Glucocorticoid generation in the adrenals and adipose tissue in obesity. Brian Walker Endocrinology Unit University of Edinburgh

Transcription

1 Glucocorticoid generation in the adrenals and adipose tissue in obesity Brian Walker Endocrinology Unit University of Edinburgh

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3 Cushing s or Metabolic Syndrome? Similarities The clinical problem telling them apart Does cortisol contribute to Metabolic Syndrome? Can manipulating cortisol treat Metabolic Syndrome?

4 Central obesity Metabolic Syndrome (IDF) Cushing s Syndrome + Two from: Dyslipidaemia Hypertension intolerance + other features Cardiovascular Disease Glucose?

5 EMO ose of glucocorticoids and all cardiovascular events Wei et al Ann Int Med 2004 Crude Adjusted* None Low topical Medium <7.5 High >7.5 None Low Medium High RR (95%CI) ( ) 1.78 ( ) 4.83 ( ) ( ) 1.03 ( ) 2.70 ( ) *Age, gender, social deprivation, cardiovascular drug use, HRT & OCP, NSAIDs, DMARDs, bronchodilators, noncardiovascular hospitalisation in the 6 months prior to study entry, diabetes mellitus, cancer, renal disease, interaction between exposure and cardiovascular drug use, propensity score

6 Cushing s or Metabolic Syndrome? Similarities The clinical problem telling them apart Does cortisol contribute to Metabolic Syndrome? Can manipulating cortisol treat Metabolic Syndrome?

7 HPA axis abnormalities in Metabolic Syndrome + Increased urinary free cortisol excretion Marin Metabolism 1992; Pasquali JCEM Loss of diurnal cortisol variation Rosmond JCEM 1998 (Increased responses to CRH/AVP and ACTH) Pasquali Horm Metab Res 2000 Normal response to dexamethasone at conventional doses Chalew Obes Res 1995; Pasquali JCEM 2002

8 n=13 n=36 n=21 n=51 Variation in cortisol suppression explained by: Gender [dexamethasone] not BMI asquali, R. et al. J Clin Endocrinol Metab 2002;87: Conclusion how do you tell? Use dexamethasone suppression at conventional doses

9 Cushing s or Metabolic Syndrome? Similarities The clinical problem telling them apart Does cortisol contribute to Metabolic Syndrome? Can manipulating cortisol treat Metabolic Syndrome?

10 Blood cortisol and cardiovascular risk Umea Edinburgh Uppsala Phoenix Preston Sheffield Hertfordshire London

11 Plasma [cortisol] and cardiovascular risk factors Systolic blood pressure (mmhg) p< Plasma glucose Fasting 120 min in OGTT p<0.001 p< < >400 All < >400 All se Triglyceride < >400 All p< Insulin resistance (HOMA index) Fasting 0900 h plasma [cortisol] (nm) < >400 All p<0.03 Phillips et al JCEM 1998

12 Cortisol metabolites & familial BP Urinary excretion (mg/day) Offspring Parents C Low Low * NS * A High Low D Low High B High High F 5ß-THF 5α-THF THE O A B C D P E 5βTHF 5αTHF THE Walker et al Hypertension 1998

13 HPA axis in lean insulin resistance syndrome Negative Feedback (dexamethasone) NORMAL CRH ACTH Central drive Habituation IMPAIRED Stress? Programming? SynACTHen response ENHANCED Cortisol mplified by obesity? Reynolds JCEM 2001a, 2001b Brunner Circulation 2002 Phillips Hypertension 2000

14 Cortisol in obesity in men 50 Total cortisol metabolites (mg/d) h plasma [cortisol] (nm) Waist circumference (cm) Waist circumference (cm) N Sweden (28-65 y) n=33 p<0.01 Preston (47-56 y) n=31 p=0.30 Sheffield (69-74y) n=87 p<0.02 Hertfordshire (60-65y) n=140 p=0.06 Overall r=+0.19, 217µg/cm, p<0.001 N Sweden (25-65 y) n=147 p=0.67 Preston (45-55 y) n=133 p<0.01 Hertfordshire (60-65 y) n=203 p=0.06 Overall r=-0.17, 2nM/cm, p<0.001

15 5α-Reductase 1 is increased in obesity Human 5alpha-D4-Cortisol Excretion mrna Zucker obese rat protein ** * 0.8 * Lean Obese 0 Lean Obese 0.0 Lean Obese

16 Consequences of enhanced cortisol clearance in obesity Negative Feedback CRH Central drive ACTH Adrenal Androgens Cortisol 5α-Reductase 1 GR activation? Clearance

17 Cushing s or Metabolic Syndrome? Similarities The clinical problem telling them apart Does cortisol contribute to Metabolic Syndrome? Can manipulating cortisol treat Metabolic Syndrome?

18 Hypothalamic-pituitary-adrenal-tissue axis Negative Feedback CRH Central drive ACTH Cortisol Tissue responses

19 Steroid hormone action

20 11β-HSD2 in kidney Stewart, Edwards et al. Cortisol (F) F 11HSD2 Congenital deficiency Cortisone (E) E MR Inhibition with liquorice Na retention Hypertension Impaired in 1/3 of patients with hypertension

21 Liver Adipose CNS GR F Cortisol (F) F 11HSD2 Kidney 11HSD1 Cortisone (E) E E MR

22 Lessons from 11HSD1 transgenic mice AP2-11HSD1 TG 11HSD1 knockouts Masuzaki Science 2001 Kotelevtsev PNAS 1997 Morton Diabetes 2004 non-tg Tg 45 weight (g) Obese Hypertensive Diabetic 40 ** 35 wild type 30 11ß-HSD1-/- ApoE-11HSD1 TG Paterson PNAS 2004 hypertensive Fatty liver hyperinsulinaemic dyslipidaemia not obese not diabetic :00 pm12:00 am12:00 pm12:00 am12:00 pm12:00 am ** weeks on high fat diet Protected from: Obesity Diabetes dyslipidaemia

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24 Quantifying cortisol regeneration in humans D4 cortisol HO D D 2 CH 2 OH CO OH O D D3 cortisol O D3 cortisone CH 2 OH O D 2 CO OH D D3-cortisol production nmol/min HO D 2 CH 2 OH CO OH 4 2 O D 0 Placebo CBX Andrew et al JCEM 2002

25 Regional cortisol production in humans Adrenals D4-Cortisol Cortisone ~38 nmol/min D4-Cortisol Cortisol D3-Cortisol 45 ~11 nmol/min ~15 nmol/min Liver Kidney other Fat~2nmol/ etc min/kg [Cortisol] 155nM Cortisone D3-Cortisone [Cortisol] 118nM Visceral fat ~30 nmol/min Andersson Andrew Basuet et al al Diabetes unpublished

26 Tissue-specific dysregulation of 11-HSD1 in obese men Liver sc adipose tissue 700 Plasma cortisol (nmol/l) %11-HSD1 activity Time after oral cortisone (min) Incubation time (h) 34 (16) men in tertiles of BMI: Highest Middle Lowest Rask et al. JCE&M 2001

27 SC adipose 11HSD1 in obesity - microdialysis Tracer 3 Hcortisone Analysis 3 Hcortisol Skin Adipose interstitial fluid Dialysis membrane 3 H 4 -cortisone to 3 H 4 -cortisol * 0 Lean Obese Sandeep et al Diabetes 200

28 O H CO 2 H 11HSD1 in human obesity C O 2 H C H 2 C H2 C O O Carbenoxolone cortisol 11HSD1 cortisone

29 Drug discovery Target Biology Lead Finding Lead Optimisation In vitro & In Vivo Models Drug Candidate Clinical Development Potent selective inhibitors of 11HSD1 in mice eg Biovitrum/Amgen, Merck, Johnson & Johnson, Wyeth, Abbott. Lower blood glucose in KKAy, ob/ob, db/db, DIO Lower body weight Atheroprotective eg in ApoE -/- mice Alberts et al Diabetologia 2002; Endocrinology 2003; Vosatka J Exp Med 2005

30 Key points Glucocorticoids cause cardiovascular disease Dexamethasone discriminates Cushing s vs Metabolic Syndrome Plasma cortisol: elevated in Metabolic Syndrome lower in obesity Liver glucocorticoid action depends on: 11HSD1 in visceral adipose 5α-reductase 1 in liver? 11HSD1 generates more cortisol within adipose tissue in obesity 11HSD1 inhibitors may be useful in Metabolic Syndrome

31 Edinburgh Jonathan Seckl Nik Morton John Mullins Ruth Andrew Dawn Livingstone Paddy Hadoke Natalie Homer Ken Smith Rob Andrews Greg Jones Rebecca Reynolds Thekkepat Sandeep Gary Small Debbie Wake Alison Ayres Wendy Barron Jill Campbell Scott Denham Thanks! Helsinki Hannele Yki-Jarvinen Jukka Westerbacka Jussi Sutinen Stockholm John Wahren Dundee Tom MacDonald Li Wei London Eric Brunner Michael Marmot Umea Tommy Olsson Stefan Soderberg et al Phoenix Antonio Tataranni Paska Permana Robbie Lindsay Southampton David Phillips Cyrus Cooper Utrecht Tjeerd van Staa Patrick Souverein

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