hemoglobin a1c in the diagnosis and management of diabetes grand... · hemoglobin a1c in the...
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Hemoglobin A1c in the Diagnosis and Management of
Diabetes
Separation Science
Non-enzymaticBiochemistry
DiabetesMonitoring
A1c AssayStandardization
DCCT UKPDS
Ignoring BiologicalVariation in A1c
1.1. Describe what clinical laboratories actually Describe what clinical laboratories actually measure as HbA1cmeasure as HbA1c
2.2. Show that HbA1c and mean blood glucose are Show that HbA1c and mean blood glucose are not interchangeable estimates of glycemic not interchangeable estimates of glycemic controlcontrol
3.3. Explain how biological variation in HbA1c Explain how biological variation in HbA1c complicates new guidelines for the diagnosis complicates new guidelines for the diagnosis and management of diabetesand management of diabetes
ObjectivesObjectives
Main Take-home Message
The quantitative relationship between
blood glucose concentration and
hemoglobin A1c is not the same in all people
MBG = A1c
MBG A1c
(A415 nm)
globins
→
+
Monomers
+
Dimers
↔
Tetramer
Higher Hemoglobin ConcentrationHigher pH
Oxygenation
Globin Association is DynamicMW 15258 15867 31125 62249
Order of affinity Val1 Lys66 Lys61 Lys17 Val1 Lys40 Lys8
Known Glucose Binding Sites
8
17
1
40
61
V--NHNH22 HC=OHC=O׀ ׀
HCOHHCOH׀ ׀
HOCH HOCH ׀ ׀
HCOHHCOH׀ ׀
HCOHHCOH׀ ׀
CHCH22OHOHGlucoseGlucose
++
globinglobin
Non-enzymatic Hb glycation
V--NHNH--CHCH22 ׀ ׀C=OC=O׀ ׀
HOCH HOCH ׀ ׀
HCOHHCOH׀ ׀
HCOHHCOH׀ ׀
CHCH22OHOHStable A1cStable A1c
(ketoamine/Amadori)(ketoamine/Amadori)
Slow 2
V --N=N=CHCH׀ ׀
HCOHHCOH׀ ׀
HOCH HOCH ׀ ׀
HCOHHCOH׀ ׀
HCOHHCOH׀ ׀
CHCH22OHOH
Labile A1cLabile A1c(aldimine/Schiff base)(aldimine/Schiff base)
Rapid 1
+ + HH22OO
MaillardMaillardReactionReaction
Role of lysine and -amino groups
HC=OHC=O׀ ׀
HCOHHCOH׀ ׀
HOCH HOCH ׀ ׀
HCOHHCOH׀ ׀
HCOHHCOH׀ ׀
CHCH22OHOHGlucoseGlucose
++
globinglobin
V--NHNH22
--NHNH22K
Slow 2
--NHNH--CHCH22 ׀ ׀C=OC=O׀ ׀
HOCH HOCH ׀ ׀
HCOHHCOH׀ ׀
HCOHHCOH׀ ׀
CHCH22OHOHAmadoriAmadori
V--NHNH22
K
Schiff baseSchiff base
CHCH׀ ׀
HCOHHCOH׀ ׀
HOCH HOCH ׀ ׀
HCOHHCOH׀ ׀
HCOHHCOH׀ ׀
CHCH22OHOH
N=N=
V--NHNH22
K
Rapid 1+ + HH22OO
1960 1970 1980 1990 2000 2010 20201950
Sickle
Kunkel HG, Wallenius G. New hemoglobin in normal adult blood. Science 122:288, 1955
Discovery of Hemoglobin Heterogeneity
Fast Hb
Morrison M, Cook JL. Chromatographic fractionation of normal adult oxyhemoglobin. Science 122:920-1,1955
Fast HbIRC-50 (Bio-Rex) cation exchange
Fast HbHemoglobin Heterogeneity
in Normal Blood
1960 1970 1980 1990 2000 2010 20201950Identification of Hemoglobin A1c
AI AII
Allen DW, Schroeder, W.A. and Balog, J. J Am Chem Soc 80:1628-34, 1958
IRC-50 (Bio-Rex) cation exchange
Morrison M, Cook JL. Chromatographic fractionation of normal adult oxyhemoglobin. Science 122:920-1,1955
Fast Hb
Fast HbSickle AIc
1960 1970 1980 1990 2000 2010 20201950Identification of Hemoglobin A1c
AI AII
Allen DW, Schroeder, W.A. and Balog, J. J Am Chem Soc 80:1628-34, 1958
AIc
Fast HbSickle
AIc
AIa
AIb
Hemoglobin AI HeterogeneityPeaks designated a, b, c in order of appearance
1960 1970 1980 1990 2000 2010 20201950Identification of Hemoglobin A1c
“The designations, AI, AII and others, are given for
convenience of reference in this discussion. It is not our purpose
to propose a system of nomenclature”
Allen DW, Schroeder, W.A. and Balog, J. J Am Chem Soc 80:1628-34, 1958
AIc
Fast HbSickle
AIc
AIa
AIb
Hemoglobin AI HeterogeneityPeaks designated a, b, c in order of appearance
1960 1970 1980 1990 2000 2010 20201950Identification of Hemoglobin A1c
AIc
Fast HbSickle
Clegg MD, Schroeder WA. J Am Chem Soc 1959;81:6065-9.
Additional heterogeneity of normal hemoglobin
Nomenclature Problem
1960 1970 1980 1990 2000 2010 20201950
Holmquist, W. R. & Schroeder, W. A. A new N-terminal blocking group involving a Schiff base in hemoglobin AIc. Biochemistry 5: 2489-2503, 1966
Chromatography of tryptic peptides
Paper electrophoresis of chromatography fractionsAIcT-1
Fraction 5 of hemoglobin AIc, but not AII, contained chemically modified N-terminal
beta globin peptides
Characterization of Hemoglobin A1c
AIc
Fast HbSickle
1960 1970 1980 1990 2000 2010 20201950
dimers
Globinchains
“The studies described in the present report indicate that a hexose is linked to the N-terminal of the AIc chain - the possible attachment of other structures to the hexose has not been excluded…”
- +
Bookchin, R. M. & Gallop, P. M. Structure of hemoglobin AIc: nature of the N-terminal beta chain blocking group. Biochem Biophys. Res Commun. 32: 86-93, 1968
Characterization of Hemoglobin A1c
AIc
Fast HbSickle
Mass Spectrometry
1960 1970 1980 1990 2000 2010 20201950Hemoglobin A1c Elevated in Diabetes
AIc and Diabetes
Normal
Diabetic
Fetal
Rahbar S. An abnormal hemoglobin in red cells of diabetics. Clinica ChimicaActa 22:296-8, 1968
Fast Hb
L.A. Trivelli et al. Hemoglobin components in patients with diabetes mellitus. N Engl J Med 284 (7):353-357, 1971
Fast Hb Higher in People with Diabetes
AIc
Fast HbSickle
1960 1970 1980 1990 2000 2010 20201950Hemoglobin A1c Elevated in Diabetes
AIc and Diabetes
Koenig RJ et al. Correlation of glucose regulation and hemoglobin AIc in diabetes mellitus. NEJM 1976;295:417-20.
AIccorrelated with blood
glucose
AIc
Fast Hb
L.A. Trivelli et al. Hemoglobin components in patients with diabetes mellitus. N Engl J Med 284 (7):353-357, 1971
Fast Hb Higher in People with Diabetes
Sickle
1960 1970 1980 1990 2000 2010 20201950
Sickle
Hemoglobin A1c Elevated in Diabetes
AIc and Diabetes
Koenig RJ et al. Correlation of glucose regulation and hemoglobin AIc in diabetes mellitus. NEJM 1976;295:417-20.
AIccorrelated with blood
glucose
Blo
od G
luco
se (m
g/dl
)B
lood
Glu
cose
(mg/
dl)
00 1010 2020 3030 4040 5050 6060 7070
100100200200300300400400500500600600700700 Type I DiabetesType I Diabetes
Time (days)Time (days)
Assessing GlycemiaAssessing Glycemia
Blood glucose variation within individuals
AIc
Fast Hb
1960 1970 1980 1990 2000 2010 20201950
Sickle
Hemoglobin A1c Elevated in Diabetes
AIc and Diabetes
Blo
od G
luco
se (m
g/dl
)B
lood
Glu
cose
(mg/
dl)
00 1010 2020 3030 4040 5050 6060 7070
100100200200300300400400500500600600700700 Type I DiabetesType I Diabetes
Time (days)Time (days)
Assessing GlycemiaAssessing Glycemia
Blood glucose variation within individuals
R. J. Jarrett; et al. "Instant" blood sugar measurement using Dextrostix and a reflectance meter. Diabetes. 19 (10):724-726, 1970
AIc
Fast Hb
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
Diabetes
H. F. Bunn; et al. The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 200 (7):21-27, 1978
Two-step model of hemoglobin glycation
Labile A1c Stable A1c
Bunn HF, et al. Further identification of the nature and linkage of the carbohydrate in hemoglobin A1c. Biochem Biophys Res Commun1975;67:103-9
glu
IS
gluman
man?
Gas ChromatographyOf CHO
Characterization of Hemoglobin A1c
AIc
Fast Hb
1960 1970 1980 1990 2000 2010 20201950
Sickle
Diabetes Control and Complications Trial
AIc and Diabetes
H. F. Bunn; et al. The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 200 (7):21-27, 1978
Two-step model of hemoglobin glycation
Labile A1c Stable A1c
D. E. Goldstein, et al. In: Methods in Diabetes Research, edited by J. Larner, S. L. Pohl, and W. L Clarke, New York:Wiley, 1986, p. 475-504
A1c
Bio-Rex 70Cation
Exchange
Labile fraction removed by
RBC incubation in physiological saline >5 h
DCCT
Highly Variable
AIc
Fast Hb
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
Diabetes
D. E. Goldstein, et al. In: Methods in Diabetes Research, edited by J. Larner, S. L. Pohl, and W. L Clarke, New York:Wiley, 1986, p. 475-504
A1c
Bio-Rex 70Cation
Exchange
DCCTFeasibility
The DCCT Research Group. Diabetes Control and Complications Trial (DCCT): results of feasibility study.Diabetes Care 10 (1):1-19, 1987
Labile fraction removed by
RBC incubation in physiological saline >5 h
Wide population variation
7-po
int p
rofil
e se
ts
Diabetes Control and Complications Trial
AIc
Fast Hb
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
DiabetesDCCTFeasibility
The DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. NEJM 1993;329:977-86.
Effect of Intensive ManagementOn Hemoglobin A1c Levels
Development of RetinopathyPrimary Prevention Cohort
Complications
EDIC
Diabetes Control and Complications Trial
AIc
Fast Hb
Clinical Monitoring of Blood Glucose
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
DiabetesDCCTFeasibility Complications
Cation Exchange HPLC
Boronate Affinity Chromatography
Immunoaffinity
AIc
Fast Hb
Commercial Glycated Hemoglobin Assays
D. E. Goldstein, et al. Methods for quantitating glycosylated hemoglobins: high performance liquid chromatography and thiobarbituric acid colorimetry. In: Methods in Diabetes Research, edited by J. Larner, S. L. Pohl, and W. L Clarke, New York:Wiley, 1986, p. 475-504
Bio-Rex 70Cation Exchange
HPLC
Boronate Affinity Chromatography
Immunoaffinity
Non-diabetic
Diabetic
A1c A1c
Labile fraction removed by
RBC incubation in
PBS >5 h
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
DiabetesDCCTFeasibility ComplicationsAIc
Fast Hb
Commercial Glycated Hemoglobin Assays
Cation Exchange HPLC
Boronate Affinity Chromatography
Immunoaffinity
Tosoh A1c 2.2
Khuu et al. Evaluation of a fully automated high-performance liquid chromatography assay for hemoglobin A1c. Arch Pathol Lab Med 123:763-7, 1999
Non-diabeticDiabetic
Good ControlDiabetic
Poor Control
Labile
A1c
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
DiabetesDCCTFeasibility ComplicationsAIc
Fast Hb
Commercial Glycated Hemoglobin Assays
Cation Exchange HPLC
Boronate Affinity Chromatography
Immunoaffinity
|HO-C
|HO-C
|
Vicinal diol
R. L. Garlick; et al. Characterization of glycosylated hemoglobins. Relevance to monitoring of diabetic control and analysis of other proteins. J Clin Invest 71 (5):1062-1072, 1983
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
DiabetesDCCTFeasibility ComplicationsAIc
Fast Hb
Commercial Glycated Hemoglobin Assays
|HO-C
|HO-C
|
Vicinal diol
R. L. Garlick; et al. Characterization of glycosylated hemoglobins. Relevance to monitoring of diabetic control and analysis of other proteins. J Clin Invest 71 (5):1062-1072, 1983
Add mixture ofglycated and non-glycatedhemoglobins
Non-diol hemoglobins pass through (N, non-glycated)
Hemoglobins modified by vicinal diols bind (G, glycated)
Boronate Affinity Chromatography
Doesn’t measure
labile A1c
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
DiabetesDCCTFeasibility ComplicationsAIc
Fast Hb
Commercial Glycated Hemoglobin Assays
Cation Exchange HPLC
Boronate Affinity Chromatography
ImmunoaffinityAntibodies made from
synthetic N-terminal beta globin peptides or purified A1c
chromatography fractions
Doesn’t measure
labile A1c
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
DiabetesDCCTFeasibility ComplicationsAIc
Fast Hb
Commercial Glycated Hemoglobin Assays
Immunoaffinity
A1c
Whatever is present inthe A1c peak;
modified Val1
What do these assays measure?
Whatever is present inthe bound fraction;vicinal diols on any
amino group
Whatever the antibody
recognizes
Cation Exchange HPLC
Boronate Affinity Chromatography
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
Diabetes Feasibility ComplicationsAIc
Fast Hb
National Glycohemoglobin Standardization Program
Cation Exchange HPLC
Boronate Affinity Chromatography
Immunoaffinity
A1c
DCCT NGSP
DCCT Bio-Rex 70 Cation Exchange Reference Method
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
Diabetes Feasibility ComplicationsAIc
Fast Hb
National Glycohemoglobin Standardization Program
DCCT NGSP
MinutesMinutesA
A
415
415
AA22 FF
SS
AA1c1c
AA00
5 6 7 8 9 10 11 12 13 14 150.00
0.02
0.040.04
0.06
0.08cIEFcIEF –– Sickle Cell TraitSickle Cell Trait
1960 1970 1980 1990 2000 2010 20201950
AIc and DiabetesSickle Complications
DCCTFeasibility
CIEF for hemoglobinopathies
Hempe JM, Craver RD. Quantification of hemoglobin variants by capillary isoelectric focusing. Clin Chem 40:2288-95, 1994
A1c
Capillary ElectrophoresisCapillary Electrophoresis
AnodeAnodeBufferBuffer
CathodeCathodeBufferBuffer
Sample Sample InjectionInjection
CapillaryCapillaryOutletOutlet
Detector50 50 µµm i.d.m i.d.27 cm long27 cm long
AutosamplerAutosampler
CapillaryCapillaryInletInlet
High VoltageHigh VoltagePower SupplyPower Supply
++ --
Children’s Hospital Studies
AIc
Fast Hb NGSP
1960 1970 1980 1990 2000 2010 20201950
AIc and DiabetesSickle Complications
DCCTFeasibility
Hempe JM, Vargas A, Craver RD. In: Petersen JR, Mohammad AA, eds. Clinical and Forensic Applications of Capillary Electrophoresis. Totowa, NJ: Humana Press, 2001:145-63
vs DCCT Assay
cIEFcIEF CorrelationCorrelation
0 5 10 15 200
5
10
15
20
25
5 10 15 20 25% % HbHb AA1c 1c (HPLC (HPLC -- Overnight incubation)Overnight incubation)
%
% H
bH
bAA
1c
1c (( c
IEF
cIEF
))
cIEFcIEF18 h incubation18 h incubation
cIEFcIEF6 h incubation6 h incubation
y =1.33x y =1.33x -- 1.401.40rr22=0.95, n=21=0.95, n=21
y =1.07x + 1.28y =1.07x + 1.28rr22=0.94, n=40=0.94, n=40
cIEFcIEF Reference RangeReference Range
Num
ber o
f Obs
erva
tions
Num
ber o
f Obs
erva
tions
% % HbHb AA1c1c
4 6 8 10 12 14 16 18 20 22 240
15
30
45
Correlation studyCorrelation studynn 139139MeanMean 12.7%12.7%
Normal subjects Normal subjects AgeAge >1 y>1 ynn 124124MeanMean 6.8%6.8%SDSD 0.80.8Range Range 5.3 5.3 -- 8.4%8.4%
CIEF for hemoglobinopathiesA1c
Children’s Hospital Studies
AIc
Fast Hb NGSP
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
DiabetesDCCTFeasibility Complications
CIEF for hemoglobinopathies
Comparison of A1c and MBG in
Children
A1c and
A1c
Hemoglobin Glycation Index
AIc
Fast Hb NGSP
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
DiabetesDCCTFeasibility Complications
CIEF for hemoglobinopathies
Comparison of A1c and MBG in
Children
A1c and
A1c
Hemoglobin Glycation Index
AIc
Fast HbFeasibility
The DCCT Research Group. Diabetes Control and Complications Trial (DCCT): results of feasibility study.Diabetes Care 10 (1):1-19, 1987
Wide population variation
7-po
int p
rofil
e se
ts
NGSP
Mean Blood Glucose (mg/dl)Mean Blood Glucose (mg/dl)
% H
bA1c
% H
bA1c
00 100100 200200 300300 400400
AA
551010151520202525
High HGPHigh HGP
Low HGPLow HGP
ModerateModerateHGPHGP
ChildrenChildren’’s Hospital s Hospital Study:Study:
2.3 years2.3 years128 children128 children
Type 1 diabetesType 1 diabetes
HbA1c levels are HbA1c levels are influenced by factors in influenced by factors in
addition to glucoseaddition to glucose
Hemoglobin Glycation Hemoglobin Glycation PhenotypesPhenotypes
Hempe et al. J Diab Comp 16:313,2002
BB
551010151520202525
Three individual patients
Hemoglobin Glycation IndexHemoglobin Glycation IndexHGI = Observed HGI = Observed -- Predicted HbA1cPredicted HbA1c
Predicted HbA1c = (MBG Predicted HbA1c = (MBG ×× slope) + interceptslope) + intercept
Mean Blood Glucose (mg/dl)Mean Blood Glucose (mg/dl)
% H
bA1c
% H
bA1c
00 100100 200200 300300 400400 500500 600600
5510101515202025253030
HGI=0HGI=0
HGI<0HGI<0
HGI>0HGI>0
Mean Blood Glucose (mg/dl)Mean Blood Glucose (mg/dl)
% H
bA1c
% H
bA1c
00 100100 200200 300300 400400
AA
55
1010
1515
55
1010
1515BB High HGPHigh HGP
Low HGPLow HGP
n=1441n=1441
Diabetes Control and Complications Trial (DCCT)Diabetes Control and Complications Trial (DCCT)
--2.22.2 --1.21.2 --0.20.2 0.80.8 1.81.8 2.82.800
5050
100100
150150Low HGPLow HGP
Moderate HGPModerate HGP
High HGPHigh HGP
HGIHGIFr
eque
ncy
Freq
uenc
y
Hypothesis: High HGP patientsHypothesis: High HGP patientsare more susceptible toare more susceptible tomicrovascular complicationsmicrovascular complications
Three individual patients
First 100 patients
ModerateModerateHGPHGP
Diabetes Control and Complications Trial (DCCT)Diabetes Control and Complications Trial (DCCT)
0.020.02
0.040.04
0.060.06
0.080.08
0.100.10NephropathyNephropathy
Ris
k Pr
obab
ility
Ris
k Pr
obab
ility
00 11 22 33 44 55 66 77
Years of FollowYears of Follow--upup
0.050.050.100.100.150.150.200.200.250.250.300.300.350.35
RetinopathyRetinopathy
--2.22.2 --1.21.2 --0.20.2 0.80.8 1.81.8 2.82.800
5050
100100
150150Low HGPLow HGP
Moderate HGPModerate HGP
High HGPHigh HGP
HGIHGIFr
eque
ncy
Freq
uenc
yConclusion: HGI reflects Conclusion: HGI reflects biological variation in A1c and biological variation in A1c and complications risk due to factors complications risk due to factors other than mean blood glucoseother than mean blood glucoseMcCarter et al. Diabetes Care 27: 1259, McCarter et al. Diabetes Care 27: 1259, 20042004
HGI and Biological Variation in A1cStudy Reference Patients A1c Blood glucose
Children’s Hospital
JDC 2002 Type 1 children
CIEF MBG - 30 d meter data
DCCT Diabetes Care 2004
Type 1 adults
BioRex HPLC
MBG - 7 pt profile set
UKPDS ADA 2005
Type 2 adults
BioRad HPLC
Fasting glucose
DirecNet Diabetes Care 2007
Type 1 children
NGSPImmunoassay
MBG - CGM
Children’s Hospital
Pediatric Diab 2010
Type 1 children
NGSPImmunoassay
MBG – Raw meter data
100
150
200
250
300
100
150
200
250
300 MBG
6789
101112 A1C
6789101112
%
m
g/dl
Sequential Clinic Visits
ModerateLow High
-4
-2
0
2
4 HGI
-4
-2
0
2
4
%
Soros AA, Chalew SA, McCarter RJ, Shepard R, Hempe JM. Hemoglobin glycation index: a robust measure of hemoglobin A1c bias in pediatric type 1 diabetes patients. Pediatric Diabetes 11:455-461, 2010
1960 1970 1980 1990 2000 2010 20201950
SickleAIc and
DiabetesDCCTFeasibility Complications
CIEF for hemoglobinopathies
HGI
Hemoglobin Glycation Index
AIc
Fast Hb
A1c
IFCCNGSP
Diabetes Care 30(9):2399-2400, 2007
1. The NGSP cation exchange reference A1c method is non-specific2. The IFCC developed a mass spectrometry based reference method
that quantifies N-terminal hexapeptides of globin modified by glucose
3. IFCC standardized results were 25% lower than NGSP standardized results
4. Recommended reporting A1c in mmol A1c/mol of Hb5. And since MBG = A1c, consider reporting A1c as “estimated
average glucose” - eAG
AG
(mg/
dl)
Nathan DM, Kuenen J, Borg R, Zheng H, Schoenfeld D, Heine RJ. Translating the A1C Assay Into Estimated Average Glucose Values. Diabetes Care 31:1-6, 2008
HbA1c (%) Average of 4 different assays
CG
M +
SM
BG
AG (mg/dl) = 28.7 x HbA1c – 46.7r2 = 0.84, p < 0.0001
Underlying assumption: A1c is related to MBG the same way in all people
Diabetes Care 31:1-6, 2008
Diabetologia 51:904, 2008
Brick, J. C. et al. (2009) A Randomized Comparison of the Terms Estimated Average Glucose Versus Hemoglobin A1C. Diabetes Educ. 35: 596-602.
eAG does not improve patient understanding
of diabetes management
Low Moderate High75
100
125
150
175
200
225
250 MBGeAG
HGI Group
mg/
dl
eAG<MBGunderestimates
eAG = 28.7 A1c - 46.7
eAG=MBG
eAG>MBGoverestimates
Hempe, J.M., Soros, A.A. & Chalew, S.A. Diabetes Care 33:1449, 2010
A1c 6% = eAG of 126
Low Moderate High75
100
125
150
175
200
225
HGI Group
4
5
6
7
8
9
10MBGA1c
MB
G (m
g/dl
)
A1c (%
)
Failure to reachtarget MBG Exceed target
MBG/risk forhypoglycemia
American Diabetes Association. Standards of medical care in diabetes--2010. Diabetes Care 2010;33 Suppl 1:S11-S61.
Low Moderate High75
100
125
150
175
200
225
HGI Group
4
5
6
7
8
9
10MBGA1c
MB
G (m
g/dl
)
A1c (%
)
Failure to reachtarget MBG Exceed target
MBG/risk forhypoglycemia
Low Moderate High75
100
125
150
175
200
225
HGI Group
4
5
6
7
8
9
10MBGA1c
MB
G (m
g/dl
)
A1c (%
)
Failure to reachtarget MBG Exceed target
MBG/risk forhypoglycemia
American Diabetes Association. Standards of medical care in diabetes--2010. Diabetes Care 2010;33 Suppl 1:S11-S61.
American Diabetes Association. Standards of medical care in diabetes--2010. Diabetes Care 2010;33 Suppl 1:S11-S61.
Diabetes Care 32 (7):1327-1334, 2009
Non-proliferative retinopathy graded by fundus photography(n=28,000 from 9 countries)
van 't Riet E.; et al. Relationship between A1C and glucose levels in the general Dutch population: the new Hoorn study. Diabetes Care 33 (1):61-66, 2010.
NG
DiabetesBoth
DiabetesOGTT
DiabetesA1c
NG
DiabetesBoth
DiabetesFPG
DiabetesA1c
van 't Riet E.; et al. Relationship between A1C and glucose levels in the general Dutch population: the new Hoorn study. Diabetes Care 33 (1):61-66, 2010.
NG
DiabetesBoth
DiabetesOGTT
DiabetesA1c
NG
DiabetesBoth
DiabetesFPG
DiabetesA1c
Hypoglycemia
Hyperglycemia
Coma and Death
Microvascular and Macrovascular Disease
Acute Chronic
InsulinMetformin + sulfonylureas
Hypoglycemia
Currie CJ, et al. Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study. The Lancet 2010;In Press, Corrected Proof.
Diabetes Care 33:1025-1027, 2010
Clinical Research Basic Research
Hemoglobin Analysis
Analysis of Existing
Clinical Trial Data
Prospective Diabetes
Study
Mechanisms of Non-enzymatic
Hemoglobin Glycation
Mouse Model of
Hemoglobin Glycation
Best way to use HGI and
hemoglobin assays to
improve patient care
HGI association with clinical phenotype
and outcome in large populations
Quantitative in vitro bioassay of non-
enzymatic hemoglobin
glycation
In vivo assessment of factors that influence non-
enzymatic hemoglobin
glycation
Development of multidimensional hemoglobin separation techniquesIdentification of chemical modifiers
Translational Research Program
1.1. Describe what clinical laboratories actually Describe what clinical laboratories actually measure as HbA1cmeasure as HbA1c
2.2. Show that HbA1c and mean blood glucose are Show that HbA1c and mean blood glucose are not interchangeable estimates of glycemic not interchangeable estimates of glycemic controlcontrol
3.3. Explain how biological variation in HbA1c Explain how biological variation in HbA1c complicates new guidelines for the diagnosis complicates new guidelines for the diagnosis and management of diabetesand management of diabetes
ObjectivesObjectives
1.1. MBG MBG A1cA1c2.2. Consider both MBG and A1c for more Consider both MBG and A1c for more
personalized patient carepersonalized patient care3.3. Even expert committee recommendations Even expert committee recommendations
should be taken with a grain of saltshould be taken with a grain of salt
ConclusionsConclusions
SS Medical-Industrial Complex
It Takes a Long Time to Change Course
FundingFundingChildrenChildren’’s Hospital RICs Hospital RICADA, JDRF, ADA, JDRF, P & C Carroll FoundationP & C Carroll Foundation
StudentsStudentsAmanda McGeeheeAmanda McGeeheeRachel ShepardRachel ShepardAllyson BazarskyAllyson BazarskyThanksThanksChildrenChildren’’s Hospital Labs Hospital LabEndocrine NursesEndocrine Nurses
CollaboratorsCollaboratorsStuart Chalew, M.D.Stuart Chalew, M.D.Bob McCarter, Sc.D.Bob McCarter, Sc.D.Alfonso Vargas, M.D.Alfonso Vargas, M.D.Ricardo Gomez, M.D.Ricardo Gomez, M.D.Randal Craver, M.D.Randal Craver, M.D.Arlette Soros, M.D.Arlette Soros, M.D.
"An important scientific innovation rarely makes its way by gradually winning over and converting its opponents. What does happen is that its opponents gradually die out and that the growing generation is familiar with the idea from the beginning."
Max Planck1858-1947