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 Differentiation Cell survival Healing Metabolism Antioxidant
IGF-1 Markör för: Anabolism/katabolism Tillväxt GH-sekretion Nutritionsstatus Insulinsekretion IUGR (intrauterin tillväxthämning)
Före och efter operation För mycket IGF-I = akromegali
Insulin Cytokiner _ + + Glukagon + IGFBP-1 + + + Hypoxi Aminosyror Stress Fasta Östradiol/ Progesteron GH Aminosyror + + Cytokiner IGF-I Fasta Insulin + + Testosteron/DHEA
Association of IGF-I with diseases Inflammation CVD Diabetes compl. Cancer DM Insulin IGF-I
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-1 Insulin-like Growth Factor Binding Protein-1 Effects IGF-dependent IGF-independent pigfbp inhibits IGF effects npigfbp enhances IGFeffects Stimulate cell migration and proliferation, NOsyntes
Insulin Cytokiner _ + + Glukagon + IGFBP-1 + + + Hypoxi Aminosyror Stress Fasta Östradiol/ Progesteron GH Aminosyror + + Cytokiner IGF-I Fasta Insulin + + Testosteron/DHEA
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
(OR) Risk of type 2 diabetes within 8-10 yes Glu > 5.1 mmol/l BMI > 28.5 M/L > 5 cm 2 /m/1000 Insulin > 150 M > 90 w IGFBP-1 < 11 M < 26 w
IGFBP-1 (microg/l) Good correlation between biological marker and response to a risk score 50 45 40 35 30 25 20 15 10 5 0 IGFBP-1 och FINDRISC 43 34 27 p=0.01 p <0.0001 Low, n=143 Slightly Elevated, n=121 Moderate to High, n=51 FINDRISC Group
Changes in serum IGF-1 and IGFBP-1 after 6 months of life style intervention in 160 middle-age men Journal of Internal Medicine, 1995, 238:121-130 Kerstin Brismar 2 October 2017 45
IGFBP-1 before and after bariatric surgery by gender 2 October 2017 Kerstin Brismar 46
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 Per oral treatment (OHA) HbA1c Insulin treatment IGFBP-1 0 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
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) Wallander et al. In press Diabetes Care 2007
Association of IGFBP-1 with diseases Cancer Insulin CVD Diabetes complications DM IGFBP-I
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
Cancer Demens ( amyloid) Hyperkoagulation IGF-I IGFBP-1 Puls WBC Sug / Begär Kolhydrater Glukos / Stärkelse Insulin Insulinresistens PCOS Inaktivitet Inflammation Stress Rökning ROS hyperglykemi Progesteron/östrogen kvot Hjärnan Inflammation (leptin resistens) ( ACTH GH FSH/LH) Fettmassa Midja/Inflammation Blodtryc k Glukos Lipider Metabola Syndromet Hjärt-kärlsjukdom Njursjukdom Tg / FFA Fettlever IGFBP-1
GH deficiency (and Metabolic Syndrome) INSULIN RESISTANCE
Kalorirestriktion normaliserar IGF-I and IGFBP-1 och kardiovaskulära riskfaktorer hos de med metabola syndromet
30,0 29,5 29,0 28,5 28,0 27,5 27,0 26,5 26,0 25,5 BMI Baseline 3 Månader 6 månader 1 år Kvinnor Män
110,0 108,0 106,0 104,0 102,0 100,0 98,0 96,0 94,0 92,0 90,0 Midja Baseline 3 Månader 6 månader 1 år Kvinnor Män
1,9 HDL 1,7 1,5 1,3 1,1 0,9 Kvinnor Män 0,7 0,5 Baseline 3 Månader 6 månader 1 år
3,5 LDL 3,4 3,3 3,2 3,1 Kvinnor Män 3,0 2,9 Baseline 3 Månader 6 månader 1 år
6,6 Glukos 6,4 6,2 6,0 5,8 Kvinnor Män 5,6 5,4 Baseline 3 Månader 6 månader 1 år
45,0 IGFBP-1 40,0 35,0 30,0 25,0 20,0 Kvinnor Män 15,0 10,0 Baseline 3 Månader 6 månader 1 år