Diagnostic Profile

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1,5-anhydroglucitol
(GlycoMark™) as a marker of
short-term glycemic control
and glycemic excursions
Expert Rev. Mol. Diagn. 8(1), 9–19 (2008)

Kathleen M Dungan 1,5-anhydroglucitol (1,5-AG) is a validated marker of short-term glycemic control. It is a

Ohio State University,
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kathleen.dungan@osumc.edu
metabolically inert polyol that competes with glucose for reabsorption in the kidneys.
Otherwise stable levels of 1,5-AG are rapidly depleted as blood glucose levels exceed the renal
threshold for glucosuria. 1,5-AG more accurately predicts rapid changes in glycemia than
hemoglobin A1C (A1C) or fructosamine. It is also more tightly associated with glucose
fluctuations and postprandial glucose. Thus, 1,5-AG may offer complementary information to
A1C. This review will summarize the limitations of current methods of assessing glycemic
control, assess the data to support 1,5-AG as a glycemic marker and highlight the scenarios by
which 1,5-AG may fill the gap in assessing glycemic control.

KEYWORDS: 1,5-anhydroglucitol • A1C • glucose • glycemic control • glycemic excursion • glycemic variability
• post-prandial glucose

The Diabetes Control and Complications Trial
(DCCT) and the United Kingdom Prospective
Diabetes Study (UKPDS) have demonstrated that
improved glycemic control reduces the complica-
tions of diabetes [1,2]. Currently, hemoglobin A1C
(A1C) is the traditional standard for determining
overall glycemic control, and a target of less than
7.0% has been established by the American Dia-
betes Association [3]. However, in the UKPDS, at
best approximately 50% of patients achieved an
A1C less than 7.0%, regardless of therapy, and
fewer than 30% were able to maintain that target
over time [4]. In routine clinical practice, glycemic
control may be even more difficult to achieve, and
despite recent advances in therapy, only 50% of
patients with diabetes reach recommended A1C
targets [5]. Further complicating the matter are the
more recent calls that advocate for normo-
glycemia (A1C <6.0%) where it can be done safely
[3]. Quality improvement initiatives may benefit
patients with the worst glycemic control [6], but
patients with more modest control (A1C ∼8%)
pose a tremendous challenge to clinicians [7].
Glycemic monitoring is of paramount impor-
tance for adjusting various treatment modalities.
Conventional methods of assessing glycemic
control, such as A1C or self-monitored blood
glucose (SMBG), focus on mean glucose or fast-
ing glucose. However, several lines of evidence
suggest that glycemic fluctuations may also be
important. Despite the beneficial effect of lower-
ing A1C to less than 7.0% on microvascular dis-
ease, a substantial risk of macrovascular compli-
cations still remains [2,8]. Epidemiologic studies
demonstrate that post-load glucose and post-
prandial glucose (PPG) are more strongly associ-
ated with all-cause, (particularly cardiovascular)
mortality than fasting glucose measurements
[9,10]. Therefore, quantification of glycemic fluc-
tuations (e.g., glycemic variability, PPG or glu-
cose excursions) might predict macrovascular dis-
ease better than mean glucose. In vitro data
suggest that intermittent glycemic excursions
may be more harmful to endothelial cells than
chronic hyperglycemia, as the latter may induce
relative conditioning of cellular inflammatory
responses [11–13]. Oxidative stress, an important
mediator of hyperglycemia-mediated cellular
damage, is also associated with glycemic variabil-
ity in patients with diabetes, independent of
mean glucose [14]. A prospective randomized con-
trolled study demonstrated that repaglinide,

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 Diagnostic Profile Dungan
which specifically lowers PPG, was associated with reduced
carotid intima media thickness compared with a sulfonylurea,
even though the drugs resulted in similar reductions in A1C
[15]. Finally, in the DCCT, patients treated with physiologic
intensive insulin therapy using multiple injections per day had
fewer microvascular complications than those in the conven-
tional group with similar A1Cs, again suggesting that improve-
ments in glycemic variability are important [16]. Thus,
approaches focusing on mean glucose alone may overlook key
opportunities to reduce diabetes-related morbidity.
Traditional methods of monitoring glycemic control, includ-
ing A1C and SMBG, are highly regarded and engrained in the
literature as the foundations for monitoring glycemic control
and making adjustments in therapy. However, current
approaches do not capture the full glycemic profile and there
are other limitations to these approaches that must be acknow-
ledged. If we are to achieve tight glycemic control in the major-
ity of our patients, we must broaden our scope to consider alter-
native or complementary monitoring strategies. 1,5-anhydro-
glucitol (1,5-AG) is a marker of short-term glycemic control
and has been proposed as a marker of PPG and glycemic vari-
ability. This article will assess the gaps in current modalities for
glycemic monitoring and then review the evidence for 1,5-AG,
placing particular emphasis on recent literature and the role for
assessing glycemic variability. Finally, the review will explore a
potential niche for 1,5-AG in glycemic monitoring.
Summary & limitations of available methods of
assessing glycemic control
A comparison of gycemic markers is listed in TABLE 1.
Capillary glucose monitoring
Studies have found that as part of an integrated program,
SMBG is associated with significantly improved glycemic con-
trol [17–19]. SMBG has also been associated with decreased all-
cause and diabetes-related mortality in a long-term epidemio-
logic study [20]. SMBG provides real-time assessments that are
instrumental for identifying hypoglycemia and hyperglycemia
and for adjusting therapy. Expert groups recommend that regu-
lar assessment of both preprandial glucose and PPG levels is an
Table 1. Comparison of glycemic markers.
Parameter Hemoglobin A1C
Time required for significant change 1–3 months
Reflection of mean glucose ++
Reflection of glucose excursions/postprandial glucose + +
Association with complications ++
Variance Small
Greatest degree of change is found during Moderate-to-severe
hyperglycemia
10
essential component of any diabetes management program [21].
Unfortunately, SMBG is underutilized for a variety of reasons,
including inconvenience, physical discomfort and disability,
along with expense [22]. The procedure is complex for some
patients, and despite advances in technology, errors in tech-
nique are common [23,24]. Moreover, SMBG provides only peri-
odic assessments, and may miss important hypoglycemic and
hyperglycemic events.
A1C
A1C is associated with the incidence of complications in
patients with Type 1 and 2 diabetes [25,26]. Therefore, A1C is
currently the most widely recognized marker for glycemic con-
trol. However, in the DCCT, there was no level of A1C below
which the risk of retinopathy is eliminated [27], and 10% of
patients with a mean A1C less than 6.8% still developed retino-
pathy [28]. This finding has been attributed partly to the effect
of poor glycemic control prior to study entry. However, other
evidence suggests that despite performing well on a population
level, A1C can have limitations in the individual patient:
• First, it is well-known that alteration of red cell life span
results in false A1C values.
• Second, there are unexplained variations in the relationship
between mean glucose and A1C among and within patients
with diabetes [29,30]. This variability is more pronounced at
lower values for A1C [31].
• Third, A1C reflects mean glucose over a 3-month period [32].
Although the most recent 30 days is disproportionately rep-
resented, the A1C is of limited value in patients with recently
changing glycemic control.
• Fourth, A1C does not discriminate between the patient who
achieves adequate glycemic control with frequent hyperglycemic
and hypoglycemic events, from those who achieve glycemic tar-
gets more smoothly [33]. Thus, an A1C of less than 7.0% may
provide false reassurance of adequate glycemic control.
• Fifth, as discussed later in this manuscript, A1C inade-
quately differentiates postprandial hyperglycemia from fast-
ing hyperglycemia. Therefore, in patients with moderate
glycemic control, A1C can not direct treatment decisions
beyond simply heralding the need for further intervention.
Fructosamine 1,5-anhydroglucitol
1–2 weeks 1–3 days
++ +
++
NA NA
Small Large
Moderate-to-severe Mild-to-moderate
hyperglycemia hyperglycemia
Expert Rev. Mol. Diagn. 8(1), (2008)

Fructosamine
Fructosamine is a measure of the glycosylation of serum proteins,
thus reflecting glycemia over a 1–2-week period [34]. Unfortu-
nately, fructosamine predicts A1C in patients with otherwise sta-
ble glycemic control somewhat imprecisely, such that at 350
mmol/l, the 95% prediction interval for A1C ranges from 6.6 to
11.2% [35]. Another study demonstrated a greater area under the
receiver operator curve (ROC) for A1C than for fructosamine in
discriminating fasting glucose [36]. Furthermore, fructosamine
may be affected by variations in albumin levels [37]. Although gly-
cemic control may be achieved earlier with fructosamine testing, it
does not result in overall lower A1C levels than SMBG measure-
ments alone [38]. As with A1C, fructosamine is a marker of mean
glucose, and therefore has the same limitations for identifying
PPG or glycemic variability. Nevertheless, fructosamine remains
an established alternative to A1C for estimating glycemic control,
particularly where there are discrepancies between SMBG and
A1C and where short-term glycemic monitoring is desired.
Continuous glucose monitoring
Real-time continuous subcutaneous glucose monitoring has
been shown to improve glycemic control and glycemic excur-
sions, particularly in highly motivated subjects with Type 1 dia-
betes [39–42]. Continuous subcutaneous glucose monitoring is
quickly becoming an indispensable tool for capturing glycemic
variability. However, current devices approved for continuous
glucose monitoring are still invasive and costly. Furthermore,
current real-time methods still require confirmation with a
fingerstick glucose before intervention [43]. Careful selection of
patients is necessary since some concerns linger about whether
less sophisticated patients may become overloaded with too
much information [44]. The most obvious potential advantage
of continuous glucose monitoring may one day lie in a closed
loop system, whereby glucose sensing is automatically tied to
adjustments in insulin administration via the insulin pump [44].
Summary of 1,5-AG
1,5-AG is a naturally occurring 1-deoxy form of glucose
(FIGURE 1) that was discovered in 1888. It has been widely studied
in Japan and received US FDA approval for short-term glyce-
mic monitoring in 2003 (FIGURE 2). 1,5-AG circulates in the
body mainly in its free form, approximately 500–1000 mg in
total [45,46].
Sources of 1,5-AG
1,5-AG is thought to originate in the diet,
averaging 4.4 mg/day [45]. The largest food
source is soy, constituting approximately
22.6 µg/gm, while rice and pasta contain
1888: Isolation
1.8–3.8 µg/gm. 1,5-AG may also be found from Polygara
in small quantities in meats, fish, fruits, veg- amara plant
etables, tea, milk and cheese. A negligible
Figure 2. Historical context of 1,5-anhydroglucitol.
amount is produced de novo [45].
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GlycoMark™ Diagnostic Profile
D-glucose 1,5-anhydro-D-glucitol
HO HO
O O
OH OH
OH OH OH
OH OH
Figure 1. Comparison of D-gluocse and 1,5-anhydroglucitol.
Physiology of 1,5-AG
1,5-AG intake is balanced by urinary excretion, and nearly
99.9% is reabsorbed by the kidneys [45]. Reabsorption is com-
petitively inhibited by glucose (FIGURE 3) [45] and is thought to
occur at a specific fructose-mannose active transporter [47].
SGLT4 is a recently described candidate transporter of 1,5-AG.
SGLT4 mRNA is expressed in the small intestine and kidney in
humans and shows substrate specificity for D-mannose, D-glu-
cose, D-fructose, 1,5-AG and D-galactose [48]. As glucose levels
surpass the renal threshold for glucosuria (generally around
180 mg/dl), 1,5-AG is excreted in the urine, leading to a rapid
reduction in serum levels [46,49]. Therefore, poor glycemic con-
trol is associated with low, rather than high, serum 1,5-AG
levels. There exists a variation in the renal threshold for gluco-
suria, but this does not appear to substantially affect changes in
1,5-AG levels during serial measurements over time [49,50]. A
steady state level is reached in all tissues and is reinforced by its
metabolic inertness and the very small dietary intake relative to
the total body pool [51]. The precise physiologic role of 1,5-AG
in humans, if any, is unknown. In insulinoma cell lines, 1,5-AG
appeared to have an insulin secretory effect at physiologic con-
centrations, raising the possibility that it could play a role in
regulating glucose-mediated insulin secretion [52].
1,5-AG assay
An automated, commercially available assay for 1,5-AG in the
USA is marketed as GlycoMark™ [53,54]. The first step in the
assay uses glucokinase to convert glucose to glucose-6-phos-
phate in order to avoid its interference with the second enzy-
matic step. In the second step, 1,5-AG is oxidized with pyranose
oxidase, and the resulting H2O2 is detected colorimetrically.
1975: Low levels
discovered in
patients with diabetes
1900 2000
1943: Chemical 1991: First 2003:
structure defined commercial US FDA
assay (Japan) approval
11
 Diagnostic Profile Dungan

to intake [51,57]. However, extensive studies of dietary habits in

Normoglycemia Hyperglycemia
the USA are not available. Indeed, 1,5-AG levels are approxi-
mately 0.5 µg/ml lower in subjects of Japanese descent com-
Glomerulus Glomerulus pared with those in a US study, a finding that was attributed to
differences in diet, not purely to race [59]. Certain Chinese
herbal supplements may also raise 1,5-AG levels because they
contain large amounts of Polygalae Radix, a crude form of
1,5-AG [60]. Acarbose, an α-glucosidase inhibitor, may poten-
tially reduce 1,5-AG levels by interfering with the intestinal
Renal tubule
absorption of 1,5-AG [61]. Small differences were found
Renal tubule
between women and men in a US study, such that the reference
range for US females (6.8–29.3 µg/ml) was reported to be
lower than that for males (10.7–32.0 µg/ml) [53]. However, a
significant difference between genders was not observed in all
studies [62].
Clinicians should exercise caution when interpreting 1,5-AG
levels under several clinical conditions, such as renal failure
Normal urine Glycosuria (TABLE 2) [62]. Although there are differences in 1,5-AG levels

Glucose active transporter Glucose

Fructose, mannose active transporter 1,5-AG
Figure 3. Competitive tubular reabsorption of 1,5-AG and
glucose during hyperglycemia.
1,5-AG: 1,5-anhydroglucitol.
The method is applicable to serum or plasma samples. The
intra- and interassay precision is 1.3–3.8% and 0.8–3.8%,
respectively, and the assay is linear from 0.49 µg/ml to 110
µg/ml, encompassing the entire range expected for normal indi-
viduals and for those with diabetes [53]. Therefore, although
levels may vary considerably between normal individuals
(12–40 µg/ml), intra-individual variability and assay variability
are small.
Alternatively, 1,5-AG in serum or urine may be measured using
chromatography techniques [55,56]. These methods are sensitive
and precise, but can also be time-consuming and cumbersome.
Clinical determinants of 1,5-AG
1,5-AG is not affected substantially by meals or activity levels in
Japanese studies, despite the observation that diet is the major
source [45,57,58]. This is attributed to the large body pool relative
between normal individuals and those with other co-morbidi-
ties, 1,5-AG still discriminates these patients from those with
diabetes in the vast majority of cases [62]. Furthermore, the Glyco-
Mark assay was not significantly affected by perturbations of
hemoglobin, bilirubin, lipids, uric acid, creatinine, ascorbic
acid or maltose [53]. Unlike A1C, 1,5-AG is unaffected by red
blood cell life span.
1,5-AG as a marker of glycemia
1,5-AG as a short-term marker of glycemic control
Serum 1,5-AG falls rapidly with the onset of glucosuria [46,49].
1,5-AG varies inversely with changes in glucosuria according to
a constant formula: 1,5-AG × urinary glucose = 16 [50]. Upon
return of strict glycemic control, serum 1,5-AG levels recover at
0.3 µg/dl/day, independent of other patient variables [50]. In
patients with the poorest control, 1,5-AG takes approximately
5 weeks to recover fully. Changes in 1,5-AG more closely
reflect recent changes in glycemic control than A1C or, arguably,
fructosamine [63].
The first US trial of the automated assay enrolled 77 patients
with diabetes, 55 with Type 2 diabetes and 22 with Type 1 dia-
betes and an A1C of greater than 7% [59]. Patients with

Table 2. Clinical determinants of 1,5-anhydroglucitol.

Increased Decreased Unknown No difference
Some enteral nutrition products Females High soy diet Age
Pregnancy (>34 weeks) Acute renal failure
Chinese herbal drugs containing Newborns (<4 weeks) Fanconi syndrome
Polygalae Radix End-stage liver disease Obesity
Creatinine >2.0 mg/dl
Malignancy
Prolonged total parenteral nutrition
Glomerulonephritis
Acarbose

12 Expert Rev. Mol. Diagn. 8(1), (2008)


advanced renal disease were excluded. Each patient underwent
pharmacologic and nutritional interventions resulting in an
average reduction in A1C of 1.3% by week 8. 1,5-AG levels
were not used to drive treatment decisions. 1,5-AG was signifi-
cantly correlated with A1C (r -0.6459; p < 0.0001) and fructo-
samine (r -0.657, p < 0.0001). By week 8, random glucose
declined 23.3%. The change from baseline was 2.5-fold for
1,5-AG, but 1.2- and 1.3-fold for A1C and fructosamine,
respectively. By week 2, 1,5-AG was already increased by 57%,
whereas a significant change in A1C was not noted until
week 4. Directional change in 1,5-AG was reported to be con-
cordant with A1C by week 8 in 89.6% of patients, compared
with 58.4% at 2 weeks. The authors speculate that discordance
may be a result of excessive depletion of 1,5-AG stores in
patients with prolonged, poorly controlled hyperglycemia;
however, individual values were not reported. This observation
was reported previously [50,58] and is supported by a dynamic
mass balance model [51].
In a small, uncontrolled study, 12 patients with Type 2 diabe-
tes and average baseline A1C of 6.6% received troglitazone,
400 mg twice daily [64]. After 6 months, A1C dropped signifi-
cantly from 6.6 to 5.8% (p < 0.05), paralleling a drop in fasting
glucose from 110 to 96 mg/dl (p < 0.05) and a significant
decrease in glucose AUC following a 75 g oral glucose tolerance
test (OGTT). In comparison, 1,5-AG rose from 12.6 to 18.5
µg/ml (p < 0.05). This study suggests that 1,5-AG can effec-
tively discriminate changes in glycemic control at near normal
A1C levels.
1,5-AG as a marker of glycemic excursions
Glycemic variability may be described in terms of the fre-
quency or amplitude of glucose excursions, or as a combination
of glucose excursions in the hyperglycemic and hypoglycemic
range. 1,5-AG may be particularly suited for monitoring
hyperglycemic excursions.
Glycemic excursions: no two A1Cs are alike
1,5-AG has been reported by several studies to show signifi-
cant variability among patients with diabetes that appear to be
well controlled by A1C criteria. Unlike A1C, 1,5-AG is not
affected by hypoglycemia. As a result, 1,5-AG appears to dif-
ferentiate patients with extensive glycemic excursions despite
having similar A1Cs.
Yamanouchi and colleagues reported that in 54 patients strat-
ified within narrow A1C bands (mean 7.6 or 8.7%), those
patients requiring insulin had lower levels of 1,5-AG than
patients on other therapies [65]. This was explained by larger
coefficient of variation of glucose and greater urinary glucose
excretion in patients requiring insulin. The study was the first
to raise the possibility that 1,5-AG may serve as a marker for
glucose excursions.
In a subsequent study of 76 patients with Type 2 diabetes
and an A1C under 8.0%, patients treated with multiple injec-
tions of insulin per day had significantly higher 1,5-AG levels
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GlycoMark™ Diagnostic Profile
(p < 0.05) than patients who received conventional insulin
therapy [66]. Furthermore, 1,5-AG, but not A1C, correlated
significantly (albeit inversely) with M-values (an established
measure of glycemic variability). M-values were higher and
1,5-AG levels were lower in patients receiving conventional insu-
lin therapy compared with those receiving multiple injections
per day.
A small, randomized, placebo-controlled trial found that
4 weeks of voglibose (an α-glucosidase inhibitor) reduced
M-values and raised 1,5-AG levels, despite no change in plasma
glucose or A1C [67].
In another report, 130 patients with Type 2 diabetes on a sta-
ble sulfonylurea or insulin regimen were studied, of which
90 patients had an 8-point venous glucose profile [68]. Both
1,5-AG and A1C were significantly correlated with mean glu-
cose, maximum glucose and M-value. Multiple regression anal-
ysis determined that while 1,5-AG was primarily dependent on
maximal glucose (B = -0.55; p = 0.015), A1C was largely deter-
mined by fasting glucose (B = 0.5; p = 0.003). Moreover, in
patients with A1C values less than 6.5%, there was still a wide
range of 1,5-AG levels (2.0–29.0 mg/l), while in patients with
1,5-AG levels greater than 14 mg/l, A1C levels were consistently
lower than 6.5%. Thus, 1,5-AG appears to offer complimentary
information to the A1C.
Postprandial glucose
Reporting of glucose excursions may or may not be limited to
PPG levels [69]. PPG is of particular interest because its mea-
surement provides an easily identifiable conduit for imple-
menting changes in diet or pharmacologic therapies. Further-
more, PPG becomes an increasingly important contributor to
glycemic control as the A1C approaches 8% [70]. As 1,5-AG is
a predictor of glycemic excursions, it would also be expected to
predict PPG. Recently, the International Diabetes Federation
highlighted the importance of evaluating PPG and issued
guidelines for management [101]. 1,5-AG was recognized in the
guidelines as an emerging tool for assessing PPG. Further-
more, recent studies highlight dynamic changes in PPG that
are recognized by 1,5-AG, but missed by A1C in moderately
controlled patients.
The author and colleagues conducted a prospective longitudi-
nal study of 32 patients with Type 1 or 2 diabetes and an A1C
between 6.5 and 8% [71]. Patients were carefully screened to
ensure that they were stable in terms of glycemic control.
Patients were included only if the A1C varied by less than 0.5%
and if there were no changes to diabetes medications in the pre-
vious 6 months. Thus, even though patients were only moni-
tored for a relatively short period, A1C would still be expected
to adequately reflect continuous subcutaneous glucose monitor-
ing (CGMS) values. Patients underwent CGMS for two consec-
utive 72-h periods. 1,5-AG, A1C and fructosamine were col-
lected at baseline and at days 4 and 7. We found that the AUC
for glucoses greater than 180 mg/dl (AUC-180) and maximum
post-meal glucose (MPMG) were significantly correlated with
13
 Diagnostic Profile Dungan

1,5-AG (r = -0.48, p = 0.002 and r = -0.50, p = 0.008, respec-
tively). A1C and fructosamine also correlated significantly with
AUC-180 (r = 0.36; p = 0.02 and r = 0.33; p = 0.03, respec-
tively), and A1C correlated with MPMG (r = 0.40, p = 0.03).
However, Steiger Z (1 bar) values demonstrated that the correla-
tions were statistically not as strong for A1C or fructosamine as
they were for 1,5-AG. These relationships did not change sub-
stantially over shorter intervals (72 h), indicating that 1,5-AG
reflects consistent patterns of excursions, not just isolated events.
Furthermore, we determined that the relationship between
1,5-AG and AUC-180 persisted regardless of A1C. Multivariate
regression analyses determined that A1C and fructosamine
reflect pre-meal and mean glucose better than 1,5-AG, but con-
firmed that 1,5-AG reflects postprandial hyperglycemia to a
greater extent than A1C or fructosamine [72]. Finally, when
patients are separated into two groups according to AUC-180,
A1C, fructosamine and fasting glucose were very similar, while
MPMG and 1,5-AG were significantly different (FIGURE 4).
Preliminary data from other studies have also shown that
1,5-AG is an independent predictor of postprandial hyper-
glycemia in moderately controlled patients, and was more sen-
sitive and specific than A1C [73,74] . It must be recalled that
1,5-AG would be expected to best reflect PPG in patients who
are at least moderately controlled by A1C, because poorly con-
trolled patients are likely to experience glucosuria continuously,
not just in the postprandial state.
Finally, 1,5-AG has been used to determine a differential
effect of various drug strategies on PPG [75]. For example, after
29 weeks of therapy with pramlintide or placebo in 18 patients
with Type 1 diabetes, A1C was unchanged, but there was a sig-
nificant 37-mg/dl difference in PPG and a 21% difference in
1,5-AG in favor of pramlintide [76]. 1,5-AG has also been shown
250 9.0 9 350
8 340
8.5
200 7 330
8.0 6
150
µmol/l
mg/dl
to be effective for monitoring PPG in other agents that target
PPG, including exenatide [77], sitagliptin [78] and biphasic insu-
lin aspart [79]. These studies support the concept that 1,5-AG
can identify underlying treatment effects on PPG that are
missed by A1C.
Special populations
1,5-AG for diabetes screening
Several studies have assessed the potential for 1,5-AG to iden-
tify patients with diabetes. Although 1,5-AG may perform
better than A1C for diagnosing diabetes, studies are conflicting
with regard to its suitability as a first-line screening tool, which
is likely to be a result of the wide normal range [80–82]. Further
studies are currently underway to evaluate this.
Pregnancy
The data supporting PPG monitoring in pregnancy is surpassed
by no other patient population [83]. However, during pregnancy,
doubts still remain surrounding the utility of 1,5-AG, namely
because of the large variability in glucosuria [84]. The most recent
study examined 55 pregnant women with diabetes or gestational
diabetes who provided venous glucose samples every 2 h for
24 h. Mean glucose, maximal glucose, M-value, A1C and
1,5-AG were assessed [85]. The authors found that maximal glu-
cose and M-value, but not mean glucose, were significantly cor-
related with 1,5-AG. Multiple regression showed that maximal
glucose was most predictive of 1,5-AG (B = -0.68; p = 0.01),
with M-value also being significant (B = -0.41; p < 0.05). No
association was found between gestational age and 1,5-AG lev-
els. Finally, when patients were divided into two groups based on
an A1C threshold of 6%, M-value and 1,5-AG levels were simi-
lar in both groups, but mean glucose was significantly higher in
the group with the higher A1C. Again, this
demonstrates that 1,5-AG may offer com-
plementary information to the A1C. The
authors argue that the variability in normal
values serves as a limitation for screening,
320 but not for monitoring diabetes, and that
310 1,5-AG could serve as a useful adjunct to

µg/ml

5 A1C. In conclusion, monitoring changes in

%

7.5 300
4 1,5-AG over time could be advantageous in
100 290
7.0 3
pregnant patients, where frequent adjust-
280 ments in therapy are required to obtain and
50 2 270 maintain glycemic control.
6.5
1 260
Children
0 6.0 0 250
MPMG* A1C 1,5-AG* Fructosamine Very few data on 1,5-AG are available in
children with diabetes. Nguyen and asso-
Top 50% AUC for glucose >180 mg/dl Bottom 50% AUC for glucose >80 mg/dl ciates recently published their results of
1,5-AG levels in ten children with Type 1
Figure 4. 1,5-AG is complementary to A1C. diabetes and A1C <8.0%, and ten con-
*p < 0.05. trols [86] . They found a fivefold decrease
1,5-AG: 1,5-anhydroglucitol; A1C: Hemoglobin A1C; MPMG: Mean post-meal in 1,5-AG levels in the patients with dia-
maximum glucose.
betes. Interestingly, 1,5-AG was more

14 Expert Rev. Mol. Diagn. 8(1), (2008)


tightly correlated with A1C (r = -0.9366, p < 0.001), and peak
post-meal plasma glucose (r = -0.723, p = 0.0003) than in
adult studies.
Hospitalized patients
In the hospital setting, many patients without previously
known diabetes develop stress hyperglycemia, and increasing
emphasis has been placed on attaining glycemic control by
expert groups [87,88]. In this scenario, A1C is not generally a
useful marker due to its slow response to changes in glucose.
Furthermore, a preliminary report in patients with acute coro-
nary syndrome suggests that 1,5-AG may be useful in discrimi-
nating patients with stress hyperglycemia from normoglycemic
controls [89]. However, the use of either marker must be consid-
ered with caution in the hospital setting, as A1C can be affected
by blood transfusions and hematologic disorders, and 1,5-AG
might be affected by several severe chronic diseases and renal
function (although the effect of acute renal failure is generally
much less than that of chronic kidney disease) [90].
Coronary artery disease
Because PPG is linked more tightly to cardiovascular disease
than fasting glucose, a marker that can differentiate between
PPG and fasting glucose would be advantageous for investigating
cardiovascular risk. The relationship between 1,5-AG and coro-
nary artery disease is currently being investigated. Recently,
Dworacka and colleagues demonstrated that 1,5-AG is a stron-
ger predictor of circulating CD4+ and CD8+ perturbations than
either A1C or fasting glucose [91]. Alterations in lymphocyte distri-
bution in the peripheral blood may be associated with enhanced
arterial intima lymphocyte infiltration and atherosclerotic plaque
formation [92].
Expert commentary
1,5-AG is more sensitive than A1C for detecting hyperglycemia
in patients undergoing rapid glucose changes. In addition, the
clinical scenarios limiting the use of 1,5-AG are complementary
to that of A1C, allowing its use where A1C is inaccurate. There
are mounting data to suggest that 1,5-AG provides complemen-
tary information to A1C in terms of detecting glycemic excur-
sions in otherwise moderate to well-controlled patients. 1,5-AG
is a marker of PPG but it also reflects every acute hyperglycemic
spike, even in the fasting state. Assessment of 1,5-AG would be
especially suited for the patient who does not have frequent
SMBG readings available.
The precise role of 1,5-AG in the usual clinical setting remains
open to debate. More data are required to evaluate whether inter-
ventions based on 1,5-AG, either in isolation or in combination
with A1C, result in improved glycemic control. Of note, mea-
sures of utility might not be based on A1C alone, because
1,5-AG offers novel glycemic data. Moreover, although several
studies suggest that glycemic excursions or PPG independently
predict complications, it is unknown whether targeting isolated
www.future-drugs.com
GlycoMark™ Diagnostic Profile
PPG or glycemic excursions in the setting of a near-normal A1C
will improve these outcomes. Therefore, it is also unclear whether
measuring 1,5-AG in such settings will also improve outcomes.
In general, 1,5-AG is ideally suited for interpretation on an
individual basis by evaluating trends in a single patient over time,
and less useful as a comparison between individual patients. As
discussed, there is noticeable variation in 1,5-AG that may be
partly explained by variability in the renal threshold for glucose,
making it a questionable screening test. More data regarding its
utility in combination with other modalities for screening (e.g.,
A1C) are needed, as well as more data regarding dietary influ-
ences. Finally, further data are needed regarding the utility of
1,5-AG measurements in patients with special circumstances (e.g.,
pregnancy, chronic kidney disease and chronic medical illnesses).
Five-year view
Owing to the wealth of data supporting A1C in predicting dia-
betes complications, 1,5-AG is unlikely to replace A1C. Cur-
rently, there are few data to show that 1,5-AG reflects micro-
vascular or macrovascular complications. A long-term marker
like A1C still rightfully holds considerable appeal when the
goal is to follow patients long term.
However, each tool for measuring glycemic control has unique
limitations. Therefore, it seems likely that future approaches will
utilize 1,5-AG in combination with A1C. This may be accom-
plished through two different approaches. First, 1,5-AG could
serve as a useful tool to evaluate interval glycemic control
between 3-month A1Cs in patients who are undergoing active
adjustment of therapy. The automated assay also has features
that would be compatible for a home test. As a home test, it may
serve as a prompt to institute behavioral change, and could con-
ceivably substitute for routine glucose checks in some patients
with Type 2 diabetes. Second, a step-wise approach to utilizing
1,5-AG may be envisioned, in which the A1C is first utilized to
determine whether a patient is moderately controlled (FIGURE 5). If
Measure A1C
Controlled or Uncontrolled
suboptimal A1C (<8.0%) A1C (>8.0%)
1,5-AG may be used
1,5-AG <6 µg/ml 1,5-AG >6 µg/ml
to monitor short-term
overall glycemic control
Target PPG Target mean or
fasting glucose
Figure 5. Proposed algorithm for utilizing 1,5-AG in
treatment decisions.
1,5-AG: 1,5-anhydroglucitol; A1C: Hemoglobin A1C;
PPG: Postprandial glucose.
15
 Diagnostic Profile Dungan

the 1,5-AG level is moderate to normal in such patients, the cli-
nician should consider targeting fasting or mean glucose levels.
If, on the other hand, the 1,5-AG level is low, therapy could
focus on PPG. Therapies that target PPG might include pran-
dial insulin, exenatide and dipeptidyl peptidase-IV inhibitors
pramlintide, α-glucosidase inhibitors, or meglitinides. This
approach has not been formally evaluated in clinical trials.
Obviously, 1,5-AG would offer more benefit to the patient that
does not perform frequent SMBG assessments or use real-time
subcutaneous glucose monitoring.
Despite the novelty and wealth of data provided by continu-
ous subcutaneous glucose sensing technologies, 1,5-AG is
increasingly being utilized on a research or population level. In
particular, 1,5-AG is an inexpensive, automated marker for
determining the efficacy of interventions that aim to reduce glu-
cose excursions, particularly in large patient samples or over long
treatment periods, where continuous glucose monitoring might
be impractical. The utility of 1,5-AG in clinical trials is likely to
continue to evolve in concert with that of PPG monitoring and
treatment in general, particularly in light of new medications
(such as incretin-based therapies) that specifically target PPG.
Financial & competing interests disclosure
The author would like to report royalties from UpToDate and research
support from and pending patent application with GlycoMark™. The
author has not received honoraria or salary from GlycoMark. The author
has no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Traditional markers of glycemic control have limitations in many clinical scenarios.
• 1,5-anhydroglucitol (1,5-AG) is a naturally occurring polyol that competes with glucose for reabsorption in the kidneys. Serum levels
of 1,5-AG are rapidly reduced following glucose excursions that exceed the renal threshold (~180 mg/dl).
• 1,5-AG may be affected by gender, conditions that affect renal reabsorption of glucose and possibly extremes in diet.
• 1,5-AG is superior to hemoglobin A1C (A1C), and arguably even to fructosamine, for short-term glycemic monitoring.
• 1,5-AG may be abnormal in patients with A1Cs at or near goal, reflecting glycemic excursions.
• 1,5-AG reflects postprandial glucose better than A1C or fructosamine.
• More studies are needed to determine whether monitoring 1,5-AG improves overall glycemic control or reduces complications.

therapies (UKPDS 49). UK Prospective comparison of fasting and 2-hour

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_final.pdf
Affiliation
• Kathleen M Dungan, MD
Ohio State University, 4th Floor
McCampbell Hall, 1581 Dodd Drive,
Columbus, OH 43210, USA
Tel.: +1 614 292 3800
Fax: +1 614 292 1550
kathleen.dungan@osumc.edu
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