• Genes • Autoantibodies
• HbA1c
• Signal Transmitter • Receiver Transducer
Changes in Insulin Secretion and Sensitivity
500
AIR ( U/mL)
400
300
200
100
0
0
1
2
3
Insulin Sensitivity
4
5
Changes in Insulin Secretion and Sensitivity
500
AIR ( U/mL)
400
Insulin Treatment
300
200
Metabolic Syndrome
100
0
0
1
2
3
Insulin Sensitivity
4
5
Mutated KATP channel fails to close in response to increased ATP which decreases insulin secretion ATP does not lead to KATP channel closure
Membrane Hyperpolarised
No calcium influx
No insulin secretion
ATP
Site of Kir6.2 mutations associates with phenotype ATP-binding site: isolated PNDM
Selectivity Filter
Slide Helix
ATP
Gating/pore: neurological features
Membrane Outside
I296 V59 Q52
Inside
R50 R201 Y330
Haider, Sansom and Ashcroft
The Genetic Causes of MODY MODY
22% Glucokinase
75% Transcription factors
61% 4% 2% HNF1 HNF4 HNF1
11% MODY x
<1% <1% IPF1 NeuroD1
Ellard, Frayling et al Diabetes 2001
HNF1 patients respond better to Gliclazide than Type 2 patients 1
Change in fasting plasma glucose with treatment (mmol/l)
0
HNF1 Type 2 MODY Gliclazide
HNF1 Type 2 MODY Metformin
-1 -2 -3
Metformin
-4 -5
Gliclazide -6 -7
p<0.0001
Pearson et al Lancet 2003
Cumulative prevalence of diabetes 0
100
Type 1
Type 2
% 50
% 50
100
0
LADA 0
20
40 Age at onset (years)
60
80
Latent Adult onset Autoimmune Diabetes (LADA) • Age at diagnosis 30 - 70 years. • Diabetes-Associated Autoantibody positive.
• Treatment without insulin for 6 months.
Autoimmune Diabetes Spectrum Immunity T1D in children
T1D in adults
LADA
Age
Genes
BMI
Insulin
ction ADA Adult-onset diabetes (age 30 â&#x20AC;&#x201C; 70 years) (n=6,136) GADA positive 538 (8.8%) : T1DM (n=109)
(20.2%)
LADA (n=277)
(51.5%)
Unclassified (n=152) (29.3%)
GADA negative 5, 598 (91.2%)
Usual Clinical Phenotype Type 1 Diabetes • Adult-onset • Non-insulin requiring. Type 2 Diabetes • Adult-onset • Non-insulin requiring.
UKPDS: Need for insulin treatment
% 100 Ab-ve 80 60
GAD +ve
40 GAD +ve ICA +ve
20 0 0
1
2
3
4
5
6
Years from diagnosis Turner et al 1997
Lowering HbA1c reduces the risk of complications (UKPDS) 21%
Deaths related to diabetes
37%
Microvascular complications
HbA1c 1%
14%
Myocardial infarction
Stratton IM, et al. BMJ 2000; 321:405â&#x20AC;&#x201C;412.
DCCT: HbA1c and risk of microvascular complications Retinopathy
15
Nephropathy
Relative Risk
13
11 9
Neuropathy
7 5 Microalbuminuria
3 1 6
7
8
9 10 HbA1c (%)
11
12
Skyler. Endocrinol Metab Clin 1996;25:243â&#x20AC;&#x201C;254
HbA1c in DCCT ACCOUNTS FOR ONLY:
•
11%
OF THE MICROVASCULAR RISK
Mean Plasma Glucose vs. HbA1c
Rohlfing CL et al Diabetes Care. 2002 ;25:275-8
Between instrument imprecision
Mean 7.89%, SD 0.27%, n=327
UKNEQAS Dec 2007
Standardisation of HbA1c
National Glycohemoglobin Standardization Program
DCCT vs. IFCC HbA1c DCCT HbA1c (%) 6 7 8 9 10
IFCC HbA1c (mmol/mol) 42 53 64 74 85
Mean Plasma Glucose vs. HbA1c
Rohlfing CL et al Diabetes Care. 2002 ;25:275-8
The appeal of eAG • Patients with diabetes can converse with clinicians in a common ‘currency’ • Especially if they self-monitor their BG • Clinicians are also already familiar with the concept of eGFR and estimated LDL
Acceptability of Data n=427
18
calcAG = 1.58x -2.52 R2=0.84
16 14 12 10 8 6 4 2 0
3
4
5
6
7
8
HbA1c (%)
9
10
11
12
13
Acceptability of Data 18
calcAG = 1.58x -2.52 R2=0.84
16
90% of values fall in this range
14 12 10 8 6 4 2 0
3
4
5
6
7
8
HbA1c (%)
9
10
11
12
13
Biological variation in HbA1c • • • • •
Not all individuals with the same mean glucose levels have the same HbA1c. Race and age associated with higher HbA1c. Variation in red blood cell half life (0.9% HbA1c). Heritability of HbA1c (62 – 74%). Hexokinase associated with HbA1c in genome study.
Hyperglycemia Mitochondria Glycated protein
Polyol Pathway AGE Formation
O2PKC
Hexosamine Flux NF-kB
iNOS NAD(P)H oxidase
eNOS
NO
O2-
Peroxynitrite
DNA damage
Endothelial disfunction
Diabetic Complications
Worldwide standardisation?
Conclusion • ‘Worldwide Standardisation’ is forcing us to choose the way we report HbA1c. • Different countries seem likely to make different choices. • HbA1c and eAG are not interchangeable.
• Genes • Autoantibodies
• HbA1c