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Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.
Open accessAbstract
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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“Insulin resistance in adipocytes is associated with impaired phosphorylation of insulin receptor substrate 1 (IRS-1) in obesity, which is further impaired in T2DM”
From Effect of Exercise Training on Fat Loss—Energetic Perspectives and the Role of Improved Adipose Tissue Function and Body Fat Distribution (2021) · cites this paper as Copps and White, 2012
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3 retracted
Insulin Stimulates PKCζ-mediated Phosphorylation of Insulin Receptor Substrate-1 (IRS-1)
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The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome
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“Irs1 [33] and Sirt1 contribute to improving insulin sensitivity.”
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“Tyrosine phosphorylation activates IRS proteins and enhances insulin sensitivity, whereas serine phosphorylation—often triggered by inflammatory sig-nals—serves as a negative regulatory mechanism [76].”
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“IRS serine/threonine phosphorylation is critical in human IR (Copps and White 2012).”
BackgroundInfluentialWhite sweet potato ameliorates hyperglycemia and regenerates pancreatic islets in diabetic mice
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“It is well established that JNK1, a member of the MAPK family, also as the downstream effector of TAK1, is central to the development of obesity‐induced IR, which could profoundly influence insulin sensitivity (Copps & White, 2012; Zick, 2001).”
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Oxidative RNA Damage in the Pathogenesis and Treatment of Type 2 Diabetes
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“IRS1 is the receptor substrate of insulin, which plays important roles in glucose utilization [26].”
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“To test whether the observed KYCCSRK-induced IR and IRS1 activation was associated with the stimulation of the entire signaling, we evaluated AKT levels and activation since AKT is one of the main intracellular proteins activated in response to insulin [48,49].”
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“IRS1 serine-phoshporylation is often elevated in insulin resistant models [30].”
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“Apart from indicating insulin-resistance and decreased glucose uptake, it suggests a relationship between IRS-1, tau (NFT) and Aβ pathology. p53 Tumor Suppressor Gene Wild-type p53 regulates many cell functions including cell cycle arrest, apoptosis and metabolism (87).”
BackgroundInfluential
Metadata
- Authors
- Copps, K. D., & White, M. F.
- Affiliations
- Boston Children's Hospital (US)
- Corresponding author
- White, M. F.
- ORCID
- White, M. F.
- Venue
- Diabetologia
- Published
- 2012-08-08
- Volume
- 55
- Issue
- 10
- Pages
- 2565-2582
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- 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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