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Key Event Title
Insulin resistance, increased
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|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 Do not cite|
Key Event Description
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
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
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
There are currently no examples of IR being used in a regulatory role.
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.