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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