dr. rafn benediktsson the diagnosis of diabetes rests on glucose values * should be confirmed on a...

Dr. Rafn Benediktsson

The Diagnosis of Diabetes rests on Glucose Values

Fastings- glucose

2h s- glucose(75g OGTT)

Normal < 6,0 < 7,7

Impaired Fasting Glucose 6,1 – 6,9

Impaired Glucose Tolerance 7,8 – 11,0

Diabetes* > 7,0 > 11,1

* should be confirmed on a second occasion


Type 2 Diabetes: DevelopmentType 2 Diabetes: Development

Adapted from Saltiel AR, Olefsky JM. Diabetes 1996;45:1661-1669.

Insulin resistance and declining insulin levels Insulin resistance and declining insulin levels with impaired glucose tolerancewith impaired glucose tolerance

Insulin resistance and declining insulin levels Insulin resistance and declining insulin levels with impaired glucose tolerancewith impaired glucose tolerance

Type 2 DiabetesType 2 Diabetes

Insulin resistanceInsulin resistanceInsulin resistanceInsulin resistance

Insulin resistance and hyperinsulinaemia with

normal glucose tolerance

Insulin resistance and hyperinsulinaemia with

normal glucose tolerance

Impaired Impaired -cell function-cell functionImpaired Impaired -cell function-cell function


What is Insulin Resistance?What is Insulin Resistance?

• An impaired biological response to An impaired biological response to either exogenous or endogenous insulineither exogenous or endogenous insulin

• Biological responses could reflect:Biological responses could reflect:– metabolicmetabolic (CHO, lipid or protein metabolism) (CHO, lipid or protein metabolism)

and and – mitogenicmitogenic processes processes

(changes in growth, differentiation, DNA (changes in growth, differentiation, DNA synthesis, regulation of gene transcription)synthesis, regulation of gene transcription)

Anonymous. Diabetes Care 1998; 21:310-314.


Insulin Resistance: Associated ConditionsInsulin Resistance: Associated Conditions

Atherosclerosis

Type 2 diabetesImpaired

glucose tolerance

Polycysticovarian syndrome

Obesity (central)

Dyslipidaemia Hypertension

Microalbuminuria

Hyperuricemia

Decreasedfibrinolytic activity

InsulinResistance


Risk Ratios of CV Events in Adultswith Diabetes Age 35-64

0

5

10

Total CVD CHD Cardiac Failure IntermittentClaudication

Stroke

Men

Women

3

1.8

6.1

2.8 2.8

4 3.9

9.89.1

1.9

Adapted from Wilson & Kannel. In Ruderman et al. Hyperglycaemia, Diabetes and Atherosclerosis 1992:21

†

†

†

†

†

†

*

††

† p <0.001 *p < 0.05

Ris

k R

ati o


Drug Treatment in T2DM

Glucose (G)

Carbohydrate

GlucoseDIGESTIVE ENZYMES

Insulin(I)

I

I

I

II

I

I

I

G

G

G

G

G

G

G

GI

G

G

G

AcarboseReduces absorption

SulphonylureaRepaglinide

Stimulates pancreas

MetforminReduces hepatic glucose output

(? muscle / fat effects)

Insulin“Replaces” pancreas


Lowering HbA1C Reduces Risk of Complications*

UKPDS. Lancet 1998; 352:837

*Percent risk reduction for 0.9% decrease in HbA1C

-40

-35

-30

-25

-20

-15

-10

-5

0

Re

du

cti

on

in

Ris

k (

%)

Any diabetesrelated endpoint

Microvascularendpoint

MI

Cataractextraction

Retinopathy

Albuminuria at12 years

-12

-25

-16

-24-21

-34

p=0.029

p=0.009

p=0.052

p=0.046p=0.015

p=0.00005


UKPDS: Value of Good Blood Pressure Control in T2DM

0%

5%

10%

15%

20%

25%

0 3 6 9

Years from randomisation

Tight Blood Pressure Control (758)

Less Tight Blood Pressure Control (390)

risk reduction37% p=0.0092


36

2823

18

0

5

10

15

20

25

30

35

40

Placebo Gemfibrozil Placebo GemfibrozilPatients with Diabetes

n=627, P=0.05Patients without Diabetes

n=1904, P=0.009

24%Risk Reduction

24%Risk Reduction

% of Patients with CHD Death, Nonfatal MI, or Stroke % of Patients with CHD Death, Nonfatal MI, or Stroke

VA - HIT Study: Effect of Gemfibrozil on Vascular Events - 5.1 Years

Rubins HB, et al. N Engl J Med 1999;341:410

% D

evel

op

ing

a C

V E

ven

t


Drug Treatment in T2DM

Glucose (G)

Carbohydrate

GlucoseDIGESTIVEENZYMES

Insulin(I)

II

I

II

I

I

I

G

G

G

G

G

G

G

GI

G

G

G

AcarboseReduces absorption

SulphonylureaRepaglinide

Stimulates pancreas

MetforminReduces hepatic glucose output

(? muscle / fat effects)

Insulin“Replaces” pancreas

Thiazolidinediones(TZD)


TZD = thiazolidinedionePPAR - RXR = nuclear receptorsTF = transcription factors

TZD: Mechanism of Insulin Sensitization

TZD

PPAR RXR

PPAR RXR

TZDTF

RNA

DNA

Protein– signalling– downstream events

RECEPTOR

INSULIN

Saltiel & Olefsky. Diabetes 1996;45:1661


Rosiglitazone Enhances Insulin Action by Modulating Tissue Lipid Supply

Rosiglitazoneand Insulin

PPAR

Preadipocyte

Adipocyte

IncreasedDifferentiation

Reversal of TNF-InducedInsulin Resistance

Increased Insulin Sensitivity and Capacity for Glucose Disposal/Lipid Storage

Reduced Lipolysis, Glycerol, & FFAs

Availability

Skeletal Muscle

Liver

Euglycemia

IncreasedGlucose Disposal

ReducedHepatic Glucose Output

PPAR

GLUT-4

TG


Effect of Pioglitazone on Insulin Resistance (HOMA R)

-12.4

30.3

-15

-5

5

15

25

35

Ch

ang

e (%

)

placebo (n=81)

pioglitazone 30 mg(n=96)

Baseline IR: placebo 10.1, pioglitazone 30 mg 9.8* p = 0.0002 vs baseline† p = 0.0001 vs placebo

Rosenstock I, et al. Diabetologia 2000;43(suppl 1):A738

30.3*

†


Before After p-value

Body weight (kg) 82 85 < 0.01

Fat mass (kg) 24 29 < 0.01

Subcu fat area (cm2) 300 342 < 0.01

Visc fat area (cm2) 144 131 < 0.05

V/S ratio 0.59 0.44 < 0.01

Effect of Pioglitazone on Abdominal Fat Distribution

Miyazaki Y et al. Diabetes 2000;49(SI);A299.


TRIPOD: Buchanan et al. Diabetes 2001;50(S2):A327

Placebo for 30 months

Troglitazone for 30 months

235 Latino womenwith GDMA

% w

ith d

iab

ete

s

0

4

8

12

16

20

Placebo Troglitazone

B Observ. for8 mo.: OGTT


PCOS: Improvement in hirsutism by troglitazone

% change in F

G score

PBO TGZ150 TGZ300 TGZ600

-20-18-16-14-12-10-8-6-4-2024

Azziz et al JCEM 2001;86:1626

*


LOCF* p0.05 vs. placebo

-13.6

4.6

9.5

1.62.1

11.5

1.2

- 15.1-20

-10

0

10

20 Glycaemic Non-Responders (45 mg)

Total Cohort (45 mg)

from placebo at 26 weeks

HDL Cholesterol LDL CholesterolTriglycerides Total Cholesterol

(%)

Baseline (mmol/L) 3.281.056.272.93

**

2.66 5.45 1.07 3.29

*

Effect of Pioglitazone on Serum Lipids Effect of Pioglitazone on Serum Lipids Effects by Glycaemic ResponseEffects by Glycaemic Response

Takeda Pharmaceuticals America, Inc., data on file, study 001


Inflammation: Effect of rosiglitazone on CRP

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

CR

P %

Ch

an

ge

fro

m b

as

elin

e a

t 2

6w

Placebo

Rosiglitazone

N = 357, treatment for 26 weeks

Greenberg et al @ EASD 2001


PPAR activators inhibit migration of VSMC

0

50

100

PDGF

% o

f mig

ratio

n c

ompa

red

to P

DG

F-B

B

- + ++

5 µM

troglitazone

10 µM

Marx et al.; Circ Res 1998; 83: 1097-1103


Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human subcutaneous adipocytes

30

40

50

60

70

80

90

100

110

0,1 1 10 100 1000

PA

I-1

secr

etio

n [

ng

/ml]

Insulin

Insulin + Rosi

CTRL

Insulin [nM]

Mcternan @ EASD 2001


Nitric oxide synthaase inhibition decreases the increased insulin action by piogllitazone in the fructose–fed rat

3 mU/kg/min insulin iv

Glucose disposal rate [m

g/kg/min] 0

2

4

6

8

10

12

STD FRUCT FRUCT FRUCT

PIOGLITAZONE

L-NMMA ++ +-

--

- -Koshinaka @ EASD A98


The ischaemic obese Zucker rat heart

0

0,2

0,4

0,6

0,8

1

1,2

Lean Rosi Lean

Obese RosiObese

Glu

co

se

up

tak

e

*

Sidell @ EASD 2001


Rosiglitazone reduces atherosclerosis in ApoE KO mice

Benson et al @ EASD 2001

potential antiatherogenic effects

potentialproatherogenic effects

VCAM-1, endothelin

IL-6, prostaglandin,

COX-2

apoptosis Tissue factor, TNF-

ECs

SMCs

Mo / MØ

CXC chemokines,

endothelin, PAI-1ECs

SMCs

Mo / MØMMP-9; cytokines,

SR A,I-NOS

PAI-1

migration, MMP-9,

Ang-II-receptor

NO production

CD 36Foam cell formation

apoptosis

MCP-1, IL-8

PPAR

PPAR

ECs

SMCs

Mo / MØ

ECs

SMCs

Mo / MØ

TH-1 cytokines T-cells


Niðurstaða

• Thiazolidinedione lyf eru leyfð á Íslandi sem meðferð við sykursýki

• Eingöngu sem viðbót við eitt annað per os blóðsykurlækkandi lyf

• TZD lyf ráðast að kjarna málsins – Insúlín viðnám – og þannig á ýmsa áhættuþætti hjarta og æðasjúkdóma

• In-vitro rannsóknir og dýratilraunir gefa vísbendingar um að TZD lyf geti hugsanlega tafið nýmyndun og framgang atherosclerosis

• Ekki eru til klínískar mannarannsóknir á áhrifum TZD á atherosclerosu eða dánartíðni !

dr. rafn benediktsson the diagnosis of diabetes rests on glucose values * should be confirmed on a...

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