Monitoring of Patients with Diabetes
Guidelines & Recommendations for Laboratory Analysis in the Diagnosis & Management of Diabetes Mellitus
NON & MINIMALLY INVASIVE
Jay McDonald, MD
1. Use. The oral glucose tolerance test (OGTT), once the gold standard for diagnosing diabetes mellitus, is now not recommended by the American Diabetes Association (ADA) for diagnosing either type 1 or type 2 diabetes, but continues to be recommended in a limited fashion by the World Health Organization (WHO) (1, 2). The oral glucose challenge (or glucose tolerance test) continues to be recommended by both the ADA and the WHO for establishing the diagnosis of gestational diabetes mellitus. In all cases, the extended 3-5 hour glucose tolerance test is not recommended for routine practice.
2. Rationale. Inability to respond appropriately to a glucose challenge, i.e., glucose intolerance, represents the fundamental defect in diabetes mellitus. The rationale for the ADA not recommending that the glucose tolerance test be used routinely to diagnose type 1 and 2 diabetes was that appropriate use of the FPG could identify approximately the same degree of glucose tolerance as the OGTT. Furthermore, in ordinary practice the OGTT is impractical. The consensus was that an OGTT with a 2h plasma glucose value of ³ 200 mg/dL (11.1 mmol/L) was the correct value for diagnosing diabetes mellitus because it corresponds to the value above which microangiopathy occurs (1). However, only approximately one-fourth of the individuals with 2h plasma glucose ³ 200 mg/dL (11.1 mmol/L) have a FPG of ³ 140 mg/dL (7.8 mmol/L), which was the FPG previously recommended to diagnose diabetes mellitus. The currently recommended FPG value of 126 mg/dL (7.0 mmol/L) was felt to correspond better to the GTT of 2h > 200 mg/dL, and thus correlate with development of complications.
There continues to be controversy over the use of the OGTT to classify individuals with impaired glucose tolerance and diabetes. Recent studies (3-6) indicate that individuals classified as having IGT by the OGTT (WHO criteria) have increased risk of cardiovascular disease but many of these individuals do not have IFG (ADA criteria). Furthermore, use of the OGTT and the WHO criteria to diagnose diabetes identifies approximately 2% more individuals as diabetic than if the ADA FPG criteria are used (7).
The 2h glucose tolerance test continues to be recommended for the diagnosis of gestational diabetes mellitus by both the ADA and WHO (1, 2). Deterioration of glucose tolerance occurs normally in pregnancy especially in the third trimester. Diagnosing and treating gestational diabetes is critical for preventing associated prenatal morbidity and mortality.
3. Analytical. The reproducibility of the OGTT has received considerable attention. In numerous studies, the reproducibility of the OGTT in classifying patients ranges from 50-66% (6). Possible reasons for lack of reproducibility include random variation of plasma glucose concentrations, the effects of administration of a hyperosmolar glucose solution on gastric emptying and effects of ambient temperature (8-11).
a) For diagnosing type 1 and 2 diabetes, the ADA and WHO have different recommendations:
1) ADA: Not recommended for use (1).
2) WHO: When FPG levels fall in the range of IFG [6.1 mmol/L (110)-7.0 mmol/L (126)] an OGTT is recommended (2). After three days of unrestricted diet and an overnight fast (8-14 h), an FPG is obtained, following which 75g anhydrous glucose (or partial hydrolysates of starch of the equivalent carbohydrate) in 250-300 ml of water is taken orally over 5 min. For children, the load is 1.75g glucose/kg up to 75g glucose. Blood samples are collected 2 hr after the load, and plasma glucose analyzed. Results are interpreted as follows:
b) Gestational Diabetes Mellitus
Screening should be performed between 24-28th week of gestation in women defined as at risk by the ADA (12). At risk patients are defined as:
³ 25 yo
< 25 yo and obese
Family history of diabetes in a first degree relative
Member of an ethnic/racial group with a high prevalence of diabetes.
The test recommended for screening is a 50g oral glucose load followed by a plasma glucose determination at 1h. A plasma glucose value ³ 7.8 mmol/L (140 mg/dL) indicates the need for definitive testing.
Definitive diagnosis is made by performing a 100g 3h OGTT. Two or more values must exceed:
Fasting 5.8 105
1 h 10.5 190
2 h 9.2 165
3 h 8.0 145
2) WHO recommends the same test (75g OGTT) and diagnostic criteria as for type 1 and 2 diabetes mellitus (2).
5. Emerging considerations. The main issues of controversy are 1) the value of classifying individuals having impaired glucose tolerance (recommended by WHO but not the ADA) and 2) the appropriate use in gestational diabetes mellitus. The latter is particularly controversial. In the Fourth International Workshop – Conference on Gestational Diabetes Mellitus (13), even tighter criteria (5-10% lower glucose values) than those accepted by the ADA were recommended for establishing the diagnosis. This discrepancy in recommendations reflects the state of knowledge about GDM, which continues to evolve with enhanced and expanded clinical research.
Intravenous Glucose Tolerance Test (IGTT):
Not recommended for routine use in the diagnosis and/or treatment of diabetes.
1. Use. Semiquantitative urine glucose testing, once the hallmark of diabetes care in the home setting, has now been replaced by self monitoring of blood glucose. Semiquantitative urine glucose monitoring should only be considered for patients who can't or won't monitor their own blood glucose (14, 15).
2. Rationale. Although urine glucose correlates roughly with blood glucose, it provides no information about blood glucose levels below the variable renal glucose threshold [~ 10 mmol/L (180 mg/dL)]. This alone limits its usefulness for monitoring diabetes under modern care recommendations. Furthermore, the concentration of the urine affects urine glucose values and only average glucose values between voidings are reflected, further minimizing the value of urine glucose determinations.
3. Analytical. Semiquantitative test-strip methods utilizing specific reactions for glucose are recommended. Most commercially available strips utilize the glucose oxidase reaction. Test methods that detect reducing substances are not recommended due to numerous interferences, including numerous drugs, and non-glucose sugars. When used, single voided urine samples are recommended (15).
4. Interpretation/use. Because of the limited use of urine glucose determinations, semiquantitative specific reaction-based test strip methods are adequate.
5. Emerging considerations. None.
Non- or Minimally-Invasive Glucose Analyses:
1. Use/introduction. The need for a device for "continuous" in vivo monitoring of glucose levels in blood is a very high priority as patients are required to control their blood glucose more closely (1,16). Currently, there are only two devices that have been approved by the FDA for non- or minimally-invasive glucose sensing, the "Gluco Watch Biographer" (Cygnus), and the "Continuous Glucose Monitoring System" (MiniMed). Although promising, routine use of these devices cannot be recommended at this time because clinical studies remain limited.
2. Rationale. The first goal for developing a reliable in vivo glucose sensor is to detect unsuspected hypoglycemia. Emphasis on achieving this goal has become more intense since it became recognized that strict glucose control is accompanied by a marked increase in hypoglycemia (16). In contrast, a full range reliable in vivo glucose monitor is a prerequisite for development of an artificial pancreas that measures glucose and automatically adjusts insulin administration.
3. Analytical. The goal here is not to review comprehensively the status of research in this important area, but to make recommendations for current use. There have been a number of recent reviews on this topic (17, 18) and it has been the subject of national conferences. For example, non-invasive testing technology was the focus of the Oak Ridge Conference in 1999, with considerable attention being focused on glucose sensing technology (19) and a symposium at the 1999 American Diabetes Association meeting focused on non-invasive glucose sensing (20).
The technological advances in minimally or non-invasive glucose monitoring can generally be overviewed as shown in Table I.
The transcutaneous sensors and implanted sensors employ similar detection systems including enzyme (usually glucose oxidase), electrodes and fluorescence-based techniques. Alternatives to enzymes as glucose recognition molecules are being developed, including artificial glucose "receptors" (21, 22). Fluorescence technologies include use of engineered molecules whose fluorescence intensity or spectrum changes upon binding glucose or use of competitive binding assays that employ two fluorescent molecules, so-called fluorescent resonance energy transfer (FRET) (23-27).
Different methods of tissue sampling "non-invasively" have been employed in various test systems. The general concept employed is that the concentration of glucose in the interstitial fluid will correlate with blood glucose. Most microdialysis systems are inserted subcutaneously (28-31). In contrast, "reverse iontophoresis", which is the basis of the FDA approved "Gluco Watch", (Cygnus) is "non-invasive" in concept. Iontophoresis employs a low level electrical current on the skin, which by convective transport (electro-osmosis) transports glucose across the skin. Then the concentration of glucose is measured by a glucose oxidase electrode detector (32, 33).
Finally, considerable research has been focused on developing totally non-invasive technology for glucose sensing. Of these, near infrared spectroscopy has been most intensively investigated, however, unpredictable spectral variations continue to hinder progress (34-38). Similar problems have hindered the successful use of light scattering (39, 40). Finally, photoacoustic spectroscopy, although less studied, has led to some encouraging preclinical results. In this technique, pulsed infrared light when absorbed by molecules results in detectable ultrasound waves, the intensity and patterns of which can theoretically be tuned to detect glucose (41-43).
4. Interpretation. Only the Gluco Watch Biographer (G-W) (Cygnus) and the Continuous Monitoring System (CMS) (Minimed) have received FDA approval. Therefore, only they will be considered here. The two devices have vastly differing applications. The G-W is designed to analyze "glucose" approximately three times/h for up to 12h, and appears best suited for detecting unsuspected hypoglycemia. In contrast, the CMS is intended for one-time or occasional use, rather than ongoing daily use. The information is intended to assist physicians help patients treat their diabetes, the values being downloaded into a computer in the physicians' offices.
The CMS consists of a glucose sensor inserted subcutaneously, which is connected to an externally worn monitor. Glucose is monitored every 5 min for up to 72 h and at the end of that period, the data are transferred to another computer for analyses. Values are not displayed on the externally worn monitor.
The Gluco Watch provides up to three readings/hour for as long as 12h after a single calibration. Calibration with reference blood glucose values requires a three-hour equilibration time and sampling time limits the number of measurements to approximately three/h. In limited, but promising, clinical trials, the Gluco Watch provides reasonable correlation with self glucose monitoring (32, 33). Despite the recent approval of the Gluco Watch by the FDA, its use has not been rigorously tested in a true clinically relevant home setting and it has not been tested in children. However, if it proves to reliably detect unsuspected hypoglycemic episodes in such settings, we should see widespread use of the Gluco Watch and continued improvement of the technology.
5. Emerging considerations. With the first approvals of self-monitoring non-invasive glucose sensors by the FDA, it is anticipated that there will be renewed efforts to bring other technologies forward into clinical studies. Ultimately, we will see improved methods for non-invasive or minimally-invasive glucose measurements that will complement current self glucose monitoring techniques.
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