igf-systemet som diagnostiskt hjälpmedel kerstin brismar inst för molekylär medicin ...€¦ ·...

IGF-Systemet som diagnostiskt hjälpmedel

Kerstin Brismar

Inst för molekylär medicin och kirurgi,

Karolinska Institutet

kerstin.brismar@ki.se 21 sept 2017

First publications

IGF-I Kerstin Hall et al 1972

IGFBP-1 Kerstin Hall et al 1984

Why this difference?

Gillian has too little IGF-I activity due to the diet

which leads to premature aging in skin, bone,

heart and brain

Nigella has higher IGF activity due to her diet

which increases the risk for cancer and T2DM

IGF-I

Insulin-like Growth Factor-I

Effects

Growth Metabolism

Differentiation Antioxidant

Cell survival

Healing

IGF-1

Markör för: Anabolism/katabolism

Tillväxt

GH-sekretion

Nutritionsstatus

Insulinsekretion

IUGR (intrauterin tillväxthämning)

Före och efter operation

För mycket IGF-I = akromegali

IGF-I

IGFBP-1

Insulin

Stress

Fasta

Östradiol/

ProgesteronAminosyror

Hypoxi

Glukagon

Cytokiner

GH

Insulin

Testosteron/DHEA

Fasta

Cytokiner

Aminosyror ++

+

+

+

++ +

+

_

_

_

_

_

+

Association of IGF-I with diseases

IGF-I

Insulin

Inflammation

Cancer

CVD

Diabetes

compl. DM

When and why is IGF-I important in clinical diagnosis

and treatment?

Marker of GH activity

Marker of nutrition

Marker of anabolism

Marker of insulin activity

Riskmarker for cancer

Riskmarker of CVD and

diabetes

The Insulin-like Growth Factor Bindingproteins

are needed to control IGF activity

IGFBP-1-6

What is IGFBP-1?Insulin-like growth factor binding protein-1

A protein which is mainly produced in the

liver mainly regulated by insulin, which inhibit

the production

IGFBP-1: Bildas i levern

Produktionen regleras av insulin (hämmas), av

stresshormoner och cytokiner (ökar)

Är måltidsberoende – varierar under dygnet

Reglerar effekten av IGF-1

Transporterar IGF-1 till målcellerna

Har egna effekter, bl a av betydelse för reparation av

vävnadsskador, stimulera cellmigration (chemotaxi)

N NO syntes= kärlreaktivitet

IGFBP-1Insulin-like Growth Factor Binding Protein-1

Effects

IGF-dependent IGF-independent

pIGFBP inhibits IGF effects Stimulate cell migration

npIGFBP enhances IGFeffects and proliferation, NOsyntes

IGF-I

IGFBP-1

Insulin

Stress

Fasta

Östradiol/

ProgesteronAminosyror

Hypoxi

Glukagon

Cytokiner

GH

Insulin

Testosteron/DHEA

Fasta

Cytokiner

Aminosyror ++

+

+

+

++ +

+

_

_

_

_

_

+

IGFBP-1

Markör för: Fritt IGF-1

Insulinsekretion

Insulinresistens

Glukostolerens

Leverresistens

Metabola syndromet

Nutritionsstatus

Inflammation

Endotelfunktion

Riskmarkör för typ 2 diabetes, CVD, cancer

IGFBP-1

a surrogate marker for IGF-1

IGFBP-1 is a marker of diurnal insulin

secretion and response to glucose

IGFBP-1 can predict type 2 diabetes

Risk of type 2 diabetes within 8-10 yes(OR)

Glu > 5.1 mmol/L

BMI > 28.5

M/L > 5

cm2/m/1000

Insulin > 150 M

> 90 w

IGFBP-1 < 11 M

< 26 w

Good correlation between biological

marker and response to a risk score

43

34

27

0

5

10

15

20

25

30

35

40

45

50

Low, n=143 Slightly Elevated, n=121 Moderate to High, n=51

IGFB

P-1

(m

icro

g/l)

FINDRISC Group

IGFBP-1 och FINDRISC

p=0.01

p <0.0001

Changes in serum IGF-1 and IGFBP-1 after 6 months of life style intervention

in 160 middle-age men

2 October 2017Kerstin Brismar 45

Journal of Internal Medicine, 1995, 238:121-130

2 October 2017 Kerstin Brismar 46

IGFBP-1 before and after bariatric surgery by gender

IGFBP -1 and IGF-I are markers of

catabolism/malnutrition

IGFBP-1 is a marker of hepatic insulin

resistance

IGFBP-1 is a marker of insulin

insufficiency

DM type 2

IGFBP-1 avgör bästa behandl

IGFBP-10

HbA1c

Insulin treatment

Per oral treatment (OHA)

Jonas Tovi, Thesis 1998

IGF-I and IGFBP-1 can predict late

diabetes complications

New riskfactor for diabetes complications

• High IGFBP-1– death after MI

• High IGFBP-1- instable plaque

• High IGFBP-1– neuropathy

• High IGFBP-1- retinopathy

• High IGFBP-1 - nephropathy

Wallander et al. In press Diabetes Care 2007

Kaplan-meier – IGFBP-1

tertiles – cv death

Sudden death (n=15)

Index infarction (n=16)

Reinfarction (n=9)

CHF (n=5)

Stroke (n=2)

Other (n=3)

Association of IGFBP-1 with diseases

IGFBP-I

Diabetes

complications

Cancer

CVD

DM

Insulin

• Free IGF-I is regulated by IGFBP-1

• IGFBP-1 is a surrogate marker for free IGF-1

• IGFBP-1, high level, is a marker for diabetes complications: microangiopathy, neuropathy and morbidity and mortality after MI in type 2 diabetes

• IGFBP-1 is a marker for endothelial function and low level a risk marker for atherosclerosis in the metabolic syndrome and CVD

• IGFBP-1 is a marker for changes in insulin sensitivity after increased physical activity

• IGFBP-1 is a marker for insulin sensitivity in the liver

• IGFBP-1, low level, is a risk marker for future type 2 DM

Diabetologia 2006, 2008, Diab and Metabol 2009, JCEM 2008, Diabetes Care 2007, 2009

Insulin

Insulinresistens

Sug / Begär

KolhydraterGlukos / Stärkelse

Hjärnan Inflammation

(leptin resistens)

( ACTH GH FSH/LH)

Midja/InflammationFettmassa

PCOS

Hyperkoagulation

Demens

( amyloid)

Tg / FFA

Fettlever

Hjärt-kärlsjukdom

Njursjukdom

Inaktivitet

Inflammation

Stress

Rökning

ROS

hyperglykemi

Progesteron/östrogen kvot

IGF-I

IGFBP-1

Puls

WBC

Cancer

Blodtryc

k

Glukos

Lipider

Metabola

Syndromet

IGFBP-1

GH deficiency (and Metabolic Syndrome)

INSULIN RESISTANCE

Kalorirestriktion normaliserar IGF-I and

IGFBP-1 och kardiovaskulära riskfaktorer

hos de med metabola syndromet

Baseline 3 Månader 6 månader 1 år

25,5

26,0

26,5

27,0

27,5

28,0

28,5

29,0

29,5

30,0

BMI

Kvinnor

Män

Baseline 3 Månader 6 månader 1 år

90,0

92,0

94,0

96,0

98,0

100,0

102,0

104,0

106,0

108,0

110,0

Midja

Kvinnor

Män

Baseline 3 Månader 6 månader 1 år

0,5

0,7

0,9

1,1

1,3

1,5

1,7

1,9

HDL

Kvinnor

Män

Baseline 3 Månader 6 månader 1 år

2,9

3,0

3,1

3,2

3,3

3,4

3,5

LDL

Kvinnor

Män

Baseline 3 Månader 6 månader 1 år

5,4

5,6

5,8

6,0

6,2

6,4

6,6

Glukos

Kvinnor

Män

Baseline 3 Månader 6 månader 1 år

10,0

15,0

20,0

25,0

30,0

35,0

40,0

45,0

IGFBP-1

Kvinnor

Män