• Genes

• Autoantibodies

• HbA1c

• Signal

Transmitter

• Receiver

Transducer

100

200

300

400

500

00 1 2 3 4 5

Insulin Sensitivity

AIR

(U

/mL)

Changes in Insulin Secretion and Sensitivity

100

200

300

400

500

00 1 2 3 4 5

Insulin Sensitivity

AIR

(U

/mL)

Changes in Insulin Secretion and Sensitivity

Insulin Treatment

Metabolic Syndrome

Mutated KATP channel fails to close in

response to increased ATP which decreases

insulin secretion

ATP

ATP does not lead to

KATP channel closure

Membrane

Hyperpolarised

No insulin secretion

No calcium influx

Slide

Helix

OutsideSelectivity

Filter

Site of Kir6.2 mutations associates

with phenotypeATP-binding site: isolated PNDM Gating/pore: neurological features

V59

R50R201Y330

Inside

Membrane

I296

Haider, Sansom and Ashcroft

ATP

Q52

MODY

11%

MODY x

75%

Transcription factors22%

Glucokinase

2%

HNF1

61%

HNF14%

HNF4

<1%

IPF1

The Genetic Causes of MODY

Ellard, Frayling et al Diabetes 2001

<1%

NeuroD1

-7

-6

-5

-4

-3

-2

-1

0

1

p<0.0001

Gliclazide Metformin

Change

in fasting

plasma

glucose

with

treatment

(mmol/l)

HNF1

MODYType 2HNF1

MODYType 2

Gliclazide

Metformin

HNF1 patients respond better to

Gliclazide than Type 2 patients

Pearson et al Lancet 2003

0

50

100

Cumulative prevalence of diabetes

0 20 40 60 80

100

50

0

Type 1 Type 2

% %

Age at onset (years)

LADA

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

T1D in children

T1D in adults

LADA

InsulinImmunity BMIAge Genes

ction

ADA

Adult-onset diabetes (age 30 – 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 PhenotypeType 1 Diabetes

• Adult-onset

• Non-insulin requiring.

Type 2 Diabetes

• Adult-onset

• Non-insulin requiring.

UKPDS: Need for insulin treatment

100

80

60

40

20

0

0 1 2 3 4 5 6

Years from diagnosis

Ab-ve

GAD +ve

GAD +ve

ICA +ve

Turner et al 1997

%

Microvascular

complications

Myocardial infarction

HbA1c

37%

14%

Lowering HbA1c reduces the risk of

complications (UKPDS)

Deaths related to

diabetes21%

1%

Stratton IM, et al. BMJ 2000; 321:405–412.

Re

lative

Ris

k

Retinopathy

Nephropathy

Neuropathy

Microalbuminuria

HbA1c (%)

15

13

11

9

7

5

3

16 7 8 9 10 11 12

Skyler. Endocrinol Metab Clin 1996;25:243–254

DCCT: HbA1c and risk of microvascular

complications

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=327UKNEQAS 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

HbA1c (%)

0

2

4

6

8

10

12

14

16

18

3 4 5 6 7 8 9 10 11 12 13

calcAG = 1.58x -2.52

R2=0.84

n=427

Acceptability of Data

HbA1c (%)

0

2

4

6

8

10

12

14

16

18

3 4 5 6 7 8 9 10 11 12 13

90% of

values

fall in this

range

calcAG = 1.58x -2.52

R2=0.84

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

O2-

PKC

O2-

NAD(P)H

oxidase

Peroxynitrite

NF-kB

iNOS eNOS

NO

DNA damage

Endothelial disfunction

Polyol Pathway

AGE Formation

Hexosamine Flux

Diabetic

Complications

Mitochondria

Glycated protein

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