Glucose monitoring

Cover photo.

Glucometer II with Glucostix packs, 1986. Courtesy of Bayer AG, Bayer Archive Leverkusen

“Blood sugar determinations have been overworked and given an emphasis out of all proportion to their actual importance. They are expensive and often provide no information not already available from the results of simple qualitative urine sugar analyses.” ¹

Russell M Wilder, 1949.

The doctor’s bag of the 19th century physician was part dispensary, part scientific laboratory. Alongside the stethoscopes, bandages, syringes and medication, sat a urine testing kit—a battered leather case with vials of caustic chemicals, droppers, spirit lamps and charred test tubes. Burns and stains on the doctor’s clothing bore witness to the regular use of this equipment, while the medical literature was full of letters pleading for more practical solutions.

Reagent papers were one possibility. They had been used by the scientific community since the 17th century when Robert Boyle first dropped his ‘good syrup of violets, impregnated with the tincture of the flowers’ onto white paper, noting that the subsequent addition of acid led the solution to turn red.^2,3 By 1876, litmus and turmeric papers were present in urine kits alongside the usual bottles of chemicals. In 1883, Dr George Oliver, a London-based physician and physiologist, published his experiences with reagent-impregnated paper for detecting glucose and albumin. His suggestions were rapidly adopted by Parke Davis who marketed pocket urine analysis kits with a complete set of reagent papers. ⁴ Alongside these they also sold a slightly larger kit with compressed tablets, another potential solution to the requirement for bottles of caustic chemicals.^{4 –7} Although ingenious, both methods had problems. Dry reagents spoiled in damp conditions, detached paper fibres confused results and heating of the specimen was still required; by the turn of the century, they had faded into obscurity.

When insulin was discovered in the 1920s, newly diagnosed patients with diabetes were taught to perform urine tests with reagent bottles, test tubes and pipettes.^1,8,9 There was nothing else to guide them or their doctors as they navigated the new world of regular insulin injections and strict calorie-controlled diets. Blood glucose measurement was a complicated, protracted laboratory procedure, useful in hospital but of limited value even to the general practitioner. Patients tested their urine regularly for the presence of glucose—and occasionally ketones—with home testing kits. Good diabetic control meant aiming for low levels of glucose in the urine. To avoid hypoglycaemia, patients were instructed to decrease their insulin dose if their urine was free of glucose for several days.

The first breakthrough occurred as a result of the overwhelming commercial success of Alka Seltzer®, an effervescent mixture of aspirin, sodium bicarbonate and anhydrous citric acid, marketed extensively by Miles Laboratories in Elkhart, Indiana as a ‘health drink’ for headache, indigestion and hangovers. ¹⁰ When Dr Walter Ames Compton joined the company in 1938, he used their experience with Alka Seltzer to produce an effervescent urine testing tablet. The resultant Clinitest® contained cupric sulphate, sodium hydroxide and citric acid, plus bicarbonate to make it fizz. The chemical process generated enough heat to activate the ingredients and, as with earlier tests, the solution turned red in the presence of glucose. Levels were measured against a colour chart. Although more expensive than traditional methods, it quickly became popular due to its convenience and improved accuracy.

Encouraged by this successful foray into diagnostic testing, in 1946, Miles Laboratories created the Ames division (after Walter Ames Compton), a biochemical research and development department led by Alfred Free. Around 10 years later they released the Clinistix®, a urine stick utilising enzymatic reactions, impregnated with glucose oxidase, peroxidase and orthotolidine. ¹¹ Unlike earlier reagent-impregnated papers, which were added to the urine specimen, the Clinistix® was dipped into the urine and withdrawn; the resultant blue colour change on the stick indicated the presence of glucose. The test was more specific than previous tests but not sufficiently sensitive to estimate the amount of glucose present, other than being able to ‘differentiate between small and large amounts’. ¹¹

Clinistix® was not the first dipstick based on enzymatic reactions; Eli Lilly and Co described one a year earlier, and there were soon others.^8,12 But Clinistix® was chosen by pathologist Joachim Kohn for the first trial of enzymatic dipsticks to estimate blood glucose because ‘the background is white and the texture firm’. ¹³ After carefully developing a colour scale based on samples with known blood glucose levels, Kohn conducted 545 tests on patients, comparing results with laboratory blood glucose tests. While the tests required careful timing and rinsing of the sticks, their results were encouraging and indicated the ‘clinically important blood sugar ranges’ without providing exact figures.

Subsequent developments related to the quality and properties of the paper. By 1964, the Ames division had created the Dextrostix®, with a semipermeable membrane designed specifically for blood testing. The membrane excluded red blood cells but allowed the diffusion of glucose.^9,14 Boehringer Mannheim then produced the ChemstripbG®, a beige and blue strip which could be wiped with a cotton bud and was easier to read. ¹⁵ Both strips were prone to inaccuracy if not stored correctly, away from heat, moisture, air or light. ¹⁶ These simple diagnostic tests soon found wide application in hospitals, operating theatres and doctors’ surgeries. Despite endless debate about the accuracy of the strips, it was clear that ‘in the diagnosis of coma, the speed and reliability of a method are more important than a high degree of accuracy …’ ¹⁷ Anaesthetists embraced them in the operating theatre where ‘reliability, speed and direction of change, are more important than absolute values’. ¹⁸

As evidence accumulated that the long-term complications of diabetes could be diminished with early diagnosis and better glucose control, the strips became invaluable for general practitioners and endocrinologists. ¹⁷ Despite this, there was a prevailing belief that good results could only be obtained by skilled personnel, and there does not seem to have been any push for home monitoring of blood glucose. ¹⁹

The development of the Ames Reflectance Meter® by Anton Clemens at Ames was a major breakthrough, allowing more consistent and accurate reading of the strips. Created during the 1960s, the first commercial model was available by 1970. With heavy lead acid rechargeable batteries, it weighed 1.2 kg and displayed three analogue scales, equivalent to 0–4, 4–10 and 10–55 mmol/l blood glucose, with a moving pointer. The meter retailed for US$495 and could only be sold to doctors or hospital departments.

Ames then partnered with Japanese company, Kyoto-Daiichi to produce a number of lighter, more compact models, beginning with the mains-powered Eyetone® in 1972. ¹⁵ The Dextrometer®, released in 1980, was a much smaller device and the first with a digital display; it was followed quickly by the even lighter Glucometer®. As these devices became smaller and simpler to use, they appeared in increasing numbers around hospitals, finding new uses in places like neonatal wards and obstetric clinics.

Eventually, as the technology improved, home monitoring gained more attention. In 1978, two comprehensive studies clearly established that patients could improve their diabetes management with home testing. Interestingly many patients taking part in these trials also noted that seeing graphs of their blood glucose levels ‘made sense of their diabetes at last’.^19,20 Further studies established that patients could successfully use the sticks without a meter if a more cost-effective method was required. ²¹

Driven by the increasing demand for point-of-care testing in both hospitals and the home, the technology advanced rapidly in the 1980s. Devices became smaller with in-built timers, self-calibrating features and even some data storage capacity, but inaccuracies, due to inadequate blood sampling, wiping the stick at the wrong time or irregular calibration, remained problematic. ¹⁵ During the 1990s, companies succeeded in removing most of these operator-dependent steps.

In 2012, a review article on blood glucose monitoring concluded, ‘There is little doubt that blood glucose meter/strip systems used effectively will continue to be an essential component of diabetic self-care.’ ¹⁵ Yet, just 12 years later, the growth of wearable devices has seen strip testing largely eliminated for many patients with diabetes. ²² While the possibilities for this technology for diabetes management are exciting, wearable devices have seen blood glucose monitoring enter into the wider ‘wellness industry’. There are now a plethora of websites and apps offering wearable sensors to monitor blood glucose to help with dietary planning, exercise programmes and even sleep.^23,24 Whether this technology will have a positive impact on preventative medicine, early detection of disease and health education campaigns remains to be seen.