Monitoring blood glucose levels

According to the American Diabetes Association, 29.1 million Americans, 9.3% of the population, had diabetes in 2012. The association provides further breakdowns by age and race, but the bottom line is that “diabetes remained the seventh leading cause of death in the United States in 2010, with 69,071 death certificates listing it as the underlying cause of death, and a total of 234,051 death certificates listing diabetes as an underlying or contributing cause of death.”¹

There is no question that the disease is life-threatening if not properly managed. On the other hand, it can be controlled through diet and exercise for the large percentage of patients with type 2 diabetes or through insulin injections for the approximately 1.25 million Americans with type 1 diabetes. For both these groups as well as for people with related conditions such as hypoglycemia—low blood sugar—periodic blood sugar (glucose) testing is necessary.

The human body metabolizes food into glucose, and it’s glucose that provides the fuel for virtually everything people do. The normal average level is about 90 mg/dl but may range from 70 to 150 at different times of the day. Without the stabilizing influence of insulin, a diabetic’s glucose level can become very high and if not treated can lead to organ and tissue damage. Conversely, if a diabetic receives too much insulin or misjudges the glucose-level reducing effects of exercise, hypoglycemia can result very quickly with possible loss of consciousness.

The good news is that most diabetics can manage their condition if they know how their blood sugar level is changing, and that requires frequent testing. Understandably, sticking your finger multiple times per day is not pleasant, so a number of initiatives are underway to develop noninvasive glucose testing methods. Several smartphone apps also are available to help patients monitor their condition. Nevertheless, sticking your finger, applying a small drop of blood to a special test strip, and reading the strip’s output on a meter remains the predominant method of glucose-level testing.

Traditional glucose-level testing

There’s a lot of electrochemistry involved in traditional test strips. The sensor material needs to be very sensitive only to glucose to avoid erroneous measurements. A first-generation test strip uses glucose oxidase (GO_x)-based chemistry. GO_x is a naturally occurring enzyme that has a high specificity toward D-glucose, the dextrose form of glucose. When it reacts with glucose, GO_x produces hydrogen peroxide (H₂O₂) by using oxygen as the electron acceptor. Glucose-level meters used with this type of test strip measure the use of oxygen or the production of H₂O₂.

As shown in Figure 1, second-generation chemistry replaces the oxygen electrode with an electron mediator or redox dye to reduce the effect of other reactions that might use oxygen. Only third-generation sensors provide direct electron transfer to an electrode. Obviously, the chemistry is significantly changed from one sensor generation to another. This is a major reason why test strips must be used with a matching meter.

Figure 1. The evolution of test strip chemistry
Courtesy of the Journal of Diabetes Science and Technology

A number of considerations accompany more recently isolated enzymes. A 2011 paper stated, “Of particular importance for glucose sensors is the enzyme’s substrate specificity. Patients undergoing peritoneal dialysis or other treatments may have significant quantities of maltose in their blood. Glucose sensors that employ oxidoreductases with broad specificity may give falsely elevated glucose readings …. A Food and Drug Administration public health notification warned against potential fatal errors from PQQ-GDH-based sensing technology. GO_x has long been envied for its high specificity for glucose. However, protein engineering studies on PQQ GDH and bacterial FAD GDH, as well as the increasing use of fungal FAD GDH, are challenging GO_x‘s historical supremacy.”²

An article describing the use of COMSOL’s Multiphysics software in the design of glucose-level test strips added more details about how the amount of glucose is inferred by the meter. LifeScan is part of Johnson & Johnson and has developed the OneTouch range of blood glucose monitoring products. In particular, the test strips “comprise a plastic substrate, two carbon-based electrodes (called working and counter electrodes), a thin dry reagent layer, and a capillary volume where the blood is placed.

“Conceptually, the blood mixes with and hydrates the dry reagent, producing an enzymatic reaction that generates a chemical product. The amount of this product is proportional to the amount of glucose in the blood. Then, when the strip is inserted into a meter, the battery-powered device polarizes the strip’s working electrode. This sets in motion an oxidation process that generates a transient electrical signal whose strength is proportional to the amount of the chemical product oxidized. The meter then applies an algorithm to convert the signal strength into a numerical value for the user.”

In addition to a user’s assumption that a blood glucose measuring system will comply with regulations governing safety and accuracy, there also is an expectation that it will be convenient and easy to use. Factors affecting these aspects include the amount of blood required and the time required for the meter to perform a reading. It can be very frustrating to have stuck your finger only to find that the amount of blood produced was insufficient, wasting a test strip and requiring yet another finger stick.

The Multiphysics software, as the name suggests, handles complicated problems with many interactions and helps to optimize the measuring system’s performance. Stephen Mackintosh, senior scientist at LifeScan, explained that, “The underlying physics is complex, often incorporating Fick’s laws of mass diffusion coupled with both Michaelis-Menten-based descriptions of enzyme-catalyzed chemical reaction kinetics, and Butler-Volmer expressions to understand concentration-dependent potential changes in addition to the battery-supplied potential of the meter.”³

Commercial examples

The Bayer Diabetes Care CONTOUR-NEXT test strip requires a 0.6-ml blood sample. This is less than LifeScan’s OneTouch UltraMini and several Roche meters that need 1 ml and more than the True2go meter from Home Diagnostics that takes 0.5 ml. Bayer’s system also features second-chance sampling that allows you to add more blood to the sample if the first attempt was unsuccessful. Several types of meters can audibly announce the measurement results, eliminating the chance of misreading the display, especially for patients with impaired sight.

Older meters typically require coding to identify the batch of test strips being used. Users can verify that their meter and test strip are working properly by applying a special test solution with the meter in a test mode. Meters that do not require coding may still be using test strips with a relatively wide range of characteristics, but as an article about the importance of coding errors explained, “While most test strips require the user to enter a code, insert a coding strip, or insert a chip into the glucose meter, Ascensia meters automatically calibrate by checking the strip electronically when it is inserted into the meter, and the Bayer company, which makes the Ascensia Contour and Ascensia Breeze meters, claims that they cannot be miscoded using this system.”⁴

Figure 2. Accu-Chek nano blood glucose meter
Courtesy of Roche

It’s not possible to know exactly how each company has achieved “no coding,” but a number of recently introduced meters include this feature—LifeScan’s Verio IQ, FreeStyle’s Precision Neo, and Roche’s Accu-Chek NANO (Figure 2), for example. Not matching the meter’s code to that of the test strip is one of the major causes of inaccuracy. Different meter models may have innovative approaches to test-strip analysis. Bayer’s CONTOUR-NEXT meters feature MULTIPULSE technology that evaluates the sample seven times to improve accuracy. Similarly, LifeScan’s Ultra2 tests each sample twice.

Meters vary in their capacity to communicate with cell phones and/or PCs. For example, the iGLUCUSE meter communicates via GSM to send text messages or emails. As explained on the iGLUCUSE website, “Every glucose reading is automatically sent to a personalized diabetes management web portal, which includes easy-to-read graphics and your trends.” Patient data can be accessed by authorized doctors and family members. The iGLUCUSE meter is not FDA approved and is not for sale in the United States.

LifeScan’s OneTouch Verio Sync meter automatically and wirelessly sends test readings to your iPhone or iPad using the OneTouch Reveal mobile app (Figure 3). Bayer’s CONTOUR-LINK meter wirelessly communicates with a Medtronic insulin pump (Figure 4), automating application of the right dosage each time you test your blood sugar level. In addition, Medtronic’s web-based CareLink Personal application “serves as a secure virtual diabetes management system where you can view, print, and evaluate a report snapshot of all your pump, glucose, and daily diabetes management activities,” as explained on the CareLink website.

Figure 3. OneTouch Verio Sync meter wirelessly communicating readings to a cell phone
Courtesy of LifeScan

Figure 4. CONTOUR-LINK meter communicating with Medtronic insulin pump
Courtesy of Bayer HealthCare

Wireless data transmission has only recently become available in glucose meters, and just a few meters have this feature. Nevertheless, Polymap Wireless has developed the Polytel system that adds a wireless capability to many types of commercial glucose meters. As described on the Polymap website, “… [the system] consists of products that use Bluetooth wireless technology to transfer medical data wirelessly from in-home medical devices to communications devices like cell phones or smart modems. The data then is transmitted over the Internet to a predetermined server/service for delivery to healthcare providers, doctors, or loved ones.”

Similarly, Telcomed, a Medic4All Group company, offers the GL-100 glucose meter that “wirelessly transmits the measurements data to a telemedicine monitoring center through the Telcomed gateways,” as described on the Telcomed website. For mobile applications, transmission is by Bluetooth to a smartphone or PDA and from there via Wi-Fi or GPRS to the telemedicine monitoring center or personal health record. Telcomed is based in Ireland and specializes in wireless telemedicine products and software.

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