and Recommendations for Laboratory Analysis in the Diagnosis and
Management of Diabetes Mellitus
Role of Glucose Management in
Harvard Medical School & Brigham and Women's Hospital
Glucose should be measured in plasma in an accredited laboratory both
to establish the diagnosis of diabetes and for population screening.
Analysis in an accredited laboratory is not necessary for routine
of diabetes is established exclusively by the documentation of hyperglycemia
(increased glucose concentrations in the blood). In 1997, the earlier
diagnostic criteria 1 were modified 2 to better
identify subjects 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
"e 11.1 mmol/L (200 mg/dL), (b) fasting plasma glucose (FPG)
"e 7 mmol/L (126 mg/dL) or (c) 2-h postload glucose "e
11.1 mmol/L (200 mg/dL) during an oral glucose tolerance test (OGTT)
2. If any one of these three criteria is met, confirmation
by repeat testing on a subsequent day is necessary to establish
the diagnosis. Although included as a criterion, the OGTT was not
recommended for routine clinical use in non-pregnant individuals
for diabetes, previously controversial, is now recommended2.
The ADA propose that FPG should be measured in all asymptomatic
people aged 45 years or more. If results are normal, 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 2 for conditions
associated with increased risk). Despite these recommendations,
there is no published evidence that treatment based on screening
has value. Furthermore, the cost-effectiveness of screening is
Although there is evidence linking high glucose concentrations to
adverse outcome, substantially more data are available that directly
correlate increased glycated hemoglobin with diabetic complications.
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 (? Of value in patients
who respond to diet/exercise).
There is a direct
relationship between the degree of blood glucose control and the
risk of late renal, retinal and neurological complications. This
correlation has been demonstrated for type 1 3 and more
recently for type 2 4 diabetes. Type 1 diabetic persons
who maintained lower average blood glucose concentrations exhibited
a significantly lower incidence of diabetic retinopathy, nephropathy
and neuropathy 3. 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 4. Intensive blood
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) 4.
In both studies, patients in the intensive group maintained lower
median plasma glucose concentrations. Analyses of the outcomes
were linked to Hb A1c, which was used to evaluate glycemic
control, rather than glucose concentration. Moreover, most clinicians
use the ADA recommendations which define a target Hb A1c
concentration as the goal for optimum glycemic control 5.
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 "e 140 mg/dL 6.
Similar findings were obtained in 1939 patients with type 2 diabetes
followed for a mean of 15 years where multiple logistic regression
revealed that the risk of death was significantly increased if FPG
"e 140 mg/dL 7. Type 2 diabetic subjects with FPG
"e 140 mg/dL had increased cardiovascular mortality 8.
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 9. Notwithstanding
these observations, neither random nor fasting glucose concentrations
should be measured in an accredited laboratory as the primary means
of routine monitoring. Laboratory blood 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 10. A possible exception is the
rare situation where no access to Hb A1c is available.
carbohydrate metabolism that underlies diabetes manifests as hyperglycemia.
Therefore, measurement of blood 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, blood glucose
concentrations are likely to remain the exclusive diagnostic modality.
Screening is recommended
for several reasons. The onset of diabetes is estimated to occur
~10 years before clinical diagnosis 11 and epidemiological
evidence indicates that complications may begin several years before
clinical diagnosis. Furthermore, 50% of people in the U.S. with type
2 diabetes are undiagnosed 12. Notwithstanding this recommendation,
there is no evidence that population screening of blood glucose concentrations
provides any benefit. Outcome studies should be performed to justify
Blood for fasting plasma glucose analysis should be drawn after
the subject 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 sodium fluoride should be used for collecting
be drawn after an overnight fast (no caloric intake for at least
8 h) during which time the subject may consume water 2.
Glucose concentrations decrease ex vivo with time in whole
blood due to glycolysis. The rate of glycolysis—reported to average
5-7% (~10 mg/dL) per hour 13—varies with the glucose
concentration, temperature, white blood cell count and other factors
14. Glycolysis can be attenuated by inhibition of enolase
with sodium fluoride or, less commonly, lithium iodoacetate. 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 13. (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 for 72 h at room temperature in
the presence of fluoride 13. In separated, nonhemolysed
sterile serum without fluoride the glucose concentration is stable
for 8 h at 25 °C and 72 h at 4 °C 15.
be measured in whole blood, serum or plasma, but plasma is recommended
for diagnosis. Although red blood cells are freely permeable to
glucose, the water content of plasma is approximately 12% higher
than that of whole blood. The glucose concentrations during an
OGTT in capillary blood are significantly higher than those in venous
blood (mean of 30 mg/dL, equivalent to 20-25%) 16, but
the mean difference in fasting samples is 2 mg/dL 16,
Glucose concentrations in healthy individuals vary with age. Neonatal
fasting glucose values are low — 20-60 mg/dL in premature infants
and 30-60 mg/dL at term 15. Reference intervals in children
are 60-100 mg/dL, similar to the adult range of 74-106 mg/dL 15.
Note that the ADA criteria 2, 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 18, but does not increase significantly with age
beyond 60 years 19, 20. By contrast, glucose
concentrations after a glucose challenge are substantially higher
in older individuals 19, 20.
Enzymatic methods for glucose analysis are relatively well standardized.
Despite the low imprecision at the diagnostic decision limits (126
mg/dL and 200 mg/dL), classification errors may occur. Because
of the relatively large intraindividual biological variability (CVs
of ~ 5-15%), individuals with FPG of 105-125 mg/dL should be considered
for follow-up at intervals shorter than the current ADA recommendation
of every 3 years.
measured almost exclusively by enzymatic methods. Analysis of proficiency
surveys conducted by the College of American Pathologists (CAP)
reveals that hexokinase or glucose oxidase is used in virtually
all the analyses performed in the U.S. 15. A few laboratories
use glucose dehydrogenase. At a plasma glucose concentration of
~147 mg/dL, imprecision among laboratories using the same method
had a CV <4% (excluding glucose dehydrogenase) and among the
different methods the range of variability was 145.7-151.9 mg/dL
(4%) 15. Similar findings have been reported for glucose
analysis in blood samples from patients. For example, comparison
of plasma samples from 240 subjects revealed mean glucose concentrations
of 101.6 ± 4 and 96.7 ± 3.9 mg/dL (5% difference) using hexokinase
and glucose oxidase, respectively 21.
No consensus has
been achieved on the analytical goals for glucose analysis. Numerous
criteria have been proposed to establish analytic goals. These include
expert opinion (consensus conferences), opinion of clinicians, regulation,
state of the art and biological variation 22. A rational
and realistic recommendation that has received some support is to
use biological criteria as the basis for analytic goals. It has been
suggested that imprecision should not exceed one half of the within-subject
biological CV 23, 24. For plasma glucose, a
CV "d 2.2% has been suggested as a target for imprecision 24
(seems too low?). Although this recommendation was proposed for within-laboratory
error, it would be desirable to achieve this goal for inter-laboratory
imprecision to avoid variability among laboratories in the diagnosis
of diabetes in individuals whose glucose concentrations are close
to the threshold value.
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 in 22 (71%) subjects varied by <10% and 30 (97%) varied
by <20% 25. Biological variation includes variation
in assay, blood drawing technique, measurement conditions and intraindividual
variation 26. Careful evaluation over several consecutive
days revealed that intraindividual variation of FPG in 12 healthy
subjects (mean glucose of 89 mg/dL) exibited a biological CV of
4.8-6.1 % 27, 26. Larger studies have revealed
14% CV of FPG in 246 normal 28 and 193 newly diagnosed
untreated type 2 diabetic subjects 29. The latter study,
which measured FPG by glucose oxidase on two consecutive days, obtained
95% confidence intervals (CI) of 13.7% for biological variability.
If this figure of 14% is applied to a true glucose concentration
of 126 mg/dL, the 95% CI would encompass glucose concentrations
of 108-144 mg/dL. If the CV of the glucose assay (~4%) is included,
the 95% CI is ~ 18%. Thus, the 95% CI for a fasting glucose concentration
of 126 mg/dL would be 126 ± 18%, namely 103-149 mg/dL. Using assay
imprecision only (excluding biological variability) would yield
95% CI of 116-136 mg/dL among laboratories for a true glucose concentration
of 126 mg/dL. One should bear in mind that these ranges include
95% of subjects and other individuals will be outside this range.
A short turnaround
time for glucose analysis is not usually necessary for the diagnosis
and management of diabetes. In some clinical situations, such as
acute hyper- or hypoglycemic episodes in the Emergency Department
or treatment of diabetic ketoacidosis, rapid analysis is desirable.
A turnaround time of 30 min has been proposed (Howanitz 93), but
no outcome data have been published that validate this figure.
The frequency of
measurement of blood glucose is dictated by the clinical situation.
To establish the diagnosis of diabetes, the ADA recommends that FPG
should be measured on two occasions 2. Screening by FPG
is recommended every 3 years if normal, more frequently in high-risk
individuals. Monitoring is performed by patients themselves who measure
blood glucose with meters and by assessment in an accredited laboratory
of Hb A1c (see below). The frequency of measurement of
glucose in acute clinical situations (e.g., diabetic ketoacidosis,
neonatal hypoglycemia, etc.) is highly variable, ranging from every
30 min to once a day.
or minimally-invasive analysis of glucose is addressed below.
of Blood Glucose
meters for measurement of blood glucose concentrations are used in
three major settings: i) in hospitals (at the patient’s bedside and
in clinics); ii) in physicians’ offices and iii) by patients at home.
The last, self-monitoring of blood glucose (SMBG), is performed at
least once a day by 40% and 26% of individuals with type 1 and 2
diabetes, respectively 30. The worldwide market for SMBG
is $2.7 billion-per-year, with annual growth estimated at 10-12% 31.
The ADA lists the following indications for SMBG: i) achievement and
maintenance of glycemic control; ii) prevention and detection of hypoglycemia;
iii) avoidance of severe hyperglycemia; iv) adjusting to changes in
life-style and v) determining the need for initiating insulin therapy
in gestational diabetes mellitus (GDM) 32. It is recommended
that most individuals with diabetes attempt to achieve and maintain
blood glucose levels as close to normal levels as is safely possible
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 and screening for diabetes.
(How to deal with meters in physicians’ offices?).
for the diagnosis of diabetes are based upon 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 a central laboratory 2. 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
SMBG should be performed once to several times per day by patients
with diabetes treated with insulin or sulfonylureas. Insulin-requiring
patients adjust the dose of insulin based on SMBG. Both groups of
patients use SMBG to detect asymptomatic hypoglycemia. In patients
with type 2 diabetes, SMBG facilitates better control, particularly
when therapy is initiated or changed. The role of SMBG in patients
with stable type 2 diabetes controlled by diet alone is not known.
SMBG is recommended
for all patients with diabetes who are receiving insulin. Tight
glycemic control can decrease microvascular complications in individuals
with type 1 3 or type 2 4 diabetes. Intensive
blood 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 3. Therapy
in patients with type 2 diabetes in the UK Prospective Diabetes
Study 4 was adjusted according to FPG concentrations
– SMBG was not evaluated.
review was performed of studies, published between 1976 and 1996,
that evaluated SMBG in patients with type 2 diabetes 33.
Only one of the published studies reported that SMBG produced a
significantly positive improvement, namely lower Hb A1c.
The authors of the review concluded that the efficacy of SMBG in
type 2 diabetes is questionable 33. 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.
patients with diabetes to achieve and maintain specific glycemic
goals. Knowledge of blood glucose concentrations is necessary for
insulin-requiring patients to determine appropriate insulin doses
at different times of the day 32. Patients adjust the
amount of insulin according to their blood glucose concentration.
Frequent SMBG is particularly important for tight glycemic control.
is a major, potentially life-threatening complication of the treatment
of diabetes. The risk of hypoglycemia increases significantly with
pharmacologic therapy directed towards maintaining the glycemic
range as close to normal as possible 3, 4.
The incidence of major hypoglycemic episodes—requiring third-party
help or medical intervention—was 2- to 3-fold higher in the intensive
group than in the conventional group in clinical trials of patients
with type 1 and type 2 diabetes 3, 4. Furthermore,
many diabetic patients, particularly those with type 1 diabetes,
lack the autonomic warning symptoms that normally precede neuroglycopenia
(“hypoglycemic unawareness”) 34, increasing the risk
of hypoglycemia. SMBG can be useful for detecting asymptomatic
hypoglycemia and allowing patients to avoid major hypoglycemic episodes.
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.
can interfere with glucose analysis with portable meters. Several
of these, such as proper application, timing and removal of excess
blood 15, have been eliminated by advances in technology.
Important variables that may influence the results of bedside glucose
monitoring include changes in hematocrit, altitude, environmental
temperature or humidity, hypotension, hypoxia and high triglyceride
concentrations 35. 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 result in lack of correlation
among meters, even from a single manufacturer. In fact, two meters
of the same brand have been observed to differ in accuracy 36.
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 together to improve the imprecision of
current meters. We recommend meters that measure and report plasma
glucose concentrations to facilitate comparison with the vast body
of literature in which complications and outcomes are correlated
with plasma glucose concentrations. (What to do with meters that
measure whole blood, but use “fudge factor” to report plasma glucose?).
At least 25
different meters are commercially available. 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. The technology used is reflectance
photometry or electrochemical analysis, both of which can measure
the rate of the reaction or the final concentration of the products.
The meter provides a digital readout of blood glucose concentration.
Most meters claim a reportable range of 30-600 mg/dL, with a few
having a lower limit of zero. Several important technological 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, no results if sample volume is inadequate,
“lock out” if controls are not assayed, bar code readers and the
ability to store up to several hundred results that can subsequently
be downloaded for analysis. Together these improvements have resulted
in superior performance by new meters 37.
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 of total error (user plus analytical) of < 10% at glucose
concentrations of 30-400 mg/dL 100% of the time 38.
In addition, it was proposed that values should differ by "d
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 32 is for analytic error < 5%.
To our knowledge, there are no published studies of glucose meters
that have achieved the ADA goal of analytic error of <5%. The
CLIA 88 goal is less stringent than the ADA; results with meters
should be within 10% of target values or ± 6 mg/dL, whichever is
larger. NCCLS recommendations (1994) are ± 20% of laboratory glucose
at >100 mg/dL and ±15 mg/dL of laboratory glucose if the glucose
concentration is "d 100 mg/dL. A different approach was proposed
by Clarke 39 who developed an Error Grid that attempts
to define clinically important errors by identifying fairly broad
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 37, imprecision remains high.
For example, a study conducted under carefully controlled conditions
where all assays were performed by a single medical technologist
resulted in only ~ 50% of analyses meeting the ADA criterion of
< 5% deviation from reference values 37. Performance
of older meters was substantially worse with 2 of the 4 meters able
to achieve results < 5% of reference values in only 33% of analyses.
Another recent study evaluated meter performance in 226 hospitals
by split samples run simultaneously on meters and laboratory glucose
analyzers revealed that 45.6%, 25% and 14% differed from each other
by > 10%, > 15% and > 20%, respectively 40.
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 only 2 meters
had 100% of the estimations in the clinically acceptable zones by
Error Grid analysis 41.
Clinical studies are needed to determine the analytic goals
for glucose meters. At a minimum, the end-point should be hemoglobin
A1c. Ideally, outcomes (e.g., long-term complications
and hypoglycemia) should also be examined.
be performed at least four times per day in insulin-deficient patients
with type 1 diabetes. Monitoring less frequently than four times
a day results in a deterioration of glycemic control 32.
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 5 to detect
hypoglycemia. There is no known role for SMBG in patients with
type 2 diabetes who are treated with diet alone.
Issues for the Committee
How to deal with meters in physician’s offices?
Should meters report whole blood or plasma glucose?
Should criteria for meter performance (including operator) by patients
at home be different from those in a medical setting?
What imprecision is necessary/achievable for meters?
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