Thyroid and energy expenditure

Francesco S. Celi, M.D.Staff Clinician

Clinical Endocrinology Branch

Overview

• The thyroid hormone action as a modulator of the energy and substrate metabolism homeostasis

• Tissue-specific thyroid hormone metabolism• Recent clinical studies on the interaction between

thyroid hormone homeostasis and glucose and energy metabolism

• Technical challenges in the assessment of the metabolic status of healthy individuals

• Ongoing studies on the role of thyroid hormones conversion in the energy and substrate metabolism

• Preliminary results• Future perspectives

A few (unresolved) questions…

• Why is the clinical presentation of thyroid diseases so variable?

• Where does (circulating) T3 come from?• What is the action of thyroid hormone on

glucose metabolism?• What makes the thyroid hormone actions

tissue-specific?• Can we exploit the action of thyroid hormone?

(without paying the price)

Hypothalamus

Pituitary

Thyroid

Plasma transport

Cellular transport

Local conversion

Receptors/Co-activators

The researcher’s view of the universe“The thyroid hormone action is controlled by a redundant,

multilevel highly regulated mechanism”

I

I

I

R RX

RXRTR

The researcher’s view of the universe

Local conversion

The Deiodinases :Activation and Inactivation of Thyroid Hormones

OHO R

I

55’

33’

II

I

OHO R

55’

33’

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I

OHO R

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55’

33’

I

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T4

T3 rT3

D 1, D 2 D 3, ( D 1)

I

mRNA

The role of the Selenocysteine Insertion Sequence (SECIS) in the incorporation of the selenocysteine

NH2

50 S

UGA UAA

STOP

AA A

30 S

SeCys SECIS Element

AAAAAAAAA

5’(STOP)

Deiodinases: types and characteristics

Type 1 Type 2 Type 3

Site of action 5’ and 5 5’ 5

Substrate rT3>T4>T3 T4>T3 T3>T4

Localization Kidney, liver,thyroid

Pituitary, CNS, muscle, BAT, thyroid,placenta

placenta,CNS

Hypothyroidism Inhibition InhibitionStimulation

Hyperthyroidism InhibitionStimulation Stimulation

Km (T4) 2 M 2 nM 37 nM

The peripheral metabolism of thyroid hormone in the local

modulation thyroid homeostasis

• The peripheral conversion of thyroid hormone and the pre-receptor modulation of the hormonal message– Aromatase– 11-hydroxysteroid dehydrogenase– 5-reductase

• The deiodinase type-2 as a candidate gene for tissue-specific hypothyroidism

Type 2 deiodinase local pre-receptor modulation of hormonal action

• Differentially expressed in many tissues• Provides T3 for local use (autocrine secretion)

– Possible role in the regulation of circulating T3

• Critical step in pituitary for thyroid axis feedback

• Critical step in non-shivering thermogenesis• Highly regulated

– Transcription– Post-transcription– Post-translation

Clinical relevance of deiodinases• Type 1

– Euthyroid sick syndrome– Effects of pharmacological intervention– Graves’, Toxic nodule, MAS

• Type 2– Pituitary thyroid hormone resistance– Graves’, Toxic nodule, MAS– Euthyroid sick syndrome

• Type 3– Protection of fetus from toxic levels of

thyroid hormone– Euthyroid sick syndrome– “Paraneoplastic hypothyroidism”

The Deiodinases and the Euthyroid Sick Syndrome

“Changes in circulating thyroid hormones secondary to underlying illness in the absence of primary thyroid pathology”

Low T3: Deiodinase type-1 inhibition, easy!…Not exactly…Why is the rT3 elevated?Why is the TSH inappropriately low?And if we assume an accumulation of substrate, why is the T4 low?

The deiodinases in the pathogenesis of euthyroid sick syndrome

Hypothalamus

Pituitary

D2

T4 T3TRH

TSH

Inflammatory mediators

T4

D1 T4 T3

Liver

Hypoxia D3 T4 rT3

Ectopic D3 activity

• low T3• low T4• low TSH• high rT3

rT3 T2

The role of the deiodinases in the pathophysiology of the euthyroid sick

syndrome

• Type 1: decreased transcription due to recruitment of co-activators by the inflammatory cytokines, further decrease by the lack of T3– Decrease in T3, increase in rT3

• Type 2: increased activity in the glial cells feeding the hypothalamus TRH neurons, ultimately inhibiting the TRH-TSH axis– Decrease in TSH, inhibition of thyroid activity

• Type 3: increased transcription and activity due to hypoxia– Increase in rT3, decrease in T4

The action of thyroid hormone on glucose and energy metabolism

Lessons from patients

• Thyrotoxicosis

– Increased energy expenditure

– Increased lipid oxidation

– Weight loss

Energy Metabolism

• Hypothyroidism

– Decreased energy expenditure

– Increased sympathetic tone

– Weight gain?

The action of thyroid hormone on glucose and energy metabolism

Lessons from patients

• Thyrotoxicosis– Increased hepatic

gluconeogenesis– Decreased insulin

half-life– Muscle mass loss– Increased glucose

disposal

Glucose Metabolism

• Hypothyroidism– Decreased hepatic

gluconeogenesis– Increased insulin

half-life– Decreased glucose

disposal

The action of thyroid hormone on glucose and energy metabolism

Epidemiological studies

The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study.

Asvold et al, Eur J Endocrinol. 2007 Feb;156(2):181-6.

Plasma concentrations of free triiodothyronine predict weight change in euthyroid persons.

Ortega et al, Am J Clin Nutr. 2007 Feb;85(2):440-5.

Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals.

Ortega et al, Eur J Endocrinol. 2008 Feb;158(2):217-21.

The action of thyroid hormone on glucose and energy metabolism

Molecular genetics studies

Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the

Trp64Arg variant of the beta-3-adrenergic receptor Mentuccia et al, Diabetes. 2002 Mar;51(3):880-3

The type 2 deiodinase A/G (Thr92Ala) polymorphism is associated with decreased enzyme velocity and increased insulin resistance in patients with

type 2 diabetes mellitus Canani et al, J Clin Endocrinol Metab. 2005 Jun;90(6):3472-8.

The type 2 deiodinase (DIO2) A/G polymorphism is not associated with glycemic traits: the Framingham Heart Study.

Maia et al, Thyroid. 2007 Mar;17(3):199-202.

The Asp727Glu polymorphism in the TSH receptor is associated with insulin resistance in healthy elderly men

Peeters et al, Clin Endocrinol. 2007 Jun;66(6):808-15.

Thyroid disease in the geriatric populationwhat is normal?

• Prevalent condition (if assessed by TSH alone)

• Very aspecific symptoms/signs (Douchet J Am Geriatr Soc. 1994 Sep;42(9):984-6).

• Predominant symptoms: fatigue and weakness

• Paradoxicaly associated (hypothyroidism) with increased survival (Singer RB J Insur Med. 2006;38(1):14-9. Gussekloo J. et al. JAMA. 2004 Dec 1;292(21):2591-9 )

Technical challenges in the assessment of the metabolic status of healthy individuals

as related to thyroid homeostasis

• Inter-individual variability of thyroid homeostasis parameters

• Inter-individual variability of clinical expression of thyroid homeostasis as it relates to circulating thyroid hormones

• Role of thyroid hormone action as modulator of metabolic status

Technical challenges in the assessment of the metabolic status of healthy individuals

• Inter-individual variability of metabolic parameters

• Intra-individual variability of metabolic parameters (nutritional/activity/environmental)

• Relative poor performance of the assessment tools (good accuracy, poor precision)

Technical challenges in the assessment of the metabolic status of healthy individuals

study design

• Careful selection of study participants– Specific conditions (e.g. RTH, MAS)– Healthy volunteers– Specific genotypes

• Accurate evaluation of baseline conditions• Use of Clinical Research Centers • Use of study designs aimed to improve the

accuracy of the results– Cross-over– Sib-pair

Clinical Studies-ongoing

• 05-DK-0119: Peripheral Thyroid Hormone Conversion and Glucose and Energy Metabolism

• 06-DK-0133: Thyroid Hormone-Induced Lipolysis: An In Vivo Microdialysis Study

• 07-DK-0202: Thyroid hormones homeostasis and energy metabolism changes during exposure to cold temperature in humans

• 06-DK-0183: Gene Expression and Release of Inflammatory Mediators in Overweight Subjects Before and After Weight Loss

05-DK-0119 Peripheral Thyroid Hormone Conversion and Glucose and Energy Metabolism

Study Objectives

Background

• Levothyroxine replacement therapy might not be effective in assuring the thyroid homeostasis in all target organs/systems.

Study Aims:

• To assess the differential pituitary response to escalating dose TRH stimulation test.

• To assess the changes in glucose metabolism by euglycemic hyperinsulinemic clamp.

• To analyze the changes in lipid metabolism by assessing the changes in cholesterol, triglycerides and apolipoproteins

• To assess the changes in cardiovascular function by echocardiogram, vascular endothelial function and EKG, both resting and post exercise.

Subject Selection Criteria

Inclusion Criteria• Total/near total

thyroidectomy– Remnant volume < 1 mL

– LT4 dose ≥ 1.6 g/kg

• Primary Hypothyroidism– LT4 dose ≥ 1.6 g/kg

– 24-hour uptake < 5%

Exclusion Criteria• Suppressive therapy• BMI ≤20 or ≥30 kg/m2

• Cardiovascular disease

• Diabetes Mellitus• Hypercholesterolemia

05-DK-0119 Study design

T3 therapy

T4 therapy

Enrollm

ent

Random

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nTher

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adju

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Therap

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men

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Met

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test

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Therapy adjustment

Therapy adjustment

Metabolic testing

Therap

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Therap

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men

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Met

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test

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Therapy adjustment

Therapy adjustment

Metabolic testing

Therapy adjustment intervals: 10 days; TSH goal > 0.5 < 1.5 mcIU/mL

05-DK-0119 Preliminary data

• 7 study subjects (6 F, 1 M) age 49.6 4.3 years, BMI 25.8 3.1 kg/m2.

• T3 vs. T4 TSH at admission (0.51 0.16 vs. 0.62 0.46 mU/L p=0.59).

• T3 dose 41.4 12.3 mcg (0.6 0.1 mcg/kg)• T4 dose 123.2 37.2 mcg (1.7 0.3 mcg/kg)• T3:T4 ratio 0.34 0.05• Time-to-target on T4 202 81 days• Time-to-target on T3 167 87 days

Liothyronine vs. Levothyroxine Dose

LT4 dose123.2 37.2 mcg (1.7 0.3 mcg/kg)

200

150

100

90

60

30

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*

LT3 dose 41.4 12.3 mcg (0.6 0.1 mcg/kg)

LT3:LT4 ratio 0.34 0.05 mcg/mcg

05-DK-0119 Preliminary data

• Free T4 levels at admission

• T3 therapy < 0.3 ng/dL• T4 Therapy 1.610.37 ng/dL

Reference values 0.8-1.9 ng/dL

05-DK-0119 Preliminary data

• Total T3 levels at admission

• T3 therapy 167.7169.17 ng/dL• T4 Therapy 87.5724.08 ng/dL

Reference values 90-215 ng/dL

24-Hour Serum Total T3 Profile

Reference values 90-215 ng/dL

0

50

100

150

200

250

300

Hours

Liothyronine

Levothyroxine

T3

ng

/dL

24-Hour Serum TSH Profile

Reference values 0.5-4.0 mcU/mL

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Hours

Liothyronine

Levothyroxine

TS

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cu/m

L

05-DK-0119 Preliminary data

TRH 200 mcg

0

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10

0 5 10 15 20 30 60

Time (min)

TS

H (

mcU

/mL

)

Liothyronine

Levothyroxine

•AUC 0-60 after 200 mcg TRH

•T3 281.4113.6 mU*min /L •T4 282.5165.6 mU*min /L

•First steady-state pharmaco bioequivalency data on T3 vs. T4.•Proof of concept of effective substitution of T3 for T4 therapy.•Tool to study in vivo the physiological role of deiodination.

07-DK-0202 Thyroid hormones homeostasis and energy metabolism changes during

exposure to cold temperature in humans Background/study aims

• Changes in environmental temperature generate a substantial differential in energy expenditure and substrate utilization (in animal models)

• It is not clear whether changes within the thermo-neutral zone result in measurable and clinically relevant changes in these parameters

• To assess the effects of environmental temperature changes on energy expenditure, substrate utilization and thyroid hormone homeostasis parameters in healthy volunteers

07-DK-0202 Thyroid hormones homeostasis and energy metabolism changes during

exposure to cold temperature in humans Study Design

• Two-day equilibration diet• Randomization to either 19C or 24C• 12-hour metabolic chamber stay

– Energy expenditure/RQ– Frequent samples levels thyroid hormones,

cathecolamines, free fatty acids– Core temperature– Lipolysis rate (by microdialysis)– Thermic effect of food

• 36-hour resting period• Cross over to second temperature

19 C

24 C

Enrol

lmen

tM

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Uni

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Equilibra

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12-h

our met

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cham

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Equilibration diet

12-hour metabolic cham

ber

Equilibra

tion d

iet

12-h

our met

abolic

cham

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Equilibration diet

12-hour metabolic cham

berEquilibration diet: 2 days

07-DK-0202 Study protocol, overview

Conclusions

• Several epidemiological studies indicate that in healthy individuals the thyroid homeostasis plays a modulator role in the carbohydrate, lipid and energy metabolism.

• The overall effects of thyroid hormone action in healthy individuals on metabolic control is small and within the variance of the general population

• These factors should be taken in consideration in the design of intervention/association studies

Acknowledgments

• Monica Skarulis• Joyce Linderman• Valentina Congedo• Marina Zemskova• Nabeel Babar• Christopher Harris• Merel Kozlosky• Blakeley Denkinger• Nancy Sebring

• Kong Chen

• Robert Brychta• Megan Rothney• Emily Schaefer• Frank Pucino• Gyorgy Csako• Alan Remaley • Louis Simchowitz• Marvin Gershengorn

Nurses and Personnel of 5 SW-Metabolic Unit

Acknowledgments

Jacob Robbins 1923-2008

• Study Volunteers • Nursing and Clinic Personnel• Pharmacy Department• Department of Laboratory Medicine

This study was supported by the Intramural Research Program of the NIDDK-NIH