc., Sunnyvale, California; <http://www.metrika.com>) was the second to be approved, and it is intended for use by patients at home or by healthcare professionals The A1cNow+ device comes with a set of ten test cartridges to be used with one disposable monitor. [20]


An Organization with links to governmental regulatory agencies, the National Glycohemoglobin Standardization Program (NGSP) (<http://www.missouri.edu/~diabetes/ngsp.html>), evaluates every laboratory and home test for Hemoglobin A1c, sets accuracy standards, and certifies which methods meet their standards. [21]The trend in industry is for monitors to become increasingly more accurate and the trend in regulatory organizations is to require increasing accuracy for ongoing certification. Currently both home monitors for Hemoglobin A1c are certified by the NGSP. A trend in nomenclature is for the term "A1C test" to describe glycated hemoglobin measurement in healthcare practice, whereas the term "glycated hemoglobin" should continue to be used in research and scientific publications. The joint American Diabetes Association / National Committee for Quality Assurance Provider Recognition Program (<http://web.ncqa.org/tabid/139/Default.aspx>) recognizes excellence in patient care based on a set of quality care criteria. These criteria include satisfactory A1C test levels assessed by NGSP-certified measurement methods in a sample of patients with diabetes. The target A1C test levels for recognition include at least 80% of A1C values at or below 9% and at least 40% of A1C test values below 7%.


Hemoglobin A1c is an analyte found within red blood cells, comprised of glycated Hemoglobin. The glycation gap (formerly known as the glycosylation gap) (GG), based on fructosamine measurement, and the Hemoglobin Glycation Index (HGI), based on mean blood glucose, are two indices of between-individual differences in glycated hemoglobin adjusted for glycemia. GG is the difference between the measured A1C test and the A1C test result predicted from serum fructosamine testing based on a population regression equation of A1C on fructosamine [22], and HGI is the difference between the measured A1C test and A1C results predicted from the mean blood glucose level (calculated from self monitored blood glucose tests) based on a population regression equation of A1C tests on mean blood glucose levels [23]. These two indices are thought to reflect an inherent tendency for an individual's proteins to glycate, which could be thought of as a measure of type of their proteins' stickiness. Patients with high GG and HGI indices might be at increased risk of developing high A1C test results even with relatively low mean glucose levels and might also be at increased risk of basement membrane glycosylation and development of microvascular complications. Whether between-individual biological variation in Hemoglobin A1c is an independent risk factor, distinct from that attributable to mean blood glucose or fructosamine levels, for diabetic microvascular complications is controversial.



Because the A1C test is supposed to reflect the mean level of glycemia, attempts have been made to correlate this widely accepted measure with empirically measured mean blood glucose levels. Multiple glucose levels for making these types of comparisons can be obtained either through averaging many days of self monitored glucose levels or by measuring the area under the glucose concentration curve obtained with a continuous monitor. It appears that an analysis of multiple glucose data points provides important information that is unavailable from an A1C measurement. Two lines of evidence support this disconnect from a tight correlation between mean glycemia and A1C levels. First, improvements in mean glycemia and a decreased risk of complications may not necessarily be reflected by improvements in A1C in intensively treated patients. [25] Second, glucose fluctuations, compared to chronic sustained hyperglycemia, have been shown to exhibit a more specific triggering effect on oxidative stress. [26] Glycemic variability as a risk factor for diabetic complications cannot be assessed by a global measure of mean glycemia, such as A1C. Glycemic variability must be assessed by a test that incorporates multiple individual glucose values, such as what can be obtained from continuous glucose monitoring or from seven-point-per-day (or greater) self glucose testing. As a first approximation of longterm control, the A1C test remains unsurpassed, but this test is only as good as it is. Given the limitations of the A1C's test's predictive value, this measure might eventually be supplanted by another test, based on continuous glucose monitoring.



Many clinicians have expressed interest in having access to a medium-term marker (defined as reflecting the average degree of control over the past few days or weeks) for determining control over a period of days to weeks. Fructosamine is a term that refers to a family of glycated serum proteins and this family is comprised primarily of albumen and to a lesser extent, globulins, and to an even lesser extent, other circulating serum proteins [27]. No product exists for home use that measures serum fructosamine. A home blood fructosamine monitor, Duet Glucose Control System, was marketed in the early 2000's and then withdrawn from the market. No subsequent home fructosamine test has been available since then.


Glycated Albumin

The largest constituent of fructosamine is glycated albumin [28]. Several investigators and companies are developing portable assays for glycated albumin to assess overall control during periods of rapidly changing glucose levels. In these situations, an A1C test may change too slowly to capture a sudden increase or decrease in mean glycemia. The components of the necessary technology appear to be in place to build a commercial instrument for home testing of glycated albumin within the next few years. The biggest obstacle to adoption of this test into routine clinical practice will be the extensive amount of education that will be necessary to convince physicians to adopt this test. Many physicians might wish to use A1C as their sole test of mean glycemia, even though the two tests measure mean glycemia over different timeframes. Whether the cost of this massive education program can be recouped by product sales remains to be seen.



Other Blood Analyses

The aforementioned biomarkers for measuring glycemic control, (A1C, fructosamine, and glycated albumin) only reflect mean levels of glycemia. These measures can fail to portray hyperglycemic excursions if they are balanced by hypoglycemic excursions. Plasma 1,5-anhydroglucitol (1,5-AG) is a naturally occurring dietary monosaccharide, with a structure similar to that of glucose. (Figure 12) This analyte has been proposed as a marker for postprandial hyperglycemia. [29] An automated laboratory grade assay named Glycomark is approved in the U.S. for measuring 1,5-AG as a short-term marker for glycemic control. A similar laboratory assay has been used in Japan for over ten years. During normoglycemia, 1,5-AG is maintained at constant steady-state levels because of a large body pool compared with the amount of intake and because this substance is metabolically inert. Normally, 1,5-AG is filtered and completely reabsorbed by the renal tubules. During acute hyperglycemia when the blood glucose levels exceed 180 mg/dl, which is the renal threshold for spilling glucose into the urine, serum 1,5-AG falls. This fall occurs due to competitive inhibition of renal tubular reabsorption by filtered glucose. The greater the amount of unreabsorbed glucose in renal filtrate (due to hyperglycemia), the less 1, 5-AG is reabsorbed by the kidneys. The 1,5-AG levels respond sensitively and rapidly to rises in serum glucose and a fall in the serum level of this analyte can indicate transient elevations of serum glucose occurring over as short a period as a few days. Measurement of 1,5-AG can be useful in assessing the prior 1-2 weeks for: 1) the degree of postprandial hyperglycemia; and 2) the mean short-term level of glycemia. This assay might prove useful in assessing the extent of glycemic variability that is present in an individual with a close-to-normal A1C level, but who is suspected to be alternating between frequent periods of hyperglycemia and hypoglycemia. In such a patient, the 1,5-AG level would be low, which would indicate frequent periods of hyperglycemia., whereas in a patient with little glycemic variability, the 1,5-AG levels would not be particularly depressed because of a lack of frequent hyperglycemic periods.



            Figure 12. Structure of glucose (left) and 1,5-anhydroglucitol (right)



DiagnOptics BV from Netherlands has developed the AGE Reader, which is a device that also non-invasively assesses the accumulation of advanced glycation endproducts (AGEs) by measuring fluorescence of ultraviolet light reflected by skin AGE's accumulate with age but the process occurs more rapidly in patients with diabetes, and skin AGE levels correlate closely with the development of diabetic microvascular complications. This device might be useful for identifying diabetes patients who are at increased risk for developing microvascular complications. [30] This product is available in Europe but is not approved by the FDA for use in the United States. Another promising noninvasive test for assessing AGE levels by way of measuring skin autofluorescence, is the Scout. This device is being developed by Veralight, Inc. The Scout has been developed as a screening test for diagnosing diabetes. Early results suggest that this device may provide superior sensitivity and convenience, compared to traditional diagnostic screening tests, such as fasting glucose or A1C levels. [31] This device is not on currently the market anywhere.


Home monitors can be used to measure blood glucose along with blood ketones by a dual-analyte monitor that uses separate strips to measure each analyte. This measurement can be useful in a patient with hyperglycemia who is tying to ascertain whether ketoacidosis is imminent.

Blood lactic acid can be measured by single-analyte home monitors. The refinements in home lactate monitoring technology in terms of the amount of blood and the amount of time needed for the monitor to provide a reading are about 20 years behind those of SMBG technology. [32]




By combining continuous basal insulin delivery during fasting periods with discrete bolus doses of insulin at mealtimes, insulin delivery can be crafted to mimic the natural pattern of pancreatic insulin release [33]. An artificial pancreas will consist of: 1) an automatic and continuous glucose monitor which may be inserted subcutaneously or intravascularly; 2) an implanted continuous insulin delivery system for intravascular or subcutaneous insulin administration; 3) a control processor to link the insulin delivery rate to the glucose level; and 4) a radio to send the glucose level to the body surface for continuous display onto a monitor. The greatest problems with developing an artificial pancreas are with the continuous sensor and the implanted insulin delivery system. A continuous glucose sensor may be implanted subcutaneously or intravascularly. An insulin pump may be external or implanted. There are therefore four (2 x 2) combinations of sensors and pumps that could be the core of an artificial pancreas system. The safety, efficacy, cost, and cost-effectiveness of an artificial pancreas are unknown at this time.


Trials of closed loop control are underway in the US and in Europe.  In one trial,  a closed-loop control system uses frequent measurements of BG concentration along with subcutaneous delivery of both the fast-acting insulin analog lispro and glucagon (to imitate normal physiology) as directed by a computer algorithm [34]







Many new types of technology are increasingly being developed and applied to fight diabetes and its complications. New technologies will improve the lives of people with diabetes by measuring glucose and other biomarkers of glycemic control and linking glucose levels with insulin delivery to improve the lives of people with diabetes.





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