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Relationship: 2865

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

T4 in serum, Decreased leads to Insulin resistance, increased

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
T4 in serum, Decreased
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Insulin resistance, increased

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Succinate dehydrogenase inhibition leading to increased insulin resistance through reduction in circulating thyroxine adjacent Moderate Moderate Evgeniia Kazymova (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens Moderate NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed Moderate

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Adult Moderate

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Hypothyroidism in rats and humans leads to an increase in insulin resistance, as determined from in vivo or ex vivo measurements.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Step 1: Identify primary evidence for clinical overt hypothyroidism leading to increase in IR

In order to focus on T4 changes, rather than widespread changes to the hypothalamus-pituitary axis that can be involved in sub-clinical hypothyroidism, a search was made to identify clinical studies messing insulin resistance in the presence of T4 reduction below normal levels (overt hypothyroidism). 

The following Pubmed search was performed on 18/04/2023, returning 3 relevant references, spanning the period 2012 - 2021 (Prats-Puig et al; 2012, Nada, 2013; Stepanek et al, 2021).

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help

Impact of clinical overt hypothyroidism on insulin resistance

  1.  In a cross-sectional study of 234 euthyroid prepubertal children (113 boys, 121 girls) in Spain, HOMA-IR was compared to serum free T4 (Prats-Puig et al, 2012):
    1. For boys, there was no significant difference.
    2. For girls, HOMA-IR increased 30% from the highest to the lowest tertile of serum free T4.
  2. In two groups of healthy S.W. Asian females, 27 with overt hypothyroidism and 15 euthyroid, matched for age and BMI, there was no significant difference between the groups for fasting plasma glucose, insulin or HOMA-IR. Six months after starting thyroxine therapy to return the hypothyroid individuals to the euthyroid state, there was no significant change in fasting glucose or HOMA-IR, although fasting insulin had increased significantly above the level measured originally in the euthyroid cohort. However, the relevant parameters in the euthyroid group were not measured, so no longitudinal comparison was possible.
  3. In a study of 1425 middle-aged individuals (317 male, 1108 female) in Poland, divided into 3 groups (euthyroid (EU), subclinical hypothyroidism (SH) and overt hypothyroidism(OH)), HOMA-IR, fasting insulin and two-hour levels of oral glucose tolerance test (OGTT) showed steady, yet insignificant increases from the EU, through SH to OH states (Stepanek et al, 2021). Free T4 showed a positive, but not signicant, correlation with HOMA-IR. The ratio of free T3/free T4 was strongly and sigificantly correlated with HOMA-IR. This indicates that if free T4 decreases, then HOMA-IR will increase if T3 simultaneously decreases to a proportionally lesser extent than T4.

Evidence gleaned from in vivo and ex vivo rodent studies

In vivo and ex vivo experiments in the rat indicate an increase in insulin resistance in hypothyroidism. In young (50-60g) and old (160g) male Wistar rats made hypothyroid by administration of propylthiouracil for 4-5 weeks, leading to dramatic reduction in plasma triiodothyronine (T3) concentration, plasma glucose concentration was increased (approximately 10%) in the presence of an approximately 50% (but not significant) insulin concentration increase, compared to euthyroid animals (Dimitriadis et al, 1989). In a soleus muscle preparation from hypothyroid animals, total glucose disposition was decreased compared to a preparation from euthyroid animals:

  • rates of lactate formation and glucose oxidation were decreased at all insulin concentrations tested, from physiological to supraphysiological;
  • rate of glycogen synthesis was decreased at supraphysiological insulin concentrations.
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help
Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)
       
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

Brenta, G. (2011), "Why can insulin resistance be a natural consequence of thyroid dysfunction?", Journal of Thyroid Research, Vol 2011, Article ID 152850.

Dimitriadis, G.D. et al (1989) "Effects of hypothyroidism on the sensitivity of glycolysis and glycogen synthesis to insulin in the soleus muscle of the rat", Biochemical Journal, Vol 257, pp369-373.

Nada, A.M. (2013), "Effect of treatment of overt hypothyroidism on insulin resistance", World Journal of Diabetes, Vol 4, pp 157-61.

Prats-Puig, A. et al (2012), "Relative hypothyroidism, insulin resistance and increased visceral fat in euthyroid prepubertal girls with low-normal serum and free thyroxine", Obesity (Silver Spring), Vol 20, pp 1455-61.

Stepanek, L. et al (2021), "Free triiodothyronine/free thyroxine (FT3/FT4) ratio is strongly associated with insulin resistance in euthyroid and hypothyroid adults: a cross-sectional study", Endokrynologia Polska, Vol 72, pp 8-13.