Thyroid and the metabolic syndrome G. Brabant Clinical and Experimental Endocrinology, MK I, University of Lübeck, Germany Definition Basic mechanisms Clinical aspects Interesting cases

Definition Discuss the impact of metabolic syndrome on thyroid growth/function only focussed on thyroid impact on metabolism Definition of metabolic syndrome (WHO, IDF, NCEP-ATP-III) – insulin resistance / artherogenic dyslipidemia / hypertension – NCEP/ATP III criteria waist circumference (102 cm for men or 88 cm for women) elevated triglycerides ( 1.7mmol/l or on drug treatment for high TG) reduced HDL (cholesterol < 1.03 mmol/l in men or < 1.29 mmol/l in women or on drug treatment for reduced HDL-C) elevated fasting glucose ( 5.6 mmol/l). elevated blood pressure ( 130 mmHg systolic BP or 85 mmHg diastolic BP or on antihypertensive drug treatment for elevated BP)

Mortality and sc hypothyroidism Rodondi JAMA 2010 N = Epidemiology

Association of TSH with metabolic syndrome n = 7,270 euthyroid subjects Lee Korean J Int Med 2011

Odds ratio of meeting individual MetS criteria at baseline by thyroid function category Waring Clinical Endocrinology (2011) 76, 911–918 n = 3075 white and black subjects of the Health Ageing and Body Composition study n = 684 initially identified with metabolic syndrome

Impact of thyroid hormones on body weight Jonklaas Thyroid 2011 weight +3.3 kg healthy controls +1.3 kg Visceral obesity / body weight Asvold JCEM 2009

Thyroid hormones and energy regulation Coppola Cell Metab 5:21, 2007 UCP-2

Appetite regulation and REE in RTH and hyperthyroidism Mitchell JCI 120: 1345, 2010

Effects of thyroid hormones on hypothalamic AMPK signaling Lopez Nat Med 2010 Hyperthyroid Hypothyroid

Direct effects of T3 on BAT 0h 4h 24h UCP-1 ΔΨ 0h 24h T3T3 OCR 0h 4h 24h **

Odds ratio of meeting individual MetS criteria at baseline by thyroid function category Waring Clinical Endocrinology (2011) 76, 911–918 n = 3075 white and black subjects of the Health Ageing and Body Composition study n = 684 initially identified with metabolic syndrome Epidemiology

Regulation of FA in hyper- and hypothyroidism Klieverik Endocrinology 2009

Odds ratio of meeting individual MetS criteria at baseline by thyroid function category Waring Clinical Endocrinology (2011) 76, 911–918 n = 3075 white and black subjects of the Health Ageing and Body Composition study n = 684 initially identified with metabolic syndrome Epidemiology

Central regulation of endogenous glucose- production Klieverik PNAS 106: 5966, 2009 Schofl JCEM 87: 624, 02 rat model

Glucose homeostasis in Dio2 knock-out animals Marsili Plos One 2011

Glucose disposal rates in relation to DIO type 2 polymorphism Mentuccia Diabetes 51:880–883, 2002

GLUT expression in eu- and hyperthyreoidism Dimitriadis Horm Metab Res 37:15, 2005 Glut1 Glut3 Glut4 Dimitriadis JCEM 93:2413, 2008

Maratou EJE 2010 OGT Plasmainsulin and glucose levels in euthyroidism, sc and overt hyperthyroidism Glucose regulation diminished glycogen synthesis increased gluconeogenesis

Glucose and insulin response in eu-, sc or overt hypothyroidism Dimitriadis JCEM 91:4130, 2006 Maratou EJE 160: 785, 2009

Glucose transport and – uptake in subclin. and overt hypothyroidism Maratou EJE 160: 785, 2009 Glucose transport Hypothyroidism to euthyroidism Glut4 unchanged Glut5 increased 15x Visser JCEM 94:3497, 09

Glucose uptake and TSH

Metformin effects in T2Dm n = 828 Muscogiuri Obesity 2012

Insulin sensitivity and thyroid function in healthy subjects Roos J Clin Endocrinol Metab 92: 491–496, fT4 tertiles HOMA-IR (mU*mmol/l pmol/L 18.2 pmol/l

Insulin secretion, insulin sensitivity, metabolic clearance of insulin, glucose disposal rate in hypothyroidism with or without thyroid hormone therapy Stanicka Clin Chem Lab Med 43: 715, 2005

Effects on β-cells in lean and db/db mice Lin Br J Pharmacol 2011

Case from the National Institutes of Health A woman with type A insulin resistance secondary to a homozygous mutation of the α-subunit of the insulin receptor (IR; EMBO J : ) diagnosed as a child severely impaired IR transport to the cell surface high insulin requirements – poor metabolic control – hyperandrogenism aged 32 yrs diagnosis of PTC treated by total thyroidectomy, lymphadenectomy, radioiodine, TSH suppression with thyroxine (200 – 250 µg/d) TG slightly elevated Thyroid function and insulin resistance Skarulis J Clin Endocrinol Metab, 2010, 95(1):256–262

Thyroid function and insulin resistance Case 2

FDG-PET in a athyroid patient with type A insulin resistance Skarulis J Clin Endocrinol Metab, 2010, 95(1):256–262 T4 supp therapy Restart of T4 14 d Off T4 therapy

Effect of levothyroxine (L-T4) on metabolic parameters and laboratory tests Skarulis J Clin Endocrinol Metab, 2010, 95(1):256–262

Impact of thyroid hormones in diabetes mellitus Kadiyala 2010 Epidemiology thyroid disease / Diabetes mellitus

Autoimmune polyglandular syndrome Kahaly EJE 2009 / III

Frequency of further antibodies in 491 children with T1Dm Triolo Diabetes Care 2011 Screening for thyroid dysfunction ? Guidelines: yes for T1Dm ?? / no comment for T2Dm

Odds ratio of meeting individual MetS criteria at baseline by thyroid function category Waring Clinical Endocrinology (2011) 76, 911–918 n = 3075 white and black subjects of the Health Ageing and Body Composition study n = 684 initially identified with metabolic syndrome Epidemiology

Impact of thyroid function on blood pressure Ittermann JCEM 2012 Asvold JCEM 2007

Hypertension and thyroid dysfunction Cai Hypertension Res 2011 Longitudinal results (n= Voelzke et al 2012)

Glucose lipids Blood flow Glucose transport Glycogen synthesis Glucose transport Glucose oxidation Glucose oxidation Blood flow Glucose transport Lipolysis, NEFA Tg derived FA uptake Insulin Feeding behaviour Energy expenditure Hormonal, metabolic Signals LC-FA Glucose Insulin Leptin ghrelin WAT BAT muscle pancreas liver Multiple mechanisms for thyroid glucose / lipid interaction Gluconeogenesis Cortisol GH Tg Lipid oxidation Pathophysiology

Grueters Cell 149:671, 2012 Heart and energy expanditure