Glucose meter

Four generations of blood glucose meter, c. 1993-2005. Sample sizes vary from 30 to 0.3 μl. Test times vary from 5 seconds to 2 minutes (modern meters typically provide results in 5 seconds).

A glucose meter (or glucometer) is a medical device for determining the approximate concentration of glucose in the blood. It can also be a strip of glucose paper dipped into a substance and measured to the glucose chart. It is a key element of home blood glucose monitoring (HBGM) by people with diabetes mellitus or hypoglycemia. A small drop of blood, obtained by pricking the skin with a lancet, is placed on a disposable test strip that the meter reads and uses to calculate the blood glucose level. The meter then displays the level in units of mg/dl or mmol/l.

Since approximately 1980, a primary goal of the management of type 1 diabetes and type 2 diabetes mellitus has been achieving closer-to-normal levels of glucose in the blood for as much of the time as possible, guided by HBGM several times a day. The benefits include a reduction in the occurrence rate and severity of long-term complications from hyperglycemia as well as a reduction in the short-term, potentially life-threatening complications of hypoglycemia.

History

Leland C. Clark Jr. (1918– 2005) presented his first paper about the oxygen electrode, later named the Clark electrode, on 15 April 1956, at a meeting of the American Society for Artificial Organs during the annual meetings of the Federated Societies for Experimental Biology.^[1][2] In 1962, Clark and Ann Lyons from the Cincinnati Children’s Hospital developed the first glucose enzyme electrode. This biosensor was based on a thin layer of glucose oxidase (GOx) on an oxygen electrode. Thus, the readout was the amount of oxygen consumed by GOx during the enzymatic reaction with the substrate glucose. This publication became one of the most often cited papers in life sciences. Due to this work he is considered the “father of biosensors,” especially with respect to the glucose sensing for diabetes patients.^[3][4]

CDC image showing the usage of a lancet and a blood glucose meter.

Another early glucose meter was the Ames Reflectance Meter by Anton H. Clemens. It was used in American hospitals in the 1970s. A moving needle indicated the blood glucose after about a minute.

Home glucose monitoring was demonstrated to improve glycemic control of type 1 diabetes in the late 1970s, and the first meters were marketed for home use around 1981. The two models initially dominant in North America in the 1980s were the Glucometer, introduced in November 1981,^[5] whose trademark is owned by Bayer and the Accu-chek meter (by Roche). Consequently, these brand names have become synonymous with the generic product to many health care professionals. In Britain, a health care professional or a patient may refer to "taking a BM": "Mrs X's BM is 5", etc. BM stands for Boehringer Mannheim, now part of Roche, who produce test strips called 'BM-test' for use in a meter.^[6][7]

In North America, hospitals resisted adoption of meter glucose measurements for inpatient diabetes care for over a decade. Managers of laboratories argued that the superior accuracy of a laboratory glucose measurement outweighed the advantage of immediate availability and made meter glucose measurements unacceptable for inpatient diabetes management. Patients with diabetes and their endocrinologists eventually persuaded acceptance. Some health care policymakers still resist the idea that the society would be well advised to pay the consumables (reagents, lancets, etc.) needed.

Home glucose testing was adopted for type 2 diabetes more slowly than for type 1, and a large proportion of people with type 2 diabetes have never been instructed in home glucose testing.^[8] This has mainly come about because health authorities are reluctant to bear the cost of the test strips and lancets.

Non-meter test strips

Test strips that changed color and could be read visually, without a meter, have been widely used since the 1980s. They had the added advantage that they could be cut longitudinally to save money. Critics argued that test strips read by eye are not as accurate or convenient as meter testing. The manufacturer cited studies that show the product is just as effective despite not giving an answer to one decimal place, something they argue is unnecessary for control of blood sugar. This debate also happened in Germany where "Glucoflex-R" was an established strip for type 2 diabetes. As meter accuracy and insurance coverage improved, they lost popularity.

"Glucoflex-R" is Australia manufacturer National Diagnostic Products alternative to the BM test strip. It has versions that can be used either in a meter or read visually. It is also marketed under the brand name Betachek. On May 1, 2009, the UK distributor Ambe Medical Group reduced the price of their "Glucoflex-R" test strip to the NHS, by approximately 50%. This was expected to allow the NHS to save money on strips and perhaps loosen the restrictions on supply a little. Another low cost visually read strip is soon to be available on prescription according to sources at the NHS.

Types of meters

Hospital glucose meters

Special glucose meters for multi-patient hospital use are now used. These provide more elaborate quality control records. Their data handling capabilities are designed to transfer glucose results into electronic medical records and the laboratory computer systems for billing purposes.

Blood testing with meters using test strips

Illustration depicting glucose monitoring with glucometer.

Illustration depicting glucose meter and test strips.

There are several key characteristics of glucose meters which may differ from model to model:

• Size: The average size is now approximately the size of the palm of the hand, although hospital meters can be the size of a remote control. They are battery-powered.
• Test strips: A consumable element containing chemicals that react with glucose in the drop of blood is used for each measurement. For some models this element is a plastic test strip with a small spot impregnated with glucose oxidase and other components. Each strip is used once and then discarded. Instead of strips, some models use discs, drums, or cartridges that contain the consumable material for multiple tests.

• Coding: Since test strips may vary from batch to batch, some models require the user to manually enter in a code found on the vial of test strips or on a chip that comes with the test strip. By entering the coding or chip into the glucose meter, the meter will be calibrated to that batch of test strips. However, if this process is carried out incorrectly, the meter reading can be up to 4 mmol/L (72 mg/dL) inaccurate. The implications of an incorrectly coded meter can be serious for patients actively managing their diabetes. This may place patients at increased risk of hypoglycemia. Alternatively, some test strips contain the code information in the strip; others have a microchip in the vial of strips that can be inserted into the meter. These last two methods reduce the possibility of user error. One Touch has standardized their test strips around a single code number, so that, once set, there is no need to further change the code in their older meters, and in some of their newer meters, there is no way to change the code.

• Volume of blood sample: The size of the drop of blood needed by different models varies from 0.3 to 1 μl. (Older models required larger blood samples, usually defined as a "hanging drop" from the fingertip.) Smaller volume requirements reduce the frequency of unproductive pricks.
• Alternative site testing: Smaller drop volumes have enabled "alternate site testing" — pricking the forearms or other less sensitive areas instead of the middle of the fingertips; pricking the sides of the fingertips is actually the least uncomfortable method of testing. Although less uncomfortable, readings obtained from forearm blood lag behind fingertip blood in reflecting rapidly changing glucose levels in the rest of the body.
• Testing times: The times it takes to read a test strip may range from 3 to 60 seconds for different models.
• Display: The glucose value in mg/dl or mmol/l is displayed on a digital display. The preferred measurement unit varies by country: mg/dl are preferred in the U.S., France, Japan, Israel, and India. mmol/l are used in Canada, Australia, China and the UK. Germany is the only country where medical professionals routinely operate in both units of measure. (To convert mmol/l to mg/dl, multiply by 18. To convert mg/dl to mmol/l, divide by 18.) Many meters can display either unit of measure; there have been a couple of published instances in which someone with diabetes has been misled into the wrong action by assuming that a reading in mmol/l was really a very low reading in mg/dl, or the converse. In general, if a value is presented with a decimal point, it is in mmol/l, without a decimal it is most likely mg/dl.

Table of blood glucose units of measurement by country[9]
Country	Unit of measurement used	Country	Unit of measurement used
Algeria	mg/dL	Malaysia	mmol/L
Argentina	mg/dL	Malta	mmol/L
Australia	mmol/L	Mexico	mg/dL
Austria	mg/dL	Netherlands	mmol/L
Bahrain	mg/dL	New Zealand	mmol/L
Bangladesh	mg/dL	Norway	mmol/L
Belgium	mg/dL	Oman	mg/dL
Brazil	mg/dL	Peru	mg/dL
Canada	mmol/L	Philippines	mg/dL
Caribbean countries	mg/dL	Poland	mg/dL
Chile	mg/dL	Portugal	mg/dL
China	mmol/L	Qatar	mmol/L
Colombia	mg/dL	Russia	mmol/L
Czech Republic	mmol/L	Saudi Arabia	mg/dL
Denmark	mmol/L	Singapore	mmol/L
Ecuador	mg/dL	Slovakia	mmol/L
Egypt	mg/dL	South Africa	mmol/L
Finland	mmol/L	Spain	mg/dL
France	mg/dL	Sub-Saharan Africa	mg/dL mmol/L
Georgia	mg/dL	Sweden	mmol/L
Germany	mg/dL mmol/L	Switzerland	mmol/L
Greece	mg/dL	Syria	mg/dL
Hong Kong	mmol/L	Taiwan	mg/dL
India	mg/dL	Thailand	mg/dL
Indonesia	mg/dL	Tunisia	mg/dL
Ireland	mmol/L	Turkey	mg/dL
Israel	mg/dL	Ukraine	mmol/L
Italy	mg/dL	United Arab Emirates (UAE)	mg/dL
Japan	mg/dL	United Kingdom	mmol/L
Jordan	mg/dL	United States	mg/dL
Kazakhstan	mmol/L	Uruguay	mg/dL
Korea	mg/dL	Venezuela	mg/dL
Kuwait	mg/dL	Vietnam	mmol/L
Lebanon	mg/dL	Yemen	mg/dL
Luxembourg	mg/dL

• Glucose vs. plasma glucose: Glucose levels in plasma (one of the components of blood) are generally 10%–15% higher than glucose measurements in whole blood (and even more after eating). This is important because home blood glucose meters measure the glucose in whole blood while most lab tests measure the glucose in plasma. Currently, there are many meters on the market that give results as "plasma equivalent," even though they are measuring whole blood glucose. The plasma equivalent is calculated from the whole blood glucose reading using an equation built into the glucose meter. This allows patients to easily compare their glucose measurements in a lab test and at home. It is important for patients and their health care providers to know whether the meter gives its results as "whole blood equivalent" or "plasma equivalent." One model measures beta-hydroxybutyrate in the blood to detect ketosis for measuring both unhealthy ketoacidosis and healthy nutritional ketosis.

• Clock/memory: Most meters now include a clock that is set by the user for date and time and a memory for past test results. The memory is an important aspect of diabetes care, as it enables the person with diabetes to keep a record of management and look for trends and patterns in blood glucose levels over days and weeks. Most memory chips can display an average of recent glucose readings. A known deficiency of all current meters is that the clock is often not set to the correct time (i.e. - due to time changes, static electricity, etc...) and therefore has the potential to misrepresent the time of the past test results making pattern management difficult.

• Data transfer: Many meters now have more sophisticated data handling capabilities. Many can be downloaded by a cable or infrared to a computer that has diabetes management software to display the test results. Some meters allow entry of additional data throughout the day, such as insulin dose, amounts of carbohydrates eaten, or exercise. A number of meters have been combined with other devices, such as insulin injection devices, PDAs, cellular transmitters,^[10] and Game Boys.^[11] A radio link to an insulin pump allows automatic transfer of glucose readings to a calculator that assists the wearer in deciding on an appropriate insulin dose.

Cost

The cost of home blood glucose monitoring can be substantial due to the cost of the test strips. In 2006, the consumer cost of each glucose strip ranged from about $0.35 to $1.00. Manufacturers often provide meters at no cost to induce use of the profitable test strips. Type 1 diabetics may test as often as 4 to 10 times a day due to the dynamics of insulin adjustment, whereas type 2 typically test less frequently, especially when insulin is not part of treatment. A recent study on the comparative cost-effectiveness of all options for the self-monitoring of blood glucose funded by the National Health Service in the UK uncovered considerable variation in the price paid, which could not be explained by the availability of advanced meter features. It estimated that a total of £12 m was invested in providing 42 million self-monitoring of blood glucose tests with systems that fail to meet acceptable accuracy standards, and efficiency savings of £23.2 m per annum are achievable if the National Health Service were to disinvest from technologies providing lesser functionality than available alternatives, but at a much higher price.^[12] Batches of counterfeit test strips for some meters have been identified, which have been shown to produce inaccurate results.^[13]

Noninvasive meters

The search for a successful technique began about 1975 and has continued to the present without a clinically or commercially viable product.^[14] As of 1999, only one such product had ever been approved for sale by the FDA, based on a technique for electrically pulling glucose through intact skin, and it was withdrawn after a short time owing to poor performance and occasional damage to the skin of users.^[15]

Continuous glucose monitors

Blood glucose meter. The sensor and transmitter are fixed to the upper arm. The reader shows days to replacement of sensor, current blood glucose level and a diagram of the latest blood glucose levels.

Continuous glucose monitor systems can consist of a disposable sensor placed under the skin, a transmitter connected to the sensor and a reader that receives and displays the measurements. The sensor can be used for several days before it needs to be replaced. The devices provide real-time measurements, and reduce the need for fingerprick testing of glucose levels. A drawback is that the meters are not as accurate because the read the glucose levels in the interstitial fluid which lags behind the levels in the blood.^[16][17]

Accuracy

Accuracy of glucose meters is a common topic of clinical concern. Blood glucose meters must meet accuracy standards set by the International Organization for Standardization (ISO). According to ISO 15197 Blood glucose meters must provide results that are within 20% of a laboratory standard 95% of the time (for concentrations about 75 mg/dL, absolute levels are used for lower concentrations). However, a variety of factors can affect the accuracy of a test. Factors affecting accuracy of various meters include calibration of meter, ambient temperature, pressure use to wipe off strip (if applicable), size and quality of blood sample, high levels of certain substances (such as ascorbic acid) in blood, hematocrit, dirt on meter, humidity, and aging of test strips. Models vary in their susceptibility to these factors and in their ability to prevent or warn of inaccurate results with error messages. The Clarke Error Grid has been a common way of analyzing and displaying accuracy of readings related to management consequences. More recently an improved version of the Clarke Error Grid has come into use: It is known as the Consensus Error Grid. Older blood glucose meters often need to be "coded" with the lot of test strips used, otherwise, the accuracy of the blood glucose meter may be compromised due to lack of calibration.

Future

One noninvasive glucose meter has been approved by the U.S. FDA: The GlucoWatch G2 Biographer made by Cygnus Inc. The device was designed to be worn on the wrist and used electric fields to draw out body fluid for testing. The device did not replace conventional blood glucose monitoring. One limitation was that the GlucoWatch was not able to cope with perspiration at the measurement site. Sweat must be allowed to dry before measurement can resume. Due to this limitation and others, the product is no longer on the market.

The market introduction of noninvasive blood glucose measurement by spectroscopic measurement methods, in the field of near-infrared (NIR), by extracorporal measuring devices, has not been successful because the devices measure tissue sugar in body tissues and not the blood sugar in blood fluid. To determine blood glucose, the measuring beam of infrared light, for example, has to penetrate the tissue for measurement of blood glucose.

There are currently three CGMS (continuous glucose monitoring system) available. The first is Medtronic's Minimed Paradigm RTS with a sub-cutaneous probe attached to a small transmitter (roughly the size of a quarter) that sends interstitial glucose levels to a small pager sized receiver every five minutes. The Dexcom System is another system, available in two different generations in the US, the G4 and the G5. (1Q 2016). It is a hypodermic probe with a small transmitter. The receiver is about the size of a cell phone and can operate up to twenty feet from the transmitter. The Dexcom G4 transmits via radio frequency and requires a dedicated receiver.^[18] The G5 version utilizes Bluetooth low energy for data transmission, and can transmit data directly to a compatible cellular telephone. Currently, only Apple's iPhone can be used as a receiver,^[19] but Dexcom is in the process of getting an Android version approved, and anticipates availability in the second half of 2016. Aside from a two-hour calibration period, monitoring is logged at five-minute intervals for up to 1 week. The user can set the high and low glucose alarms. The third CGMS available is the FreeStyle Navigator from Abbott Laboratories.

There is currently an effort to develop an integrated treatment system with a glucose meter, insulin pump, and wristop controller, as well as an effort to integrate the glucose meter and a cell phone. These glucose meter/cellular phone combinations are under testing and currently cost $149 USD retail. Testing strips are proprietary and available only through the manufacturer (no insurance availability). These "Glugophones" are currently offered in three forms: as a dongle for the iPhone, an add-on pack for LG model UX5000, VX5200, and LX350 cell phones, as well as an add-on pack for the Motorola Razr cell phone. In US, this limits providers to AT&T and Verizon. Similar systems have been tested for a longer time in Finland.

Recent advances in cellular data communications technology have enabled the development of glucose meters that directly integrate cellular data transmission capability, enabling the user to both transmit glucose data to the medical caregiver and receive direct guidance from the caregiver on the screen of the glucose meter. The first such device, from Telcare, Inc., was exhibited at the 2010 CTIA International Wireless Expo,^[20] where it won an E-Tech award. This device is currently undergoing clinical testing in the US and internationally.

In early 2014 Google reported testing prototypes of contact lenses that monitor glucose levels and alert users when glucose levels cross certain thresholds.^[21][22][23]

Technology

two used Accu-chek test strips for their blood glucose test system for diabetics. The lower one has had the cover peeled off to show the circuit

Many glucose meters employ the oxidation of glucose to gluconolactone catalyzed by glucose oxidase (sometimes known as GOx). Others use a similar reaction catalysed instead by another enzyme, glucose dehydrogenase (GDH). This has the advantage of sensitivity over glucose oxidase but is more susceptible to interfering reactions with other substances.^[24]

The first-generation devices relied on the same colorimetric reaction that is still used nowadays in glucose test strips for urine. Besides glucose oxidase, the test kit contains a benzidine derivative, which is oxidized to a blue polymer by the hydrogen peroxide formed in the oxidation reaction. The disadvantage of this method was that the test strip had to be developed after a precise interval (the blood had to be washed away), and the meter needed to be calibrated frequently.

Most glucometers today use an electrochemical method. Test strips contain a capillary that sucks up a reproducible amount of blood. The glucose in the blood reacts with an enzyme electrode containing glucose oxidase (or dehydrogenase). The enzyme is reoxidized with an excess of a mediator reagent, such as a ferricyanide ion, a ferrocene derivative or osmium bipyridyl complex. The mediator in turn is reoxidized by reaction at the electrode,which generates an electric current. The total charge passing through the electrode is proportional to the amount of glucose in the blood that has reacted with the enzyme. The coulometric method is a technique where the total amount of charge generated by the glucose oxidation reaction is measured over a period of time. The amperometric method is used by some meters and measures the electric current generated at a specific point in time by the glucose reaction. This is analogous to throwing a ball and using the speed at which it is travelling at a point in time to estimate how hard it was thrown. The coulometric method can allow for variable test times, whereas the test time on a meter using the amperometric method is always fixed. Both methods give an estimation of the concentration of glucose in the initial blood sample.

The same principle is used in test strips that have been commercialized for the detection of diabetic ketoacidosis (DKA). These test strips use a beta-hydroxybutyrate-dehydrogenase enzyme instead of a glucose oxidizing enzyme and have been used to detect and help treat some of the complications that can result from prolonged hyperglycemia.^[25]

Blood alcohol sensors using the same approach, but with alcohol dehydrogenase enzymes, have been tried and patented but have not yet been successfully commercially developed.

Meter use for hypoglycemia

Although the apparent value of immediate measurement of blood glucose might seem to be higher for hypoglycemia than hyperglycemia, meters have been less useful. The primary problems are precision and ratio of false positive and negative results. An imprecision of ±15% is less of a problem for high glucose levels than low. There is little difference in the management of a glucose of 200 mg/dl compared with 260 (i.e., a "true" glucose of 230±15%), but a ±15% error margin at a low glucose concentration brings greater ambiguity with regards to glucose management.

The imprecision is compounded by the relative likelihoods of false positives and negatives in populations with diabetes and those without. People with type 1 diabetes usually have glucose levels above normal, often ranging from 40 to 500 mg/dl (2.2 to 28 mmol/l), and when a meter reading of 50 or 70 (2.8 or 3.9 mmol/l) is accompanied by their usual hypoglycemic symptoms, there is little uncertainty about the reading representing a "true positive" and little harm done if it is a "false positive." However, the incidence of hypoglycemia unawareness, hypoglycemia-associated autonomic failure (HAAF) and faulty counterregulatory response to hypoglycemia make the need for greater reliability at low levels particularly urgent in patients with type 1 diabetes mellitus, while this is seldom an issue in the more common form of the disease, type 2 diabetes mellitus.

In contrast, people who do not have diabetes may periodically have hypoglycemic symptoms but may also have a much higher rate of false positives to true, and a meter is not accurate enough to base a diagnosis of hypoglycemia upon. A meter can occasionally be useful in the monitoring of severe types of hypoglycemia (e.g., congenital hyperinsulinism) to ensure that the average glucose when fasting remains above 70 mg/dl (3.9 mmol/l).

References

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