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| REVIEW ARTICLE |
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| Year : 2017 | Volume
: 15
| Issue : 3 | Page : 200-207 |
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Glucose monitoring in diabetes mellitus
HS Asha1, Amit Balachandran2
1 Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of General Medicine, Christian Medical College, Vellore, Tamil Nadu, India
| Date of Web Publication | 7-Aug-2017 |
Correspondence Address:
H S Asha
Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore - 632 004, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/cmi.cmi_46_17
Diabetes is characterized by hyperglycemia due to deficiency or impaired action of insulin. The overall goal of diabetes management is to achieve as near normal glucose levels as possible, without affecting quality of life, and without causing significant hypoglycemia. Monitoring the impact of treatment and detection of abnormalities is therefore a crucial component of the management strategy. Plasma glucose and glycated hemoglobin are the most common tools used in monitoring response to treatment and each has its advantages and disadvantages. There are newer continuous glucose monitoring systems like the flash glucose monitoring system that provide an almost real-time recording of plasma glucose levels and give a better understanding of the dynamics of glucose fluctuations and the factors responsible.
Keywords: Blood glucose, diabetes mellitus, glycated hemoglobin, monitoring glucose, urine glucose
How to cite this article:
Asha H S, Balachandran A. Glucose monitoring in diabetes mellitus
. Curr Med Issues 2017;15:200-7 |
| Introduction | |  |
Our understanding of diabetes has improved significantly overtime and it has been well established that diabetes is characterized by hyperglycemia due to deficiency or impaired action of insulin. Measuring plasma glucose levels therefore are important for diagnosis and monitoring the level of control. Various landmark studies have demonstrated the impact of long-term control on the microvascular and macrovascular complications of diabetes. This has led to research and development of newer and better tools to monitor glucose levels. This article aims at summarizing the major glucose monitoring methods that are available today, the rationale behind using each, and the major advantages and disadvantages of different methods.
The overall goal of diabetes management is to achieve as near normal glucose levels as possible, without affecting quality of life, and without causing significant hypoglycemia.[1] Accurate measurement of glucose becomes relevant in this setting. The various tools that are available for glucose estimation are:
- Urine glucose
- Plasma glucose
- Glycated hemoglobin (HbA1c)
- Fructosamine
- Glucometers
- Continuous glucose monitoring systems (CGMS)
- Flash glucose monitoring.
| Urine Glucose | | |
Trommer (1841) and Fehling (1848) developed qualitative tests for urine glucose using the reducing properties of glucose which converts alkaline cupric sulfate reagents to produce colored cuprous oxide. It was Stanley Benedict who improved on the copper reagent for urine glucose in 1908 and standardized measurement of urine glucose. His method remained the mainstay of urinary glucose monitoring of diabetes for over 50 years. The conventional Benedict's test was slowly replaced by rapid dipstick tests for urine glucose.[2] However, the measurement of urine glucose has a number of drawbacks:[3]
- Urine fraction should be analyzed immediately after collection or else the bacterial metabolism of glucose in urine will give falsely low values
- If the sample has to be preserved before testing, it has to be at a pH <5 or at a temperature of 4°C to inhibit bacterial metabolism, which is often impractical
- Fluid intake and urine concentration affect test results
- Negative results do not distinguish between hypoglycemia, euglycemia, and even mild hyperglycemia. This is because glucose appears in urine only when the plasma glucose rises above the renal threshold (>180 mg/dl)
- Altered renal threshold can give false-positive results
- The enzyme used is glucose oxidase (GO)/peroxidase which can give:
- False-positive results with hydrogen peroxide
- False-negative results in the presence of ascorbic acid.
Nevertheless, measurement of urine glucose is rather cheap and easily available.
| Plasma Glucose | | |
Plasma glucose is measured by enzymatic method (GO-peroxidase). Measurements are accurate and precise with a coefficient of variance of only 2%. Plasma glucose provides information about the day-to-day level of control, variation in control and response to therapeutic intervention.
Precautions and points to note
- Red blood cells may continue to metabolize glucose after collection through glycolysis, thus leading to reductions in glucose levels. Glycolysis is avoided by rapid centrifugation, collection and storage in a refrigerator. To be transported at room temperature, blood should be collected into fluoride containing tubes which inhibit further glucose metabolism [3]
- Plasma glucose levels can be significantly affected by the site of collection of sample and time from food intake. Venous blood glucose levels are normally similar to arterial and capillary levels when fasting
- The arterial and capillary levels most closely reflect the glucose concentrations at the organ level
- After meals, venous blood glucose levels are lower than that in the arterial blood and can be as much as 10% lower.
Recommendations for plasma glucose measurement are given in [Box 1].
| Glycated Hemoglobin | | |
The short-term variation of plasma glucose levels due to several factors (e.g., exercise, stress, calorie content of meal, etc.) makes it a poor marker of long-term glycemic status. This led to a quest for newer markers for long-term glycemic status that resulted in the discovery of HbA1c.
Hemoglobin in blood normally reacts spontaneously with glucose to form glycated derivatives in a nonenzymatic manner. The extent of glycation is determined by the average concentration of glucose in blood over several days and does not vary as much as the plasma glucose level at any given point of time. Approximately 50% of the variance in HbA1c is determined by the average blood glucose concentration over the previous month, 25% by the concentration over 30–60 days and the remaining 25% by the concentration from 60 to 120 days.
It has been well established that HbA1c levels are directly related to the risk of development of diabetic complications through the landmark UK Prospective Diabetes Study (UKPDS) trial and other studies.[4] HbA1c provides a measure of the long-term control of blood glucose values during treatment. It does not provide a measure of glycemic variability or hypoglycemia. For patients prone to significant glycemic variability, especially those with Type 1 diabetes or Type 2 diabetes patients on insulin therapy, glycemic control is best evaluated by the combination of results from self-monitoring of blood glucose (SMBG) and HbA1c.[3]
Measurement of glycated hemoglobin
Point of care testing for HbA1c is now possible with clinic-based analyzers and may allow timely decisions on therapy changes.
A number of assays have been developed to measure HbA1c, which include:[5],[6]
- High-performance liquid chromatography (HPLC) and capillary electrophoresis
- HPLC and mass spectrometry
- Boron affinity chromatography
- Immunoassays – commonly used in point of care devices.
HbA1c measurements should be comparable to the Diabetes Control and Complications Trial (DCCT)/UKPDS standard. It should hence be performed in a laboratory with the National Glycated Hemoglobin Standardization Program certified assay. Ion-exchange HPLC method has an added advantage that careful inspection of chromatograms may identify the presence of aberrant peaks produced by variants like fetal hemoglobin.
The International Federation of Clinical Chemistry (IFCC) and Laboratory Medicine reference has recently suggested that HbA1c be expressed as mmol/mol of unglycated hemoglobin rather than a percentage. (IFCC − HbA1c mmol/mol = [DCCT − HbA1c% −2.15] × 10.929).
Despite being a good marker, HbA1c has pitfalls and is inaccurate when one or more of the following conditions coexist:
- Iron deficiency anemia
- Hemoglobinopathies (all HbA1c methods are inappropriate for the assessment of glycemic control in patients homozygous for HbS or HbC, with HbSC disease, or with any other condition that alters erythrocyte survival)
- Polycythemia
- Blood transfusion (gives falsely low value)
- Hemolysis (hemolytic anemia) and ineffective erythropoiesis (Vitamin B12 deficiency)
- Uremia caused by renal failure – gives false low or high values
- High levels of Vitamin C – gives false low values.
Glycated hemoglobin values in diagnosis and monitoring
The cutoff values for diagnosis and monitoring as recommended by the American Diabetes Association (ADA) are given in [Table 1].[7]
Recommendations for HbA1C testing are given in [Box 2].[7]
Estimated average glucose
The HbA1c assay measures chronic glycemia as a percentage (%) while day-to-day management is guided by self-monitoring of capillary glucose (mg/dl). A mathematical relationship between HbA1c and estimated average glucose (AG) levels was derived from a study comprising 507 individuals (268 with Type 1 diabetes, 159 with Type 2 diabetes, and 80 nondiabetics). A1C levels obtained at the end of 3 months were compared with the AG levels during the previous 3 months. Linear regression analysis between the A1C and AG values provided the tightest correlations.
AGmg/dl = 28.7 × A1C − 46.7, (R2 = 0.84, P< 0.0001).8
This correlation can be used to obtain the average blood glucose from HbA1c values and explain the level of glycemic control to the patients (especially those familiar with self-monitoring) more effectively [Table 2]. | Table 2: Glycated hemoglobin and corresponding estimated average glucose values
Click here to view |
| Fructosamine | | |
Albumin is the main component of plasma proteins. Albumin contains free amino groups which can react nonenzymatically with glucose to form fructosamine. Fructosamine reflects glucose levels over the preceding 1–3 weeks. Fructosamine measurement may be useful in pregnancy or in the preconception period where the changes can be evaluated at shorter intervals. However, the assay is markedly affected by excessive turnover or excretion of albumin like in renal disease. These assays are not standardized.[3]
| Glucometers and Self-monitoring of Blood Glucose | | |
Anton Clemens at Ames developed an instrument to produce quantitative blood glucose results with Dextrostix in 1970. He applied the key principle of using reflected light from the surface of a solid strip, which was captured by a photoelectric cell to produce a signal. This signal was displayed by a moving pointer on three analogue scales, equivalent to 0–4, 4–10, and 10–55 mmol/L blood glucose. The Ames Reflectance Meter weighed 1.2 kg. This principle of reflectance spectrophotometry was developed over the next two decades by several companies to produce reflectance meters using modified reagent strips, requiring much smaller volume of blood (20–30 μL).[2] It was not until the mid-1970s that the idea of self-testing by people with diabetes was contemplated. Glucochek, the first of a series of blood glucose meters produced by LifeScan, became available in 1980 in the UK.
Today, glucometers have become easier to use with minimal operating steps, auto-calibration, sample underfill detection, and hematocrit correction. They also provide services such as advanced data handling in tabular and graphical forms and calculation of 7-, 14-, 30-, and 90-day averages. In some meters, results can be downloaded to personal computers, iPhones or managed through specialized software.
SMBG is a standard of care for patients with Type 1 diabetes mellitus (T1DM) and is necessary for insulin-treated patients with Type 2 diabetes mellitus (T2DM). Glucometer testing of plasma glucose is, however, not without any errors. It is important to be aware of the cause for errors and try and minimize them [Table 3].[2]
Recommendations for SMBG and practical recommendations for the use of glucometers are given in [Box 3] and [Box 4], respectively.[7]
| Continuous Glucose Monitoring Systems | | |
Continuous monitoring of glucose is necessary in patients with wide fluctuations in glucose levels, to adjust and optimize therapy. CGMS is a Holter-type device. It has a GO-based electrochemical sensor which is inserted subcutaneously and a reader. The sensor measures glucose in the interstitial fluid every 5 min, and the results are transmitted to a reader for storage or immediate display (real-time continuous glucose monitoring [CGM]).
Compared to conventional blood glucose measurements performed 4–6 times a day, results are provided every 5 min for up to 3–6 days. However, about two to four glucometer tests per day may be required to calibrate some devices. CGMS gives better insight into the direction, magnitude, duration, frequency, and possible causes of glucose fluctuations in response to meals, insulin injections, hypoglycemic episodes, and exercise throughout the day. Real-time glucose readings help to make appropriate adjustments in diet, activity, and insulin dose. An example of CGMS data is given in [Figure 1]. | Figure 1: (a) Continuous glucose monitoring system data. (b) Duration distribution (continuous glucose monitoring system).
Click here to view |
Practical aspects
The CGM sensor is inserted subcutaneously. Capillary blood glucose measurements are performed using a glucometer 2–4 times/day. To optimize sensor accuracy, the device should be calibrated when the glucose level is relatively stable (ideally before meals or 3 h after meals). After 3–6 days, the sensor is removed and data downloaded following calibration with the glucometer blood glucose measurements. The stored amperometric data in the sensor are transferred and converted to glucose concentrations through a reader to a personal computer and analyzed using specific software. Real-time CGM devices have a mobile like reader which provides real-time glucose measurements. It also has alarms to alert during hypoglycemic episodes.
Advantages of continuous glucose monitoring systems
- Detects nocturnal hypoglycemia [9]
- Real-time CGM is helpful to assess the impact of day-to-day changes in lifestyle and glucose-lowering therapy on blood glucose levels.
Drawbacks of continuous glucose monitoring systems
- Sensor lag: physiologic lag between blood and interstitial glucose – about 15 min
- If the patient experiences symptoms of hypoglycemia, but this is not corroborated by the sensor reading, they should carry out a finger-stick blood glucose measurement irrespective of the sensor result. This is to prevent worsening of severity of hypoglycemia due to sensor lag and take action to avoid loss of consciousness or seizures
- Patients should be advised to perform a finger-stick blood glucose measurement before driving a vehicle if the sensor glucose reading is normal, but the trend graph arrows indicate that the glucose level is declining.
| Newer Glucose Monitoring Systems | | |
Flash glucose monitoring system
Flash glucose monitoring system (FGMS) measures interstitial glucose similar to CGMS, every 15 min for 14 days.[10] It is factory calibrated and does not require finger-stick blood glucose measurements for calibration. Interstitial glucose measurements with FGMS were found to be accurate compared with capillary blood glucose reference values, with accuracy remaining stable over 14 days. A sample FGMS recording is shown in [Figure 2]. | Figure 2: Flash glucose monitoring record of a patient with Type 1 diabetes mellitus.
Click here to view |
Advantages
- Similar to CGM but provides glucose values up to 14 days
- It is real-time and can be used to assess the effect of lifestyle modification and changes in glucose-lowering therapy
- Less expensive
- Painless and convenient installation.
Disadvantages
- Needs patient education and motivation to adjust therapy based on the glucose records
- Interstitial glucose levels are lower than corresponding capillary glucose values. This should be kept in mind and hypoglycemia confirmed with capillary blood glucose testing.
| Glucowatch | | |
This device, worn as a “wristwatch,” uses reverse iontophoresis to stimulate the secretion of subcutaneous fluid, and glucose content is measured using an electrode/GO/biosensor unit.[1]
The process allows automatic, frequent monitoring with alarms for designated low and high results.
| Closed-loop Artificial Pancreas | | |
With insulin pump therapy, the patient should make executive decisions about when to check the glucose level and what to do with different glucose values. The closed-loop system integrates a CGM and insulin pump, together with an automated algorithm to control insulin delivery. The patient would be removed from the decision loop. The system would essentially function as an artificial pancreas.[11]
| Take Home Messages | | |
- Glucose monitoring is an essential part of diabetes management
- Although HbA1c is a good marker of chronic glycemic status, it does not provide information about glycemic variability
- Frequent SMBG and preferably CGM are useful and cost-effective in those with T1DM and T2DM on insulin therapy
- CGMS and FGMS provide a better understanding of the dynamics of glucose fluctuations and the factors responsible
- A summary of recommendations for monitoring in diabetes is given in [Box 5].
Financial support and sponsorship
Nil.
Conflicts of interets
There are no conflicts of interest.
| References | | |
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| 7. | Standards of medical care in diabetes-2017: Summary of revisions. Diabetes Care 2017;40 Suppl 1:S4-5. |
| 8. | Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ, et al. Translating the A1C assay into estimated average glucose values. Diabetes Care 2008;31:1473-8. |
| 9. | JDRF CGM Study Group. JDRF randomized clinical trial to assess the efficacy of real-time continuous glucose monitoring in the management of type 1 diabetes: Research design and methods. Diabetes Technol Ther 2008;10:310-21. |
| 10. | Rebrin K, Steil GM. Can interstitial glucose assessment replace blood glucose measurements? Diabetes Technol Ther 2004;2:461-72. |
| 11. | Thabit H, Leelarathna L, Wilinska ME, Elleri D, Allen JM, Lubina-Solomon A, et al. Accuracy of continuous glucose monitoring during three closed-loop home studies under free-living conditions. Diabetes Technol Ther 2015;17:801-7. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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