IGF-Systemet som diagnostiskt hjälpmedel. Kerstin Brismar. Inst för molekylär medicin och kirurgi, Karolinska Institutet

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1 IGF-Systemet som diagnostiskt hjälpmedel Kerstin Brismar Inst för molekylär medicin och kirurgi, Karolinska Institutet 21 sept 2017

2 First publications IGF-I Kerstin Hall et al 1972 IGFBP-1 Kerstin Hall et al 1984

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5 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

6 IGF-I Insulin-like Growth Factor-I Effects Growth Differentiation Cell survival Healing Metabolism Antioxidant

7 IGF-1 Markör för: Anabolism/katabolism Tillväxt GH-sekretion Nutritionsstatus Insulinsekretion IUGR (intrauterin tillväxthämning)

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11 Före och efter operation För mycket IGF-I = akromegali

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16 Insulin Cytokiner _ + + Glukagon + IGFBP Hypoxi Aminosyror Stress Fasta Östradiol/ Progesteron GH Aminosyror + + Cytokiner IGF-I Fasta Insulin + + Testosteron/DHEA

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21 Association of IGF-I with diseases Inflammation CVD Diabetes compl. Cancer DM Insulin IGF-I

22 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

23 The Insulin-like Growth Factor Bindingproteins are needed to control IGF activity IGFBP-1-6

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26 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

27 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

28 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

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30 Insulin Cytokiner _ + + Glukagon + IGFBP Hypoxi Aminosyror Stress Fasta Östradiol/ Progesteron GH Aminosyror + + Cytokiner IGF-I Fasta Insulin + + Testosteron/DHEA

31 IGFBP-1 Markör för: Fritt IGF-1 Insulinsekretion Insulinresistens Glukostolerens Leverresistens Metabola syndromet Nutritionsstatus Inflammation Endotelfunktion Riskmarkör för typ 2 diabetes, CVD, cancer

32 IGFBP-1 a surrogate marker for IGF-1

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34 IGFBP-1 is a marker of diurnal insulin secretion and response to glucose

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41 IGFBP-1 can predict type 2 diabetes

42 (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

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44 IGFBP-1 (microg/l) Good correlation between biological marker and response to a risk score IGFBP-1 och FINDRISC p=0.01 p < Low, n=143 Slightly Elevated, n=121 Moderate to High, n=51 FINDRISC Group

45 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: Kerstin Brismar 2 October

46 IGFBP-1 before and after bariatric surgery by gender 2 October 2017 Kerstin Brismar 46

47 IGFBP -1 and IGF-I are markers of catabolism/malnutrition

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53 IGFBP-1 is a marker of hepatic insulin resistance

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56 IGFBP-1 is a marker of insulin insufficiency

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59 DM type 2 IGFBP-1 avgör bästa behandl Per oral treatment (OHA) HbA1c Insulin treatment IGFBP-1 0 Jonas Tovi, Thesis 1998

60 IGF-I and IGFBP-1 can predict late diabetes complications

61 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

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64 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

65 Association of IGFBP-1 with diseases Cancer Insulin CVD Diabetes complications DM IGFBP-I

66 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

67 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

68 GH deficiency (and Metabolic Syndrome) INSULIN RESISTANCE

69 Kalorirestriktion normaliserar IGF-I and IGFBP-1 och kardiovaskulära riskfaktorer hos de med metabola syndromet

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74 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

75 110,0 108,0 106,0 104,0 102,0 100,0 98,0 96,0 94,0 92,0 90,0 Midja Baseline 3 Månader 6 månader 1 år Kvinnor Män

76 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

77 3,5 LDL 3,4 3,3 3,2 3,1 Kvinnor Män 3,0 2,9 Baseline 3 Månader 6 månader 1 år

78 6,6 Glukos 6,4 6,2 6,0 5,8 Kvinnor Män 5,6 5,4 Baseline 3 Månader 6 månader 1 år

79 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