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Cited by 233Advanced Glycation End Products researchPancreatic function and diabetesAdipokines, Inflammation, and Metabolic Diseases

Insulin Signal Transduction Perturbations in Insulin Resistance

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Khalid, Mariyam, Alkaabi, Juma, Khan, Moien A. B., Adem, Abdu·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms22168590PMC PMC8395322
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Abstract

Type 2 diabetes mellitus is a widespread medical condition, characterized by high blood glucose and inadequate insulin action, which leads to insulin resistance. Insulin resistance in insulin-responsive tissues precedes the onset of pancreatic β-cell dysfunction. Multiple molecular and pathophysiological mechanisms are involved in insulin resistance. Insulin resistance is a consequence of a complex combination of metabolic disorders, lipotoxicity, glucotoxicity, and inflammation. There is ample evidence linking different mechanistic approaches as the cause of insulin resistance, but no central mechanism is yet described as an underlying reason behind this condition. This review combines and interlinks the defects in the insulin signal transduction pathway of the insulin resistance state with special emphasis on the AGE-RAGE-NF-κB axis. Here, we describe important factors that play a crucial role in the pathogenesis of insulin resistance to provide directionality for the events. The interplay of inflammation and oxidative stress that leads to β-cell decline through the IAPP-RAGE induced β-cell toxicity is also addressed. Overall, by generating a comprehensive overview of the plethora of mechanisms involved in insulin resistance, we focus on the establishment of unifying mechanisms to provide new insights for the future interventions of type 2 diabetes mellitus.

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  • The adaptive protective mechanism of insulin resistance can be pathway-specific during periods of growth, such as pregnancy, lactation and adolescence, so that only the metabolic signaling (PI-3K) is inhibited and not the mitogenic pathway (MAPK), which may even be up-regulated.

    “This adaptive protective mechanism can be pathway-specific during periods of growth, such as pregnancy, lactation and adolescence, so that only the metabolic signaling (PI-3K) is inhibited and not the mitogenic pathway (MAPK), which may even be up-regulated [30,65,160].”

    From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [160]

    Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Insulin resistance can be caused by a wide variety of mechanisms that disrupt any part of the metabolic signaling system, including autoantibodies, receptor agonists and antagonists, hormones, inflammatory cytokines, oxidative stress, nutrient sensors and metabolic intermediates.

    “Insulin resistance can be caused by a wide variety of mechanisms that have the ability to disrupt any part of this metabolic signaling system [53,161]. These include autoantibodies, receptor agonists and antagonists, hormones, inflammatory cytokines, oxidative stress, nutrient sensors and metabolic intermediates [160,161,162,163].”

    From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [160]

    The Introduction and Section 4 describe multiple causes and signaling perturbations associated with insulin resistance, including inflammatory cytokines, oxidative stress, and metabolic abnormalities. Section 3.7 also discusses the energy sensor AMPK. The passages do not support the full list attributed to this paper: they do not identify autoantibodies or receptor agonists and antagonists as causes. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Insulin resistance results from alterations to cellular membrane insulin-receptor function or intracellular signaling, enzyme, metabolic or gene function.

    “IR results from alterations to cellular membrane insulin-receptor function or intracellular signaling, enzyme, metabolic or gene function [146,160,161].”

    From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [160]

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Cited by

Sorted by citations

Authors
Khalid, M., Alkaabi, J., Khan, M. A. B., & Adem, A.
Affiliations
  • United Arab Emirates University (AE)
  • Khalifa University of Science and Technology (AE)
Corresponding author
Adem, Abdu
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-08-10
Volume
22
Issue
16
Pages
8590
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms22168590
PMC
PMC8395322
OpenAlex
W3190135421
Cited by
233
References
16
Citations by year
2026: 50 · 2025: 59 · 2024: 52 · 2023: 47 · 2022: 23 · 2021: 2
FWCI
4.10
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
insulin resistance, insulin signaling, type 2 diabetes, advanced glycation end products, receptor for advanced glycation end products, NF-κB, inflammation, oxidative stress, amylin, beta-cell dysfunction, lipotoxicity, glucotoxicity
MeSH terms
Animals, Diabetes Mellitus, Type 2, Humans, Inflammation, Insulin, Insulin Resistance, Signal Transduction, Oxidative Stress, Insulin-Secreting Cells

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