Thyroid and the metabolic syndromeG. 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 = 55 287

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 studyn = 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 onhypothalamic AMPK signaling

Lopez Nat Med 2010

Hyperthyroid

Hypothyroid

Direct effects of T3 on BAT

T3 effect on UCP-1

Relat

ive ex

press

ion / m

RNA

0

100

200

300

400

500

600

0h 4h 24h

*

0h 4h 24h

UCP-1

0

100

200

300

400

500

0h 24h

ΔΨ

0h 24h

T3

T3 effect on oxygen consumption: Clark electrode

Relat

ive ch

ange

0

80

100

120

140

0h 4h 24h

**

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 studyn = 684 initially identified with metabolic syndrome

Epidemiology

Regulation of FA in hyper- and hypothyroidism

KlieverikEndocrinology2009

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 studyn = 684 initially identified with metabolic syndrome

Epidemiology

Central regulation of endogenous glucose- production

Klieverik PNAS 106: 5966, 2009Schofl JCEM 87: 624, 02

rat model

Glucose homeostasis in Dio2 knock-out animals

Marsili Plos One 2011

Glucose disposal rates in relation toDIO 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

diminishedglycogen synthesis

increasedgluconeogenesis

Glucose and insulin response ineu-, 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, 2007

1 2 3fT4 tertiles

HO

MA

-IR

(m

U*m

mo

l/l2

10.6 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 1989 8:2509-17)

• 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

Skarulis J Clin Endocrinol Metab, 2010, 95(1):256–262

Thyroid function and insulin resistance

Case 2

FDG-PET in a athyroid patient withtype A insulin resistance

Skarulis J Clin Endocrinol Metab, 2010, 95(1):256–262

T4 supp therapy Restart of T4 14 dOff 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 Care2011

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 studyn = 684 initially identified with metabolic syndrome

Epidemiology

Impact of thyroid function on blood pressure

Ittermann JCEM 2012Asvold JCEM 2007

Hypertension and thyroid dysfunction

Cai Hypertension Res 2011

Longitudinal results (n= 17 028 Voelzke et al 2012)

Glucose

lipidsBlood flow

Glucose transport

Glycogen synthesis

Glycogen synthesis

Glucose transport

Glucose oxidation

Glucose oxidation

Blood flow Glucose transport

Lipolysis, NEFA

Tg derived FA uptakeTg derived FA uptake

Insulin

Feeding behaviourEnergy expenditure

Hormonal, metabolic SignalsLC-FA

GlucoseInsulinLeptinghrelin

WAT

BAT

muscle

pancreas

liver

Multiple mechanisms for thyroid glucose / lipid interaction

Gluconeogenesis

CortisolGH

Tg

Lipid oxidation

Pathophysiology

Grueters Cell 149:671, 2012

Heart and energy expanditure