Cited by 1,017Metabolism, Diabetes, and CancerAdipokines, Inflammation, and Metabolic DiseasesDiabetes, Cardiovascular Risks, and Lipoproteins

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Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.

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Copps, K. D., White, M. F.·2012·Diabetologia

DOI 10.1007/s00125-012-2644-8PMC PMC4011499

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Abstract

The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.

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3 retracted

Insulin Stimulates PKCζ-mediated Phosphorylation of Insulin Receptor Substrate-1 (IRS-1)
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Retracted
Common Inhibitory Serine Sites Phosphorylated by IRS-1 Kinases, Triggered by Insulin and Inducers of Insulin Resistance
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Retracted
G Protein–Coupled Receptor Kinase 2 Plays a Relevant Role in Insulin Resistance and Obesity
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Background
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Background
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Background

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Additional file 11 of Transcriptomic analysis to elucidate the effects of high stocking density on grass carp (Ctenopharyngodon idella)
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Additional file 5 of Transcriptomic analysis to elucidate the effects of high stocking density on grass carp (Ctenopharyngodon idella)
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Additional file 10 of Transcriptomic analysis to elucidate the effects of high stocking density on grass carp (Ctenopharyngodon idella)
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Additional file 9 of Transcriptomic analysis to elucidate the effects of high stocking density on grass carp (Ctenopharyngodon idella)
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Additional file 7 of Transcriptomic analysis to elucidate the effects of high stocking density on grass carp (Ctenopharyngodon idella)
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Additional file 8 of Transcriptomic analysis to elucidate the effects of high stocking density on grass carp (Ctenopharyngodon idella)
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Additional file 2 of Transcriptomic analysis to elucidate the effects of high stocking density on grass carp (Ctenopharyngodon idella)
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Additional file 12 of Transcriptomic analysis to elucidate the effects of high stocking density on grass carp (Ctenopharyngodon idella)
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Authors: Copps, K. D., & White, M. F.
Affiliations: Boston Children's Hospital (US)
Corresponding author: White, M. F.
ORCID: White, M. F.
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2012-08-08
Volume: 55
Issue: 10
Pages: 2565-2582
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-012-2644-8
PMC: PMC4011499
OpenAlex: W1982479748
Cited by: 1,017
References: 185
Citations by year: 2026: 72 · 2025: 56 · 2024: 76 · 2023: 83 · 2022: 103 · 2021: 113 · 2020: 83 · 2019: 76 · 2018: 75 · 2017: 70 · 2016: 59 · 2015: 63 · 2014: 51 · 2013: 31 · 2012: 5
FWCI: 4.40
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
Locations: Diabetologia (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Institutes of Health (5r01dk098655-08)
National Institute of Diabetes and Digestive and Kidney Diseases (R01- DK098655, R01DK038712)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: insulin receptor substrate, IRS-1, insulin receptor substrate 2, serine/threonine phosphorylation, insulin sensitivity, insulin resistance, diabetes mellitus, insulin signaling, AMPK, glycogen synthase kinase-3, protein kinase C, Akt, mTOR, hyperinsulinemia, metabolic disorders
MeSH terms: Animals, Diabetes Mellitus, Humans, Insulin Resistance, Mice, Transgenic, Phosphorylation, Serine, Threonine, Signal Transduction, Mice, Knockout, Models, Animal, Mice, Insulin Receptor Substrate Proteins

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Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.

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