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Event: 2119

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Insulin resistance, increased

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Insulin resistance, increased
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
Insulin resistance increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Succinate dehydrogenase inhibition leading to increased insulin resistance AdverseOutcome Simon Thomas (send email) Under development: Not open for comment. Do not cite
PM2.5-related AOP frameworks on liver diseases KeyEvent Zhou Du (send email) Under development: Not open for comment. Do not cite
ERa inactivation leads to increased fat mass and insulin resistance. KeyEvent Min Ji Kim (send email) Under development: Not open for comment. Do not cite
ERa inactivation leads to insulin resistance in skeletal muscle and metabolic syndrome AdverseOutcome Min Ji Kim (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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Adult High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Male High
Female High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Under normal physiological conditions, an increase in plasma glucose, for instance in the post-prandial phase, leads to increased insulin secretion by the pancreas, and consequent increase in plasma insulin concentration. The insulin increases glucose uptake into peripheral tissues, and inhibits hepatic glycogenolysis and gluconeogenesis. In times of stress, the insulin response can be inhibited by stress hormones and proinhibitory cytokines, a mechanism known as insulin resistance (IR), that serves to maintain blood glucose levels during stress response (Tsatsoulis et al, 2013). Inappropriate stress hormone and cytokine generation can lead to individuals showing inappropriate insulin resistance, manifested as lack of insulin-stimulation of glucose uptake into adipose and muscle, and lack of insulin suppression of hepatic glucose release. 

IR is associated with multiple health conditions including obesity, type 2 diabetes mellitus, metabolic syndrome, cardiovascular disease, metabolism associated fatty liver disease and polycystic ovary syndrome. It is a complex metabolic disorder, the exact causes of which are still to be fully resolved (Li et al, 2022). The mechanism by which IR manifests itself is primarily by abnormalities in insulin signal transduction (Pei et al, 2022).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Clinical detection of insulin resistance generally requires measurement of plasma insulin and/or glucose under controlled circumstances, or alongside specific interventions designed to elicit a physiological insulin response. Multiple methods of differing complexity, technical challenge, invasiveness and reliability have been devised (see Sharma et al, 2020 for a review). The hyperinsulineamic euglycaemic clamp (HEC), involving intravenous infusion of insulin to reach steady state glycemic is considered the gold standard, but is challenging, expensive and invasive. Other methods, such as the homeostatic model for insulin resistance (HOMA-IR), a single sample method, are simpler and less invasive, but show greater interindividual variability and only moderate agreement with the HEC. They are more suitable as epidemiological tools for population assessments (Sharma et al, 2020).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

IR, as determined by clinical measurements, as above, can be determined for male and female adult and young humans.

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

There are currently no examples of IR being used in a regulatory role.


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

Li, M. et al (2022), "Trends in insulin resistance: insights into mechanisms and therapeutic strategy", Signal Transduction and Targeted Therapy, Vol 7, 216.

Pei, J. et al (2022), "Current studies on molecular mechanisms of insulin resistance", Journal of Diabetes Research, Vol 2022, Article ID 1863429.

Sharma V.R. et al (2020), "Measuring Insulin Resistance in Humans", Hormone Research in Paediatrics, Vol 93, pp 577-588.

Tsatsoulis, A. et al (2013), "Insulin resistance: An adaptive mechanism becomes maladaptive in the current environment — An evolutionary perspective", Metabolism, Vol 62, pp 622-633.