Transcript 1,5 Anhydroglucitol and the Monitoring of Postprandial

1,5 Anhydroglucitol and
the Monitoring of
Postprandial Glucose
Control
Steven D Wittlin M.D.
U of Rochester School of
Medicine and Dentistry
Importance of PostPrandial Hyperglycemia
Duration of daily metabolic
conditions
Breakfast
Lunch
Dinner
Postprandial
Monnier L. Eur J Clin Invest 2000;30(Suppl. 2):3–11
0:00 am
Postabsorptive
4:00 am Breakfast
Fasting
2 hr after SMM plasma glucose (mmol/l)
Correlation between plasma glucose levels
after OGTT and standard mixed meal
16
14
12
10
8
6
r=0.97
4
2
0
0
5
10
15
2 hr after OGTT plasma glucose (mmol/l)
Wolever TMS et al. Diabetes Care 1998;21:336–40
20
25
Relationship between HbA1C, FPG and 2 h. PPG
Van Haeften T et al Metabolism 2000
Relative Changes in FPG and 2-h PG
as HbA1c Increases
Plasma Glucose
(mg/dL)
250
= HbA1c versus 2hppg
= HbA1c versus FPG
160
r = 0.55
y = 47.1 x -109
r = 0.48
y = 12.0 x +30
70
4
5
6
HbA1c (%)
Woerle HJ et al Arch Intern Med. 2004;164:1627-1632.
7
Relationship between FPG and 1st-Phase
Insulin Release
( van Haeften T et al Metabolism 2000 )
Relationship Between Diabetes Status
and 1st Phase Insulin Release
.Metabolism 2000 )
( van Haeften T et al
As Patients Get Closer to A1C Goal,
the Need to Successfully
Manage PPG Significantly Increases
Increasing Contribution of PPG as A1C Improves
%
Contribution
100%
30%
80%
60%
70%
60%
55%
50%
40%
20%
70%
30%
40%
45%
50%
0%
< 10.2
10.2 to 9.3 9.2 to 8.5 8.4 to 7.3
A1C Range (%)
Adapted from Monnier L, Lapinski H, Collette C. Contributions of fasting and
postprandial plasnma glucose increments to the overall diurnal hyper glycemia
of Type 2 diabetic patients: variations with increasing levels of HBA(1c).
Diabetes Care. 2003;26:881-885.
< 7.3
FPG
PPG
Post-load Hyperglycemia and The
Metabolic Syndrome
Fasting plasma
glucose
2-hr plasma
glucose
Age
0.21*
0.25*
Body mass index (BMI)
0.01
0.24*
Waist: hip ratio
0.15
0.21*
Triglycerides
0.01
0.23*
Free fatty acids
0.07
0.27‡
Tissue plasminogen
activator (TPA)
0.18
0.25‡
Cellular fibronectin
–0.03
0.25‡
C-reactive protein
–0.13
0.20*
Yudkin JS. Lancet 2002;359:166–7
*p<0.05; ‡ p<0.01
Controlling Postprandial Glucose

Prospective trial of fasting vs pc control in 164
pts w/ Type 2 DM
 Forced titration to target first FBS < 100 and
then, 90 min pc < 140 if not achieved
previously
 Results:






HbA1C fell from 8.7 % to 6.5%
Only 64% of patients achieving FPG < 100 only
reached HbA1C < 7%
94% of patients w/ pc < 140 reached HbA1C < 7%
Decreased pc BG accounted nearly twice as much
as FBS for fall in HbA1C
If HbA1C < 6.2% , pc accounted for ~ 90%
If HbA1C > 8.9%, pc accounted for ~ 40%
Woerle HJ et al Diabetes Research and Clinical Practice 2007
Contribution of Postprandial BG to HbA1C
100
*=p<0.05vs HbA1c <6.2 %
*
80
Contribution (%)
*
*
60
*
*
40
20
0
4.7-6.2
6.2-6.8
6.8-7.3
7.3-7.8
7.8-8.9
HbA1c sixtiles(%)
Woerle HJ et al Diabetes Res Clin Pract. 2007 Jan 19
8.9-15.0
Glycemic Excursions Predict
Oxidative Stress
Monnier L et al JAMA. 2006;295:1681-1687
Endogenous Glucose Production After a Mixed
Meal in Diabetic and Non-Diabetic Individuals
(Singhal P et al AJP 2002 )
Routes of Post-Prandial
Glucose Disposal
Post-Prandial Glucose Metabolism
: Mechanism
 Study
of 11 normal volunteers after a
standard test meal
 Triple isotope technique and indirect
calorimetry

Intravenous
• Tritiated Glucose
• C-14-labelled bicarbonate

Oral
• Deuterated Glucose
Woerle HJ et al .Am J Physiol Endocrinol Metab 284: E716-E725, 2003
Post-Prandial Glucose
Disposal ( Woerle Hans J et al AJP Endo Metab 2003 )
Changes in Postprandial Glucose
Metabolism in Type 2 DM

Use triple isotope technique and indirect calorimetry

DM pts had:






increased overall glucose release
Increased gluconeogenesis and glycogenolysis
~90% of the increased glucose release occurred
in the first 90 min post-prandial
In DM glucose clearance and oxidation were
reduced
Non-oxidative glycolysis was increased
Net splanchnic glucose storage was reduced ~
45% d.t. increased glycogen cycling
Woerle HJ et al Am J Physiol Endocrinol Metab 2006
Effect of Pre- or Post-Meal Exercise on
Glycemic Control
(Yamanouchi K et al Diab Res & Clin
Pract, Oct 2002 )
Effects of 2h Post-Prandial Glucose +/Vitamins C +E on Flow-Mediated Dilatation
LM et al JACC Dec 2000 )
( Title
Relative risk for death increases with
2-hour blood glucose irrespective of
the FPG level
2.5
Hazard ratio
2.0
1.5
1.0
11.1
0.5
7.8–11.0
<7.8
0.0
<6.1
6.1–6.9
7.0
Fasting plasma glucose (mmol/l)
Adjusted for age, center, sex
DECODE Study Group. Lancet 1999;354:617–621
THE FUNAGATA DIABETES STUDY
Impaired Glucose Tolerance is a CV Risk Factor
Cumulative Cardiovascular Survival
1.00
1.00
0.99
0.98
0.98
0.97
0.96
0.96
0.94
Normal
IGT (2 hr PG 140-200)
DM (2 hr PG >200)
0.95
0.94
Normal
IFG (FPG 110-126)
DM (FPG >126)
0.92
0
0
0
1
2
3
4
Year
5
6
7
0
1
2
3
4
5
6
7
Year
Tominaga M, et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose. Diabetes Care
1999;22:920-4.
Effect of Acarbose on CVD in
Patients with IGT ( STOP-NIDDM)
( Chiasson J-L et al JAMA July 2003 )
Summary
 Postprandial
glycemia plays a clinically
important role in the complications of
diabetes
 Postprandial glycemia is a major
contributor to overall glycemic control
ESPECIALLY in moderately-well to well
controlled patients
So How Can We Assess Post-Prandial
Glucose Control Clinically ??

Frequent
fingersticks
 HbA1C
 Fructosamine
 Continuous Glucose
Monitoring Systems



Historical
Real-time
1,5 Anhydroglucitol
A New Idea !
1,5 Anhydroglucitol
History of 1,5AG
1888
1,5AG was discovered in plant of Polygala Senega.
1973
Presence in human body was reported.
1977 Decrease of plasma 1,5AG concentration with uremia
and diabetes mellitus was reported.
1979
Blood 1,5AG was determined in Japan.
After this, research on relationship between diabetes
mellitus and 1,5AG has become active.
Blood test measuring 1,5-anhydroglucitol (1,5-AG)
1,5-AG is a monosaccharide (similar to glucose structure)
1/40 of glucose concentration – healthy human blood
Primary Source of 1,5-AG – Food
Further distributed to skin, muscle, and other tissues/organs
Reabsorbed very efficiently through kidney (urinary
excretion is 1/20 of total amount in body)
Large Body Pool of 1,5-AG (6-7 times > Blood)
Not metabolized much in the body (metabolic turnaround
rate at least 3 days)
1,5-AG urinary excretion remarkably increases with
hyperglycemia!
The structure of 1,5-anhydroglucitol
(1,5AG)
HO
HO
O
O
OH
OH
HO
OH
OH
D-glucose
HO
OH
1,5-anhydro-D-glucitol
（(1-deoxyglucose)
Fully Automated Enzymatic Method for 1,5 AG
Assay ( Glycomark ) Fukumura Y et al Clin Chem 1994
HRP=Horseradish peroxidase ; PROD= pyranose oxidase; HTB=3
hydroxyriiodobenzoic acid ; 4AAP= 4 aminoantipyrine
Specificity of Assay
 The
following don’t interfere in
concentrations up to 10 grams/L :






Sorbitol
Mannitol
Sucrose
Lactose
Maltose
Fructose
1,5 AG Content of Foodstuffs in
Japanese Diet
Yamanouchi T et al Am J Physiol 263: E268-E273. 1992
1,5 Anhydroglucitol Specimen
Requirements
Physiology of 1,5-AG
Oral Supply
1,5AG
(5-10mg/day)
A.
Normoglycemia
Blood
stream
Kidney
Urinary excretion
(5-10mg/day)
Tissues
Internal
Organs
(5001000 mg)
Oral Supply
1,5AG
(5-10mg/day)
Glucose
Blocks
Reabsorption
Kidney
Urinary excretion
(INCREASED)
Buse JB et al Diab Tech & Ther 2003. 5(3) : 355-363
B. Hyperglycemia
Blood
Stream
(1,5-AG
Level
Lower)
Tissues
Internal
Organs
(5001000 mg)
1,5 AG Kinetics in Humans
Yamanouchi T et al Am J Physiol 263: E268-E273. 1992
Urinary Excretion of Glucose and
1,5 AG Fluctuate in Parallel in Rats
Yamanouchi T et al Am J Physio 1990. 258: E423-E427
Urinary Excretion of Glucose and
1,5 AG Fluctuate in Parallel in Rats
Yamanouchi T et al Am J Physio 1990. 258: E423-E427
But…1,5 AG Does Not Fluctuate with
Variations in Plasma BG in Nephrectomized
Rats !!
Yamanouchi T et al Am J Physio 1990. 258: E423-E427
Fructose , Mannose and 1,5 AG Share
A Common Transport Mechanism
Yamanouchi T et al Biochim et Bipophys Acta 1996. 1291: 89-95
Fructose , Mannose and 1,5 AG Share
A Common Transport Mechanism
Yamanouchi T et al Biochim et Bipophys Acta 1996. 1291: 89-95
Renal Tubular Absorption of Glucose and
1,5 AG
Normal
Filtration at
glomerulus
Glucose active
transporter
Fructose, mannose
active transporter
Reabsorption at
renal tubule
Glucose
1,5AG
urine
Renal Tubular Absorption of Glucose and
1,5 AG
Hyperglycemia
Filtration at
glomerulus
Reabsorption at
renal tubule
Glucose active
transporter
Fructose, mannose
active transporter
Glucose
1,5AG
urine
Renal Tubular Absorption of Glucose
and 1,5 AG
Stickle D and Turk J. Am J Physiol Endocrinol Metab 273: E821-E830,
1997
Linearity of 1,5 AG Assay
Nowatzke W et al Clin Chim Acta 2004
Recovery Time of 1,5 AG in
Treated Patients with Type 2 DM
Yamanouchi T et al Jpn. J. Clin. Med. 47: 2472-2476, 1989
Histograms of serum 1,5AG concentrations
in Japanese healthy subjects
Male (n=332)
40
Female (n=207)
50
Frequency
26.6±7.2
30
20
10
0
40
21.5±6.0
30
20
10
0
10
20
30
40
1,5AG (µg/mL)
Frequency
Frequency
50
50
10
20
30
40
1,5AG (µg/mL)
Male and Female (n=539)
70
60
50
40
30
20
10
0
24.6±7.2
10
20
30
40
1,5AG (µg/mL)
50
50
Distribution of 1,5 AG in a Healthy US
Population
Nowatzke W et al Clin Chim Acta 2004
The mean 1,5AG levels in
healthy subjects during 2 years
(n=245)
40
mean±S
D
1,5AG (μg/mL)
30
20
10
0
Sep-86
Mar-87
Sep-87
Mar-88
Diurnal change of plasma glucose and 1,5AG
FPG (mg/dL)
400
300
200
100
↑B
0
8
↑L
12
↑D
16
20
24
1,5AG (μg/mL)
25
20
▲―▲: healthy
◆―◆:IGT
Others: diabetes
B: breakfast
L: lunch
D: dinner
15
10
5
0
8
12
16
20
time (hour)
24
Histogram of serum 1,5AG concentrations
30
Healthy (n=539)
24.6±7.2 µg/mL
Frequency (%)
Diabetes (n=808)
7.3±7.1 µg/mL
20
10
0
0
10
20
30
Serum 1,5AG (µg/mL)
40
50
Serum 1,5AG levels in healthy subjects, Impairedglucose-tolerance, diabetes mellitus, and various other
disorders
40
P<0.001
1,5AG (µg/mL)
P<0.001
P<0.001
P<0.001
30
20
10
0
Healthy IGT
DM
Non-DM
subjects
(n=539) (n=451) (n=808) (n=238)
Yamanouchi T et al Diabetes 1991; 40: 52-57
1,5AG Index
1,5AG x UG = 16
1,5AG x UG
30
14.0
12.0
10.0
20
10
0
8.0
0
2
4
6
8 10 12
Plasma 1,5AG (µg/mL)
6.0
N =47
Log y = -0.97 log x + 2.71
R = -0.890 (P < 0.0001)
4.0
2.0
0.0
1
10
100
Urinary glucoses (g/day)
1,5-AG Physiology Implication
 Because 1,5-AG levels fluctuate according to
glucosuria, the response is much more rapid
than glycemic markers based on the glycation
process (A1C).
Responds Rapidly and Sensitively to Glycemic
Changes
Correlation between glycemic control
markers and past fasting plasma glucose
(FPG)
Measurement
point of FPG
1, 5AG
HbA1C
Fructosamine
same time
1 week ago
2 weeks ago
3 weeks ago
4 weeks ago
r = -0.88
r = -0.84
r = -0.80
r = -0.71
r = -0.58
r = 0.27
r = 0.51
r = 0.72
r = 0.80
r = 0.73
r = 0.54
2 months ago
3 months ago
r = -0.39
r = 0.73
r = 0.65
r = 0.53
r = 0.81
Distribution of 1,5AG to FPG shows hyperbolic dispersion different from HbA1C
and fructosamine. Therefore, Spearman's rank correlation coefficient is used
here to make comparison between groups.
Glycemic control markers
Blood
glucose
1,5A
Fructosamine G
HbA1C
10
9
8
7
6
5
4
3
2
1
Weeks before measurement
0
400
Lente 12u
8 6
300
15
20
10
1
0
5
300
200
200
100
100
0
1
2
3
4
5
6
7
Weeks
8
9 1
0
11 12 13
Plasma 1,5AG (µg/mL)
510
HbA1C (%)
Renal excretion of glucose (g/day)
Changes in various glycemic control markers in
NIDDM patient with poorly controlled glycemia
after starting insulin treatment
Clinical Parameters for 1,5 AG
1,5-AG serum concentrations in normal humans vary
widely (10-40 ug/ml)
Little change day to day because of large body pool
relative to daily intake and metabolic inertness
Few normal subjects show an alteration in 1,5-AG level
in the normal range during 2-3 years
When hyperglycemia occurs (glucosuria), 1,5-AG
serum levels fall rapidly (1-2 days)
Individual variance in renal threshold does not appear to
seriously influence clinical utility of 1,5-AG (glucose
fluctuates more widely than individual renal threshold
variance)
Exception – Gestational Diabetes
Post-load glucose measurements in OGTTs
correlate well with 1,5-AG in subjects with IGT
R=0.824
R=0.281
N = 211
1,5 Anhydroglucitol is a better indicator than A1C of postprandial
blood glucose levels in IGT subjects
Yamanouchi T et al., Clinical Science 2001
Correlation between 1,5AG and HbA1c
1,5AG (µg/mL)
15
Cut-off value
10
5
5
6
7
8
9
10
11
12 (%)
HbA1c (Normal range 4.8-5.8%)
8
16
7
14
6
12
5
10
4
8
3
6
2
4
1
2
300
200
100
0
0
0
10
20
30
40
Weeks
50
60
70
80
90
Mean plasma glucose (mg/dL)
1,5AG, HbA1C, and mean plasma glucose values
during a 92-weeks period in a patient with Type 1 DM
Changes of 1,5AG and HbA1C values during a 13months period in a patient with Type 2 DM
1,5AG
HbA1C
9
12
8
11
10
6
9
5
8
4
7
3
6
2
5
exacerbation
stage
Improvement
stage
1
Improvement
stage
0
4
3
0
1
2
3
4
5
6
7
Month
8
9
10 11
12
13
HbA1C(%)
1,5AG (µg/mL)
7
Glycemic control in Type 2 DM patients
before and after the study treatment
12
Control
HbA1c (%)
11
Voglibose
10
9
8
7
6
14
35
12
30
10
25
M-value
1,5AG (μg/mL)
5
8
6
20
15
4
10
2
5
0
0
Before
after
Before
after
Measurement of 1,5AG and HbA1c between October
and April, around the new year, in 17 patients with
Type 2 DM
7.7
7.5
7.3
7.1
10
1,5AG (μg/mL)
9
8
7
6
5
Oct Nov Dec Jan Feb Mar Apr
HbA1c (%)
7.9
GlycoMark Evaluates Daily Glycemic
Excursions in Moderately-Well Controlled
Patients
11.5
6.9
HbA1c showed no significant differences among all groups
*Plasma 1,5-AG in diet group significantly higher than OHA and MIT groups (P<0.05)
**Plasma 1,5-AG in CIT significantly lower than diet, OHA, and MIT groups (P<0.05)
N = 76 well-controlled type 2 diabetes patients OHA=oral hypoglycemic agents,
CIT=Conventional Insulin Therapy, MIT=Multiple Insulin Injection Therapy
Kishimoto et al.Diabetes Care 1995)
Clinical usefulness of serum 1,5-AG in
monitoring glycemic control




Objective: Monitor glycemic control following changes in
antidiabetic medication
56 type 2 diabetic patients treated with oral hypoglycemic
agents for 4 weeks
After 4 weeks, treatment discontinued in half of patients
and monitored for 2 more weeks
1,5-AG, Glucose, A1C, and Fructosamine were measured
Yamanouchi T et al., The Lancet 1996
Serial Changes in A1C in Newly Diagnosed Type 2
Diabetes Patients
Group A – 28 patients who continued treatment for 6 weeks
Group B – 28 patients who discontinued treatment after 4 weeks
No Significant Difference
Yamanouchi T et al.Lancet 1996
Serial Changes in 1,5-AG in Newly Diagnosed Type 2
Diabetes Patients Group A – 28 patients who continued treatment
for 6 weeks
Group B – 28 patients who discontinued treatment after 4 weeks
P<0.0001
1,5 Anhydroglucitol detected slight change in glycemia
Yamanouchi T et al.Lancet 1996
Judgment standard of 1,5AG
1,5AG (µg/mL)
State of glycemic
control
Affected by other diseases
Over 14.0
Normal
10.0-13.9
Excellent
Renal glycosuria, oxyhyperglycemia
pregnancy (after 30 weeks)
Chronic renal failure (serum creatinine
over 3.0mg/dL)
Long term high calorie transfusion
through central vein starvation
6.0-9.9
Good
Pregnancy (34 weeks approximately)
Chronic renal failure (serum creatinine
over 3.0mg/dL)
Long term high calorie transfusion
through central vein starvation
2.0-5.9
Fair
Chronic renal failure (serum creatinine
over 3.0mg/dL)
Characteristics of various glycemic control markers
HbA1C
Best correlated
with
Time required for
significant change
Post glycemia
Change
Fructosamine
1,5AG
Present glycemia
1 month
Recent
glycemia
1-2 weeks
Sluggish and
approximate
Small
Sharp and analytical
Variance
Sluggish and
approximate
Small
Most changeable
in
Medium~ high
hyperglycemia
Medium~ high
hyperglycemia
Modest hyperglycemia
~ near-normoglycemia
Grapping
roughly
glycemic
control state
Monitoring
glycemic
control in
hyperglycemia
Grapping glycemic
control state
monitoring strict
glycemic control
Purpose for use
1-several days
Large
McGill J et al Diabetes Care 2004
FDA Study – Longitudinal Changes
Time point
Statistic
1,5AG
ug/ml
A1C
%
Fructosamine
umol/L
Glucose
mg/dL
1.9
9.5
410.6
225
Visit 2 (2 weeks)
Mean
Mean% Change
3.0*
57.9%
9.1
-4.2%
362.4 *
-11.7%
187.4*
-16.7%
Visit 3 (4 weeks)
Mean
Mean% Change
3.7*
94.7%
8.8*
-7.4%
340.0*
-17.2%
181.4*
-19.4%
Visit 4 (8 weeks)
Mean
Mean% Change
5.0*
163.2%
8.2*
-13.7%
317.5*
-22.7%
172.6*
-23.3%
Baseline
Mean
*p<0.05 vs. baseline
McGill J et al Diabetes Care 2004
FDA Study – Longitudinal Changes
McGill J et al Diabetes Care 2004
Assessing the Role of 1,5 AG
for Monitoring Post-Prandial
Glycemic Excursions
K Dungan, J. Buse , J Largay, M Kelly, E
Button, S Kato, S. Wittlin
University of North Carolina
University of Rochester
Dungan K et al Diabetes Care; June 2006
Study to Evaluate 1,5 AG/Glycemic Excursions as
Determined by Continuous Glucose
Measurements
Moderately-Controlled Patients (n=34) with A1Cs between 6.5 and
8.0 monitored over 7 days
Comparing 1,5 AG , Fructosamine,and Hemoglobin A1C levels to
Glycemic excursions above the renal threshold (> 180 mg/dl)
Glycemic excursions measured by CGMS
Objective: To demonstrate the relationship between serum 1,5-AG
(relative to A1C and fructosamine) and the occurrence of postprandial
hyperglycemia as reflected by CGMS in suboptimally controlled
patients with diabetes
Dungan K et al Diabetes Care; June 2006
Study Methodology
34 Patients
Type 1: 24
Male: 13
UNC: 20
Type 2: 10
Female: 21
UR: 14
Visit 1
1,5AG, A1c, FA
Day 1
CGMS
24-hr
urine
glucose
2
3
4
Interval 1
Visit 2
Visit 3
1,5AG, A1c, FA
1,5AG, A1c, FA
5
6
Interval 2
UR: University of Rochester
UNC: University of North Carolina
Dungan K et al Diabetes Care; June 2006
7
Postprandial Variables
• AUC-180 – measure of total area above 180 mg/dl
for (mg/dl*Day)
• Average Postmeal (Maximum) Glucose (mg/dl) –
maximum height of each postmeal glucose excursion
for breakfast, lunch, and dinner
• Postprandial Index (PI) – 4 variable combination
(max glucose levels for post-breakfast, lunch, dinner
and AUC-180 - 7 days)
Dungan K et al Diabetes Care; June 2006
Correlation AUC-180 vs. Glycemic Assay
AUC-180^
(mg/dl*Day)
Avg.
A1C
A1C-End
Interval*
Avg. 1,5AG
1,5-AGEnd Interval
Avg. FA
FAEnd
Interval
Interval 1 & 2
N=34
R = 0.36
p =0.02
R = 0.35
p =0.02
R = -0.48
p = 0.002
R = -0.49
p = 0.002
R = 0.33
p =0.03
R=
0.38
p =0
.01
Interval 1
N=34
R = 0.23
p =0.09
R = 0.22
p =0.11
R = -0.36
p =0.02
R = -0.37
p =0.02
R = 0.16
p =0.18
R=
0.12
p =0.25
Interval 2
N=33
R = 0.35
p = 0.02
R = 0.34
p =0.03
R = -0.42
p =0.008
R = -0.44
p =0.005
R = 0.37
p = 0.02
R=
0.39
p=
0.01
^AUC-180=area under the curve for glucose greater than 180mg/dL as determined by CGMS software.
*End-interval is visit 2 for interval 1, visit 3 for interval 2 and total (1 & 2).
1,5-AG Correlated Better than A1C or Fructosamine to AUC-180
Dungan K et al Diabetes Care; June 2006
Avg. Maximum Postmeal Glucose vs.
Avg. Glycemic Assay
Avg. A1C
Avg. 1,5-AG
Avg. FA
Avg. Postmeal Max (Breakfast)
N=20
R = 0.12
p = 0.31
R = -0.38
p =0.05
R = -0.003
p =0.494
Avg. Postmeal Max (Lunch)
N=23
R = 0.19
p = 0.19
R = -0.22
p =0.15
R = 0.06
p = 0.39
Avg. Postmeal Max (Dinner)
N=22
R = 0.25
p = 0.13
R = -0.54
p = 0.004
R = 0.35
p = 0.06
Combined Postmeal Max (Breakfast,
Lunch Dinner)- Multiple Regression
N=19
R = 0.25
R = -0.57
R = 0.36
1,5-AG Correlated Better than A1C or Fructosamine to ALL
Postmeal Max Values
Dungan K et al Diabetes Care; June 2006
Postprandial Index vs. Average Glycemic Assay
Postprandial
Index (Multivariate-PI)
N=19
Avg. A1C
Avg. 1,5AG
Avg. FA
R=0.36
R=0.58
R=0.36
*Postprandial Index is the conglomerate multivariable analysis using AUC-180 and post-meal
maximum glucose values as the independent variables.
1,5-AG Correlated Better than A1C or Fructosamine to the
Postprandial Index
Dungan K et al Diabetes Care; June 2006
Postprandial Index vs. A1C/1,5-AG Assay Ratio
Postprandial
Index (Multivariate-PI)
N=19
Avg. A1C
Avg. 1,5AG
Avg.
A1C/Avg.
1,5-AG Ratio
R=0.36
R=0.58
R=0.66
*Postprandial Index is the conglomerate multivariable analysis using AUC-180 and post-meal
maximum glucose values as the independent variables.
A1C/1,5-AG Ratio Correlated Better than A1C or 1,5-AG
independently to the Postprandial Index
Combination of 1,5-AG and A1C are more predictive of
postprandial hyperglycemia
Dungan K et al Diabetes Care; June 2006
Average and Premeal Glucose vs. Glycemic Assay
Avg. A1C
Avg. 1,5-AG
Avg. FA
Average Glucose –
CGMS Sensor
N = 34
R = 0.27
p = 0.26
R = -0.15
p = 0.23
R = 0.40
P = 0.04
Combined Premeal
(Breakfast, Lunch
Dinner) - Multiple
Regression
N=19
R = 0.42
R = -0.33
R = 0.45
Fructosamine and A1C correlated better than 1,5-AG to both
average glucose and premeal glucose variables
Dungan K et al Diabetes Care; June 2006
1,5 AG as Adjunct to A1C to Reflect Postprandial
Hyperglycemia
GlycoMark
(1,5-AG)
Range 0-6
N=17
A1C
(%)
Mean
1,5-AG
(ug/ml)
Mean
Total AUC-180
Glucose 1
PostMeal
Glucose-Max
Mean (mg/dl)
Breakfast
N=9
PostMeal
Glucose-Max
Mean (mg/dl)
Lunch
N=10
PostMeal
Glucose-Max
Mean (mg/dl)
Dinner
N=9
Higher
Postprandial
Variables
7.38
4.55
16.29
259
224
198
GlycoMark
(1,5-AG)
Range 6-18
N=16
A1C
(%)
Mean
1,5-AG
(ug/ml)
Mean
Total AUC-180
Glucose1
PostMeal
Glucose-Max
Mean (mg/dl)
Breakfast
N=11
PostMeal
Glucose-Max
Mean (mg/dl)
Lunch
N=13
PostMeal
Glucose-Max
Mean (mg/dl)
Dinner
N=13
Lower
Postprandial
Variables
7.20
9.29
10.75
228
196
162
1,5 AG is indicative of differing postmeal glucose levels in moderately
controlled patients – despite similar A1C levels!
Dungan K et al Diabetes Care; June 2006
GlycoMark Monitors Postprandial Hyperglycemia
Dungan K et al. Diabetes Care (June 2006)
Postmeal Glucose (mg/dL)
A1C (% )
(P<0.05)
250
230
180
150
100
50
0
(P<0.05)
9.00
8.00
200
GlycoMark 1,5-AG (mg/ml)
(No Significant Difference)
9.00
7.20
7.38
7.00
7.00
6.00
6.00
5.00
5.00
4.00
4.00
3.00
3.00
2.00
2.00
1.00
1.00
0.00
Patient Group 1
Patient Group 2
8.00
8.00
5.58
0.00
Patient Group 1
Patient Group 2
Patient Group 1
Patient Group 2
Patients were sorted by glycemic excursions as measured by CGMS (AUC-180) and subdivided into two
populations – bottom 50th percentile (17 patients) and top 50th percentile (17 patients).
Authors’ Conclusions
•1,5-AG (GlycoMark) assay reflects glycemic excursions, often in the postprandial state, more
robustly than other established glycemic assays.
•1,5-AG was reflective of varying postmeal glucose levels, despite similarities in A1Cs.
•In clinical practice, A1C and 1,5-AG may be used sequentially, first employing the A1C assay to
identify patients who are moderately controlled and then using the 1,5-AG assay to determine
the extent of postprandial glycemic excursions.
Representative Patients
A: Patient 1
400
350
52 year old female
with type 1 DM
A1C 7.43%
1,5-AG 12.4mcg/dL
PPG max 195 mg/dL
Glucose (mg/dL)
300
250
200
150
100
50
0
2/15
2/16
2/17
2/18
2/19
2/20
2/21
2/22
Time (days)
B: Patient 2
400
49 year old male with
type 2 DM
A1C 7.27%
1,5-AG 4.5mcg/dL
PPG max 235 mg/dL
350
Glucose (mg/dL)
300
250
200
150
100
50
0
2/8
2/9
2/10
2/11
2/12
Time (days)
2/13
2/14
2/15
UNC/Rochester Study
Conclusions
 In a subset of moderately controlled patients (A1C 6.5 to
8.0), significant postprandial hyperglycemia was present
 1,5-AG reflects postprandial hyperglycemia more
robustly than established glycemic assays
 At similar A1C levels, there may be variability in
postprandial hyperglycemia –which is reflected by 1,5AG levels!!
UNC/Rochester Study
Clinical Possibilities

1,5-AG may be used in combination with A1C for
better predictability of postprandial hyperglycemia
than either assay alone

A Two-Step Sequential Process Might be Used:
1)
2)
Use A1C to identify patients who are moderately
controlled (A1C 6.5 to 8.0)
Use1,5-AG to determine extent of postprandial
hyperglycemia
1,5-AG and Postmeal Glucose Levels
1,5 AG (ug/ml)
Approximate Mean Postmeal
Maximum Blood Glucose (mg/dl)
> 12
< 180
10
185
8
190
6
200
4
225
<2
> 290
1,5 Anhydroglucitol as Comprehensive Adjunct to A1C
Diagnostic Algorithm
Managing Short-Term Glucose Control
1,5 AG
(ug/ml)
> 10
5 – 10*
Diabetes
WellControlled
Moderately
Controlled
Managing Postprandial Glucose Control (PPG)
1,5 AG (ug/ml)
Approximate Mean
Postmeal
Maximum Blood Glucose
(mg/dl)
> 12
< 180
10
185
8
190
6
200
4
225
<2
> 290
A1C
4-6
6-8
2-5
Poor Control
8 - 10
<2
Very Poor
Control
> 10
Performance of 1,5 Anhydroglucitol
in Recent Drug Trials
Sitagliptin and 1,5 Anhydroglucitol
 Evaluated
efficacy and tolerability of
sitagliptin in Japanese patients with T2DM
over 12 weeks
 Initial A1C
levels - 6.5 to 10.0%
 Randomized
to sitagliptin (n=75) or
placebo (n=76)
Stein P et al ADA 2006. Poster 537-P
Sitagliptin and 1,5 Anhydroglucitol
Change from Baseline to Study End – Comparison of Mean Values
1,5-AG (μg/mL)
A1C (%)
Placebo
Sitagliptin
100mg
Baseline
4.1
5.3
Week 12
3.8
9.7
Baseline
7.7
7.5
Week 12
8.1
6.9
Stein P et al ADA 2006. Poster 537-P
Sitagliptin and 1,5 Anhydroglucitol
Change from Baseline to Study End
Placebo
Sitagliptin
100mg
Between Group
Comparison
LS
95% Cl
LS
95% Cl
LS
Difference
95% Cl
A1C
0.41
(0.26, 0.5)
-0.65
(-0.80, 0.50)
-1.05*
(-1.27, -0.84)
1,5AG
-0.33
(-1.05, 0.38)
4.45
(3.73, 5,17)
4.78*
(3.76, 5.80)
*P value <0.001
Change in Postmeal Glucose Compared to A1C and 1,5-AG % Changes
(Baseline to Study End)
Sitagliptin
Absolute Change
in 2 hour
postmeal glucose
(mg/dL)
A1C
Absolute %
change
1,5-AG
Absolute %
change
-69.2
-8.6%
83%
11.7
5.2%
-7.3%
100mg
Placebo
Stein P et al ADA 2006. Poster 537-P
Miglitol and 1,5 AG
Clinical Drug Trial – T. Yamanouchi (University of Teikyo)
Comparison of Mean Values
1,5-AG (μg/mL)
A1C (%)
Placebo
Miglitol
N=84
N=158
Baseline
4.5
4.5
Week 12
4.5
10.0*
Baseline
7.3
7.3
Week 12
7.5
7.0*
*p<0.001
After 4 weeks, mean 1,5-AG was 9.0 ug/ml (p<0.001) compared to baseline
BG
Patient 1: Age 75, female, type2 DM
Mean Maximum PPG
S PPG more than 180
Before
After
Breakfast Breakfast
BG
Before
Lunch
After
Lunch
Before
Dinner
After
Dinner
Patient2:Age 73, female, type2 DM
Mean Maximum PPG
S PPG more than 180
Before
After
Breakfast Breakfast
Before
Lunch
Data from Dr Mori in Japan
After
Lunch
Before
Dinner
After
Dinner
Pramlintide and 1,5 AG
 Objective:
To assess 1,5-AG as a marker
of PPG control in Pramlintide-treated
patients with type 1 diabetes (T1DM)
 Initial A1C levels - 7.2 to 8.0%
 Randomized to Pramlintide (n=18) or
placebo (n=19)
 Twenty-nine week study
Lush C et al .AACE 2007 Meeting (Poster 296)
Pramlintide and 1,5 AG
Comparison of Changes in Values from Baseline to
Week 29
Placebo (n=19)
2-hr PPG
excursions
Body Weight
A1C
1,5-AG ug/ml
Percent
Change
+6.5
+/-7.6
+1.3
0.22
Pramlintide (n=18)
mg/dL
+/-0.7
kg
+/-0.21
%
-0.65 +/-0.41
-9 +/- 8 %
-43.9
+/-10.9
-2.0
0.18
+/-
mg/dL
1.2 kg
+/-0.31
Pramlintide vs.
Placebo
P < 0.001
P < 0.01
%
+0.96 +/- 0.91
+30 +/-16 %
NS
P<0.05
P<0.01
Lush C et al .AACE 2007 Meeting (Poster 296)
Pramlintide and 1,5 AG
Conclusions

Pramlintide, as an adjunct treatment for T1DM
patients on intensive insulin therapy, led to
improved PPG and significant reduction in body
weight.
 Despite similar reductions in A1C, the change in
1,5 AG levels was consistent with improvement
in PPG control in pramlintide-treated subjects,
as measured by SMBG.
 1,5-AG, as a complement to A1C, may be a
useful marker of PPG control.
Lush C et al .AACE 2007 Meeting (Poster 296)
Exenatide and 1,5 Anhydroglucitol
 Objective:
To assess 1,5-AG as a marker
of PPG control in Exenatide-treated
patients with type 2 diabetes (T2DM)
 144 Patients
 Initial A1C levels – 8.2 +/-1%
 Randomized to Exenatide (5 or 10 ug) or
placebo
 Thirty week study
Kendall D , Holcombe J et al ADA & EASD
2007 Annual Meetings
Exenatide and 1,5 Anhydroglucitol
Comparison of Changes in Values from Baseline to Study End
Correlations: Changes from baseline
1,5-AG vs. HbA1C: r = - 0.74; P <0.0001
1,5-AG vs. fasting plasma glucose (FPG):
r= -0.54; P <0.0001
When grouped as HbA1C change tertiles
patients with larger HbA1C changes from
baseline had larger 1,5-AG changes from
baseline.
1,5 AG changes were more robust than
HbA1C changes
1,5-AG
ug/ml
Percent
Change
A1C %
Kendall D , Holcombe J et al ADA & EASD
2007 Annual Meetings
Exenatide
(5 ug)
Exenatide
(10 ug)
+2.7 +/- 0.6*
+2.9 +/-0.6 **
45.3 +/-11.9
69.4 +/-14.6
-0.5 +/-0.1
-0.9 +/-0.1 **
* P < 0.05; ** P < 0.01
Summary





1,5 Anydroglucitol appears to be a more robust
indicator of glycemic excursions than either HbA1C
or Fructosamine
It is currently FDA-approved and clinically
available; might a home kit be of clinical utility !!??
1,5 AG responds more rapidly and sensitively than
either HbA1C or Fructosamine
1,5 AG may be a useful clinical adjunct and
indicator for monitoring moderately well-controlled
patients with diabetes
More clinical trials are necessary and underway to
explore how effective this tool can be and to define
other areas in which it may be limited or most
helpful
1,5 Anhydroglucitol – Key References
Dungan K et al Diabetes Care 2006 29:1214- 1219
McGill, J. et al. Circulating 1,5 Anhydroglucitol Levels in Adult Patients With Diabetes
Reflect Longitudinal Changes of Glycemia: A U.S. Trial of the GlycoMark assay
Diabetes Care 2004
Buse, J. et al. Serum 1,5-Anhydroglucitol (GlycoMark): A Short-Term Glycemic Marker. Diabetes
Technology and Therapeutics 2003; 5:355-363.
Dworacka M. et al. 1.5-Anhdro-D-glucitol: A Novel Marker of Glucose Excursions. International
J. of Clinical Practice 2002; Supplement 129:40-44 (Eli Lilly Symposium)
Kishimoto M. et al. 1,5-Anhydroglucitol Evaluates Daily Glycemic Excursions in Well-Controlled
NIDDM. Diabetes Care 1995; 18(8):1156-1159.
Matsumoto, K. et al. Effects of Voglibose on Glycemic Excursions, Insulin Secretion, and Insulin
Sensitivity in Non-Insulin-Treated NIDDM Patients. Diabetes Care 1998; 21(2):256-260.
Yamanouchi T. et al. Estimation of Plasma Glucose Fluctuation With a Combination Test of
HbA1c and 1,5-AG. Metabolism 1992; 8: 862-867.
Yamanouchi T. et al. Clinical usefulness of serum 1,5-anhydroglucitol in maintaining glycaemic
control. Lancet 1996;347:1514-1518.
Yamanouchi T. et al. Post-load glucose measurements in oral glucose tolerance tests correlate
well with 1,5-AG in subjects with impaired glucose tolerance. Clinical Science
2001;101:227-233.
Many Thanks To:
 Mary
Kelly RN…Who is asked to do it
all..and succeeds !!
 John Buse
 Kathleen Dungan
 Eric Button
 Shuhei Kato
Questions ??