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1
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Thorn 530, 75 Francis St., Boston, MA 02115.
2
Department of Pathology, University of Virginia Medical School, PO Box 800214, Charlottesville, VA 22908.
3
Department of Child Health, University of Missouri School of Medicine, 1 Hospital Dr., Columbia, MO 65212.
4
Weill Medical College of Cornell University, 1300 York Ave., Suite LC-623, New York, NY 10021.
5
Department of Pathology, University of Alabama at Birmingham, 701 S. 19th St., Birmingham, AL 35294.
6
Veterans Administration Medical Center, Birmingham, AL 35233.
7
American Diabetes Association, 1701 Beauregard St., Alexandria, VA 22311.
aAuthor for correspondence. Fax 617-278-6921; e-mail dsacks{at}rics.bwh.harvard.edu.
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Abstract |
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 Top Abstract Executive SummaryIntroductionGlucoseMetersOGTTUrinary GlucoseNoninvasive or Minimally...Ketone TestingGHbGenetic MarkersAutoimmune MarkersMicroalbuminuriaMiscellaneous Potentially...References |
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Approach: An expert committee drafted evidence-based recommendations for the use of laboratory analysis in patients with diabetes. An external panel of experts reviewed a draft of the guidelines, which were modified in response to the reviewers’ suggestions. A revised draft was posted on the Internet and was presented at the AACC Annual Meeting in July, 2000. The recommendations were modified again in response to oral and written comments. The guidelines were reviewed by the Professional Practice Committee of the American Diabetes Association.
Content: Measurement of plasma glucose remains the sole diagnostic criterion for diabetes. Monitoring of glycemic control is performed by the patients, who measure their own plasma or blood glucose with meters, and by laboratory analysis of glycated hemoglobin. The potential roles of noninvasive glucose monitoring, genetic testing, autoantibodies, microalbumin, proinsulin, C-peptide, and other analytes are addressed.
Summary: The guidelines provide specific recommendations based on published data or derived from expert consensus. Several analytes are of minimal clinical value at the present time, and measurement of them is not recommended.
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Executive Summary |
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TopAbstractExecutive SummaryIntroductionGlucoseMetersOGTTUrinary GlucoseNoninvasive or Minimally...Ketone TestingGHbGenetic MarkersAutoimmune MarkersMicroalbuminuriaMiscellaneous Potentially...References |
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glucose
Accredited laboratory
Glucose should be measured in an accredited laboratory to establish the diagnosis of diabetes and to screen high-risk individuals. Analysis in an accredited laboratory is not recommended as the primary means for routine monitoring or evaluating therapy in individuals with diabetes. Blood should be drawn after the individual has fasted overnight. If plasma cannot be separated from the cells within 60 min, a tube containing a glycolytic inhibitor should be used. Glucose should be measured in plasma.
Although methods for glucose analysis exhibit low imprecision at the diagnostic decision limits of 7.0 mmol/L [(126 mg/dL), fasting] and 11.1 mmol/L [(200 mg/dL), post glucose load], the relatively large intraindividual biological variability (CVs of 
5–7%) may produce classification errors. On the basis of biological variation, glucose analysis should have analytical imprecision 
3.3%, bias 2.5%, and total error 7.9%.
Portable meters
Portable meters are used by healthcare workers in acute and chronic care facilities, in physicians’ offices, and by patients. Because of the imprecision and variability among meters, they should not be used to diagnose diabetes and have limited value in screening.
Self-monitoring of blood glucose (SMBG) is recommended for all insulin-treated patients. It should be performed at least three times a day for patients with type 1 diabetes. The efficacy of SMBG in patients with type 2 diabetes has not been established.
Multiple performance goals for portable glucose meters have been proposed. These targets vary widely and lack consensus. Clinical studies are needed to determine these analytical goals. We recommend meters that measure and report plasma glucose concentrations.
Oral glucose tolerance test (OGTT)
We do not recommend the OGTT for the routine diagnosis of type 1 or 2 diabetes. This issue is controversial, and the WHO supports its use. The key limitation of the OGTT is its poor reproducibility. Proponents, however, argue that it has slightly higher sensitivity than fasting glucose for diagnosing diabetes.
Noninvasive or minimally invasive glucose analyses
Noninvasive glucose analyses cannot be recommended at present as replacements for SMBG or glucose measurements by an accredited laboratory. Although promising, clinical studies remain limited. Several methodologies are available, but no analytical performance goals have been established.
ketones
Ketones should be measured in urine or blood by patients with diabetes at home and in hospitals or clinics as an adjunct to the diagnosis of diabetic ketoacidosis (DKA). Methods based on the nitroprusside reaction should not be used to monitor treatment of DKA. Although specific measurement of ß -hydroxybutyrate is available, further studies are needed to ascertain whether this offers clinical advantage.
glycated hemoglobin (GHb)
GHb should be measured at least biannually in all patients with diabetes to document their glycemic control. Treatment goals should be based on the results of prospective randomized clinical trials, such as the Diabetes Control and Complications Trial (DCCT), that documented the relationship between glycemic control (quantified by GHb analysis) and the risks for the development and progression of chronic complications of diabetes.
US laboratories should use GHb assays certified by the National Glycohemoglobin Standardization Program (NGSP) as traceable to the DCCT reference. GHb concentrations should be maintained at <7%, and the treatment regimen should be reevaluated if GHb is >8% as measured by NGSP-certified methods. Laboratories should participate in proficiency testing. Efforts to achieve global harmonization of GHb testing, an important goal, are underway.
genetic markers
Routine measurement of genetic markers is not recommended at this time for the diagnosis or management of patients with diabetes.
autoimmune markers
Several autoantibodies have been detected in individuals with type 1 diabetes. However, these lack specificity and are not recommended for routine diagnosis or screening of diabetes. Until type 1 diabetes can be prevented, islet cell autoantibody measurement should be essentially confined to research protocols.
microalbuminuria
Diabetes is the leading cause of end-stage renal disease. Annual microalbuminuria testing should be performed in patients without clinical proteinuria. To be useful, semiquantitative or qualitative screening tests must be shown to be positive in >95% of patients with microalbuminuria. Positive results of such tests must be confirmed by quantitative testing in an accredited laboratory.
miscellaneous potentially important analytes
Several other analytes are measured in patients with diabetes. All adults with diabetes should receive annual lipid profiles. There is no role for routine testing for insulin, C-peptide, or proinsulin in most patients with diabetes. These assays are useful primarily for research purposes. Similarly, measurement of amylin or leptin is not of value at this time in the management of patients with diabetes.
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Introduction |
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TopAbstractExecutive SummaryIntroductionGlucoseMetersOGTTUrinary GlucoseNoninvasive or Minimally...Ketone TestingGHbGenetic MarkersAutoimmune MarkersMicroalbuminuriaMiscellaneous Potentially...References |
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1. Type 1 diabetes mellitus, formerly known as insulin-dependent diabetes mellitus or juvenile-onset diabetes mellitus, is caused by autoimmune destruction of the ß-cells of the pancreas, rendering the pancreas unable to synthesize and secrete insulin (2). Type 2 diabetes mellitus, formerly known as non-insulin-dependent diabetes mellitus or adult-onset diabetes, results from a combination of insulin resistance and inadequate insulin secretion (3)(4). Other types of diabetes are rare. Type 2 is the most common form, accounting for 90–95% of diabetes in developed countries.
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In 1992, the costs of diabetes in the US were estimated to be $98 billion (5). The mean annual per capita healthcare costs for an individual with diabetes are approximately fourfold higher than those for individuals who do not have diabetes (5). Similarly, in the United Kingdom, diabetes accounts for roughly 10% of the National Health Service budget (£49 billion).
The high costs of diabetes are attributable to care for both acute conditions (such as hypoglycemia and ketoacidosis) and debilitating complications (6). The latter include both microvascular complications—predominantly retinopathy, nephropathy, and neuropathy—and macrovascular complications, particularly stroke and coronary artery disease (CAD). 1 Together these make diabetes the seventh most common cause of death in the developed world (7).
The American Diabetes Association (ADA) publishes in January each year a supplement, entitled Clinical Practice Recommendations, to Diabetes Care. This is a compilation of all ADA position statements related to clinical practice and is an important resource for healthcare professionals who care for people with diabetes. The National Academy of Clinical Biochemistry has developed evidence-based guidelines for the practice of laboratory medicine. The guidelines in this document are based on the best available published evidence. An assessment was made of virtually all analytes used in the diagnosis and management of individuals with diabetes. The resulting guidelines, intended for use by laboratorians and providers of patient care, have been reviewed by the ADA Professional Practice Committee and found to be consistent in those areas where the ADA has also published Clinical Practice Recommendations. The guidelines in this document are not intended to supplant the ADA Recommendations. The objective is to supplement the ADA Recommendations, with an emphasis on the laboratory aspects of diabetes.
The ADA has developed a system to grade the quality of scientific evidence (Table 2
). This scheme has been used in this report to describe the quality of the evidence on which each recommendation is based. The ratings range from A to C, with A exhibiting the highest quality of evidence. Category E, expert opinion, is used for recommendations for which no evidence from clinical trials is available or where conflicting evidence has been published.
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To facilitate comprehension and assist the reader, each analyte is divided into several headings and subheadings. These are use (diagnosis, screening, monitoring, and prognosis), rationale (diagnosis and screening), analytical considerations [preanalytical (including reference values) and analytical (such as methods)], interpretation (including frequency of measurement and turnaround time), and where applicable, emerging considerations, which alert the reader to ongoing studies and potential future aspects relevant to that analyte.
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Glucose |
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TopAbstractExecutive SummaryIntroductionGlucoseMetersOGTTUrinary GlucoseNoninvasive or Minimally...Ketone TestingGHbGenetic MarkersAutoimmune MarkersMicroalbuminuriaMiscellaneous Potentially...References |
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Level of evidence: A
Glucose should be measured in plasma in an accredited laboratory for screening of high-risk individuals.
Level of evidence: E
Analysis in an accredited laboratory is not necessary for routine monitoring.
Level of evidence: E
The diagnosis of diabetes is established exclusively by the documentation of hyperglycemia (increased glucose concentrations in the plasma). In 1997, the diagnostic criteria (8) were modified (1) to better identify individuals at risk of retinopathy and nephropathy. The revised (current) criteria include: (a) symptoms of diabetes and casual (i.e., regardless of the time of the preceding meal) plasma glucose 
11.1 mmol/L (200 mg/dL); (b) fasting plasma glucose (FPG) 7.0 mmol/L (126 mg/dL); or (c) 2-h postload glucose 11.1 mmol/L (200 mg/dL) during an oral glucose tolerance test (OGTT) (1). If any one of these three criteria is met, confirmation by repeat testing on a subsequent day is necessary to establish the diagnosis. (Note that repeat testing is not necessary in patients who have unequivocal hyperglycemia with acute metabolic decompensation.) Although included as a criterion, the OGTT was not recommended for routine clinical use in nonpregnant individuals (see below).
Population screening for type 2 diabetes, previously controversial, is now recommended for those at risk of developing the disease (1)(9). The ADA proposes that FPG should be measured in all asymptomatic people 45 years of age. If results are <6.1 mmol/L (110 mg/dL), testing should be repeated at 3-year intervals. Screening should be considered at a younger age or be carried out more frequently in individuals at increased risk of diabetes [see Ref (1) for conditions associated with increased risk]. Because of the increasing prevalence of type 2 diabetes in children, screening of children has been suggested recently (10). Starting at age 10 years, testing should be performed every 2 years in overweight individuals who have two other risk factors, namely family history, race/ethnicity, and signs of insulin resistance (10). Despite these recommendations, there is no published evidence that treatment based on screening has value. The cost-effectiveness of screening for type 2 diabetes has been estimated. The incremental cost of screening all persons 25 years or older was estimated to be $236 449 per life-year gained and $56 649 per quality-adjusted life-year gained (11). Interestingly, screening was more cost-effective at ages younger than the 45 years currently recommended.
Monitoring/Prognosis
Recommendation: Although there is evidence linking high plasma glucose concentrations to adverse outcome, substantially more data are available that directly correlate increased glycated hemoglobin (GHb) with complications of diabetes. Routine measurement of plasma glucose concentrations in an accredited laboratory is not recommended as the primary means of monitoring or evaluating therapy in individuals with diabetes.
Level of evidence: E
There is a direct relationship between the degree of plasma glucose control and the risk of late renal, retinal, and neurologic complications. This correlation has been demonstrated for type 1 (12) and more recently for type 2 (13) diabetes. Persons with type 1 diabetes who maintained lower average plasma glucose concentrations exhibited a significantly lower incidence of microvascular complications, namely diabetic retinopathy, nephropathy, and neuropathy (12). Although intensive insulin therapy reduced hypercholesterolemia by 34%, the risk of macrovascular disease was not significantly decreased. Similar results were obtained in patients with type 2 diabetes (13). Intensive plasma glucose control in patients with type 2 diabetes significantly reduced microvascular complications, but no significant difference was detected for macrovascular disease (myocardial infarction or stroke) (13). In both studies, patients in the intensive group maintained lower median plasma glucose concentrations. Analyses of the outcomes were linked to GHb, which wasused to evaluate glycemic control, rather than glucose concentration. Moreover, most clinicians use the ADA recommendations, which define a target GHb concentration as the goal for optimum glycemic control (14).
There is some evidence directly linking higher glucose concentrations to a poor prognosis. For example, the 10-year survival of 6681 people in a Japanese town was reduced if FPG was 7.8 mmol/L (140 mg/dL) (15). Similar findings were obtained in 1939 patients with type 2 diabetes followed for a mean of 15 years; multiple logistic regression revealed that the risk of death was significantly increased for patients with FPG 7.8 mmol/L (140 mg/dL) (16). Individuals with type 2 diabetes with FPG >7.8 mmol/L (140 mg/dL) had increased cardiovascular mortality (17). Furthermore, comparison of 300 patients with a first myocardial infarction and 300 matched controls revealed that a moderately increased FPG was a risk factor for infarction (18). Notwithstanding these observations, neither random nor fasting glucose concentrations should be measured in an accredited laboratory as the primary means of routine monitoring of patients with diabetes. Laboratory plasma glucose testing can be used to supplement information from other testing, to test the accuracy of self-monitoring (see below), or when adjusting the dose of oral hypoglycemic agents (9). In addition, individuals with well-controlled type 2 diabetes who are not on insulin therapy can be monitored with periodic measurement of FPG, although analysis need not be done in an accredited laboratory (19)(20).
rationale
Diagnosis
The disordered carbohydrate metabolism that underlies diabetes manifests as hyperglycemia. Therefore, measurement of plasma glucose is the sole diagnostic criterion. This strategy is indirect as hyperglycemia reflects the consequence of the metabolic derangement, not the cause. However, until the underlying molecular pathophysiology of the disease is identified, plasma glucose concentrations are likely to remain an essential diagnostic modality.
Screening
Screening is recommended for several reasons. The onset of type 2 diabetes is estimated to occur 4–7 years before clinical diagnosis (21), and epidemiologic evidence indicates that complications may begin several years before clinical diagnosis. Furthermore, at least 30% of people in the US with type 2 diabetes are undiagnosed (22). Notwithstanding this recommendation, there is no evidence that population screening of plasma glucose concentrations provides any benefit. Outcome studies should be performed to justify screening.
analytical considerations
Preanalytical
Recommendation: Blood for fasting plasma glucose analysis should be drawn after the individual has fasted overnight (at least 8 h). Plasma should be separated from the cells within 60 min; if this is not possible, a tube containing a glycolytic inhibitor such as sodium fluoride should be used for collecting the sample.
Level of evidence: B
Blood should be drawn in the morning after an overnight fast [no caloric intake for at least 8 h, during which time the individual may consume water ad libitum (1)]. Recent evidence revealed a diurnal variation in FPG, with mean FPG higher in the morning than in the afternoon, indicating that many cases of undiagnosed diabetes would be missed in patients seen in the afternoon (23). Glucose concentrations decrease ex vivo with time in whole blood because of glycolysis. The rate of glycolysis, reported to average 5–7% [0.6 mmol/L (10 mg/dL)] per hour (24), varies with the glucose concentration, temperature, white blood cell count, and other factors (25). Glycolysis can be attenuated by inhibition of enolase with sodium fluoride (2.5 mg fluoride/mL of blood) or, less commonly, lithium iodoacetate (0.5 mg/mL of blood). These reagents can be used alone or, more commonly, with anticoagulants such as potassium oxalate, EDTA, citrate, or lithium heparin. Although fluoride maintains long-term glucose stability, the rates of decline of glucose in the first hour after sample collection in tubes with and without fluoride are virtually identical (24). (Note that leukocytosis will increase glycolysis even in the presence of fluoride if the white cell count is very high.) After 4 h, the glucose concentration is stable in whole blood for 72 h at room temperature in the presence of fluoride (24). In separated, nonhemolyzed, sterile serum without fluoride, the glucose concentration is stable for 8 h at 25 °C and 72 h at 4 °C (26).
Glucose can be measured in whole blood, serum, or plasma, but plasma is recommended for diagnosis. The molality of glucose (i.e., amount of glucose per unit water mass) in whole blood and plasma is identical. Although red blood cells are essentially freely permeable to glucose (glucose is taken up by facilitated transport), the concentration of water (kg/L) in plasma is 11% higher than that of whole blood. Therefore, glucose concentrations in plasma are 11% higher than whole blood if the hematocrit is normal. Glucose concentrations in heparinized plasma are reported to be 5% lower than in serum (27). The reasons for the latter difference are not apparent, but may be attributable to the shift in fluid from erythrocytes to plasma caused by anticoagulants. The glucose concentrations during an OGTT in capillary blood are significantly higher than those in venous blood [mean of 1.7 mmol/L (30 mg/dL), equivalent to 20–25% (28)], but the mean difference in fasting samples is only 0.1 mmol/L (2 mg/dL) (28)(29).
Reference values. Glucose concentrations in healthy individuals vary with age. Reference intervals in children are 3.3–5.6 mmol/L (60–100 mg/dL), similar to the adult interval of 4.1–5.9 mmol/L (74–106 mg/dL) (26). Note that the ADA criteria (1), not the reference values, are used for the diagnosis of diabetes. Moreover, the threshold for diagnosis of hypoglycemia is variable. The reference values are not useful to diagnose these conditions. In adults, mean fasting plasma glucose increases with increasing age from the third to the sixth decade (30), but does not increase significantly after age 60 (31)(32). By contrast, glucose concentrations after a glucose challenge are substantially higher in older individuals (31)(32). Evidence of an association of increasing insulin resistance with age is inconsistent (33).
Analytical
Recommendation: Enzymatic methods for glucose analysis are relatively well standardized. Despite the low imprecision at the diagnostic decision limits of 7.0 mmol/L (126 mg/dL) and 11.1 mmol/L (200 mg/dL), classification errors may occur. Because of the relatively large intraindividual biological variability (CVs of 5–7%), FPG values of 5.8–6.9 mmol/L (105–125 mg/dL) should be repeated and individuals with FPG of 5.3–5.7 mmol/L (96–104 mg/dL) should be considered for follow-up at intervals shorter than the current ADA recommendation of every 3 years.
Level of evidence: E
Glucose is measured almost exclusively by enzymatic methods. Analysis of proficiency surveys conducted by the College of American Pathologists (CAP) revealed that hexokinase or glucose oxidase is used in virtually all analyses performed in the US (26). A few laboratories (1%) use glucose dehydrogenase. At a plasma glucose concentration of 8.2 mmol/L (147 mg/dL), imprecision among laboratories using the same method had a CV <4%, excluding glucose dehydrogenase (26). Similar findings have been reported for glucose analysis in samples from patients. For example, comparison of plasma samples from 240 patients revealed a 5% difference in mean glucose concentrations measured by the hexokinase and glucose oxidase methods (34).
No consensus has been achieved on the goals for glucose analysis. Numerous criteria have been proposed to establish analytical goals. These include expert opinion (consensus conferences), opinion of clinicians, regulation, state of the art, and biological variation (35). A rational and realistic recommendation that has received some support is to use biological criteria as the basis for analytical goals. It has been suggested that imprecision should not exceed one-half of the within-subject biological CV (36)(37). For plasma glucose, a CV 2.2% has been suggested as a target for imprecision, with 0% bias (37). Although this recommendation was proposed for within-laboratory error, it would be desirable to achieve this goal for interlaboratory imprecision to minimize differences among laboratories in the diagnosis of diabetes in individuals whose glucose concentrations are close to the threshold value. Therefore, the goal for glucose analysis should be to minimize total analytical error, and methods should be without measurable bias. A national program using samples (e.g., fresh-frozen plasma) that eliminate matrix effects should be developed to assist in the achievement of this objective.
interpretation
Knowledge of intraindividual variability of FPG concentrations is essential for meaningful interpretation of patient values. An early study, which repeated the OGTT in 31 nondiabetic adults at 48-h intervals, revealed that FPG varied by <10% in 22 participants (77%) and by <20% in 30 participants (97%) (38). Biological variation includes within- and between-subject variation. Careful evaluation over several consecutive days revealed that intraindividual variation of FPG in healthy individuals [mean glucose, 4.9 mmol/L (88 mg/dL)] exhibited within- and between-subject CVs of 4.8–6.1% and 7.5–7.8%, respectively (39)(40). Larger studies have revealed CVs of 6.4–6.9% for FPG in 246 apparently healthy (41) and 193 newly diagnosed untreated patients with type 2 diabetes (42). The latter study, which measured FPG by glucose oxidase (intra- and interassay CVs <2%) on 2 consecutive days, obtained 95% confidence intervals (CIs) of ± 14.8% for total variability and ± 13.7% for biological variability. If a CV (biological) of 6.9% is applied to a true glucose concentration of 7.0 mmol/L (126 mg/dL), the 95% CI would encompass glucose concentrations of 6.1–7.9 mmol/L (109–143 mg/dL). If the CV of the glucose assay (4%) is included, the 95% CI is approximately ± 18%. Thus, the 95% CI for a fasting glucose concentration of 7.0 mmol/L (126 mg/dL) would be 7.0 mmol/L ± 18% (126 mg/dL ± 18%), namely, 5.7–8.3 mmol/L (103–149 mg/dL). Use of an assay imprecision of 4% (CV) only (excluding biological variability), would yield a 95% CI of 6.4–7.6 mmol/L (116–136 mg/dL) among laboratories for a true glucose concentration of 7.0 mmol/L (126 mg/dL). One should bear in mind that these ranges include 95% of individuals and that other individuals will be outside this range. The biological variability is substantially greater than analytical variability. Using biological variation as the basis for deriving analytical performance characteristics (35), Ricos et al. (43) have proposed the followingdesirable specifications for glucose: analytical imprecision 3.3%, bias 2.5%, and total error 7.9%.
A short turnaround time for glucose analysis is not usually necessary for the diagnosis of diabetes. In some clinical situations, such as acute hyper- or hypoglycemic episodes in the Emergency Department or treatment of diabetic ketoacidosis (DKA), rapid analysis is desirable. A turnaround time of 30 min has been proposed (44). However, this value is based on requirements by clinicians, and no outcome data have been published that validate this value. Inpatient management of diabetic patients may on occasion require a rapid turnaround time (minutes, not hours). Bedside monitoring with glucose meters (see below) has been adopted by many as a practical solution (45).
Frequency of measurement. The frequency of measurement of plasma glucose is dictated by the clinical situation. The ADA recommends that an increased FPG or abnormal OGTT must be confirmed to establish the diagnosis of diabetes (1). Screening by FPG is recommended every 3 years if it is <6.1 mmol/L (<110 mg/dL), more frequently in high-risk individuals; however, frequency of analysis in the latter group is not specified. Monitoring is performed by patients themselves, who measure glucose with meters, and by assessment of GHb in an accredited laboratory (see below). Appropriate intervals between measurements of glucose in acute clinical situations (e.g., patients in hospital or patients with DKA or neonatal hypoglycemia) are highly variable and may range from 30 min to 24 h.
emerging considerations
Noninvasive or minimally invasive analysis of glucose is addressed below.
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Meters |
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TopAbstractExecutive SummaryIntroductionGlucoseMetersOGTTUrinary GlucoseNoninvasive or Minimally...Ketone TestingGHbGenetic MarkersAutoimmune MarkersMicroalbuminuriaMiscellaneous Potentially...References |
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use
Diagnosis/Screening
Recommendation: There are no published data to support a role for portable meters in the diagnosis of diabetes or for population screening. The imprecision of the meters, coupled with the substantial differences among meters, precludes their use in the diagnosis of diabetes and limits their usefulness in screening for diabetes.
Level of evidence: E
The criteria for the diagnosis of diabetes are based on outcome data (the risk of micro- and macrovascular disease) correlated with plasma glucose concentrations, both fasting and 2 h after a glucose load, assayed in an accredited laboratory (1). Whole blood is used in portable meters. Although many portable meters have been programmed to report a plasma glucose concentration, the imprecision of the current meters (see below) precludes their use in the diagnosis of diabetes. Similarly, screening by portable meters, although attractive because of convenience, ease, and accessibility, would generate many false positives and false negatives.
Monitoring/Prognosis
Recommendation: SMBG is recommended for all insulin-treated patients with diabetes. For type 1 patients, SMBG is recommended three or more times a day. SMBG may be desirable in patients treated with sulfonylureas or other insulin secretagogues and in all patients not achieving goals.
Level of evidence: B
In patients with type 2 diabetes, SMBG may help achieve better control, particularly when therapy is initiated or changed. However, there are no data to support this concept. The role of SMBG in patients with stable type 2 diabetes controlled by diet alone is not known.
Level of evidence: C
SMBG is recommended for all patients with diabetes who are receiving insulin. Tight glycemic control can decrease microvascular complications in individuals with type 1 (12) or type 2 (13) diabetes. Intensive plasma glucose control in patients with type 1 diabetes was achieved in the Diabetes Control and Complications Trial (DCCT) by participants performing SMBG at least four times per day (12). Therapy in patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study (UKPDS) (13) was adjusted according to FPG concentrations; SMBG was not evaluated.
Faas et al. (49) reviewed 11 studies, published between 1976 and 1996, that evaluated SMBG in patients with type 2 diabetes. Only one of the published studies reported that SMBG produced a significantly positive improvement, namely lower GHb. The authors of the review concluded that the efficacy of SMBG in type 2 diabetes is questionable (49). Similar conclusions were drawn in a recent metaanalysis (50) and in a sample of patients with type 2 diabetes in the National Health and Nutrition Examination Survey (NHANES) (51). Although SMBG may be useful in initiating or changing therapy in patients with type 2 diabetes, clinical studies are needed to define its role in outcome in patients with type 2 diabetes.
rationale
SMBG allows patients with diabetes to achieve and maintain specific glycemic goals. Knowledge of plasma or blood glucose concentrations is necessary for insulin-requiring patients, particularly those with type 1 diabetes, to determine appropriate insulin doses at different times of the day (48). Patients adjust the amount of insulin according to their plasma or blood glucose concentration. Frequent SMBG is particularly important for tight glycemic control in type 1 diabetes.
Hypoglycemia is a major, potentially life-threatening complication of the treatment of diabetes. The risk of hypoglycemia increases significantly with pharmacologic therapy directed toward maintaining the glycemic range as close to those found in nondiabetic individuals as possible (12)(13). The incidence of major hypoglycemic episodes, requiring third-party help or medical intervention, was two- to threefold higher in the intensive group than in the conventional group in clinical trials of patients with type 1 and type 2 diabetes (12)(13). Furthermore, many diabetic patients, particularly those with type 1 diabetes, lose the autonomic warning symptoms that usually precede neuroglycopenia ("hypoglycemic unawareness") (52), increasing the risk of hypoglycemia. SMBG can be useful for detecting asymptomatic hypoglycemia and allowing patients to avoid major hypoglycemic episodes.
analytical considerations
Preanalytical
Recommendation: Patients should be instructed in the correct use of glucose meters, including quality control. Comparison between SMBG and concurrent laboratory glucose analysis should be performed at regular intervals to evaluate the accuracy of patient results.
Level of evidence: B
Multiple factors can interfere with glucose analysis with portable meters. Several of these, such as improper application, timing, and removal of excess blood (26), have been eliminated by advances in technology. Important variables that may influence the results of bedside glucose monitoring include changes in hematocrit (53), altitude, environmental temperature or humidity, hypotension, hypoxia, and high triglyceride concentrations (54). Furthermore, most meters are inaccurate at very high or very low glucose concentrations. Another important factor is variability of results among different glucose meters. Different assay methods and architecture lead to lack of correlation among meters, even from a single manufacturer. In fact, two meters of the same brand have been observed to differ substantially in accuracy (55)(56). Patient factors are also important, particularly adequate training. Recurrent education at clinic visits and comparison of SMBG with concurrent laboratory glucose analysis improved the accuracy of patients’ blood glucose readings (57). In addition, it is important to evaluate the patient’s technique at regular intervals (9).
Analytical
Recommendation: Multiple performance goals for portable glucose meters have been proposed. These targets vary widely and are highly controversial. No published study has achieved the goals proposed by the ADA. Manufacturers should work to improve the imprecision of current meters.
Level of evidence: E
We recommend meters that measure and report plasma glucose concentrations to facilitate comparison with assays performed in accredited laboratories.
Level of evidence: E
At least 25 different meters are commercially available and are reviewed annually in the ADA’s Buyer’s Guide to Diabetes Products (58). Virtually all the meters use strips that contain glucose oxidase or hexokinase. A drop of whole blood is applied to a strip that contains all the reagents necessary for the assay. Some meters have a porous membrane that separates erythrocytes, and analysis is performed on the resulting plasma. Meters can be calibrated to report plasma glucose values, even when glucose is measured in whole blood. An IFCC working group recently recommended that glucose meters be harmonized to the concentration of glucose in plasma, irrespective of the sample type or technology (59). The meters use reflectance photometry or electrochemistry to measure the rate of the reaction or the final concentration of the products. The meter provides a digital readout of glucose concentration. Most meters claim a reportable range of 1.7–33.3 mmol/L (30–600 mg/dL).
Several important technologic advances that decrease operator error have been made in the last few years. These include "no wipe" strips, automatic commencement of timing when both the sample and the strip are in the meter, smaller sample volume requirements, an error signal if sample volume is inadequate, "lock out" if controls are not assayed, barcode readers, and the ability to store up to several hundred results that can subsequently be downloaded for analysis. Together these improvements have produced superior performance by new meters (60).
Multiple analytical goals have been proposed for the performance of glucose meters. The rationale for these is not always clear. In 1987, the ADA recommended a goal for total error (user plus analytical) of <10% at glucose concentrations of 1.7–22.2 mmol/L (30–400 mg/dL) 100% of the time (61). In addition, it was proposed that values should differ by 15% from those obtained by a laboratory reference method. The recommendation was modified in response to the significant reduction in complications by tight glucose control in the DCCT. The revised performance goal, published in 1996 (48), is for analytical error <5%. To our knowledge, there are no published studies of glucose meters that have achieved the ADA goal of analytical error of <5%.
The CLIA ‘88 goal is less stringent than that of the ADA; results with meters should be within 10% of target values or ± 0.3 mmol/L (6 mg/dL), whichever is larger. NCCLS recommendations (62) are ± 20% of laboratory glucose at >5.5 mmol/L (100 mg/dL) and ± 0.83 mmol/L (15 mg/dL) of laboratory glucose if the glucose concentration is 5.5 mmol/L (100 mg/dL). These are undergoing revisions. New NCCLS guidelines, anticipated to be published in 2002, propose that for test readings >4.2 mmol/L (75 mg/dL), the discrepancy between meters and the central laboratory should be <20%; for a glucose concentrations 4.2 mmol/L (75 mg/dL), the discrepancy should not exceed 0.83 mmol/L (15 mg/dL; NCCLS, in preparation).
A different approach was proposed by Clarke et al. (63), who developed an error grid that attempts to define clinically important errors by identifying fairly broad target ranges. In addition, two novel approaches were suggested very recently. In the first, 201 patients with longstanding type 1 diabetes were questioned to estimate quality expectations for glucose meters (64). On the basis of patients’ perceptions of their needs and of their reported actions in response to changes in measured glucose concentrations, a goal for analytical quality at hypoglycemic concentrations was a CV of 3.1%. Excluding hypoglycemia, the analytical CV to meet the expectations of 75% of the patients was 6.4–9.7%. The authors recommended an analytical CV of 5%, with a bias 5% (64). The second method used simulation modeling of errors in insulin dose (65). The results revealed that meters that achieve both a CV and a bias <5% rarely lead to major errors in insulin dose. However, to provide the intended insulin dosage 95% of the time, the bias and CV needed to be <1–2%, depending on the dosing schedule for insulin and the ranges of glucose concentrations for individual patients (65). No meters have been shown to achieve CVs of 1–2% in routine use. Given the bias and imprecision of meters, no studies have evaluated this target, which is based on simulation modeling. The lack of consensus on quality goals for glucose meters reflects the absence of agreed objective criteria. Using the same biological variation criteria described in the "Interpretation" section above for glucose analysis in accredited laboratories, we suggest a goal for total error (including both bias and imprecision) of 7.9%. However, additional studies are necessary to accurately define this goal.
There is a very large variability in the performance of different meters. Although current meters, as predicted, exhibit performance superior to prior generations of meters (60), imprecision remains high. For example, in a study conducted under carefully controlled conditions where all assays were performed by a single medical technologist, only 50% of analyses met the ADA criterion of <5% deviation from reference values (60). The performance of older meters was substantially worse: two of the four meters produced results within 5% of reference values for only 33% of analyses. Another recent study that evaluated meter performance in 226 hospitals by split samples analyzed simultaneously on meters and laboratory glucose analyzers revealed that 45.6%, 25%, and 14% differed from each other by >10%, >15%, and >20%, respectively (66). Recent analysis of the clinical and analytical accuracy of portable glucose meters (all measurements done by one person) demonstrated that none of the meters met the ADA criterion and that only two meters had 100% of the estimations in the clinically acceptable zones by error grid analysis (67).
Recommendation: Clinical studies are needed to determine the analytical goals for glucose meters. At a minimum, the end-points should be GHb and frequency of hypoglycemic episodes. Ideally, outcomes (e.g., long-term complications and hypoglycemia) should also be examined.
Level of evidence: E
Frequency of measurement. SMBG should be performed at least four times per day in patients with type 1 diabetes. Monitoring less frequently than four times a day can lead to deterioration of glycemic control (48)(68)(69). Published studies reveal that self-monitoring is performed by patients much less frequently than recommended. Data from NHANES III collected between 1988 and 1994 revealed that SMBG was performed at least once a day by 39% of patients taking insulin and by 5–6% of those treated with oral agents or diet alone (51). Moreover, 29% and 65% of patients treated with insulin and oral agents, respectively, monitored their blood glucose less than once per month. However, no evaluation has been performed to verify that four times a day is ideal or whether some other frequency or timing (e.g., postprandial testing) would improve glycemic control. For example, adjustment of insulin therapy in women with GDM according to the results of postprandial, rather than preprandial, plasma glucose concentrations improved glycemic control and reduced the risk of neonatal complications (70). The optimal frequency of SMBG for patients with type 2 diabetes is unknown.
Current ADA recommendations suggest daily SMBG for patients treated with insulin or sulfonylureas (14) to detect hypoglycemia. However, published evidence shows no correlation between the frequency of SMBG in type 2 diabetes and glycemic control (49)(50)(51). There is no known role for SMBG in patients with type 2 diabetes who are treated with diet alone.
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OGTT |
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TopAbstractExecutive SummaryIntroductionGlucoseMetersOGTTUrinary GlucoseNoninvasive or Minimally...Ketone TestingGHbGenetic MarkersAutoimmune MarkersMicroalbuminuriaMiscellaneous Potentially...References |
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Level of evidence: B
use
The OGTT, once the gold standard for diagnosing diabetes mellitus, is now not recommended by the ADA for diagnosing either type 1 or 2 diabetes, but it continues to be recommended in a limited fashion by the WHO (71)(72). The oral glucose challenge (or glucose tolerance test) continues to be recommended by both the ADA and the WHO for establishing the diagnosis of GDM. Neither group recommends use of the extended 3- to 5-h glucose tolerance test in routine practice.
rationale
Inability to respond appropriately to a glucose challenge, i.e., glucose intolerance, represents the fundamental pathologic 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 is that appropriate use of FPG could identify approximately the same prevalence of abnormal glucose metabolism in the population as the OGTT. Furthermore, the OGTT is impractical in ordinary practice. The consensus was that a 2-h plasma glucose cutoff of 11.1 mmol/L (200 mg/dL) should be used because it was predictive of the occurrence of microangiopathy (72). However, only approximately one-fourth of individuals with 2-h plasma glucose 11.1 mmol/L (200 mg/dL) have a FPG 7.8 mmol/L (140 mg/dL), which was the FPG previously recommended to diagnose diabetes mellitus. The currently recommended FPG value of 7.0 mmol/L (126 mg/dL) corresponds better to a 2-h value in the OGTT of >11.1 mmol/L (200 mg/dL), and thus with development of complications.
Use of the OGTT to classify individuals with impaired glucose tolerance (IGT) and diabetes remains controversial. Recent studies (73)(74)(75)(76) indicate that individuals classified with IGT by the OGTT (WHO criteria) have increased risk of cardiovascular disease, but many of these individuals do not have impaired fasting glucose (IFG) by the new ADA criteria. Furthermore, the OGTT (WHO criteria) identifies diabetes in 2% more individuals does than FPG (ADA criteria) (77). Finally, diabetic patients with both abnormal FPG and 2-h OGTT have a higher risk of premature death than those with only an increased FPG concentration (78).
The 2-h glucose tolerance test continues to be recommended for the diagnosis of GDM by both the ADA and WHO (71)(72). Deterioration of glucose tolerance occurs frequently in pregnancy, especially in the third trimester. Diagnosing and treating GDM is essential to prevent associated perinatal morbidity and mortality.
analytical considerations
The reproducibility of the OGTT has received considerable attention. In numerous studies, the reproducibility of the OGTT in classifying patients was 50–66% (79). Possible factors contributing to the lack of reproducibility include biological variation of plasma glucose concentrations, the variable effects of administration of a hyperosmolar glucose solution on gastric emptying, and effects of ambient temperature (41)(79)(80)(81). The accuracy and reproducibility of glucose assays are not limiting factors in this regard.
interpretation
Diagnosing type 1 and 2 diabetes
The ADA and WHO have different recommendations:
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GDM
The ADA modified their recommendations for laboratory diagnosis of GDM in 2000 (82). Their guidelines are as follows:
1. Low-risk patients require no testing. Low risk status is limited to women meeting all of the following:
2. Average-risk patients (all patients who fall between low and high risk) should be tested at 24–28 weeks of gestation (see below for testing strategy).
3. High-risk patients should undergo immediate testing. They are defined as having any of the following:
The first step in laboratory testing is identical to that for diagnosing type 1 or 2 diabetes, i.e., a FPG 7.0 mmol/L (126 mg/dL) or a casual plasma glucose 11.1 mmol/L (200 mg/dL) confirmed on a subsequent day. However, if the above tests are normal, the ADA recommends that average- and high-risk patients receive a glucose challenge test following one of two methods:
must be met or exceeded for a positive diagnosis. 7.8 mmol/L (140 mg/dL) indicates the need for definitive testing. A value 7.2 mmol/L (130 mg/dL) may be used because it will detect 10% more diabetic patients. The second and definitive test is one of the two OGTTs described above.
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emerging considerations
The main issues of controversy are: (a) the lower sensitivity of FPG compared with the OGTT in diagnosing diabetes mellitus (2% of cases missed with FPG); (b) the value of classifying individuals as having IGT (recommended by WHO, but not the ADA); and (c) the appropriate use in GDM.
The lower sensitivity of the FPG compared with the OGTT in diagnosing diabetes mellitus is closely linked to epidemiologic evidence that the OGTT better identifies patients at risk for developing complications of diabetes. This includes assessment of the risk of developing cardiovascular disease (83), macrosomia (84) and of predicting increased risk of death (85). The continuing use of the OGTT to diagnose diabetes mellitus has been supported by Australian and New Zealand diabetes professional organizations (86).
The appropriate use of the OGTT for diagnosing GDM is particularly controversial. The recommendation at the Fourth International Workshop—Conference on Gestational Diabetes Mellitus (87), that 5–10% lower glucose values be adopted for diagnosing gestational diabetes, is now adopted by the ADA.
There remains a lack of consensus regarding the use of the 100-g vs 75-g OGTT for the definitive diagnosis of GDM. It would seem practical and probably diagnostically acceptable to use primarily the 75-g OGTT. However, appropriate diagnostic thresholds continue to be in dispute (86)(88). These discrepancies in recommendations reflect the state of knowledge about GDM, which continues to evolve with enhanced and expanded clinical research.
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Urinary Glucose |
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TopAbstractExecutive SummaryIntroductionGlucoseMetersOGTTUrinary GlucoseNoninvasive or Minimally...Ketone TestingGHbGenetic MarkersAutoimmune MarkersMicroalbuminuriaMiscellaneous Potentially...References |
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Level of evidence: C
use
Semiquantitative urine glucose testing, once the hallmark of diabetes care in the home setting, has now been replaced by SMBG (see above). Semiquantitative urine glucose monitoring should be considered only for patients who are unable to or refuse to perform SMBG because urine glucose concentration does not accurately reflect plasma glucose concentration (89)(90).
rationale
Although glucose is detectable in the urine in patients with grossly increased blood glucose concentrations, it provides no information about blood glucose concentrations 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 concentrations, and only average glucose values between voidings are reflected, further minimizing the value of urine glucose determinations.
analytical considerations
Semiquantitative test-strip methods using specific reactions for glucose are recommended. Most commercially available strips use the glucose oxidase reaction (26). Test methods that detect reducing substances are not recommended because they are subject to numerous interferences, including numerous drugs and nonglucose sugars. When used, single voided urine samples are recommended (90).
interpretation
Because of the limited use of urine glucose determinations, semiquantitative specific reaction-based test strip methods are adequate.
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Noninvasive or Minimally Invasive Glucose Analyses |
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TopAbstractExecutive SummaryIntroductionGlucoseMetersOGTTUrinary GlucoseNoninvasive or Minimally...Ketone TestingGHbGenetic MarkersAutoimmune MarkersMicroalbuminuriaMiscellaneous Potentially...References |
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Level of evidence: E
use
The need for a device for "continuous" in vivo monitoring of glucose concentrations in blood is a very high priority because patients are required to control their plasma glucose more closely (12)(72)(90). Currently, there are only two devices that have been approved by the Food and Drug Administration (FDA) for noninvasive 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. Both devices require calibration and confirmation of accuracy with conventional SMBG.
rationale
The first goal for developing a reliable in vivo glucose sensor is to detect unsuspected hypoglycemia. The importance of this goal has been increasingly appreciated with the recognition that strict glucose control is accompanied by a marked increase in the risk of hypoglycemia (12)(90). Therefore, a sensor designed to detect severe hypoglycemia alone would be of value. In contrast, a full-range, reliable in vivo glucose monitor is a prerequisite for the development of an artificial pancreas that measures blood glucose concentrations and automatically adjusts insulin administration.
analytical considerations
The goal here is not to comprehensively review the status of research in this important area, but to make recommendations for current use. There have been several reviews recently on this topic (91)(92), and it has been the subject of national conferences. For example, noninvasive testing technology was the subject of the AACC Oak Ridge Conference in 1999, with considerable attention focused on glucose-sensing technology (93), and a symposium at the 1999 ADA meeting concentrated on noninvasive glucose sensing (94).
Key technologic advances in minimally invasive or noninvasive glucose monitoring can be summarized as shown in Table 5
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The transcutaneous sensors and implanted sensors use multiple detection systems, including enzyme-based (usually glucose oxidase), electrode-based, and fluorescence-based techniques. Alternatives to enzymes as glucose recognition molecules are being developed, including artificial glucose "receptors" (95)(96). Fluorescence technologies include the use of engineered molecules that exhibit altered fluorescence intensity or spectral characteristics upon binding glucose or the use of competitive binding assays incorporating two fluorescent molecules in the fluorescent resonance energy transfer technique (97)(98)(99)(100)(101).
Methods to sample tissue, often referred to as "noninvasive" but are in fact "minimally invasive", vary among test systems. The underlying fundamental concept is that the concentration of glucose in the interstitial fluid correlates with blood glucose. Most microdialysis systems are inserted subcutaneously (102)(103)(104)(105). In contrast, "reverse iontophoresis", which is the basis of the FDA-approved "Gluco Watch" (Cygnus), uses a low-level electrical current on the skin, which by convective transport (electroosmosis) moves glucose across the skin. The concentration of glucose is then measured by a glucose oxidase electrode detector (106)(107).
Finally, considerable research has been focused on developing totally noninvasive technology for glucose sensing. Of these, near-infrared spectroscopy has been most intensively investigated, but unpredictable spectral variations continue to hinder progress (108)(109)(110)(111)(112). Similar problems have impaired the successful use of light scattering (113)(114). Finally, photoacoustic spectroscopy, although less studied, has yielded some encouraging preclinical results. In this technique, pulsed infrared light, when absorbed by molecules, produces detectable ultrasound waves, the intensity and patterns of which can theoretically be tuned to detect glucose (115)(116)(117).
interpretation
Only the Gluco Watch Biographer and the Continuous Monitoring System have received FDA approval at the time of writing. Therefore, only they will be considered here. The two devices have vastly differing applications. The Gluco Watch is designed to analyze "glucose" approximately three times per hour for up to 12 h and appears best suited for detecting unsuspected hypoglycemia. In contrast, the Continuous Monitoring System is intended for one-time or occasional use, rather than ongoing daily use. The information derived by these devices is intended to assist physicians to guide patients to improve their diabetes control, the values being downloaded into a computer in the physicians’ offices.
The Continuous Monitoring System consists of a subcutaneous glucose sensor, which is connected to a monitor worn externally. 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 frequent measurements for up to 12 h after a single calibration. Calibration with reference plasma glucose values is required, and sampling time limits the frequency of measurements to approximately three per hour. In limited but promising clinical trials, the Gluco Watch provided reasonable correlation with SMBG (106)(107). For example, in 28 patients with type 1 diabetes tested in a clinical setting, the Gluco Watch values had a correlation of 0.90 (n = 1554 pairs of data) with capillary blood glucose. In 12 patients in the home setting, the correlation of Gluco Watch values with SMBG values was r = 0.85 (205 paired data points). The correlation between two Gluco Watches worn simultaneously was r = 0.94 (107). Despite the recent approval of the Gluco Watch by the FDA, its use has not been rigorously tested in a clinically relevant home setting, nor has it been tested in children. However, if it is demonstrated to reliably detect unsuspected hypoglycemic episodes in such settings, we may see widespread use of the Gluco Watch and continued improvement of the technology.
Currently, there are no analytical standards for noninvasive and minimally invasive glucose analyses. Such standards will clearly need to be different for different proposed uses. For example, the reliability, precision, and accuracy requirements for a glucose sensor that is linked to a system that automatically adjusts insulin doses will be vastly different from the requirements for a sensor in a system designed to sound an alarm in cases of apparent extreme hyper- or hypoglycemia. It seems intuitively obvious that a larger imprecision can be tolerated in instruments that make frequent readings during each hour than in an instrument used only two or three times per day to adjust a major portion of a person’s daily insulin dose.
emerging considerations
With the first approvals of self-monitoring, noninvasive glucose sensors by the FDA, it is anticipated that there will be renewed efforts to bring other technologies forward into clinical studies. Ultimately, we shall see improved methods for noninvasive or minimally invasive glucose measurements that will complement current self glucose monitoring techniques.
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Ketone Testing |
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TopAbstractExecutive SummaryIntroductionGlucoseMetersOGTTUrinary GlucoseNoninvasive or Minimally...Ketone TestingGHbGenetic MarkersAutoimmune MarkersMicroalbuminuriaMiscellaneous Potentially...References |
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Level of evidence: E
The ketone bodies acetoacetate (AcAc), acetone, and ß-hydroxybutyric acid (ßHBA) are catabolic products of free fatty acids. Determinations of ketones in urine and
