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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

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thyroid and energy expenditure

Thyroid and energy expenditure

Francesco S. Celi, M.D.

Staff Clinician

Clinical Endocrinology Branch

overview
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
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)

slide4

I

I

R

I

The researcher’s view of the universe“The thyroid hormone action is controlled by a redundant, multilevel highly regulated mechanism”

Hypothalamus

Pituitary

Thyroid

Plasma transport

Cellular transport

Local conversion

RX

RXR

TR

Receptors/Co-activators

slide6

3’

3

I

I

HO

O

R

5’

5

I

I

3’

3

3’

3

I

I

I

HO

O

R

HO

O

R

5’

5

5’

5

I

I

The Deiodinases :

Activation and Inactivation of Thyroid Hormones

T4

D 1, D 2

D 3, ( D 1)

I

T3

rT3

slide7

The role of the Selenocysteine Insertion Sequence

(SECIS) in the incorporation of the selenocysteine

NH2

AAAAAAAAA

SECIS

Element

SeCys

A

A

A

30 S

UGA

UAA

5’

STOP

(STOP)

mRNA

50 S

slide8

Type 1

Type 2

Type 3

Site of action

5’

5

5’ and 5

Substrate

rT3>T4>T3

T4>T3

T3>T4

Localization

Kidney, liver,

thyroid

placenta,

CNS

Pituitary, CNS, muscle, BAT, thyroid,

placenta

Hypothyroidism

Inhibition

Stimulation

Inhibition

Hyperthyroidism

Stimulation

Inhibition

Stimulation

Km (T4)

2 mM

2 nM

37 nM

Deiodinases: types and characteristics

the peripheral metabolism of thyroid hormone in the local modulation thyroid homeostasis
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
    • 11b-hydroxysteroid dehydrogenase
    • 5a-reductase
  • The deiodinase type-2 as a candidate gene for tissue-specific hypothyroidism
type 2 deiodinase local pre receptor modulation of hormonal action
Type 2 deiodinaselocal 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
slide11

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
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

D2

T4

T4

T3

rT3

The deiodinases in the pathogenesis of euthyroid sick syndrome

Hypothalamus

Inflammatory mediators

TRH

  • low T3
  • low T4
  • low TSH
  • high rT3

Pituitary

Liver

TSH

T4

T4

T3

D1

Hypoxia D3

rT3

T2

Ectopic D3 activity

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

The action of thyroid hormone on glucose and energy metabolismLessons from patients

Energy Metabolism

  • Hypothyroidism
    • Decreased energy expenditure
    • Increased sympathetic tone
    • Weight gain?
the action of thyroid hormone on glucose and energy metabolism lessons from patients16
The action of thyroid hormone on glucose and energy metabolismLessons from patients

Glucose Metabolism

  • Thyrotoxicosis
    • Increased hepatic gluconeogenesis
    • Decreased insulin half-life
    • Muscle mass loss
    • Increased glucose disposal
  • Hypothyroidism
    • Decreased hepatic gluconeogenesis
    • Increased insulin half-life
    • Decreased glucose disposal
the action of thyroid hormone on glucose and energy metabolism epidemiological studies
The action of thyroid hormone on glucose and energy metabolismEpidemiological 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
The action of thyroid hormone on glucose and energy metabolismMolecular 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 population what is normal
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)
slide20
Technical challenges in the assessment of the metabolic status of healthy individualsas 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
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
Technical challenges in the assessment of the metabolic status of healthy individualsstudy 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
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
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 mg/kg

Primary Hypothyroidism

LT4 dose ≥ 1.6 mg/kg

24-hour uptake < 5%

Exclusion Criteria

Suppressive therapy

BMI ≤20 or ≥30 kg/m2

Cardiovascular disease

Diabetes Mellitus

Hypercholesterolemia

Subject Selection Criteria
05 dk 0119 study design

Therapy adjustment

Therapy adjustment

Therapy adjustment

Therapy adjustment

Metabolic testing

Metabolic testing

T3 therapy

Randomization

Enrollment

T4 therapy

Metabolic testing

Metabolic testing

Therapy adjustment

Therapy adjustment

Therapy adjustment

Therapy adjustment

05-DK-0119 Study design

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

05 dk 0119 preliminary data
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

*

*

Liothyronine vs. Levothyroxine Dose

200

90

LT3 dose

41.4  12.3 mcg

(0.6  0.1 mcg/kg)

LT4 dose

123.2  37.2 mcg

(1.7  0.3 mcg/kg)

150

60

100

30

LT3:LT4 ratio

0.34 0.05 mcg/mcg

05 dk 0119 preliminary data29
05-DK-0119 Preliminary data
  • Free T4 levels at admission
  • T3 therapy < 0.3 ng/dL
  • T4 Therapy 1.610.37 ng/dL

Reference values 0.8-1.9 ng/dL

05 dk 0119 preliminary data30
05-DK-0119 Preliminary data
  • Total T3 levels at admission
  • T3 therapy 167.7169.17ng/dL
  • T4 Therapy 87.5724.08 ng/dL

Reference values 90-215 ng/dL

24 hour serum total t 3 profile
24-Hour Serum Total T3 Profile

T3 ng/dL

Reference values 90-215 ng/dL

24 hour serum tsh profile
24-Hour Serum TSH Profile

TSH mcu/mL

Reference values 0.5-4.0 mcU/mL

05 dk 0119 preliminary data33
05-DK-0119 Preliminary data
  • AUC 0-60 after 200 mcg TRH
  • T3 281.4113.6 mU*min /L
  • T4 282.5165.6 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.
slide34
07-DK-0202 Thyroid hormones homeostasis and energy metabolism changes during exposure to cold temperature in humansBackground/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

slide35
07-DK-0202 Thyroid hormones homeostasis and energy metabolism changes during exposure to cold temperature in humansStudy Design
  • Two-day equilibration diet
  • Randomization to either 19C or 24C
  • 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
slide36

07-DK-0202 Study protocol, overview

19 C

12-hour metabolic chamber

12-hour metabolic chamber

Equilibration diet

Equilibration diet

Metabolic Unit admission

Enrollment

24 C

Equilibration diet

Equilibration diet

12-hour metabolic chamber

12-hour metabolic chamber

Equilibration diet: 2 days

conclusions
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
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

acknowledgments39
Acknowledgments
  • 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

Jacob Robbins 1923-2008