| Symbol | IRS1 |
| Full Name | Insulin Receptor Substrate 1 |
| Protein | [IRS-1](/entities/irs1-protein) |
| Chromosome | 2q35 |
| NCBI Gene ID | 3667 |
| UniProt ID | P35568 |
| Aliases | HIRS-1, IRS-1 |
IRS1 encodes insulin receptor substrate 1, a key adaptor protein that mediates signaling downstream of the insulin and insulin-like growth factor 1 (IGF-1) receptors.[1] IRS-1 plays a central role in brain insulin signaling, and its dysfunction contributes to insulin resistance and metabolic disturbances observed in neurodegenerative diseases.[2]
The IRS1 gene spans approximately 130 kb on chromosome 2q35 and contains multiple exons encoding a 1242-amino acid protein.[3] IRS-1 contains:
IRS-1 is ubiquitously expressed but particularly abundant in:
IRS-1 serves as the primary adaptor for insulin and IGF-1 receptor signaling:
Reduced IRS-1 expression and increased inhibitory serine phosphorylation have been observed in postmortem brains of patients with neurodegenerative diseases, representing a form of central insulin resistance that impairs neuronal metabolism and survival.[6]
Alzheimer's disease is associated with brain insulin resistance characterized by IRS-1 dysfunction:[7]
Amyloid-beta oligomers induce IRS-1 serine phosphorylation via inflammatory kinase activation, contributing to insulin resistance. IRS-1 dysfunction may enhance tau hyperphosphorylation through GSK-3β activation.
In Parkinson's disease, IRS-1 signaling is impaired in dopaminergic neurons and the substantia nigra.[8] This contributes to:
Type 2 diabetes is a major risk factor for cognitive impairment and dementia. Peripheral insulin resistance often accompanies brain insulin resistance, with IRS-1 dysfunction as a common mechanism.[9] The APOE4 allele exacerbates IRS-1 dysfunction in AD brains.
IRS-1 mediates canonical insulin signaling:
IRS-1 function is inhibited by serine phosphorylation:
These modifications reduce IRS-1 tyrosine phosphorylation and promote degradation.[11]
IRS-1 dysfunction promotes tau hyperphosphorylation through:
| Protein | Relationship | Function |
|---|---|---|
| Insulin Receptor | Upstream | Phosphorylates IRS-1 |
| IGF-1 Receptor | Upstream | Phosphorylates IRS-1 |
| PI3K | Downstream | Binds phospho-IRS-1 |
| AKT | Downstream | Activated via PI3K |
| GSK-3β | Downstream | Inhibited by AKT |
White MF. The IRS proteins and the common pathway of insulin action. Journal of Leukocyte Biology. 1998. ↩︎
Talbot K, Wang HY, Kazi H, et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. Journal of Clinical Investigation. 2012. ↩︎
Araki E, Lipes MA, Patti ME, et al. Alternative pathway of insulin signalling in mice with targeted disruption of IRS-1 gene. Nature. 1994. ↩︎
Patti ME, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001. ↩︎
Sun XJ, Rothenberg P, Kahn CR, et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991. ↩︎
de Felice FG, Ferreira ST. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes. 1954. ↩︎
Moloney AM, Griffin RJ, Timmons S, et al. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer's disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiology of Aging. 2010. ↩︎
Morris JK, Bomhoff GL, Stanford JA, Gerhardt GA. Impaired dopaminergic neurotransmission and microglial activation in rats following chronic diabetes. Neuropharmacology. 2011. ↩︎
Biessels GJ, Strachan MW, Visseren FL, et al. [Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions](https://doi.org/10.1016/S2213-8587(14). Lancet Diabetes & Endocrinology. 2014. ↩︎
Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nature Reviews Molecular Cell Biology. 2006. ↩︎
Boura-Halfon S, Zick Y. Phosphorylation of IRS proteins, insulin action, and insulin resistance. American Journal of Physiology-Endocrinology and Metabolism. 2008. ↩︎
El Khoury NB, Gratuze M, Petry F, et al. Metformin promotes neurogenesis and enhances spatial memory formation in mice. Journal of Alzheimer's Disease. 2019. ↩︎
Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Exenatide and the treatment of patients with Parkinson's disease. Journal of Clinical Investigation. 2014. ↩︎